UpToDate Dermatology 2020 Edition [2020 Edition]

Table of contents :
Cover......Page 1
Contents......Page 2
Overview of dermoscopy......Page 17
Dermoscopic evaluation of skin lesions......Page 26
Dermoscopy of pigmented lesions of the palms and soles......Page 40
Patch testing......Page 98
Evaluation and diagnosis of hair loss......Page 106
Approach to the clinical dermatologic diagnosis......Page 124
Approach to the patient with a scalp disorder......Page 213
Approach to the patient with an intertriginous skin disorder......Page 225
Approach to the patient with annular skin lesions......Page 237
Approach to the patient with cutaneous blisters......Page 250
Approach to the patient with facial erythema......Page 357
Approach to the patient with pustular skin lesions......Page 402
Approach to the patient with retiform (angulated) purpura......Page 461
Approach to the differential diagnosis of leg ulcers......Page 473
Evaluation of adults with cutaneous lesions of vasculitis......Page 486
Office-based dermatologic diagnostic procedures......Page 498
Longitudinal melanonychia......Page 507
Erythroderma in adults......Page 518
Acquired hyperpigmentation disorders......Page 533
Overview of nail disorders......Page 557
Atopic dermatitis......Page 581
allergic contact dermatitis......Page 665
Contact dermatitis in children......Page 692
Irritant contact dermatitis in adults......Page 703
Chronic hand eczema......Page 720
Patch testing......Page 732
Management of allergic contact dermatitis......Page 740
Poison ivy (Toxicodendron) dermatitis......Page 748
Eyelid dermatitis (eczema)......Page 758
Keratosis pilaris......Page 768
Keratosis pilaris atrophicans......Page 773
Cheilitis......Page 778
Acute palmoplantar eczema (dyshidrotic eczema)......Page 789
Cradle cap and seborrheic dermatitis in infants......Page 799
Intertrigo......Page 805
Nummular eczema......Page 813
Overview of dermatitis (eczema)......Page 819
Prurigo nodularis......Page 916
Seborrheic dermatitis in adolescents and adults......Page 927
Stasis dermatitis......Page 940
Vulvar dermatitis......Page 952
Urticarial dermatitis......Page 966
Radiation dermatitis......Page 985
Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris......Page 1003
Postadolescent acne in women......Page 1022
Treatment of acne vulgaris......Page 1032
Oral isotretinoin therapy for acne vulgaris......Page 1061
Hormonal therapy for women with acne vulgaris......Page 1075
Light-based, adjunctive, and other therapies for acne vulgaris......Page 1087
Perioral (periorificial) dermatitis......Page 1095
Rosacea Pathogenesis, clinical features, and diagnosis......Page 1107
Management of rosacea......Page 1120
PsoriasisEpidemiology, clinical manifestations, and diagnosis......Page 1139
Pathophysiology of plaque psoriasis......Page 1211
Nail psoriasis......Page 1223
Guttate psoriasis......Page 1260
Treatment of psoriasis in adults......Page 1289
Erythrodermic psoriasis in adults......Page 1333
Treatment selection for moderate to severe plaque psoriasis in special populations......Page 1358
Psoriasis in children epidemiology clinical manifestation and dianosis......Page 1381
Psoriasis in childrenManagement of chronic plaque psoriasis......Page 1415
Management of psoriasis in pregnancy......Page 1441
Comorbid disease in psoriasis......Page 1459
Patient education Psoriasis (Beyond the Basics)......Page 1478
Pustular psoriasisPathogenesis, clinical manifestations, and diagnosis......Page 1497
Pustular psoriasisManagement......Page 1524
Palmoplantar pustulosisEpidemiology, clinical features, and diagnosis......Page 1546
Palmoplantar pustulosis Treatment......Page 1576
Lichen planus......Page 1598
Lichen Planopilaris......Page 1612
Vulvar lichen planus......Page 1629
Oral lichen planusPathogenesis, clinical features, and diagnosis......Page 1646
Oral lichen planus Management and prognosis......Page 1655
Pityriasis rosea......Page 1666
Pityriasis lichenoides chronica......Page 1698
Pityriasis lichenoides et varioliformis acuta (PLEVA)......Page 1722
Pityriasis rubra pilaris......Page 1754
Confluent and reticulated papillomatosis......Page 1786
Lichen striatus......Page 1814
New-onset urticaria......Page 1842
Chronic spontaneous urticariaClinical manifestations, diagnosis, pathogenesis, and natural history......Page 1875
Chronic spontaneous urticariaStandard management and patient education......Page 1908
Chronic spontaneous urticaria Treatment of refractory symptoms......Page 1936
An overview of angioedemaPathogenesis and causes......Page 1955
An overview of angioedemaClinical features, diagnosis, and management......Page 1971
Hereditary angioedemaPathogenesis and diagnosis......Page 2001
Hereditary angioedema Epidemiology, clinical manifestations, exacerbating factors, and prognosis......Page 2015
Hereditary angioedema (due to C1 inhibitor deficiency)General care and long-term prophylaxis......Page 2026
Hereditary angioedema with normal C1 inhibitor......Page 2052
Hereditary angioedemaAcute treatment of angioedema attacks......Page 2067
Hereditary angioedema Temporary prophylaxis before procedures or stress to prevent angioedema episodes......Page 2092
Acquired C1 inhibitor deficiencyClinical manifestations, epidemiology, pathogenesis, and diagnosis......Page 2105
Acquired C1 inhibitor deficiencyManagement and prognosis......Page 2116
ACE inhibitor-induced angioedema......Page 2130
Physical (inducible) forms of urticaria......Page 2144
Cold urticaria......Page 2182
Urticarial vasculitis......Page 2203
Pathogenesis, clinical manifestations, and diagnosis of pemphigus......Page 2236
Paraneoplastic pemphigus......Page 2251
Initial management of pemphigus vulgaris and pemphigus foliaceus......Page 2264
Management of refractory pemphigus vulgaris and pemphigus foliaceus......Page 2279
Fogo selvagem Brazilian endemic pemphigus foliaceus......Page 2290
Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid......Page 2303
Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid......Page 2313
Ocular cicatricial pemphigoid......Page 2330
Management and prognosis of bullous pemphigoid......Page 2345
Management of mucous membrane pemphigoid......Page 2360
Dermatitis herpetiformis......Page 2371
Epidermolysis bullosa acquisita......Page 2384
Friction blisters......Page 2398
Linear IgA bullous dermatosis......Page 2405
Evaluation and diagnosis of hair loss......Page 2419
Overview of dermoscopy of the hair and scalp......Page 2437
Alopecia areataClinical manifestations and diagnosis......Page 2450
Alopecia areataManagement......Page 2460
Androgenetic alopecia in menPathogenesis, clinical features, and diagnosis......Page 2475
Treatment of androgenetic alopecia in men......Page 2485
Female pattern hair loss (androgenetic alopecia in women) Pathogenesis, clinical features, and diagnosis......Page 2495
Female pattern hair loss (androgenetic alopecia in women)Treatment and prognosis......Page 2505
Telogen effluvium......Page 2513
Traction alopecia......Page 2526
Lichen planopilaris......Page 2538
Acne keloidalis nuchae......Page 2555
Central centrifugal cicatricial alopecia......Page 2571
Dissecting cellulitis of the scalp......Page 2586
Erosive pustular dermatosis of the scalp......Page 2595
Folliculitis decalvans......Page 2605
Hair shaft disorders......Page 2620
Pseudofolliculitis barbae......Page 2630
Overview of nail disorders......Page 2640
Overview of dermoscopy......Page 2755
Dermoscopic evaluation of skin lesions......Page 2764
Dermoscopy of facial lesions......Page 2778
Dermoscopy of pigmented lesions of the palms and soles......Page 2841
Dermoscopy of nail pigmentations......Page 2897
Dermoscopy of nonpigmented nail lesions......Page 2935
Dermoscopic algorithms for skin cancer triage......Page 2967
Dermoscopy of mucosal lesions......Page 3003
MelasmaEpidemiology, pathogenesis, clinical presentation, and diagnosis......Page 3024
MelasmaManagement......Page 3035
Acquired melanocytic nevi (moles)......Page 3052
Benign pigmented skin lesions other than melanocytic nevi (moles)......Page 3062
Atypical (dysplastic) nevi......Page 3071
Spitz nevus and atypical Spitz tumors......Page 3086
Congenital melanocytic nevi......Page 3105
Congenital and inherited hyperpigmentation disorders......Page 3115
VitiligoPathogenesis, clinical features, and diagnosis......Page 3131
VitiligoManagement and prognosis......Page 3144
Acquired hypopigmentation disorders other than vitiligo......Page 3160
Lentigo maligna Clinical manifestations, diagnosis, and management......Page 3173
Melanoma Clinical features and diagnosis......Page 3187
Risk factors for the development of melanoma......Page 3205
Screening and early detection of melanoma in adults and adolescents......Page 3222
Melanoma in children......Page 3242
Epidemiology and risk factors for skin cancer in solid organ transplant recipients......Page 3257
Pathologic characteristics of melanoma......Page 3269
Pathologic evaluation of regional lymph nodes in melanoma......Page 3283
Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma......Page 3289
Surgical management of primary cutaneous melanoma or melanoma at other unusual sites......Page 3301
Staging work-up and surveillance after treatment of melanoma......Page 3315
Primary prevention of melanoma......Page 3325
Prevention and management of skin cancer in solid organ transplant recipients......Page 3338
Cellulitis and skin abscessClinical manifestations and diagnosis......Page 3355
Cellulitis and skin abscess in adultsTreatment......Page 3366
Erythrasma......Page 3379
Impetigo......Page 3386
Pitted keratolysis......Page 3394
Pseudomonas aeruginosa skin and soft tissue infections......Page 3403
Cutaneous manifestations of tuberculosis......Page 3416
Cutaneous manifestations of gonorrhea......Page 3433
Staphylococcal scalded skin syndrome......Page 3440
Necrotizing soft tissue infections......Page 3453
Trichomycosis (trichobacteriosis)......Page 3469
Botryomycosis......Page 3475
Yaws, bejel, and pinta......Page 3482
Pediculosis capitis......Page 3501
Pediculosis corporis......Page 3515
Pediculosis pubis and pediculosis ciliaris......Page 3531
ScabiesEpidemiology, clinical features, and diagnosis......Page 3539
Scabies Management......Page 3548
Bedbugs......Page 3557
Chigger bites......Page 3567
Jellyfish stings......Page 3572
Lepidopterism Skin disorders secondary to caterpillars and moths......Page 3587
Dermatophyte (tinea) infections......Page 3595
Tinea versicolor (pityriasis versicolor)......Page 3608
Tinea capitis......Page 3617
Tinea nigra......Page 3634
OnychomycosisEpidemiology, clinical features, and diagnosis......Page 3641
OnychomycosisManagement......Page 3652
Candida infections in children......Page 3668
Chromoblastomycosis......Page 3682
Lobomycosis......Page 3694
Piedra......Page 3703
Cutaneous warts (common, plantar, and flat warts)......Page 3710
Condylomata acuminata (anogenital warts) in adults Epidemiology, pathogenesis, clinical features, and diagnosis......Page 3725
Condylomata acuminata (anogenital warts) Management of external condylomata acuminata in men......Page 3734
Condylomata acuminata (anogenital warts) in children......Page 3749
Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection......Page 3758
Treatment of genital herpes simplex virus infection......Page 3773
Prevention of genital herpes virus infections......Page 3787
Treatment of herpes simplex virus type 1 infection in immunocompeten patients......Page 3797
Epidemiology, clinical manifestations, and diagnosis of herpes zoster......Page 3807
Treatment of herpes zoster in the immunocompetent host......Page 3822
Molluscum contagiosum......Page 3832
Orf virus infection......Page 3848
HIV-associated eosinophilic folliculitis......Page 3854
Fever and rash in the immunocompetent patient......Page 3864
Gianotti-Crosti syndrome (papular acrodermatitis)......Page 3936
Clinical manifestations, diagnosis, and management of diabetic infections of the lower etremities......Page 3944
Infectious folliculitis......Page 3959
Soft tissue infections following water exposure......Page 3973
Skin lesions in the returning traveler......Page 3984
Drug eruptions......Page 3993
Exanthematous (maculopapular) drug eruption......Page 4004
Lichenoid drug eruption (drug-induced lichen planus......Page 4015
Acute generalized exanthematous pustulosis (AGEP)......Page 4027
Drug reaction with eosinophilia and systemic symptoms (DRESS)......Page 4035
Fixed drug eruption......Page 4052
Stevens-Johnson syndrome and toxic epidermal necrolysis......Page 4062
Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors......Page 4097
Cutaneous side effects of conventional chemotherapy agents......Page 4111
Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors......Page 4133
Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy......Page 4143
Epidemiology, natural history, and diagnosis of actinic keratosis......Page 4157
Treatment of actinic keratosis......Page 4167
Actinic cheilitis......Page 4182
Epidemiology, pathogenesis, and clinical features of basal cell carcinoma......Page 4189
Treatment and prognosis of basal cell carcinoma at low risk of recurrence......Page 4206
Treatment of basal cell carcinomas at high risk for recurrence......Page 4223
Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma......Page 4233
Systemic treatment of advanced cutaneous squamous and basal cell carcinomas......Page 4242
Nevoid basal cell carcinoma syndrome (Gorlin syndrome)......Page 4252
Cutaneous adnexal tumors......Page 4268
Microcystic adnexal carcinoma......Page 4362
Epidemiology and risk factors for cutaneous squamous cell carcinoma......Page 4372
Cutaneous squamous cell carcinoma (cSCC) Clinical features and diagnosis......Page 4387
Treatment and prognosis of low-risk cutaneous squamous cell carcinoma......Page 4395
Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma......Page 4412
Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma......Page 4431
Systemic treatment of advanced cutaneous squamous and basal cell carcinomas......Page 4440
Keratoacanthoma......Page 4450
Merkel cell (neuroendocrine) carcinoma......Page 4470
Epidemiology and risk factors for skin cancer in solid organ transplant recipients......Page 4501
Prevention and management of skin cancer in solid organ transplant recipients......Page 4513
Sebaceous carcinoma......Page 4530
Atypical fibroxanthoma......Page 4539
Porokeratosis......Page 4547
Overview of cutaneous lupus erythematosus......Page 4563
Initial management of discoid lupus and subacute cutaneous lupus......Page 4614
Management of refractory discoid lupus and subacute cutaneous lupus......Page 4636
Tumid lupus erythematosus......Page 4657
Bullous systemic lupus erythematosus......Page 4687
Cutaneous dermatomyositis in adultsOverview and initial management......Page 4709
Initial treatment of dermatomyositis and polymyositis in adults......Page 4740
Management of refractory cutaneous dermatomyositis in adults......Page 4760
Treatment of recurrent and resistant dermatomyositis and polymyositis in adults......Page 4777
Malignancy in dermatomyositis and polymyositis......Page 4790
Juvenile dermatomyositis and polymyositis Epidemiology, pathogenesis, and clinical manifestations......Page 4799
Juvenile dermatomyositis and polymyositis Diagnosis......Page 4812
Juvenile dermatomyositis and polymyositisTreatment, complications, and prognosis......Page 4830
Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis......Page 4848
Treatment of Langerhans cell histiocytosis......Page 4880
Necrobiotic xanthogranuloma......Page 4902
Juvenile xanthogranuloma (JXG)......Page 4922
Pathology and pathogenesis of sarcoidosis......Page 4948
Cutaneous manifestations of sarcoidosis......Page 4968
Clinical manifestations and diagnosis of pulmonary sarcoidosis......Page 5014
Cutaneous sarcoidosisManagement......Page 5054
Pathogenesis of systemic sclerosis (scleroderma)......Page 5080
Risk factors for and possible causes of systemic sclerosis (scleroderma)......Page 5104
Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults......Page 5113
Pretreatment evaluation of adults with systemic sclerosis (scleroderma)......Page 5147
Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults......Page 5156
Juvenile systemic sclerosis (scleroderma)Classification, clinical manifestations, and diagnosis......Page 5173
Juvenile systemic sclerosis (scleroderma)Assessment and approaches to treatment......Page 5196
Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults......Page 5218
Treatment of morphea (localized scleroderma) in adults......Page 5253
Localized scleroderma in childhood......Page 5263
Scleredema......Page 5306
Scleromyxedema......Page 5327
Nephrogenic systemic fibrosis-nephrogenic fibrosing dermopathy in advanced kidney disease......Page 5355
Evaluation of adults with cutaneous lesions of vasculitis......Page 5382
Overview of cutaneous small vessel vasculitis......Page 5415
Management of adults with idiopathic cutaneous small vessel vasculitis......Page 5422
Urticarial vasculitis......Page 5435
Livedoid vasculopathy......Page 5468
IgA vasculitis (Henoch-Schönlein purpura)Clinical manifestations and diagnosis......Page 5487
IgA vasculitis (Henoch-Schönlein purpura)Management......Page 5511
Erythema induratum (nodular vasculitis)......Page 5520
Erythema elevatum diutinum......Page 5538
Acanthosis nigricans......Page 5560
Anetoderma......Page 5593
Cutaneous polyarteritis nodosa......Page 5611
Cutaneous xanthomas......Page 5630
Erythema annulare centrifugum......Page 5673
Erythema nodosum......Page 5704
Erythromelalgia......Page 5728
Localized lichen myxedematosus......Page 5744
Palisaded neutrophilic and granulomatous dermatitis......Page 5761
Necrobiosis lipoidica......Page 5774
Panniculitis Recognition and diagnosis......Page 5806
Pathogenesis of Raynaud phenomenon......Page 5841
Perforating dermatoses......Page 5852
Pernio (chilblains)......Page 5893
Pigmented purpuric dermatoses (capillaritis)......Page 5911
Calcinosis cutis Etiology and patient evaluation......Page 5957
Calcinosis cutisManagement......Page 5999
Neutrophilic dermatoses......Page 6006
Pyoderma gangrenosum Pathogenesis, clinical features, and diagnosis......Page 6070
Pyoderma gangrenosum Treatment and prognosis......Page 6097
Sweet syndrome......Page 6113
Cutaneous manifestations of amyloidosis......Page 6153
Cutaneous manifestations of graft-versus-host disease (GVHD)......Page 6196
Cutaneous manifestations of internal malignancy......Page 6256
Parapsoriasis (small plaque and large plaque parapsoriasis)......Page 6321
Classification of primary cutaneous lymphomas......Page 6331
Approach to the patient with a diagnosis of atypical lymphocytic infiltrate of the skin......Page 6339
Variants of mycosis fungoides......Page 6347
Primary cutaneous T cell lymphomas, rare subtypes......Page 6361
Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified......Page 6373
Treatment of early stage (IA to IIA) mycosis fungoides......Page 6382
Treatment of advanced stage (IIB to IV) mycosis fungoides......Page 6397
Treatment of Sézary syndrome......Page 6417
Primary cutaneous anaplastic large cell lymphoma......Page 6438
Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma......Page 6450
Jessner's lymphocytic infiltrate......Page 6463
Cutaneous B cell pseudolymphomas......Page 6468
Cutaneous T cell pseudolymphomas......Page 6475
Eosinophilic cellulitis (Wells syndrome)......Page 6485
Lymphomatoid papulosis......Page 6495
Primary cutaneous follicle center lymphoma......Page 6513
Primary cutaneous large B cell lymphoma, leg type......Page 6524
Primary cutaneous marginal zone lymphoma......Page 6533
Angiolymphoid hyperplasia with eosinophilia and Kimura disease......Page 6546
Overview of benign lesions of the skin......Page 6557
PruritusEtiology and patient evaluation......Page 6576
Pruritus Overview of management......Page 6592
Oral lesions......Page 6604
Recurrent aphthous stomatitis......Page 6627
Oral lichen planus Pathogenesis, clinical features, and diagnosis......Page 6641
Oral lichen planusManagement and prognosis......Page 6650
Oral leukoplakia......Page 6661
Vulvar dermatitis......Page 6668
Vulvar lichen sclerosus......Page 6682
Extragenital lichen sclerosus......Page 6701
Primary focal hyperhidrosis......Page 6712
Bromhidrosis......Page 6728
Chromhidrosis......Page 6736
Fox-Fordyce disease (apocrine miliaria)......Page 6743
Miliaria......Page 6752
Granular parakeratosis......Page 6761
Granuloma annulare......Page 6769
Granuloma faciale......Page 6786
Dermatoses of pregnancy......Page 6796
Erythema multiformePathogenesis, clinical features, and diagnosis......Page 6811
Erythema multiforme Management......Page 6822
Grover's disease (transient and persistent acantholytic dermatosis)......Page 6832
Hidradenitis suppurativaPathogenesis, clinical features, and diagnosis......Page 6837
Hidradenitis suppurativa Treatment......Page 6850
Surgical management of hidradenitis suppurativa......Page 6869
Keloids and hypertrophic scars......Page 6879
Laser therapy for hypertrophic scars and keloids......Page 6893
Mastocytosis (cutaneous and systemic)Epidemiology, pathogenesis, and clinical manifestations......Page 6907
Mastocytosis (cutaneous and systemic)Evaluation and diagnosis in children......Page 6921
Mastocytosis (cutaneous and systemic)Evaluation and diagnosis in adults......Page 6933
Treatment and prognosis of cutaneous mastocytosis......Page 6951
Systemic mastocytosisDetermining the subtype of disease......Page 6961
Indolent and smoldering systemic mastocytosis Management and prognosis......Page 6972
Advanced systemic mastocytosisManagement and prognosis......Page 6986
Cutaneous manifestations of amyloidosis......Page 7004
Necrobiosis lipoidica......Page 7016
Atrophoderma of Pasini and Pierini......Page 7030
Paronychia......Page 7037
Pernio (chilblains)......Page 7047
Skin picking (excoriation) disorder and related disorders......Page 7056
Skin biopsy techniques......Page 7073
Subcorneal pustular dermatosis......Page 7088
Technique of incision and drainage for skin abscess......Page 7099
Management of ingrown toenails......Page 7116
Office-based dermatologic diagnostic procedures......Page 7130
Intralesional corticosteroid injection......Page 7139
Topical corticosteroidsUse and adverse effects......Page 7146
Pyogenic granuloma (lobular capillary hemangioma)......Page 7158
Acute genital ulceration (Lipschutz ulcer)......Page 7206
Vesicular, pustular, and bullous lesions in the newborn and infant......Page 7224
Aplasia cutis congenita......Page 7298
Approach to the patient with a scalp disorder......Page 7321
Approach to the patient with pustular skin lesions......Page 7410
Atypical exanthems in children......Page 7472
Candida infections in children......Page 7501
Capillary malformations (port wine stains) and associated syndromes......Page 7536
Condylomata acuminata (anogenital warts) in children......Page 7568
Contact dermatitis in children......Page 7587
Cradle cap and seborrheic dermatitis in infants......Page 7615
Cutaneous developmental anomalies in the newborn and infant......Page 7642
Diaper dermatitis......Page 7671
Epidermal nevus and epidermal nevus syndrome......Page 7717
Evaluation of purpura in children......Page 7749
Gianotti-Crosti syndrome (papular acrodermatitis)......Page 7784
IgA vasculitis (Henoch-Schonlein purpura)Clinical manifestations and diagnosis......Page 7811
IgA vasculitis (Henoch-Schonlein purpura)Management......Page 7835
Infantile hemangiomasEpidemiology, pathogenesis, clinical features, and complications......Page 7844
Infantile hemangiomasEvaluation and diagnosis......Page 7873
Infantile hemangiomasManagement......Page 7894
Juvenile dermatomyositis and polymyositisEpidemiology, pathogenesis, and clinical manifestations......Page 7922
Juvenile dermatomyositis and polymyositisDiagnosis......Page 7935
Juvenile dermatomyositis and polymyositisTreatment, complications, and prognosis......Page 7953
Juvenile systemic sclerosis (scleroderma)Classification, clinical manifestations, and diagnosis......Page 7971
Juvenile systemic sclerosis (scleroderma)Assessment and approaches to treatment......Page 7994
Juvenile xanthogranuloma (JXG)......Page 8016
Klippel-Trenaunay syndromeClinical manifestations, diagnosis, and management......Page 8042
Localized scleroderma in childhood......Page 8064
Melanoma in children......Page 8107
Mycoplasma pneumoniae-induced rash and mucositis (MIRM)......Page 8135
Neonatal and infantile erythroderma......Page 8161
Nevus sebaceus and nevus sebaceus syndrome......Page 8204
Overview of vulvovaginal complaints in the prepubertal child......Page 8232
PHACE syndrome......Page 8263
Rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH)......Page 8280
Sclerema neonatorum......Page 8305
Skin lesions in the newborn and infant......Page 8316
Skin nodules in newborns and infants......Page 8353
Sturge-Weber syndrome......Page 8386
Subcutaneous fat necrosis of the newborn......Page 8402
Tufted angioma, kaposiform hemangioendothelioma, and the Kasabach-Merritt phenomenon......Page 8412
Vascular lesions in the newborn......Page 8439
Vasculitis in children Evaluation overview......Page 8473
Venous malformations......Page 8503
Overview of cutaneous photosensitivityPhotobiology, patient evaluation, and photoprotection......Page 8528
Photosensitivity disorders (photodermatoses)Clinical manifestations, diagnosis, and treatment......Page 8537
Polymorphous light eruption......Page 8567
PorphyriasAn overview......Page 8586
Porphyria cutanea tarda and hepatoerythropoietic porphyriaPathogenesis, clinical manifestations, and diagnosis......Page 8613
Porphyria cutanea tarda and hepatoerythropoietic porphyria Management and prognosis......Page 8633
Congenital erythropoietic porphyria......Page 8645
Variegate porphyria......Page 8661
Erythropoietic protoporphyria and X-linked protoporphyria......Page 8681
Hereditary coproporphyria......Page 8702
Pseudoporphyria......Page 8727
Sunburn......Page 8756
Selection of sunscreen and sun-protective measures......Page 8793
Targeted phototherapy......Page 8809
UVB therapy (broadband and narrowband)......Page 8819
UVA1 phototherapy......Page 8837
Psoralen plus ultraviolet A (PUVA) photochemotherapy......Page 8844
The genodermatoses An overview......Page 8866
Epidemiology, pathogenesis, classification, and clinical features of epidermolysis bullosa......Page 8878
Diagnosis of epidermolysis bullosa......Page 8897
Overview of the management of epidermolysis bullosa......Page 8907
Overview and classification of the inherited ichthyoses......Page 8925
Ichthyosis vulgaris......Page 8936
Autosomal recessive congenital ichthyosis......Page 8944
Recessive X-linked ichthyosis......Page 8956
The dyschromatoses......Page 8967
Birt-Hogg-Dube syndrome......Page 8975
Brooke-Spiegler syndrome (CYLD cutaneous syndrome)......Page 8986
Buschke-Ollendorff syndrome......Page 8995
Carney complex......Page 9005
Cutaneous leiomyomatosis......Page 9014
Cutis verticis gyrata......Page 9022
Darier disease......Page 9028
Ectodermal dysplasias......Page 9040
Epidermodysplasia verruciformis......Page 9077
Focal dermal hypoplasia (Goltz syndrome)......Page 9085
Hailey-Hailey disease (benign familial pemphigus)......Page 9092
Hereditary palmoplantar keratodermas......Page 9102
Hermansky-Pudlak syndrome......Page 9121
Hutchinson-Gilford progeria syndrome......Page 9129
Incontinentia pigmenti......Page 9137
Keratinopathic ichthyoses......Page 9147
Kindler syndrome......Page 9155
Lipoid proteinosis......Page 9165
Muir-Torre syndrome......Page 9174
Netherton syndrome......Page 9180
Nevoid basal cell carcinoma syndrome (Gorlin syndrome)......Page 9192
Oculocutaneous albinism......Page 9208
Pachyonychia congenita......Page 9223
Peeling skin syndromes......Page 9232
Piebaldism......Page 9243
Pigmentary mosaicism (hypomelanosis of Ito)......Page 9252
Tumor protein p63-related disorders......Page 9263
Xeroderma pigmentosum......Page 9269
Skin biopsy techniques......Page 9282
Fusiform - elliptical excision - UpToDate.pdf (p.16-24)......Page 9297
Minor dermatologic procedures......Page 9306
Skin surgeryPrevention and treatment of complications......Page 9322
Mohs surgery......Page 9333
Anatomic danger zones in cutaneous surgery of the head and neck......Page 9347
Nail biopsy Indications and techniques......Page 9356
Principles and overview of nail surgery......Page 9363
Nail avulsion and chemical matricectomy......Page 9377
Overview of botulinum toxin for cosmetic indications......Page 9386
Botulinum toxin for cosmetic indications Treatment of specific sites......Page 9401
Injectable soft tissue fillersOverview of clinical use......Page 9413
Injectable soft tissue fillers Permanent agents......Page 9424
Injectable soft tissue fillersTemporary agents......Page 9432
Anatomic danger zones for facial injection of soft tissue fillers......Page 9443
Chemical peels Principles......Page 9453
Chemical peels Procedures and complications......Page 9461
Principles of laser and intense pulsed light for cutaneous lesions......Page 9474
Laser and light therapy for cutaneous hyperpigmentation......Page 9485
Laser and light therapy for cutaneous vascular lesions......Page 9500
Ablative laser resurfacing......Page 9518
Nonablative skin resurfacing......Page 9533
Photodynamic therapy......Page 9548
Laser therapy of lower extremity telangiectasias, reticular veins, and small varicose veins......Page 9562
sclerotherapy techniques for lower extremity veins......Page 9570
Topical skin-lightening agents Complications associated with misuse......Page 9588
Management of acne scars......Page 9595
Photoaging......Page 9613
Postinflammatory hyperpigmentation......Page 9626
Removal of unwanted hair......Page 9638
Striae distensae (stretch marks)......Page 9646
Tattoo removal......Page 9662
What's new in dermatology......Page 9672

Citation preview

Contents Cover

1

Overview of dermoscopy

2

Dermoscopic evaluation of skin lesions

11

Dermoscopy of pigmented lesions of the palms and soles

25

Patch testing

83

Evaluation and diagnosis of hair loss

91

Approach to the clinical dermatologic diagnosis

109

Approach to the patient with a scalp disorder

198

Approach to the patient with an intertriginous skin disorder

210

Approach to the patient with annular skin lesions

222

Approach to the patient with cutaneous blisters

235

Approach to the patient with facial erythema

342

Approach to the patient with pustular skin lesions

387

Approach to the patient with retiform (angulated) purpura

446

Approach to the differential diagnosis of leg ulcers

458

Evaluation of adults with cutaneous lesions of vasculitis

471

Office-based dermatologic diagnostic procedures

483

Longitudinal melanonychia

492

Erythroderma in adults

503

Acquired hyperpigmentation disorders

518

Overview of nail disorders

542

Atopic dermatitis

566

allergic contact dermatitis

650

Contact dermatitis in children

677

Irritant contact dermatitis in adults

688

Chronic hand eczema

705

Patch testing

717

Management of allergic contact dermatitis

725

Poison ivy (Toxicodendron) dermatitis

733

Eyelid dermatitis (eczema)

743

Keratosis pilaris

753

Keratosis pilaris atrophicans

758

Cheilitis

763

Acute palmoplantar eczema (dyshidrotic eczema)

774

Cradle cap and seborrheic dermatitis in infants

784

Intertrigo

790

Nummular eczema

798

Overview of dermatitis (eczema)

804

Prurigo nodularis

901

Seborrheic dermatitis in adolescents and adults

912

Stasis dermatitis

925

Vulvar dermatitis

937

Urticarial dermatitis

951

Radiation dermatitis

970

Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris

988

Postadolescent acne in women

1007

Treatment of acne vulgaris

1017

Oral isotretinoin therapy for acne vulgaris

1046

Hormonal therapy for women with acne vulgaris

1060

Light-based, adjunctive, and other therapies for acne vulgaris

1072

Perioral (periorificial) dermatitis

1080

Rosacea Pathogenesis, clinical features, and diagnosis

1092

Management of rosacea

1105

PsoriasisEpidemiology, clinical manifestations, and diagnosis

1124

Pathophysiology of plaque psoriasis

1196

Nail psoriasis

1208

Guttate psoriasis

1245

Treatment of psoriasis in adults

1274

Erythrodermic psoriasis in adults

1318

Treatment selection for moderate to severe plaque psoriasis in special

1343

Psoriasis in children epidemiology clinical manifestation and dianosis

1366

Psoriasis in childrenManagement of chronic plaque psoriasis

1400

Management of psoriasis in pregnancy

1426

Comorbid disease in psoriasis

1444

Patient education Psoriasis (Beyond the Basics)

1463

Pustular psoriasisPathogenesis, clinical manifestations, and diagnosis

1482

Pustular psoriasisManagement

1509

Palmoplantar pustulosisEpidemiology, clinical features, and diagnosis

1531

Palmoplantar pustulosis Treatment

1561

Lichen planus

1583

Lichen Planopilaris

1597

Vulvar lichen planus

1614

Oral lichen planusPathogenesis, clinical features, and diagnosis

1631

Oral lichen planus Management and prognosis

1640

Pityriasis rosea

1651

Pityriasis lichenoides chronica

1683

Pityriasis lichenoides et varioliformis acuta (PLEVA)

1707

Pityriasis rubra pilaris

1739

Confluent and reticulated papillomatosis

1771

Lichen striatus

1799

New-onset urticaria

1827

Chronic spontaneous urticariaClinical manifestations, diagnosis,and natural

1860

Chronic spontaneous urticariaStandard management and patient education

1893

Chronic spontaneous urticaria Treatment of refractory symptoms

1921

An overview of angioedemaPathogenesis and causes

1940

An overview of angioedemaClinical features, diagnosis, and management

1956

Hereditary angioedemaPathogenesis and diagnosis

1986

Hereditary angioedema Epidemiology, clinical manifestations, exacerbating prognosis

2000

Hereditary angioedema (due to C1 inhibitor deficiency)General care andterm

2011

Hereditary angioedema with normal C1 inhibitor

2037

Hereditary angioedemaAcute treatment of angioedema attacks

2052

Hereditary angioedema Temporary prophylaxis before procedures or stress angioedema episodes

2077

Acquired C1 inhibitor deficiencyClinical manifestations, epidemiology,and

2090

Acquired C1 inhibitor deficiencyManagement and prognosis

2101

ACE inhibitor-induced angioedema

2115

Physical (inducible) forms of urticaria

2129

Cold urticaria

2167

Urticarial vasculitis

2188

Pathogenesis, clinical manifestations, and diagnosis of pemphigus

2221

Paraneoplastic pemphigus

2236

Initial management of pemphigus vulgaris and pemphigus foliaceus

2249

Management of refractory pemphigus vulgaris and pemphigus foliaceus

2264

Fogo selvagem Brazilian endemic pemphigus foliaceus

2275

Epidemiology and pathogenesis of bullous pemphigoid and mucous 2288 Clinical features and diagnosis of bullous pemphigoid and mucous 2298 Ocular cicatricial pemphigoid

2315

Management and prognosis of bullous pemphigoid

2330

Management of mucous membrane pemphigoid

2345

Dermatitis herpetiformis

2356

Epidermolysis bullosa acquisita

2369

Friction blisters

2383

Linear IgA bullous dermatosis

2390

Evaluation and diagnosis of hair loss

2404

Overview of dermoscopy of the hair and scalp

2422

Alopecia areataClinical manifestations and diagnosis

2435

Alopecia areataManagement

2445

Androgenetic alopecia in menPathogenesis, clinical features, and diagnosis

2460

Treatment of androgenetic alopecia in men

2470

Female pattern hair loss (androgenetic alopecia in women) Pathogenesis, and diagnosis

2480

Female pattern hair loss (androgenetic alopecia in women)Treatment and

2490

Telogen effluvium

2498

Traction alopecia

2511

Lichen planopilaris

2523

Acne keloidalis nuchae

2540

Central centrifugal cicatricial alopecia

2556

Dissecting cellulitis of the scalp

2571

Erosive pustular dermatosis of the scalp

2580

Folliculitis decalvans

2590

Hair shaft disorders

2605

Pseudofolliculitis barbae

2615

Overview of nail disorders

2625

Overview of dermoscopy

2740

Dermoscopic evaluation of skin lesions

2749

Dermoscopy of facial lesions

2763

Dermoscopy of pigmented lesions of the palms and soles

2826

Dermoscopy of nail pigmentations

2882

Dermoscopy of nonpigmented nail lesions

2920

Dermoscopic algorithms for skin cancer triage

2952

Dermoscopy of mucosal lesions

2988

MelasmaEpidemiology, pathogenesis, clinical presentation, and diagnosis

3009

MelasmaManagement

3020

Acquired melanocytic nevi (moles)

3037

Benign pigmented skin lesions other than melanocytic nevi (moles)

3047

Atypical (dysplastic) nevi

3056

Spitz nevus and atypical Spitz tumors

3071

Congenital melanocytic nevi

3090

Congenital and inherited hyperpigmentation disorders

3100

VitiligoPathogenesis, clinical features, and diagnosis

3116

VitiligoManagement and prognosis

3129

Acquired hypopigmentation disorders other than vitiligo

3145

Lentigo maligna Clinical manifestations, diagnosis, and management

3158

Melanoma Clinical features and diagnosis

3172

Risk factors for the development of melanoma

3190

Screening and early detection of melanoma in adults and adolescents

3207

Melanoma in children

3227

Epidemiology and risk factors for skin cancer in solid organ transplant

3242

Pathologic characteristics of melanoma

3254

Pathologic evaluation of regional lymph nodes in melanoma

3268

Tumor, node, metastasis (TNM) staging system and other prognostic factors melanoma

3274

Surgical management of primary cutaneous melanoma or melanoma at sites

3286

Staging work-up and surveillance after treatment of melanoma

3300

Primary prevention of melanoma

3310

Prevention and management of skin cancer in solid organ transplant

3323

Cellulitis and skin abscessClinical manifestations and diagnosis

3340

Cellulitis and skin abscess in adultsTreatment

3351

Erythrasma

3364

Impetigo

3371

Pitted keratolysis

3379

Pseudomonas aeruginosa skin and soft tissue infections

3388

Cutaneous manifestations of tuberculosis

3401

Cutaneous manifestations of gonorrhea

3418

Staphylococcal scalded skin syndrome

3425

Necrotizing soft tissue infections

3438

Trichomycosis (trichobacteriosis)

3454

Botryomycosis

3460

Yaws, bejel, and pinta

3467

Pediculosis capitis

3486

Pediculosis corporis

3500

Pediculosis pubis and pediculosis ciliaris

3516

ScabiesEpidemiology, clinical features, and diagnosis

3524

Scabies Management

3533

Bedbugs

3542

Chigger bites

3552

Jellyfish stings

3557

Lepidopterism Skin disorders secondary to caterpillars and moths

3572

Dermatophyte (tinea) infections

3580

Tinea versicolor (pityriasis versicolor)

3593

Tinea capitis

3602

Tinea nigra

3619

OnychomycosisEpidemiology, clinical features, and diagnosis

3626

OnychomycosisManagement

3637

Candida infections in children

3653

Chromoblastomycosis

3667

Lobomycosis

3679

Piedra

3688

Cutaneous warts (common, plantar, and flat warts)

3695

Condylomata acuminata (anogenital warts) in adults Epidemiology,clinicaland

3710

Condylomata acuminata (anogenital warts) Management of external in men

3719

Condylomata acuminata (anogenital warts) in children

3734

Epidemiology, clinical manifestations, and diagnosis of genital herpesvirus

3743

Treatment of genital herpes simplex virus infection

3758

Prevention of genital herpes virus infections

3772

Treatment of herpes simplex virus type 1 infection in immunocompeten

3782

Epidemiology, clinical manifestations, and diagnosis of herpes zoster

3792

Treatment of herpes zoster in the immunocompetent host

3807

Molluscum contagiosum

3817

Orf virus infection

3833

HIV-associated eosinophilic folliculitis

3839

Fever and rash in the immunocompetent patient

3849

Gianotti-Crosti syndrome (papular acrodermatitis)

3921

Clinical manifestations, diagnosis, and management of diabetic infections of etremities

3929

Infectious folliculitis

3944

Soft tissue infections following water exposure

3958

Skin lesions in the returning traveler

3969

Drug eruptions

3978

Exanthematous (maculopapular) drug eruption

3989

Lichenoid drug eruption (drug-induced lichen planus

4000

Acute generalized exanthematous pustulosis (AGEP)

4012

Drug reaction with eosinophilia and systemic symptoms (DRESS)

4020

Fixed drug eruption

4037

Stevens-Johnson syndrome and toxic epidermal necrolysis

4047

Acneiform eruption secondary to epidermal growth factor receptor (EGFR) inhibitors

4082

Cutaneous side effects of conventional chemotherapy agents

4096

Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors

4118

Cutaneous adverse events of molecularly targeted therapy and otheragents cancer therapy

4128

Epidemiology, natural history, and diagnosis of actinic keratosis

4142

Treatment of actinic keratosis

4152

Actinic cheilitis

4167

Epidemiology, pathogenesis, and clinical features of basal cell carcinoma

4174

Treatment and prognosis of basal cell carcinoma at low risk of recurrence

4191

Treatment of basal cell carcinomas at high risk for recurrence

4208

Evaluation for locoregional and distant metastases in cutaneous squamous basal cell carcinoma

4218

Systemic treatment of advanced cutaneous squamous and basal cell

4227

Nevoid basal cell carcinoma syndrome (Gorlin syndrome)

4237

Cutaneous adnexal tumors

4253

Microcystic adnexal carcinoma

4347

Epidemiology and risk factors for cutaneous squamous cell carcinoma

4357

Cutaneous squamous cell carcinoma (cSCC) Clinical features and diagnosis

4372

Treatment and prognosis of low-risk cutaneous squamous cell carcinoma

4380

Recognition and management of high-risk (aggressive) cutaneous squamous 4397 Evaluation for locoregional and distant metastases in cutaneous squamous basal cell carcinoma

4416

Systemic treatment of advanced cutaneous squamous and basal cell

4425

Keratoacanthoma

4435

Merkel cell (neuroendocrine) carcinoma

4455

Epidemiology and risk factors for skin cancer in solid organ transplant

4486

Prevention and management of skin cancer in solid organ transplant

4498

Sebaceous carcinoma

4515

Atypical fibroxanthoma

4524

Porokeratosis

4532

Overview of cutaneous lupus erythematosus

4548

Initial management of discoid lupus and subacute cutaneous lupus

4599

Management of refractory discoid lupus and subacute cutaneous lupus

4621

Tumid lupus erythematosus

4642

Bullous systemic lupus erythematosus

4672

Cutaneous dermatomyositis in adultsOverview and initial management

4694

Initial treatment of dermatomyositis and polymyositis in adults

4725

Management of refractory cutaneous dermatomyositis in adults

4745

Treatment of recurrent and resistant dermatomyositis and polymyositis in

4762

Malignancy in dermatomyositis and polymyositis

4775

Juvenile dermatomyositis and polymyositis Epidemiology, pathogenesis, and 4784 Juvenile dermatomyositis and polymyositis Diagnosis

4797

Juvenile dermatomyositis and polymyositisTreatment, complications, and

4815

Clinical manifestations, pathologic features, and diagnosis of Langerhans 4833 Treatment of Langerhans cell histiocytosis

4865

Necrobiotic xanthogranuloma

4887

Juvenile xanthogranuloma (JXG)

4907

Pathology and pathogenesis of sarcoidosis

4933

Cutaneous manifestations of sarcoidosis

4953

Clinical manifestations and diagnosis of pulmonary sarcoidosis

4999

Cutaneous sarcoidosisManagement

5039

Pathogenesis of systemic sclerosis (scleroderma)

5065

Risk factors for and possible causes of systemic sclerosis (scleroderma)

5089

Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in

5098

Pretreatment evaluation of adults with systemic sclerosis (scleroderma)

5132

Overview of the treatment and prognosis of systemic sclerosis (scleroderma) 5141 Juvenile systemic sclerosis (scleroderma)Classification, clinicaland diagnosis

5158

Juvenile systemic sclerosis (scleroderma)Assessment and approaches to

5181

Pathogenesis, clinical manifestations, and diagnosis of morphea (localizedin

5203

Treatment of morphea (localized scleroderma) in adults

5238

Localized scleroderma in childhood

5248

Scleredema

5291

Scleromyxedema

5312

Nephrogenic systemic fibrosis-nephrogenic fibrosing dermopathy inkidney

5340

Evaluation of adults with cutaneous lesions of vasculitis

5367

Overview of cutaneous small vessel vasculitis

5400

Management of adults with idiopathic cutaneous small vessel vasculitis

5407

Urticarial vasculitis

5420

Livedoid vasculopathy

5453

IgA vasculitis (Henoch-Schönlein purpura)Clinical manifestations and

5472

IgA vasculitis (Henoch-Schönlein purpura)Management

5496

Erythema induratum (nodular vasculitis)

5505

Erythema elevatum diutinum

5523

Acanthosis nigricans

5545

Anetoderma

5578

Cutaneous polyarteritis nodosa

5596

Cutaneous xanthomas

5615

Erythema annulare centrifugum

5658

Erythema nodosum

5689

Erythromelalgia

5713

Localized lichen myxedematosus

5729

Palisaded neutrophilic and granulomatous dermatitis

5746

Necrobiosis lipoidica

5759

Panniculitis Recognition and diagnosis

5791

Pathogenesis of Raynaud phenomenon

5826

Perforating dermatoses

5837

Pernio (chilblains)

5878

Pigmented purpuric dermatoses (capillaritis)

5896

Calcinosis cutis Etiology and patient evaluation

5942

Calcinosis cutisManagement

5984

Neutrophilic dermatoses

5991

Pyoderma gangrenosum Pathogenesis, clinical features, and diagnosis

6055

Pyoderma gangrenosum Treatment and prognosis

6082

Sweet syndrome

6098

Cutaneous manifestations of amyloidosis

6138

Cutaneous manifestations of graft-versus-host disease (GVHD)

6181

Cutaneous manifestations of internal malignancy

6241

Parapsoriasis (small plaque and large plaque parapsoriasis)

6306

Classification of primary cutaneous lymphomas

6316

Approach to the patient with a diagnosis of atypical lymphocytic infiltrate of 6324 Variants of mycosis fungoides

6332

Primary cutaneous T cell lymphomas, rare subtypes

6346

Clinical manifestations, pathologic features, and diagnosis of peripheral T

not otherwise specified

6358

Treatment of early stage (IA to IIA) mycosis fungoides

6367

Treatment of advanced stage (IIB to IV) mycosis fungoides

6382

Treatment of Sézary syndrome

6402

Primary cutaneous anaplastic large cell lymphoma

6423

Clinical manifestations, pathologic features, and diagnosis of systemiclarge 6435 Jessner's lymphocytic infiltrate

6448

Cutaneous B cell pseudolymphomas

6453

Cutaneous T cell pseudolymphomas

6460

Eosinophilic cellulitis (Wells syndrome)

6470

Lymphomatoid papulosis

6480

Primary cutaneous follicle center lymphoma

6498

Primary cutaneous large B cell lymphoma, leg type

6509

Primary cutaneous marginal zone lymphoma

6518

Angiolymphoid hyperplasia with eosinophilia and Kimura disease

6531

Overview of benign lesions of the skin

6542

PruritusEtiology and patient evaluation

6561

Pruritus Overview of management

6577

Oral lesions

6589

Recurrent aphthous stomatitis

6612

Oral lichen planus Pathogenesis, clinical features, and diagnosis

6626

Oral lichen planusManagement and prognosis

6635

Oral leukoplakia

6646

Vulvar dermatitis

6653

Vulvar lichen sclerosus

6667

Extragenital lichen sclerosus

6686

Primary focal hyperhidrosis

6697

Bromhidrosis

6713

Chromhidrosis

6721

Fox-Fordyce disease (apocrine miliaria)

6728

Miliaria

6737

Granular parakeratosis

6746

Granuloma annulare

6754

Granuloma faciale

6771

Dermatoses of pregnancy

6781

Erythema multiformePathogenesis, clinical features, and diagnosis

6796

Erythema multiforme Management

6807

Grover's disease (transient and persistent acantholytic dermatosis)

6817

Hidradenitis suppurativaPathogenesis, clinical features, and diagnosis

6822

Hidradenitis suppurativa Treatment

6835

Surgical management of hidradenitis suppurativa

6854

Keloids and hypertrophic scars

6864

Laser therapy for hypertrophic scars and keloids

6878

Mastocytosis (cutaneous and systemic)Epidemiology, pathogenesis, and 6892 Mastocytosis (cutaneous and systemic)Evaluation and diagnosis in children

6906

Mastocytosis (cutaneous and systemic)Evaluation and diagnosis in adults

6918

Treatment and prognosis of cutaneous mastocytosis

6936

Systemic mastocytosisDetermining the subtype of disease

6946

Indolent and smoldering systemic mastocytosis Management and prognosis

6957

Advanced systemic mastocytosisManagement and prognosis

6971

Cutaneous manifestations of amyloidosis

6989

Necrobiosis lipoidica

7001

Atrophoderma of Pasini and Pierini

7015

Paronychia

7022

Pernio (chilblains)

7032

Skin picking (excoriation) disorder and related disorders

7041

Skin biopsy techniques

7058

Subcorneal pustular dermatosis

7073

Technique of incision and drainage for skin abscess

7084

Management of ingrown toenails

7101

Office-based dermatologic diagnostic procedures

7115

Intralesional corticosteroid injection

7124

Topical corticosteroidsUse and adverse effects

7131

Pyogenic granuloma (lobular capillary hemangioma)

7143

Acute genital ulceration (Lipschutz ulcer)

7191

Vesicular, pustular, and bullous lesions in the newborn and infant

7209

Aplasia cutis congenita

7283

Approach to the patient with a scalp disorder

7306

Approach to the patient with pustular skin lesions

7395

Atypical exanthems in children

7457

Candida infections in children

7486

Capillary malformations (port wine stains) and associated syndromes

7521

Condylomata acuminata (anogenital warts) in children

7553

Contact dermatitis in children

7572

Cradle cap and seborrheic dermatitis in infants

7600

Cutaneous developmental anomalies in the newborn and infant

7627

Diaper dermatitis

7656

Epidermal nevus and epidermal nevus syndrome

7702

Evaluation of purpura in children

7734

Gianotti-Crosti syndrome (papular acrodermatitis)

7769

IgA vasculitis (Henoch-Schonlein purpura)Clinical manifestations and

7796

IgA vasculitis (Henoch-Schonlein purpura)Management

7820

Infantile hemangiomasEpidemiology, pathogenesis, clinical features, and

7829

Infantile hemangiomasEvaluation and diagnosis

7858

Infantile hemangiomasManagement

7879

Juvenile dermatomyositis and polymyositisEpidemiology, pathogenesis, and 7907 Juvenile dermatomyositis and polymyositisDiagnosis

7920

Juvenile dermatomyositis and polymyositisTreatment, complications, and

7938

Juvenile systemic sclerosis (scleroderma)Classification, clinicaland diagnosis

7956

Juvenile systemic sclerosis (scleroderma)Assessment and approaches to

7979

Juvenile xanthogranuloma (JXG)

8001

Klippel-Trenaunay syndromeClinical manifestations, diagnosis, and

8027

Localized scleroderma in childhood

8049

Melanoma in children

8092

Mycoplasma pneumoniae-induced rash and mucositis (MIRM)

8120

Neonatal and infantile erythroderma

8146

Nevus sebaceus and nevus sebaceus syndrome

8189

Overview of vulvovaginal complaints in the prepubertal child

8217

PHACE syndrome

8248

Rapidly involuting congenital hemangioma (RICH) and noninvoluting NICH)

8265

Sclerema neonatorum

8290

Skin lesions in the newborn and infant

8301

Skin nodules in newborns and infants

8338

Sturge-Weber syndrome

8371

Subcutaneous fat necrosis of the newborn

8387

Tufted angioma, kaposiform hemangioendothelioma, and the Kasabach8397 Vascular lesions in the newborn

8424

Vasculitis in children Evaluation overview

8458

Venous malformations

8488

Overview of cutaneous photosensitivityPhotobiology, patient evaluation, and

8513

Photosensitivity disorders (photodermatoses)Clinical manifestations,and

8522

Polymorphous light eruption

8552

PorphyriasAn overview

8571

Porphyria cutanea tarda and hepatoerythropoietic porphyriaPathogenesis, and diagnosis

8598

Porphyria cutanea tarda and hepatoerythropoietic porphyria Management 8618 Congenital erythropoietic porphyria

8630

Variegate porphyria

8646

Erythropoietic protoporphyria and X-linked protoporphyria

8666

Hereditary coproporphyria

8687

Pseudoporphyria

8712

Sunburn

8741

Selection of sunscreen and sun-protective measures

8778

Targeted phototherapy

8794

UVB therapy (broadband and narrowband)

8804

UVA1 phototherapy

8822

Psoralen plus ultraviolet A (PUVA) photochemotherapy

8829

The genodermatoses An overview

8851

Epidemiology, pathogenesis, classification, and clinical features ofbullosa

8863

Diagnosis of epidermolysis bullosa

8882

Overview of the management of epidermolysis bullosa

8892

Overview and classification of the inherited ichthyoses

8910

Ichthyosis vulgaris

8921

Autosomal recessive congenital ichthyosis

8929

Recessive X-linked ichthyosis

8941

The dyschromatoses

8952

Birt-Hogg-Dube syndrome

8960

Brooke-Spiegler syndrome (CYLD cutaneous syndrome)

8971

Buschke-Ollendorff syndrome

8980

Carney complex

8990

Cutaneous leiomyomatosis

8999

Cutis verticis gyrata

9007

Darier disease

9013

Ectodermal dysplasias

9025

Epidermodysplasia verruciformis

9062

Focal dermal hypoplasia (Goltz syndrome)

9070

Hailey-Hailey disease (benign familial pemphigus)

9077

Hereditary palmoplantar keratodermas

9087

Hermansky-Pudlak syndrome

9106

Hutchinson-Gilford progeria syndrome

9114

Incontinentia pigmenti

9122

Keratinopathic ichthyoses

9132

Kindler syndrome

9140

Lipoid proteinosis

9150

Muir-Torre syndrome

9159

Netherton syndrome

9165

Nevoid basal cell carcinoma syndrome (Gorlin syndrome)

9177

Oculocutaneous albinism

9193

Pachyonychia congenita

9208

Peeling skin syndromes

9217

Piebaldism

9228

Pigmentary mosaicism (hypomelanosis of Ito)

9237

Tumor protein p63-related disorders

9248

Xeroderma pigmentosum

9254

Skin biopsy techniques

9267

Fusiform - elliptical excision - UpToDate.pdf (p.16-24)

9282

Minor dermatologic procedures

9291

Skin surgeryPrevention and treatment of complications

9307

Mohs surgery

9318

Anatomic danger zones in cutaneous surgery of the head and neck

9332

Nail biopsy Indications and techniques

9341

Principles and overview of nail surgery

9348

Nail avulsion and chemical matricectomy

9362

Overview of botulinum toxin for cosmetic indications

9371

Botulinum toxin for cosmetic indications Treatment of specific sites

9386

Injectable soft tissue fillersOverview of clinical use

9398

Injectable soft tissue fillers Permanent agents

9409

Injectable soft tissue fillersTemporary agents

9417

Anatomic danger zones for facial injection of soft tissue fillers

9428

Chemical peels Principles

9438

Chemical peels Procedures and complications

9446

Principles of laser and intense pulsed light for cutaneous lesions

9459

Laser and light therapy for cutaneous hyperpigmentation

9470

Laser and light therapy for cutaneous vascular lesions

9485

Ablative laser resurfacing

9503

Nonablative skin resurfacing

9518

Photodynamic therapy

9533

Laser therapy of lower extremity telangiectasias, reticular veins, and small 9547 sclerotherapy techniques for lower extremity veins

9555

Topical skin-lightening agents Complications associated with misuse

9573

Management of acne scars

9580

Photoaging

9598

Postinflammatory hyperpigmentation

9611

Removal of unwanted hair

9623

Striae distensae (stretch marks)

9631

Tattoo removal

9647

What's new in dermatology

9657

Overview of dermoscopy - UpToDate uptodate.com/contents/overview-of-dermoscopy/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Sep 09, 2019.

INTRODUCTION

Dermoscopy is a noninvasive, in vivo technique

primarily used for the examination of pigmented skin lesions; however, it can also assist observers in assessing lesions with little to no pigment [1]. Dermatoscopy, epiluminescence microscopy, incident light microscopy, and skin-surface microscopy are synonyms. Dermoscopy is performed with a handheld instrument called a dermatoscope. The procedure allows for the visualization of subsurface skin structures in the epidermis, at the dermoepidermal junction, and in the upper dermis; these structures are usually not visible to the naked eye [2-4]. The dermoscopic images may be photographed or recorded digitally for storage or sequential analysis. The basic principles of dermoscopy will be discussed in this topic. The dermoscopic diagnosis of skin lesions, including those in special anatomic areas (eg, face, volar surfaces of palms and soles, mucosal surfaces, and glabrous skin in genital area), dermoscopy of nail pigmentation, and algorithms used for skin cancer triage are discussed separately. ●(See "Dermoscopic evaluation of skin lesions".) ●(See "Dermoscopy of pigmented lesions of the palms and soles".) ●(See "Dermoscopy of facial lesions".) ●(See "Dermoscopy of mucosal lesions".) ●(See "Dermoscopy of nail pigmentations".) ●(See "Overview of dermoscopy of the hair and scalp".) ●(See "Dermoscopic algorithms for skin cancer triage".)

2

DERMOSCOPY PHYSICS

Ambient light is reflected,

scattered, or absorbed by objects. Under normal conditions, most of the light is reflected by the skin surface because of the higher refractive index (RI) of the stratum corneum (1.55) compared with that of the air (1.0). Reduction of skin surface reflection allows for the visualization of deeper epidermal and dermal structures. This reduction can be achieved by affixing a glass plate (RI: 1.52) to the stratum corneum (RI: 1.55) and using an RI-matched immersion fluid as an interface or by using polarizing filters [5-7]. Several immersion fluids have been used, including water, alcohols (ethanol and isopropanol), oils (mineral oil, immersion oil, and olive oil), and water-soluble gels (ultrasound gel, cosmetic gels). Alcohols (in particular ethanol 70%) are the preferred immersion liquid due to their low viscosity, amphiphilic properties (ie, both water and lipid soluble), disinfectant capabilities, and image clarity. However, on some specific sites such as the mucosae and areas around the eyes and nails, watersoluble gels are preferred over alcohol since they are noncaustic and have higher viscosity [6]. Alternatively, reduction of the skin surface reflection can be achieved by using polarized light [8]. Polarized light dermoscopy utilizes two orthogonally placed filters in a process called crosspolarization (figure 1). After reaching the skin surface, part of the polarized light is reflected by the stratum corneum maintaining its polarization, whereas part enters the skin and is scattered back from the deeper layers, losing its polarization. The light reflected by the skin surface, responsible for the glare of the skin, is blocked by the cross-polarized filter, since this light maintains its polarization. The backscattered light from the deeper layers passes through the cross-polarized filter since some of the polarized light has lost its angle of polarization. This makes the subsurface structures visible to the eye [7-9].

TYPES OF DERMATOSCOPES

Dermatoscopes

consist of a transilluminating light source and magnifying optics. The most commonly used dermatoscopes have a 10-fold magnification [4]. Three types of dermatoscopes are available: ●Nonpolarized light, contact ●Polarized light, contact ●Polarized light, noncontact Nonpolarized and polarized light dermoscopy provide complementary information (table 1) [5,7,9,10]. Deeper structures are more conspicuous with polarized dermoscopy; in contrast, superficial structures are more conspicuous with nonpolarized dermoscopy. For example, epidermal structures (eg, milia cysts and comedo-like openings in seborrheic keratoses and blue-white veil due to orthokeratosis) are more conspicuous with nonpolarized dermoscopy, whereas blood vessels and

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shiny, white structures (shiny, white lines; shiny, white blotches; and strands and rosettes) are better visualized with polarized light dermoscopy [5,7,11]. Structures visible in one mode and not in the other will blink when viewed with dermatoscopes that can toggle between polarized and nonpolarized light [12].

COLORS AND STRUCTURES

The visualization of

colors and structures in the epidermis and papillary dermis has generated a new terminology for the morphologic description of skin lesions [13]. A histologic correlation has been established for most of the structures seen with dermoscopy [14-17].

Colors — The colors seen with dermoscopy include yellow, red, brown, blue, gray, black, and white (figure 2D) [18,19]. Melanin is the most important chromophore in pigmented lesions. The color of melanin as seen on the surface of the skin depends upon its concentration and its localization in the skin; it usually appears black if located in the stratum corneum, brown if in the epidermis and superficial dermis, and gray/blue to blue if in the dermis. The color red is determined by vascularity; a thrombus will appear black. White color is associated with collagen/fibrosis, and yellow is associated with keratin or sebum.

Structures — The structures visualized in skin lesions are determined by the distribution and amount of melanin, keratin, collagen, and vascularity [10,13,18,20-22]. ●Pigment network, negative network, angulated lines, streaks, aggregated or peripheral rim of globules, and homogeneous blue pigmentation are the hallmark of melanocytic lesions (picture 1AC). ●Arborizing vessels, leaf-like structures, spoke wheel-like structures, concentric structures, large blue/gray ovoid nests, multiple blue/gray nonaggregated globules, shiny white blotches and strands, ulceration, and multiple erosions are features of basal cell carcinomas (BCCs) (picture 2). ●Glomerular vessels, white circles, rosettes, white/yellow scale, brown circles, and brown dots/globules aligned radially are structures of squamous cell carcinomas (picture 3). ●Milia-like cysts, comedo-like openings, finger print-like structures, moth-eaten borders, gyri and sulci, and sharp demarcation are characteristic of seborrheic keratoses (picture 4). Red or blue/purple/black lagoons are seen in cherry angiomas or angiokeratomas (picture 5). (See "Dermoscopic evaluation of skin lesions", section on 'First step: Melanocytic versus nonmelanocytic'.) ●Atypical pigment network, blue-white veil, atypical vascular pattern, irregular streaks, atypical dots or globules, angulated lines creating a zigzag pattern or polygons, and regression structures are some of the features associated with melanoma (picture 6A-C). (See "Dermoscopic evaluation of skin lesions", section on 'Second step: Nevus versus suspicious lesion or melanoma'.)

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A detailed description of the dermoscopic structures visualized in melanocytic and nonmelanocytic lesions and their histologic correlates is provided in the figures (figure 2A-C). The diagnostic criteria for benign and malignant melanocytic and nonmelanocytic skin lesions are discussed separately. (See "Dermoscopic evaluation of skin lesions".)

Vascular structures — In amelanotic and hypomelanotic lesions, the vascular structures (morphology, distribution, and arrangement) may provide the only clues to the diagnosis. In pigmented lesions, the pigmented structures provide the primary clue to the diagnosis, and vascular morphology provides additional secondary clues to the diagnosis [23,24]. Noncontact polarized light is the preferred type of dermatoscope for the visualization of blood vessels. However, if a contact dermatoscope is utilized, an ultrasound gel should be used as a liquid interface since the gel acts as a cushion and reduces the need for pressure being applied to the skin, preventing the blanching of the vessels. The dermoscopic evaluation of vascular structures includes morphology (dotted, serpentine, comma, corkscrew, looped or hairpin, glomerular or coiled, arborizing or branched, and branched vessels with rounded endings), distribution (focal, diffuse, central, peripheral, or random), arrangement (crown, string of pearls, clustered, or radial), and presence of a white or pink halo (table 2A-B) [21,23,25-30]. Although some vessel morphologies are most commonly associated with certain types of lesions (eg, arborizing vessels are common in BCC), the presence of a given vessel morphology is not exclusive to a particular diagnosis. For example, dotted vessels can be seen in melanocytic tumors, squamous cell carcinoma (picture 3), BCC, porokeratosis, clear cell acanthoma, and psoriasis [25,28,29,31,32]. Similarly, glomerular vessels are most commonly associated with squamous cell carcinoma/Bowen disease (picture 3), but they can also be seen in clear cell acanthoma. Polymorphous vessels are typically associated with melanoma but can also be seen in BCC [28]. Arborizing vessels are commonly seen in BCC, but they can also be seen in melanoma and intradermal nevi. Hairpin vessels are commonly associated with seborrheic keratoses, although they can also be seen in melanoma. Despite this overlap, the positive predictive value for a given vessel morphology can guide the clinician to the correct diagnosis if the clinical context is carefully considered (table 2A-B). (See "Dermoscopic evaluation of skin lesions", section on 'Second step: Nevus versus suspicious lesion or melanoma'.)

CLINICAL ROLE OF DERMOSCOPY

The

importance of dermoscopy in the in vivo diagnosis of melanoma is well recognized [33], following the identification of a large set of dermoscopic features in benign and malignant lesions together with their histopathologic correlates [16-18,34].

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Dermoscopy requires some formal training to be effectively practiced. Online tutorials on dermoscopy can be found at www.dermnetnz.org/doctors/dermoscopy-course/introduction.html, www.dermoscopy-ids.org/index.php/education/podcasts, www.genomel.org/dermoscopy, or www.dermoscopedia.org. Cross-sectional studies, randomized trials, meta-analyses, and a 2018 Cochrane systematic review have indicated that dermoscopic examination has a higher discriminatory power than naked-eye examination to detect skin cancer, including melanoma either in experimental or real-life clinical settings [13,33,35-43]. For clinicians with at least minimal training in dermoscopy, the addition of this procedure to the clinical examination increases the accuracy of the in vivo diagnosis of skin cancer and reduces the number of unnecessary biopsies [36] (see "Evaluating diagnostic tests"). In fact, 86 percent of dermoscopy users from 32 European countries reported that dermoscopy increased their melanoma detection rate, and 70 percent reported that dermoscopy decreased the number of unnecessary biopsies of benign lesions they performed [44].

Diagnostic accuracy for melanoma — Three meta-analyses and a 2018 Cochrane systematic review have shown that dermoscopy improves diagnostic accuracy for melanoma over naked-eye examination [33,37-39]. In one of these meta-analyses including nine studies performed in clinical settings, the authors reported an odds ratio for the diagnosis of melanoma of 9 (95% CI 1.5-54.6) for dermoscopy plus clinical examination, compared with clinical examination alone [38]. The summary sensitivity was 90 percent (95% CI 80-95) and the specificity was 90 percent (95% CI 57-98) for dermoscopy plus clinical examination; sensitivity was 71 percent (95% CI 59-82) and specificity was 81 percent (95% CI 48-95) for clinical examination alone. Sensitivity improved without a decrease in specificity, meaning that the higher rate of melanoma detection was not associated with a concomitant increase in the number of unnecessary excisions of benign lesions. Several factors may affect the diagnostic performance of dermoscopy: ●Experience of the examiner ●Diagnostic algorithm and threshold for a positive test ●Prevalence of melanoma in the patient population examined ●Clinical context and patient-related factors [45,46] In a systematic review of 27 studies performed in clinical and experimental settings, the diagnostic accuracy of dermoscopy was lower for inexperienced examiners compared with experts, and was inversely proportional to the prevalence of melanoma in the sample [39]. The degree of experience improved the diagnostic accuracy of complex algorithms, such as pattern analysis, whereas it did not affect the performance of simpler algorithms such as the ABCD rule of dermoscopy.

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Two clinical trials performed in primary care settings have shown that a short training in dermoscopy enables nondermatologists to use simplified diagnostic algorithms and improve their accuracy in the diagnosis of melanoma [36,47]. In one trial, 73 primary care physicians received oneday training in skin cancer detection and dermoscopy and were subsequently randomly assigned to use a polarized light handheld dermatoscope or the naked eye to assess the pigmented lesions of their patients for a period of 16-months [36]. All patients were also independently evaluated by expert dermatologists. The sensitivity for the referral of suspicious lesions was significantly higher in the dermoscopy group, compared with the naked-eye examination group (79 and 54 percent, respectively), without difference in specificity (71 and 72 percent, respectively). A 2019 systematic review of 23 randomized and observational studies performed in primary care settings confirmed that dermoscopy, with appropriate training, was associated with improved diagnostic accuracy for melanoma and benign lesions and reduced unnecessary excisions and referrals [48]. However, the minimal amount of training required to achieve competence in dermoscopy has not been determined.  

Indications — Dermoscopy aids in the evaluation of pigmented and nonpigmented skin lesions and helps in the decision-making process as to whether or not a biopsy is warranted to rule out skin cancer. Dermoscopic examination is especially useful for patients with multiple common and/or atypical nevi who are at increased risk of melanoma. In those patients, dermoscopic examination of their nevi helps identify suspicious lesions not found with naked-eye preselection [49]. Although it will be beneficial to examine as many lesions as possible in patients with multiple nevi, special attention should be paid to the following [50]: ●Any new or changing lesion ●Any lesions that are a concern (including symptomatically) for the patient ●Outlier skin lesions that are clinically different from the other lesions (the "ugly duckling" sign) ●Lesions that appear clinically suspicious for skin cancer In addition, dermoscopy has been shown to be a useful tool in the evaluation of other dermatologic entities, such as inflammatory and infectious diseases and hair and nail disorders. (See "Dermoscopy of nail pigmentations" and "Dermoscopy of nonpigmented nail lesions".)

Purposes — Dermoscopy may have different purposes depending upon the clinical setting in which it is used. In general dermatology and in primary care practices, the primary purpose of dermoscopy is the evaluation of pigmented and nonpigmented skin lesions to decide whether or not a lesion should be biopsied or referred. For this purpose, a minimal amount of training is needed [36,51-53].

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In specialized dermatologic settings, which include management of high-risk patients (eg, patients with the dysplastic/atypical nevus syndrome), the main purposes of dermoscopy are to differentiate early melanoma from benign skin lesions and to minimize the unnecessary excision of benign nevi. Subtle signs of melanoma may be detected on dermoscopy by experienced clinicians before they become clinically evident to the naked eye. Digital dermoscopy may also be useful for long- or short-term follow-up of patients with multiple common and atypical nevi [54-59]. Sequential digital dermoscopy imaging (SDDI) involves the capture and comparison of sequential dermoscopic images of one or more melanocytic lesions for short-term (three to four months) or long-term (6 to 12 months) surveillance. Several studies have indicated that SDDI has high sensitivity and specificity for detecting in situ or thin invasive melanomas that are difficult to diagnose otherwise [56-58,60]. One study showed that in the primary care setting the combination of dermoscopy and short-term digital monitoring reduced the excision or referral of benign pigmented skin lesions by 56 percent and increased the sensitivity for diagnosing melanoma from 38 to 72 percent [53]. In addition to its conventional use, dermoscopy has also been shown to improve the clinical diagnosis in other fields of dermatology, including infections/infestations as well as inflammatory skin diseases and hair diseases [61].

Benefits ●Dermoscopy improves the diagnosis of melanocytic lesions in clinical practice. Several metaanalyses of studies performed in experimental and clinical settings have indicated that dermoscopy increases the sensitivity for the diagnosis of melanoma without decreasing the specificity, compared with the naked-eye examination [33,37-39]. ●Dermoscopy improves the confidence in the diagnosis of benign pigmented lesions, reducing the number of unnecessary biopsies. In a randomized trial, dermatologists using dermoscopy, compared with those using naked-eye examination, referred fewer patients for excision of benign lesions (9 versus 16 percent) without missing malignant lesions [40]. Several retrospective studies examined the numbers of excised benign and malignant lesions in dermatologic practices before and after the introduction of dermoscopy [62,63]. In one study, the ratio between benign and malignant excised lesions decreased from 18:1 to 4:1 over a three-year period [62]. ●Dermoscopy allows digital surveillance and monitoring of melanocytic lesions in patients with multiple common or atypical nevi [54-59]. ●Dermoscopy is useful in the diagnosis and differentiation of nonmelanocytic benign and malignant tumors such as basal cell carcinoma, dermatofibroma, seborrheic keratosis, and hemangioma [10,21,25,27].

Limitations 8

●The diagnostic accuracy of dermoscopy may be poorer than naked-eye examination when performed by individuals with limited experience in the interpretation of dermoscopy [39]. Dermoscopy requires at least a minimal amount of training to provide advantage over the clinical examination [64]. The correct interpretation of dermoscopic images depends upon knowledge of the significance of colors and structures manifested by a lesion. In addition, examining a lesion with reference to the clinical context and comparison to surrounding lesions is also important for rendering a correct diagnosis [45]. ●Even in expert hands, dermoscopy may fail to recognize melanomas that lack specific dermoscopic criteria (featureless melanomas) or melanomas masquerading as inflammatory or benign lesions, such as Spitzoid melanomas, amelanotic melanomas, nodular melanomas, nevoid melanomas, desmoplastic melanomas, or verrucous melanomas [65,66]. ●Although digital dermoscopic images are suitable for distance consultation, interpretation of dermoscopic photographs may be slightly less accurate than in-vivo dermoscopy [67,68].

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dermoscopy".)

SUMMARY AND RECOMMENDATIONS ●Dermoscopy is a noninvasive, in vivo technique primarily used for the examination of skin lesions. A handheld instrument called a dermatoscope, consisting of a light source and magnifying optics, allows the visualization of subsurface skin structures that are usually not visible to the naked eye. (See 'Dermoscopy physics' above and 'Types of dermatoscopes' above.) ●Colors and structures visualized in skin lesions are mainly related to the amount, distribution, and localization of melanin, vasculature structures, collagen, and keratin (figure 2A-D and table 2A-B). ●Pigment network, negative network, angulated lines, streaks, aggregated globules or peripheral rim of globules, and homogeneous, blue pigmentation are the hallmark of melanocytic lesions (picture 1A-C). Arborizing vessels, leaf-like structures, spoke wheel-like structures/concentric globules, ovoid or round blue/gray nonaggregated areas, and shiny white blotches and strands are features of basal cell carcinomas (picture 2). Glomerular vessels, white circles, rosettes, white/yellow scale crust, brown circles, and brown dots/globules aligned radially are structures of squamous cell carcinomas. Milia-like cysts, comedo-like openings, and gyri and sulci are characteristic of seborrheic keratoses (picture 4), whereas red or blue/purple/black lagoons are seen in cherry angiomas or angiokeratomas (picture 5). (See "Dermoscopic evaluation of skin lesions", section on 'First step: Melanocytic versus nonmelanocytic'.)

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●Atypical pigment network, negative network, atypical vascular pattern, irregular streaks, atypical dots or globules, regression structures, blue-white veil, angulated lines forming a zigzag pattern or polygons (such as rhomboids), and peripheral tan structureless areas are some of the features associated with melanoma (picture 6A-C). (See "Dermoscopic evaluation of skin lesions", section on 'Second step: Nevus versus suspicious lesion or melanoma'.) ●For clinicians who have been formally trained, the addition of dermoscopy to clinical examination improves the sensitivity and specificity of the in vivo diagnosis of skin cancer, including melanoma. In particular, dermoscopy improves the confidence in the diagnosis of benign lesions and reduces the number of unnecessary biopsies. However, even in expert hands, dermoscopy may fail to recognize melanomas lacking specific dermoscopic features. (See 'Diagnostic accuracy for melanoma' above and 'Benefits' above and 'Limitations' above.) ●Dermoscopy may be useful in patients with multiple common or atypical nevi who are at increased risk for melanoma. Special attention should be paid to lesions with reported history of change and lesions appearing clinically different from the other lesions (the "ugly duckling" sign) or clinically suspicious of melanoma. (See 'Indications' above.)

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Dermoscopic evaluation of skin lesions uptodate.com/contents/dermoscopic-evaluation-of-skin-lesions/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Sep 26, 2018.

INTRODUCTION

Dermoscopy is a noninvasive, in vivo technique

primarily used for the examination of pigmented and nonpigmented skin lesions. Dermatoscopy, epiluminescence microscopy, incident light microscopy, and skin-surface microscopy are synonyms. Dermoscopy is performed with a handheld instrument called a dermatoscope. The procedure allows for the visualization of subsurface skin structures in the epidermis, dermoepidermal junction, and superficial dermis; these structures are not visible to the naked eye [1-3]. Dermoscopic diagnosis involves the recognition of specific structures, or their absence, to rule out or confirm a given diagnosis. From a cognitive perspective, this task may be accomplished using a bottom-up or a top-down strategy. In the bottom-up approach, the observer performs a visual search for salient details (individual features) to arrive at a diagnosis, whereas in the top-down strategy the observer recognizes the general context, generates a hypothesis of the likely clinical diagnosis, and performs a targeted dermoscopic search for specific features to confirm the presumed clinical diagnosis [4]. This topic will review several algorithms and scoring systems that use mainly a top-down strategy to help clinicians distinguish melanocytic lesions from nonmelanocytic lesions (First Step) and differentiate nevus from melanoma or lesions suspicious for melanoma (Second Step). The general principles of dermoscopy, dermoscopic structure terminology, dermoscopic evaluation of skin lesions, and the dermoscopic evaluation of facial, mucosal, and acral volar skin lesions are discussed separately. Dermoscopy of nail pigmentation and dermoscopic algorithms for skin cancer triage are also discussed separately. ●(See "Overview of dermoscopy".) ●(See "Dermoscopy of facial lesions".)

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●(See "Dermoscopy of mucosal lesions".) ●(See "Dermoscopy of pigmented lesions of the palms and soles".) ●(See "Dermoscopy of nail pigmentations".) ●(See "Dermoscopic algorithms for skin cancer triage".)

THE TWO-STEP ALGORITHM FOR SKIN LESION EVALUATION

The two-step dermoscopy

algorithm forms the foundation for the dermoscopic evaluation of skin lesions. It was introduced by the panel of the Consensus Internet Meeting on Dermoscopy in 2003 and has since undergone several modifications (algorithm 1) [5-7]. In the first step, the observer decides whether a lesion is melanocytic or nonmelanocytic by looking for the presence or absence of specific features. In addition to differentiating melanocytic lesions from nonmelanocytic lesions, the first step of the two-step algorithm also serves as an aid to correctly sub-classify the nonmelanocytic lesions [5,6]. (See "Overview of dermoscopy".) The second step is intended only for lesions classified as melanocytic. Melanocytic lesions are further evaluated to differentiate nevi from suspicious lesions or melanoma by using one of several algorithms created for this purpose [8-12]. (See 'Second step: Nevus versus suspicious lesion or melanoma' below.)

FIRST STEP: MELANOCYTIC VERSUS NONMELANOCYTIC

One approach to

differentiate melanocytic from nonmelanocytic lesions is based on an eight-level criterion ladder [6]. In this approach the observer evaluates the lesion for the presence or absence of specific dermoscopy criteria in an ordered sequence (figure 1). The lesion is first examined for the presence of structures that are typical of melanocytic lesions. If none of those structures are found, the lesion is examined for the presence of features of dermatofibroma, basal cell carcinoma, squamous cell carcinoma, seborrheic keratosis, or angioma/hemangioma/angiokeratoma. Lesions lacking features to classify them as one of the aforementioned categories are evaluated for the presence of blood vessels. The morphology, distribution, and arrangement of blood vessels can assist in classifying these lesions into melanocytic or nonmelanocytic tumors.

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Lesions lacking features that would allow their characterization as melanocytic or nonmelanocytic lesions are classified as featureless (feature poor, nonspecific, nonclassifiable, or structureless) lesions. Melanoma needs to be ruled out for all featureless lesions. (See 'Featureless lesions (feature poor, nonspecific, nonclassifiable, or structureless)' below and 'Vascular structures in skin lesions' below.)

Criteria for melanocytic lesions — The structures that characterize melanocytic lesions include (figure 2 and picture 1A-C) [6,13] (see "Overview of dermoscopy", section on 'Colors and structures'): ●Pigment network ●Angulated lines ●Negative network ●Aggregated (three or more) or peripheral rim of globules ●Streaks (pseudopods and radial streaming) ●Homogeneous blue pigmentation ●Parallel pattern (for lesions on palm and soles) ●Pseudonetwork (facial skin) Lesions presenting with any of the above structures are classified as melanocytic and will proceed to the second step to differentiate nevi from suspicious lesions or melanoma. (See 'Second step: Nevus versus suspicious lesion or melanoma' below.)

Dermatofibroma — While the presence of a network is indicative of a melanocytic lesion, there are exceptions. One such exception is exemplified by dermatofibroma, which is a nonmelanocytic lesion displaying a delicate pigment network at its perimeter with central scar-like area containing shiny white lines when seen with polarized light (picture 2) [14,15]. The delicate gridlike network in dermatofibroma often takes on the appearance of ring-like globules as it moves towards the central scar-like area. An additional clue to the diagnosis of dermatofibroma can be obtained by palpation, which will reveal a firm lesion that dimples inward when lateral pressure, directed towards the lesion, is applied at the lesion's edge (picture 3). (See "Overview of benign lesions of the skin", section on 'Dermatofibroma'.)

Criteria for basal cell carcinoma — The diagnostic criteria for basal cell carcinoma (BCC) include the lack of a pigment network and the presence of at least one positive feature for BCC (figure 3 and picture 4) [16]:

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●Arborizing vessels ●Leaf-like areas ●Large blue-gray ovoid nests ●Multiple blue-gray, nonaggregated globules ●Spoke-wheel structures, including concentric globules ●Ulceration and small erosions ●Shiny white blotches and strands (seen with polarized dermoscopy) [17] Additional clues in BCC are the presence of multiple in-focus, fine brown to gray dots and fine short superficial telangiectasia.

Criteria for squamous cell carcinoma — The diagnostic criteria for squamous cell carcinoma (SCC) include (figure 4 and picture 5A-B) [18-20]: ●Glomerular vessels, usually focally distributed ●Rosettes ●White circles or keratin pearls ●Yellow scale ●Brown dots/globules aligned in straight, radially oriented lines, usually located towards the periphery ●Brown circles

Criteria for seborrheic keratoses — Most of the dermoscopic features of seborrheic keratoses are related to the papillomatous growth of the epidermis and the abundance of keratin in these tumors, and include (figure 5 and picture 6) [21]: ●Multiple milia-like cysts (three or more). ●Comedo-like openings. ●Moth-eaten borders. ●Gyri and sulci (also known as fissures and ridges) creating a cerebriform pattern. At times, these gyri and sulci can create a pattern resembling a network. ●Fingerprint-like structures.

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●Hairpin vessels surrounded by a white halo. Milia-like cysts can also be seen occasionally in other lesions such as BCCs and in melanocytic nevi, particularly in congenital nevi. Additional clues for seborrheic keratosis include sharp demarcation, network-like structure (due to pigment surrounding comedo-like and ostial openings), and a negative "wobble sign" [22]. The wobble sign allows differentiation of an epidermal keratinocytic lesion from a lesion with a dermal component such as a compound or intradermal nevus.

Criteria for hemangioma/angioma and angiokeratoma — Red, purple, or blue-black lagoons are the diagnostic criteria for hemangiomas/angiomas and angiokeratomas. They are small, well demarcated areas, often separated by septa, corresponding to dilated blood vessels in the dermis (picture 7).

Vascular structures in skin lesions — Both melanocytic and nonmelanocytic lesions can present as hypomelanotic or amelanotic lesions ("pink lesions") (picture 8A-B) [23]. The dermoscopic differentiation of such lesions can be challenging. Acknowledging the context of the lesion together with evaluating the morphology and architectural arrangement of vascular structures (picture 9) can provide clues to the correct diagnosis [24,25]. Comma-shaped, dotted, and linear irregular or serpentine vessels are usually seen in melanocytic lesions (table 1) [24]. Serpentine, dotted, or polymorphous vessels (two or more morphologies within the same lesion) are often seen in amelanotic melanomas. Dotted vessels can on occasion be seen in dysplastic and congenital nevi [26]. Thicker amelanotic melanomas may present a combination of dotted, serpentine, corkscrew, or arborizing vessels. Regularly distributed hairpin vessels with a white halo are characteristic of seborrheic keratoses (picture 6), whereas arborizing vessels are typically seen in basal cell carcinomas (table 2 and picture 4). Amelanotic or hypomelanotic lesions with atypical vascular morphology and/or arrangement should be biopsied to rule out amelanotic melanoma or other skin neoplasms (picture 9).

Featureless lesions (feature poor, nonspecific, nonclassifiable, or structureless) — Some skin lesions may not show any of the above criteria for melanocytic and nonmelanocytic lesions or may not display any vascular structures to assist in diagnosis. These lesions are defined as featureless (feature poor, nonspecific, nonclassifiable, or structureless) lesions (picture 10). Since a subgroup of melanomas may lack any recognizable dermoscopic structures, nonclassifiable lesions, especially if changing or symptomatic, should be biopsied to rule out melanoma.

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SECOND STEP: NEVUS VERSUS SUSPICIOUS LESION OR MELANOMA

Once a lesion is classified as melanocytic, the observer proceeds

to the second step, intended to differentiate nevus from suspicious lesions or melanoma [5]. The decision whether to reassure the patient, monitor the lesion, or perform a biopsy is based upon this second step. A small percentage of nonmelanocytic lesions may be misclassified as melanocytic in the first step. For example, some pigmented basal cell carcinomas may exhibit a dermoscopic pattern that raises suspicion of melanoma and a biopsy will be performed. There are different algorithms and methods that aid the observer in the second step, including [2,812]: ●ABCD rule of dermoscopy (table 3) ●Menzies method (table 4) ●The seven-point checklist (table 5) ●Color, architectural disorder, symmetry, homogeneity/heterogeneity of dermoscopic structures (CASH) algorithm (table 6) ●Pattern analysis (table 7) Although all methods have a similar sensitivity, pattern analysis has a superior specificity compared with the other quantitative scoring systems and is the method preferred by most experienced clinicians (table 8) [5,27]. Novices in dermoscopy will benefit from quantitative methods such as the dermoscopy ABCD rule, Menzies method, and the seven-point checklist, which are relatively simple, accurate, and reproducible [10,28,29]. Online tutorials on dermoscopy can be found at www.dermoscopedia.org, www.dermnetnz.org/doctors/dermoscopy-course/introduction.html, www.dermoscopyids.org/index.php/education/podcasts, or www.genomel.org/dermoscopy. Also, information regarding the two-step algorithm can be found in an app called Dermoscopy Two Step Algorithm.

ABCD rule of dermoscopy — The ABCD rule of dermoscopy is a semiquantitative scoring system that employs four dermoscopic criteria to evaluate a pigmented lesion: asymmetry, border sharpness, colors, and dermoscopic structures (table 3) [8]. ●Asymmetry: Asymmetry refers to the contour and distribution of colors and structures within the lesion, in none, one, or two perpendicular axes (figure 6). The score for asymmetry ranges between zero and two points. The ABCD rule of dermoscopy and the CASH algorithm are the only algorithms

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that take into account both contour and distribution of colors and structures. ●Border sharpness: The border is evaluated for the presence of abrupt cutoffs between the lesion and the normal skin. The lesion is divided into a virtual pie with eight sections. For each segment presenting with an abrupt cutoff of pigment, a score of 1 is assigned. Hence, the border scoring ranges between zero and eight points. ●Colors: Presence of any of six colors within the lesion: white, red, light brown, dark brown, blue-gray, and black. The score for color ranges from one to six points. ●Differential dermoscopic structure: Presence of any of five structures including pigment network, homogeneous/structureless areas greater than 10 percent of the lesion (ie, hypopigmented or hyperpigmented blotches and depigmented or scar-like areas), branched streaks, dots, and globules. The score for dermoscopic structures ranges between one and five points. The scores assigned to each feature are multiplied by a weighted factor and summed up in a final dermoscopy score. Sensitivity ranges from 78 to 90 percent and specificity from 45 to 90 percent among experts and non-experts [5,7,8,10,11,29-34].

Menzies method — The Menzies method was originally developed to differentiate invasive melanomas from other pigmented lesions (table 4) [35]. The method is based upon the evaluation of two negative features with a low sensitivity (0 percent) for melanoma, and nine positive features with a high specificity for melanoma (>85 percent). "Negative features" are: ●Symmetry of the pigmentation pattern ●Presence of only one color (black, gray, blue, red, dark brown, or tan) "Positive features" are: ●Blue-white veil ●Multiple brown dots ●Pseudopods ●Radial streaming ●Scar-like depigmentation ●Peripheral black dots/globules ●Broadened network ●Multiple blue/gray dots

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●Multiple (five to six) colors The presence of both negative features virtually excludes the diagnosis of melanoma. For all other lesions, the presence of any one of the positive features raises the suspicion for melanoma. Menzies method has a sensitivity of 85 to 92 percent and a specificity of 38 to 78 percent among examiners with various degrees of experience [5,7,11,30,33,35,36].

The seven-point check list — The seven-point checklist is based upon seven dermoscopic features frequently associated with melanoma (table 5) [10]: Major criteria: ●Atypical pigment network ●Blue-whitish veil ●Atypical vascular pattern Minor criteria: ●Irregular streaks ●Irregular dots/globules ●Irregular blotches ●Regression structures A score is calculated by summing points allotted as two points for each of the major three criteria and one point for each of the four minor criteria. A final score of three or more suggests melanoma [10]. The seven-point checklist has a sensitivity of 62 to 95 percent and a specificity of 35 to 97 percent among experts and non-experts [5,7,10,30-32,34,35,37]. The presence of any one of the criteria has been proposed as sufficient to warrant a biopsy in a revised version of this check list [37]. This revised seven-point checklist lowered the threshold for biopsy, using a total score of one instead of three as sufficient to warrant a biopsy. Although this revision increases the sensitivity of the criteria, the authors acknowledge that the most sensitive and specific method to diagnose melanoma requires supportive evidence based on clinical characteristics, follow-up, and the comparative approach [38].

CASH algorithm — CASH is an acronym for Color, Architectural disorder, Symmetry, and Homogeneity/Heterogeneity of dermoscopic structures (table 6) [11]. This method is based upon evaluating a pigmented lesion for the following: ●Presence of few versus many colors

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●Architectural order versus disorder ●Symmetry of shape and pattern versus asymmetry ●Homogeneity versus heterogeneity of dermoscopic structures The scoring system for the CASH algorithm is shown in a table (table 6). A total CASH score of eight or more is suspicious of melanoma (range 2 to 17) [11]. A score of eight was chosen as a threshold that optimizes sensitivity and specificity for individuals with all levels of experience. However, a lower threshold for lesion excision may be appropriate for novices. The CASH algorithm has a sensitivity of 87 to 98 percent and a specificity of 67 to 68 percent [11,39].

Pattern analysis — Pattern analysis is based upon the association of an image with a recognition template developed from previous experience (table 7) [40,41]. It therefore requires the knowledge and recognition of the global and local patterns of nevi and melanoma [9,42,43]. For experienced clinicians, pattern analysis is a sensitive and specific method, whereas for nonexperts, it may have a worse diagnostic accuracy than the unaided eye [31,44]. In analyzing a melanocytic lesion using the pattern analysis method, it should be determined whether or not the lesion manifests one of the global patterns encountered in nevi. In broad terms, benign lesions have an organized distribution of dermoscopic structures, one or a few colors, and a symmetric pattern. In contrast, melanomas often have a disorganized distribution of structures, multiple colors, and an asymmetric pattern (figure 7).

Nevi: Global and local features — Nevi tend to manifest 1 of the 10 following benign global patterns (figure 8): ●Reticular diffuse: A diffuse pigment network composed of lines that have minimal variation in their color and thickness. The holes of the network also appear relatively homogeneous in size. The network tends to fade toward the periphery. This pattern is commonly seen in melanocytic nevi with a prominent junctional component (ie, junctional nevi, superficial congenital nevi) (picture 11). ●Reticular patchy: A subclassification of reticular diffuse and represents a reticular network similar to that described above presenting in focal patches that are distributed in a symmetric and organized manner. The patches are separated by homogeneous structureless areas, which are of the same color or slightly darker than the background skin. This pattern is commonly seen in acquired melanocytic nevi and superficial congenital nevi (picture 12). ●Peripheral reticular with central hypopigmentation:Auniform network at the periphery of the lesion with a central homogeneous and hypopigmented structureless area. The structureless area has the same color, or slightly darker as compared to the background skin. This pattern is commonly seen in acquired melanocytic nevi, especially in individuals with fair skin (picture 13).

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●Peripheral reticular with central hyperpigmentation:A uniform network at the periphery of the lesion with a central homogeneous and hyperpigmented structureless area or blotch. This pattern is commonly seen in acquired melanocytic nevi, especially in individuals with darker skin (picture 14). ●Homogeneous pattern: A diffuse homogeneous structureless pattern in a stable and non-changing lesion. It may appear as gray-blue as seen in blue nevi, brown as seen in congenital nevi, or tan-pink as seen in acquired nevi in individuals with fair skin (picture 15). ●Peripheral reticular with central globules:Auniform network at the periphery of the lesion with central globules. This pattern is commonly seen in congenital nevi (picture 16). ●Peripheral globules with central network or homogeneous area, including the starburst pattern: The central component consists of a reticular or homogeneous pattern. The peripheral component can manifest in one of three ways: a single row of globules as seen in some actively growing nevi; more than one row of globules (ie, tiered globules) creating a starburst pattern as commonly seen in Spitz nevi; and streaks (classic starburst pattern) giving the appearance of an exploding star, as seen in Spitz/Reed nevi (picture 17). ●Globular pattern: Globules of similar shape, size, and color are distributed throughout the lesion. Globules may be large and angulated, creating a cobblestone pattern as seen in dermal nevi and some congenital nevi (picture 18). ●Two-component pattern: A combination of two patterns with one half of the lesion manifesting one pattern and the other half another pattern. The most common two-component pattern is the reticular-globular pattern (picture 19). ●Multicomponent pattern: A combination of three or more patterns distributed symmetrically in at least one axis (picture 20). Nevi on volar surfaces present a parallel furrow pattern, characterized by the presence of pigment along the sulci (furrows) of palms and soles (picture 21). (See "Dermoscopy of pigmented lesions of the palms and soles".) After determining whether or not the lesion adheres to 1 of the 10 benign global patterns, the observer proceeds to analyze the lesion's local features. A description of the typical and atypical variants of the local features with their diagnostic associations is provided in the table (table 7).

Melanoma: Global and local features — The melanoma specific structures are, by convention, termed atypical/irregular. Many of these atypical/irregular structures have a typical/regular counterpart that is associated with nevi (table 7). Global features of melanoma are: ●Deviation from the benign patterns and at least 1 of the 10 melanoma specific structures.

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●Multicomponent pattern: A combination of three or more patterns (eg, reticular, globular, and homogeneous), asymmetrically distributed in the lesion. It has also been defined as a lesion with three or more dermoscopic structures distributed asymmetrically. ●Nonspecific pattern: Lack of any recognizable global pattern of pigmentation. ●Volar skin patterns: Melanomas on palms and soles (ie, volar surfaces) can present with a multicomponent pattern, nonspecific pattern, or a parallel ridge pattern, which is characterized by the presence of pigment along the cristae (ridges) of palms or soles. (See "Dermoscopy of pigmented lesions of the palms and soles".) ●Facial skin patterns: Lesions on facial skin can present with a multicomponent pattern, nonspecific pattern, asymmetric follicular openings, perifollicular granularity, circle within a circle, angulated lines creating zigzag lines or coalescing to form polygons such as rhomboidal structures, and blotches obliterating follicular openings. Lesions displaying a multicomponent or nonspecific pattern are further examined for the following 10 melanoma specific structures (picture 22A-D): ●Atypical network, including angulated lines. ●Peripheral streaks (pseudopods and radial streaming). ●Negative network. ●Off-centered blotch. ●Atypical dots and/or globules. ●Regression structures, including granularity (also known as peppering), and scar-like areas. The presence of granularity and scar-like areas within the same lesion result in the appearance of a bluewhite coloration, usually overlying macular areas. ●Blue-white veil overlying raised areas. ●Atypical vascular structures. ●Shiny white lines (also known as crystalline structures). ●Tan peripheral structureless areas. The sensitivity, specificity, and predictive value of melanoma specific structures are provided in the table (table 9). A lesion is considered malignant if it deviates from the benign patterns, and has at least 1 of the 10 melanoma-specific structures. Lesions are considered suspicious if they have a benign pattern and reveal a melanoma specific structure, or if they do not adhere to one of the benign global patterns

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and lack a specific feature of melanoma.

DERMOSCOPY FROM A MANAGEMENT PERSPECTIVE

The primary

purpose of examining a skin lesion with a dermatoscope is to determine whether the lesion should be biopsied or not [45]. The decision to biopsy a suspicious lesion should be based upon the combination of clinical and dermoscopic examination of the lesion in question as well as surrounding lesions (comparative approach) and other relevant information, including history of change, associated symptoms, and personal and family history of melanoma and other skin cancers. In patients with multiple nevi, it is useful to identify the "signature nevus" pattern (the predominant type of nevus) as well as lesions that deviate from the predominant pattern ("ugly duckling" lesions), both clinically and dermoscopically [46,47]. A comparative dermoscopic approach to the patient with multiple nevi reduces the number of excisions of benign nevi [48]. (See "Melanoma: Clinical features and diagnosis", section on 'The "ugly duckling" sign'.) After a complete clinical and dermoscopic examination utilizing the two-step dermoscopy algorithm, a management decision can be rendered (algorithm 1). ●If the lesion is considered to be benign, the patient can be reassured, educated on the importance of self-skin examination, and instructed to return if changes are detected [49,50]. ●If the lesion is considered to be a melanoma, it should undergo excisional biopsy [51-54]. ●If the lesion is considered suspicious, there are two options: perform a biopsy or refer the patient to an expert clinician for further evaluation. The management decision will depend on several factors such as the pretest probability of the diagnosis of the lesion. For example, a lesion with a spitzoid morphology in a child is less likely to be a melanoma than a similar lesion in an adult. Based on the pretest probability, the clinician may be more likely to biopsy spitzoid lesions in adults than in children. Other factors that may influence the management decision include whether or not the lesion is an isolated lesion or one in a sea of many nevi, and whether or not the lesion is a clinical or dermoscopic outlier lesion. Lesions referred to an expert for further evaluation may be deemed benign, biopsied, or subjected to short-term monitoring. The rationale behind short-term monitoring is that stable lesions are biologically indolent and represent nevi, whereas changing lesions are biologically dynamic and may be atypical nevi or melanoma [55,56]. Short-term dermoscopic monitoring, which consists of comparing digital dermoscopic images of the same lesion taken approximately three to four months apart, should ideally be performed in specialized centers by experienced clinicians [55-57]. This type of monitoring is only suitable for

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macular (nonpalpable) lesions; suspicious or atypical nodular (palpable) lesions should be biopsied. Short-term dermoscopic monitoring is a safe and accepted approach to monitor these flat (nonpalpable) atypical lesions. In one study, 19 percent of 318 nevi showed a change during this time period (2.5 to 4.5 months) and 11 percent of those changing lesions were found to be early melanomas [55].

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dermoscopy".)

INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topics (see "Patient education: Seborrheic keratosis (The Basics)")

SUMMARY AND RECOMMENDATIONS ●The two-step dermoscopy algorithm forms the foundation of the dermoscopic evaluation of skin lesions. It is based upon the systematic search and recognition of specific dermoscopic structures to distinguish melanocytic and nonmelanocytic lesions, diagnose common benign and malignant nonmelanocytic lesions, and decide whether a melanocytic lesion is benign, suspicious, or malignant. (See "Overview of dermoscopy", section on 'Colors and structures'.) ●In the first step the observer decides whether a lesion is melanocytic or nonmelanocytic by looking for the presence or absence of specific features. (See 'Criteria for melanocytic lesions' above.) ●Nonmelanocytic lesions are further examined for the presence of features of dermatofibroma, basal cell carcinoma, squamous cell carcinoma, seborrheic keratosis, angioma, or other benign or malignant nonmelanocytic lesions. The possibility of a featureless or amelanotic melanoma should

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be kept in mind. (See 'Criteria for basal cell carcinoma' above and 'Criteria for seborrheic keratoses' above and 'Criteria for hemangioma/angioma and angiokeratoma' above and 'Vascular structures in skin lesions' above.) ●In the second step of the two-step algorithm, melanocytic lesions are further evaluated to differentiate benign nevi from suspicious lesions or melanoma. The decision whether to reassure the patient, monitor the lesion, or perform a biopsy is based upon this second step. (See 'Second step: Nevus versus suspicious lesion or melanoma' above.) ●The second step is performed using one of several algorithms. Clinicians with limited experience in dermoscopy may benefit from quantitative methods, such as the ABCD rule, Menzies method, and the seven-point checklist. These methods are relatively simple, accurate, and reproducible. (See 'ABCD rule of dermoscopy' above and 'Menzies method' above and 'The seven-point check list' above and 'CASH algorithm' above and 'Pattern analysis' above.) ●If a lesion is considered to be benign after a thorough clinical and dermoscopic examination, the patient can be reassured and educated on the importance of self-skin examination and instructed to return if changes occur. If the lesion is considered suspicious, there are two options: perform a biopsy or refer the patient to an expert clinician for further evaluation. Lesions referred to an expert for further evaluation may be deemed benign, biopsied, or subjected to short-term dermoscopic monitoring. (See 'Dermoscopy from a management perspective' above.) ●If the lesion is considered to be a melanoma, it should undergo excisional biopsy. (See "Melanoma: Clinical features and diagnosis", section on 'Biopsy'.)

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Dermoscopy of pigmented lesions of the palms and soles uptodate.com/contents/dermoscopy-of-pigmented-lesions-of-the-palms-and-soles/print

Dermoscopy of pigmented lesions of the palms and soles Authors: Toshiaki Saida, MD, PhD Hiroshi Koga, MD Section Editor: Hensin Tsao, MD, PhD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 31, 2018.

INTRODUCTION

In populations with darker skin, melanoma occurs most

frequently in acral areas, with a particular predilection for the soles of the feet. In Japanese, almost one-half of cutaneous melanomas occur in acral areas and approximately 30 percent affect the sole [1]. The prognosis of acral melanoma is generally poor, mainly as a consequence of a delay in diagnosis [2,3]. Dermoscopy, a noninvasive technique performed by a handheld instrument called a dermatoscope, increases the clinician's diagnostic accuracy for pigmented lesions of the palms and soles and may help in the recognition of acral melanoma at an early, curable stage [4,5]. This topic will review the dermoscopic features of melanocytic and nonmelanocytic pigmented lesions of the palms and soles and the dermoscopic criteria for differentiating benign melanocytic nevi from early melanoma. The principles of dermoscopy and the use of dermoscopy for the evaluation of lesions located on the nonglabrous skin, face, mucosal surfaces, and nails are discussed separately. Dermoscopic algorithms for skin cancer triage are also discussed separately. ●(See "Overview of dermoscopy".) ●(See "Dermoscopic evaluation of skin lesions".) ●(See "Dermoscopy of facial lesions".) ●(See "Dermoscopy of mucosal lesions".) ●(See "Dermoscopy of nail pigmentations".) ●(See "Dermoscopy of nonpigmented nail lesions".) ●(See "Dermoscopic algorithms for skin cancer triage".)

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HISTOLOGIC FEATURES OF PALMOPLANTAR SKIN

The palmoplantar skin is

anatomically and histologically unique. It is characterized by a thick, compact, cornified layer and by the presence of dermatoglyphics, consisting of ridges and furrows (sulci) that run on the surface in a parallel fashion and form loops, whorls, and arches in highly individualized patterns. Hair follicles are absent, but eccrine sweat glands, whose ducts open in the center of surface ridges, are well developed. The pattern of the epidermal rete ridge is characteristic. In a tissue section cut perpendicularly to the surface skin markings, two types of rete ridges can be identified: the crista profunda limitans, situated under the surface furrow, and the crista profunda intermedia, situated under the surface ridge (picture 1) [4]. On scanning electron microscopy, these rete ridges appear as longitudinal parallel rows protruding into the dermis (picture 2) [6]. Transverse ridges bridging the longitudinal ridges also may be seen; they are generally short and thin but are more prominent in the peripheral areas of the palms and soles and in the foot arch. The assessment of the distribution of melanin granules and melanocytes in relation to the rete ridges is critical to differentiate acral nevi from early acral melanoma [7-9]. In acral nevi, melanocytes arranged in nests are predominantly located in the crista profunda limitans, although some melanocytes may be detected also in the crista profunda intermedia [9]. Melanin granules appear as regular columns situated in the cornified layer underneath the surface furrows, but they are usually absent under the surface ridges (picture 3). In contrast, in early acral melanoma, melanocytes arranged as solitary units are present mainly in the crista profunda intermedia underlying the surface ridges, although a few melanocytes can be seen also in the crista profunda limitans (picture 4).

DERMOSCOPIC FEATURES OF ACRAL MELANOCYTIC LESIONS Overview — Melanocytic lesions of the palms and soles exhibit unique dermoscopic patterns that are significantly different from those seen in nonglabrous skin, due to the distinctive histologic characteristics of the acral skin (picture 1). (See 'Histologic features of palmoplantar skin' above.) The main pigmentation patterns of acral melanocytic lesions are as follows (figure 1) [4,10,11]: ●Parallel furrow pattern – Linear pigmentation along the furrows of the skin markings ●Lattice-like pattern – Pigmented lines along and across the furrows

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●Fibrillar pattern – Fine fibrillar or filamentous pigmentation usually arranged in the direction crossing the parallel skin markings ●Parallel ridge pattern – Band-like pigmentation located on the ridges of the skin markings The first three patterns are typically seen in benign acquired nevi, whereas the parallel ridge pattern is the hallmark of acral melanoma. Since early melanoma and benign melanocytic nevi on the palms and soles may have a similar appearance on naked eye examination, the recognition of these specific pigmentation patterns by dermoscopy is of great help for the clinician in determining whether a lesion should be biopsied or not.

Acquired melanocytic nevi — Most melanocytic nevi detected on the palms and soles are acquired [12,13]. Approximately two-thirds of acquired acral nevi show one or combinations of the three major benign dermoscopic patterns: the parallel furrow pattern, the latticelike pattern, and the fibrillar pattern (figure 1) [4,10,11,13-18].

Parallel furrow pattern and its variants — The parallel furrow pattern results from a linear distribution of the pigment along the furrows of the skin markings, which run on the skin surface in a parallel fashion (figure 1). The basic type of parallel furrow pattern shows a single solid line of pigmentation in the furrows. Variants include the double solid line, single dotted line, and double dotted line (picture 5) [18]. The parallel furrow pattern is seen in approximately 50 percent of acral nevi in any ethnic group [5,19] and is occasionally associated with a light brown background pigmentation [18]. Orderly combinations of the parallel furrow pattern with the two other major dermoscopic patterns (latticelike and fibrillar) are also common in acral nevi (picture 6A-B) [5,18,20]. Rarely, the parallel furrow pattern may be detected in acral melanoma. However, in melanoma, this pattern is present focally or unevenly within the lesion, whereas in melanocytic nevi it is regularly distributed across the lesion. (See 'Melanoma' below.)

Lattice-like pattern — The lattice-like pattern is formed by pigmented lines along and across the furrows of the skin markings (figure 1 and picture 7). A light brown background pigmentation may be present. This pattern is detected in approximately 15 percent of acral nevi, most often in those located on the arch of the foot or in peripheral areas of the palms and soles, where the skin markings lose the typical parallel pattern [5,6,20]. The lattice-like pattern can be regarded as an anatomical modification of the parallel furrow pattern [18].

Fibrillar pattern — The fibrillar pattern consists of a densely packed, fine, fibrillar or filamentous pigmentation arranged perpendicularly or obliquely to the parallel skin markings (picture 8 and figure 1). It is detected in 10 to 20 percent of plantar nevi and rarely in palmar nevi. The

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pigment fibrils typically cover at least the whole width of one surface ridge (picture 8); if the fibrils starting on a furrow do not reach the neighboring furrow, the pattern is classified as parallel furrow pattern (picture 9). The fibrillar pattern results from the oblique arrangement of the thick, cornified layer of the plantar skin, due to the mechanical pressure exerted by the body weight, and may be considered an artifactual modification of the parallel furrow pattern [5,18,20]. In some cases, particularly in young individuals, a regular fibrillar pattern can be visualized as a parallel furrow pattern by advancing the cornified layer horizontally with the probe of a contact dermatoscope or by oblique view dermoscopy performed with a noncontact dermatoscope (picture 10) [21].

Regular versus irregular fibrillar pattern — The regular fibrillar pattern typically seen in melanocytic nevi should be differentiated from the irregular fibrillar pattern occasionally detected in acral melanomas. Criteria for regular fibrillar pattern are [5]: ●Regular and symmetrical overall arrangement of the fibrillar pigmentation ●Even thickness and length of each fibril ●Alignment of the starting points of the fibrils on a surface furrow In contrast, in the irregular fibrillar pattern, the overall arrangement of the pigmentation is asymmetrical and patchy, the fibrils vary in thickness and color, and their starting points do not lineup on a straight line in most cases (picture 11).

Minor (nontypical) patterns — In addition to the three major dermoscopic patterns (ie, parallel furrow pattern, lattice-like pattern, fibrillar pattern), minor patterns, formerly collectively called nontypical patterns, can be detected in approximately one-third of acquired melanocytic nevi of the palms and soles [16-18,22]. Minor patterns include: ●Globular pattern – Dots and globules arranged in a nonparallel fashion, often accompanied by diffuse light brown background (picture 12A) ●Acral reticular pattern – Reticulated pigmentation similar to the pigment network of the nonglabrous skin (picture 12A) ●Homogeneous pattern – Light brown, mostly structureless pigmentation with no other distinctive feature ●Globulo-streak-like pattern – Brown globules attached to linear or curvilinear streaks without relation to the skin markings (picture 12B) ●Transition pattern – Pigment network on the nonglabrous side and parallel furrow pattern or lattice-like pattern on the glabrous side of the lesion (picture 13)

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Congenital melanocytic nevi — Small congenital melanocytic nevi (≤1.5 cm) may occur on the palms and soles, but their prevalence is not known. Dermoscopic features typically detected in congenital melanocytic nevus of the palms and soles include the parallel furrow pattern, crista dotted pattern, and peas-in-a-pod pattern, as described below [23].

Parallel furrow pattern — The parallel furrow pattern, a major dermoscopic pattern most frequently detected in acquired acral nevi, is frequently also seen in acral congenital melanocytic nevi. In a dermoscopic study of 24 congenital nevi, 6 showed the parallel furrow pattern [23]. (See 'Parallel furrow pattern and its variants' above.)

Crista dotted pattern — The crista dotted pattern consists of dots/globules of pigment regularly distributed on the ridges of the skin markings (picture 14). In a series of congenital acral nevi described by the author, this pattern was observed in 3 of 24 lesions [23]. The crista dotted pattern results from the adnexocentric distribution of nevus cells, which is one of the histopathologic characteristics of congenital nevi. The dots/globules on the ridges correspond to nests of nevus cells surrounding the upper portion of eccrine ducts opening in the center of the surface ridges.

Peas-in-a-pod pattern — The peas-in-a-pod pattern is a combination of the parallel furrow and the crista dotted patterns (picture 15). This pattern, seen in 8 of 24 nevi in the author's series, is the most prevalent dermoscopic pattern of acral congenital melanocytic nevi [23].

Other findings — Congenital nevi of the palms and soles may also show [5,23-25]: ●Combinations of the three major dermoscopic patterns seen in acquired melanocytic nevi (ie, parallel furrow pattern, lattice-like pattern, and fibrillar pattern) ●Features similar to the parallel ridge pattern found in melanoma (picture 16) or other minor (nontypical) patterns, such as the globular and globulo-streak-like pattern (picture 12A-B) ●A blue-gray background pigmentation mostly seen in the central areas of the lesions, reflecting the presence of pigmented nevus cells in the dermis (picture 17) ●Enlarged pink ridges, seen in central areas of the lesions [26] The symmetric distribution of dermoscopic features and an even pigmentation support the diagnosis of congenital nevus. Elements of the clinical history (eg, presence since infancy, stable course over time) may be additional clues to the diagnosis. However, lesions with equivocal or suspicious dermoscopic features should be biopsied for histopathologic evaluation.

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Influence of age on dermoscopic patterns — Several studies indicate that the prevalence of specific dermoscopic patterns of melanocytic nevi on the palms and soles varies with age [27-29]. The crista dotted pattern and the peas-in-a-pod pattern are commonly detected in acquired acral nevi of children and adolescents. In one study, evaluating the dermoscopic images of 75 acral nevi in 69 patients younger than 18 years, the parallel furrow pattern and the crista dotted pattern were the most common patterns, detected in 71 and 21 percent of nevi, respectively [27]. Digital follow-up dermoscopic images obtained after a median follow-up time of 32 months showed a change in global pattern (from parallel furrow to lattice-like or fibrillar) in 5 of 31 nevi and a decrease or increase in local criteria (eg, pigmentation, size, and number of globules/dots) in 20. In another study, the peas-in-a pod pattern was observed in 20 percent of acral nevi seen in persons younger than 20 years but only in less than 1 percent of individuals older than 59 years [28]. An opposite trend was seen for nontypical patterns, detected in 36 percent of older individuals and in less than 10 percent of those younger than 20 years.

Nevi of the glabrous/nonglabrous skin transition zone — Melanocytic nevi located on the transitional zones between glabrous and nonglabrous skin (ie, peripheral areas of the palms and soles, lateral aspects of fingers and toes) (picture 18) may show unusual dermoscopic features. One of these is the so-called transition pattern, consisting of a typical pigment network in the nonglabrous portion of the lesion and a parallel furrow pattern or lattice-like pattern in the glabrous portion (picture 13) [17]. Nevi situated in the interdigital web spaces or on the lateral aspects of fingers or toes may show another unusual dermoscopic pattern composed of a densely arranged reticular or branched pigmentation (picture 19). On histology, melanocytic nevi located on transition zones often show a prominent proliferation of melanocytes arranged as solitary units within the epidermis that mimics melanoma in situ (picture 20) [30]. However, the symmetric, orderly intraepidermal distribution of melanocytes and the absence of nuclear atypias differentiate a benign nevus from melanoma.

Melanoma — The parallel ridge pattern and an irregular, diffuse pigmentation are highly sensitive and specific features of early and advanced acral melanoma, respectively. Advanced melanoma of the palms and soles may also show dermoscopic features characteristic of melanoma of nonglabrous skin, including irregular dots/globules, irregular streaks, blue-white veil, regression structures, and polymorphous vessels (picture 21) [4,11]. (See "Dermoscopic evaluation of skin lesions", section on 'Melanoma: Global and local features'.)

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Parallel ridge pattern — The parallel ridge pattern consists of a band-like pigmentation, tan to black in color, located on the ridges of the skin markings (figure 1 and picture 22A). It is highly characteristic of melanoma of the palms and soles and reflects the preferential proliferation of melanocytes in the crista profunda intermedia during the early horizontal growth phase (picture 4) [4,10,11,14,15]. In early melanoma, the parallel ridge pattern is evenly detected within the lesion, whereas in advanced melanoma it is focally distributed (picture 22A-B). Sensitivity and specificity of the parallel ridge pattern for the diagnosis of melanoma, including melanoma in situ, are 86 and 99 percent, respectively [14]. Occasionally, the parallel ridge pattern is detected in a variety of benign pigmented lesions of palms and soles, such as drug-induced pigmentations, Peutz-Jeghers syndrome, or pigmented warts. However, in most cases, these lesions can be correctly diagnosed based upon clinical findings and additional dermoscopic characteristics. (See 'Dermoscopic features of acral nonmelanocytic pigmented lesions' below.)

Irregular diffuse pigmentation — Irregular diffuse pigmentation is defined as a structureless pigmented area, tan to black in color, which is highly characteristic of acral melanoma (picture 22C) [11,14,31]. Sensitivity and specificity of irregular diffuse pigmentation are 85 and 97 percent, respectively. As expected, sensitivity is lower for melanoma in situ (69 percent), since the diffuse pigmentation reflects the florid proliferation of melanocytes in more advanced lesions [14].

Other features — Advanced melanoma of the palms and soles may show the same dermoscopic features of advanced melanoma of nonglabrous skin, including irregular dots/globules, irregular streaks, blue-white veil, regression structures, and polymorphous vessels (picture 21) [4,11]. However, the atypical pigment network, which is a major feature of melanoma of nonglabrous skin, is extremely rare in melanomas of the palms and soles [32]. Brown globules irregularly distributed on the ridges, reflecting transepidermal elimination of melanoma cell nests, can be a characteristic dermoscopic pattern of acral melanoma [33]. Of note, brown globules are regularly distributed on the ridges in congenital nevus [23] and Spitz nevus on the palms and soles [34]. (See "Dermoscopic evaluation of skin lesions", section on 'Melanoma: Global and local features'.) Occasionally, dermoscopic patterns typically seen in acral melanocytic nevi (eg, parallel furrow, lattice-like, and fibrillar patterns) can also be seen in advanced acral melanoma [35]. However, in melanoma these patterns usually have a focal or irregular distribution within the lesion (picture 22B). Acral melanoma may be amelanotic or hypomelanotic. In a series of 126 acral lentiginous melanomas, 34 (28 percent) were unpigmented [36]. In amelanotic or hypomelanotic melanomas, the presence of microscopic remnants of pigmentation and atypical vascular structures are

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important clues to the diagnosis [37]. Lesions with these dermoscopic findings should always be biopsied and sent for histopathologic examination. (See "Dermoscopic evaluation of skin lesions", section on 'Vascular structures in skin lesions'.)

Atypical melanosis of the foot — Atypical melanosis of the foot is an unusual plantar pigmented lesion that has clinical and dermoscopic, but not histologic, features of early acral lentiginous melanoma [38-41]. These lesions present as large macules with irregular borders and variegated colors (picture 23). On dermoscopy, they usually show the parallel ridge pattern typical of melanoma (picture 24) [40,41]. Although the clinical and dermoscopic features suggest melanoma, on histologic examination only a slightly increased number of melanocytes without cytologic atypias is detected in the crista profunda intermedia (picture 25). It has been hypothesized that these lesions may represent early or slowly evolving acral melanoma in situ [8,42,43].

THE THREE-STEP DERMOSCOPIC ALGORITHM

The three-step algorithm for the diagnosis and management of

melanocytic lesions on the palms and soles was originally proposed in 2007. Step 1 of this algorithm is based upon the high sensitivity, specificity, and positive predictive value (86, 99, and 94 percent, respectively) of the parallel ridge pattern for early acral melanoma [14,18]. Sensitivity, specificity, and positive predictive value of the parallel furrow pattern/lattice-like pattern for melanocytic nevi are 67, 93, and 98 percent, respectively [14]. A revised version of the three-step algorithm was published in 2011 and is presented here (algorithm 1) [44]: ●Step 1 – The lesion is examined for the presence of the parallel ridge pattern. If the parallel ridge pattern is found in any part of the lesion, the lesion should be biopsied regardless of the size. If the lesion does not show the parallel ridge pattern, proceed to Step 2. ●Step 2 – The lesion is examined for the presence of one or an orderly combination of the typical benign dermoscopic patterns (ie, typical parallel furrow pattern, typical lattice-like pattern, regular fibrillar pattern). If the whole area of the lesion shows one or a combination of two or three typical benign patterns, further dermoscopic follow-up is not needed. If the lesion shows equivocal dermoscopic features (ie, part or total absence of any typical/regular patterns) (picture 26), proceed to Step 3. ●Step 3 – The maximum diameter of lesions that do not show typical benign patterns is measured. Lesions >7 mm should be excised or biopsied for histopathologic evaluation [45]. Lesions ≤7 mm should be monitored clinically and dermoscopically at three- to six-month intervals. For the correct use of the three-step algorithm, it is important to keep in mind the following:

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●The algorithm has been developed for the differentiation of acquired melanocytic nevi from acral melanoma of the palms and soles and may not be appropriate for the evaluation of congenital nevi in those locations. In most cases, congenital nevi can be identified on the basis of their characteristic dermoscopic features (see 'Congenital melanocytic nevi' above). However, the threestep algorithm can be used to evaluate acral nevi whose type (acquired or congenital) cannot be determined. ●In the first step, it is crucial to correctly identify the furrows and ridges of the skin markings. Their recognition can be greatly facilitated by performing the "furrow ink test" before examining the lesion under the dermatoscope [46,47]. The periphery of the lesion is marked with liquid ink (eg, from a fountain pen) or with a whiteboard marker pen, preferably blue or green in color; the skin surface is then gently wiped with a dry paper towel. The surface furrows retain the blue or green ink and become clearly visible on dermoscopic examination as thin inked lines. The test will allow the clinician to assess whether the melanin pigmentation follows the ink lines as in the parallel furrow pattern (picture 27) or is located between the ink lines, thus representing a parallel ridge pattern (picture 28). Once the examination is completed, the marker pen ink in the furrows can be easily removed by wiping the skin with a wet paper towel. ●In the second step, the clinician must assess whether the benign patterns are typical or regular. Typical parallel furrow or lattice-like patterns are symmetrically and evenly distributed across the lesion. The criteria for classifying a fibrillar pattern as regular are described above (see 'Regular versus irregular fibrillar pattern' above). Orderly combinations of benign patterns are also considered as benign. If there is any uncertainty in classifying a pattern as benign, the lesion should be biopsied or monitored as described in Step 3. The decision not to follow-up lesions that are judged unequivocally benign in Step 2 is based upon the observation that the risk of acral melanoma developing in a preexisting nevus is extremely low [48,49]. In digital follow-up studies of acral melanocytic nevi, a change from a benign to a malignant pattern has not been reported [18,22,50]. However, changes within benign patterns have been observed in 20 to 70 percent of cases [22,50]. Lesions that cannot be unequivocally classified as benign should be biopsied for histopathologic evaluation if they are larger than 7 mm.

THE BRAAFF CHECKLIST

Based upon the dermoscopic

examination of 603 acral lesions (472 nevi and 131 acral melanomas, including 42 in situ lesions), a new six-variable scoring system has been developed for the diagnosis of acral melanoma [51]. This system, called the BRAAFF checklist, consists of six variables, each with a positive or negative value: ●Irregular blotch (+1) ●Parallel ridge pattern (+3) ●Asymmetry of structures (+1) ●Asymmetry of colors (+1)

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●Parallel furrow pattern (-1) ●Fibrillar pattern (-1) A total score of ≥1 is needed for a diagnosis of melanoma. The threshold of one point provided a sensitivity of 93 percent and a specificity of 87 percent [51].

DERMOSCOPIC FEATURES OF ACRAL NONMELANOCYTIC PIGMENTED LESIONS

Dermoscopy is helpful in the diagnosis

of a variety of benign pigmented lesions of the palms and soles, some of which may mimic acral melanoma [52]. In most cases, the correct diagnosis can be made based upon clinical history and/or associated signs and symptoms. A biopsy for histopathologic evaluation may be warranted when the diagnosis is uncertain.

Hemorrhage, hematoma, and hemangioma — Dermoscopic features of hemorrhage/hematoma and hemangioma of the palms and soles are similar to those seen in nonglabrous skin. However, due to the unique anatomical structure of the acral volar skin, some hemorrhagic lesions show characteristic dermoscopic patterns, as described below. (See "Dermoscopic evaluation of skin lesions", section on 'Criteria for hemangioma/angioma and angiokeratoma'.)

Black heel (calcaneal petechiae) — Black heel, also called calcaneal petechiae or talon noir, is an asymptomatic pigmentation of the heel secondary to intraepidermal extravasation of red blood cells, caused by shear-force injuries (eg, during vigorous sports) [53]. On naked-eye examination, black heel appears as a black macule or plaque that mimics melanoma (picture 29A-B). On dermoscopic examination, black heel shows a unique dermoscopic pattern called the "pebbles on the ridges," in which a reddish-black, pebble-like pigmentation is distributed on the ridge of the skin markings (picture 30) [4,10]. The pebble-like pigmentation corresponds to aggregation of hemosiderin in the superficial skin layers, mostly in the stratum corneum. With more abundant blood extravasations, the pebble-like pigmentation becomes confluent and forms a band-like pigmentation (picture 31) that mimics the parallel ridge pattern seen in melanoma [54]. However, the reddish tone, sharp demarcation, and subtle segmentation of the pigmented bands differentiate black heel from melanoma.

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PlayStation purpura/PlayStation fingertip — The so-called PlayStation purpura or PlayStation fingertip presents as brownish macules on the index or middle fingers, which result from subcorneal hemorrhages caused by a prolonged use of the handheld game controller device. On dermoscopy, these macules show a parallel ridge pattern [55,56]. However, the symmetric location on the index or middle fingers, the rusty/reddish hue of the color, and a history of prolonged video gaming are clues to the correct diagnosis.

Drug-induced acral pigmentation — Several anticancer drugs (eg, topical fluorouracil, doxorubicin, cyclophosphamide) may induce focal acral hyperpigmentation, such as pigmented macules and melanonychia [57-59]. Multiple small, brownish macules may develop on the hands or feet and are often accompanied by a linear pigmentation of the palmar and plantar creases. On dermoscopy, the hyperpigmented macules show a parallel ridge pattern similar to that seen in early acral melanoma (picture 32). Histology shows increased melanin in the basal layer of the epidermis and melanophages in the papillary dermis [57].

Peutz-Jeghers syndrome and LaugierHunziker syndrome — Peutz-Jeghers syndrome is a rare autosomal dominant disorder characterized by gastrointestinal polyposis in association with multiple small, hyperpigmented, mucocutaneous macules most often located on the lips and buccal mucosa (picture 33) and on the dorsal and volar aspect of hands and feet (picture 34A-B). On dermoscopy, the pigmented macules located on the volar skin show the parallel ridge pattern [60]. The diagnosis is based upon the characteristic distribution of the macules, family history, and demonstration of colonic hamartomas. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".) Laugier-Hunziker syndrome is a rare, acquired, macular hyperpigmentation of the lips, oral mucosa, and acral skin frequently associated with longitudinal melanonychia. In contrast with Peutz-Jeghers syndrome, Laugier-Hunziker syndrome is not associated with systemic disorders. On dermoscopy, the pigmented macules typically show the parallel ridge pattern, but cases with a parallel furrow pattern have been reported [61,62]. Histology shows increased melanin in basal keratinocytes, particularly in those located in the crista profunda intermedia, corresponding to the epidermal rete ridges underlying the surface ridges [62].

Volar melanotic macules — Volar melanotic macules are solitary or multiple brownish macules found on the palms and soles of individuals with darker skin types [6365]. On dermoscopy, they may show a parallel ridge pattern (picture 35). Histologically, volar melanotic macules are characterized by increased deposition of melanin in all epidermal layers, hyperpigmented solitary dendritic melanocytes scattered along the basal layer, and melanophages in the dermis [64].

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Pigmented ridged wart — The pigmented ridged wart is an uncommon type of plantar wart associated with a cystic component, caused by the human papillomavirus type 60 [66]. On dermoscopy, it shows a parallel ridge pattern and may mimic a verrucous type of acral melanoma [67-69]. When the clinical diagnosis is unclear, a biopsy is necessary to exclude melanoma. Histology reveals hyperkeratosis, acanthosis, large vacuolated cells in the malpighian and granular layers, and absence of abnormal melanocyte proliferation.

Tinea nigra — Tinea nigra is a superficial fungal infection of the palms and soles that presents as a large, brownish macule (picture 36). Dermoscopy reveals light brown, fine strands arranged in a reticular pattern [70]. The pigmentation does not follow the furrow or ridges of the skin markings. The diagnosis is confirmed by potassium hydroxide (KOH) examination of scrapings from the lesion.

Pigmentation due to chemicals — Accidental staining of the plantar skin with paraphenylenediamine, a derivative of aniline used in hair dyes and rubber products, can display the parallel ridge pattern on dermoscopy [52,71,72]. Palmar or plantar pigmentation caused by self-tanning products can also show the parallel ridge pattern. A detailed history, including the patient's occupation and hobbies, is important for a correct diagnosis. The pigment can be removed by shaving the superficial cornified layer with a scalpel.

SUMMARY AND RECOMMENDATIONS ●Dermoscopy, a noninvasive diagnostic technique performed by a handheld instrument called a dermatoscope, is of great value in the diagnosis and management of pigmented lesions of the palms and soles. (See 'Introduction' above.) ●Most acral acquired melanocytic nevi show one of three major dermoscopic patterns (figure 1): the parallel furrow pattern (picture 5), the lattice-like pattern (picture 7), and the fibrillar pattern (picture 8). (See 'Acquired melanocytic nevi' above.) ●Major dermoscopic patterns seen in acral congenital melanocytic nevi are the parallel furrow pattern (picture 17), the crista dotted pattern (picture 14), and the peas-in-a-pod pattern (picture 15). In addition, congenital nevus may exhibit variegated dermoscopic features mimicking those seen in melanoma. (See 'Congenital melanocytic nevi' above.) ●The parallel ridge pattern (figure 1 and picture 22A) is highly characteristic of early melanoma of the palms and soles. Advanced melanoma typically shows irregular diffuse pigmentation (picture 22B-C) but may also show dermoscopic features seen in melanoma of nonglabrous skin (eg,

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irregular dots/globules, irregular streaks, blue-white veil, regression structures, and polymorphous vessels). (See 'Melanoma' above.) ●A three-step algorithm (algorithm 1) has been proposed for the diagnosis and management of acquired melanocytic lesions on the palms and soles. (See 'The three-step dermoscopic algorithm' above.) ●Pigmented lesions other than melanoma and melanocytic nevus that can be found on the palms and soles include the so-called black heel and other hemorrhagic conditions, drug-induced pigmentations, Peutz-Jeghers and Laugier-Hunziker syndrome, pigmented ridged wart, and tinea nigra. Dermoscopy is useful in the diagnosis of these conditions. (See 'Hemorrhage, hematoma, and hemangioma' above and 'Dermoscopic features of acral nonmelanocytic pigmented lesions' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 16551 Version 11.0

GRAPHICS

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Histopathology of the volar skin

This tissue section was cut perpendicularly to the parallel skin markings. The ridges (orange bars) and furrows (arrows) are recognized on the surface. Under the epidermis, two kinds of epidermal rete ridges are recognized: the crista profunda intermedia (dashed arrows) underlying the surface ridges and the crista profunda limitans (arrowheads) underlying the surface furrows. The crista profunda intermedia is passed through by an intraepidermal eccrine duct. Graphic 89394 Version 2.0

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Surface electron microscopy of plantar skin

On the undersurface of the epidermis, two kinds of main longitudinal ridges, the crista profunda limitans and the crista profunda intermedia, are observed as parallel rows. Eccrine ducts are recognized as tube-like projections from the crista profunda intermedia. The short transverse ridges are also detected, bridging the main longitudinal ridges. Courtesy of Tetsuya Tsuchida, MD, PhD. Graphic 89395 Version 1.0

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Histopathologic features of acral nevi

Histopathologic features of acral nevus of the junctional type. The cornified layer slants slightly. (A) Nevus cells arranged in nests are predominantly located in the crista profunda limitans (arrows), and only a few melanocytes are detected in the crista profunda intermedia (asterisks) (hematoxylineosin stain). (B) Melanin granules in the cornified layer are detected as parallel columns regularly situated under the surface furrows (arrows), whereas they are mostly absent in the cornified layer under the surface ridges (asterisks) (Fontana-Masson stain). Reproduced with permissiomn from: Saida T, Koga H, Goto Y, Uhara H. Characteristic distribution of melanin columns in the cornified layer of acquired acral nevus: An important clue for histopathologic differentiation from early acral melanoma. Am J Dermatopathol 2011; 33:468. DOI: 10.1097/DAD.0b013e318201ac8f. Copyright © 2011 International Society of Dermatopathology. Unauthorized reproduction of this material is prohibited. Graphic 89622 Version 8.0

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Histopathologic features of early acral melanoma

Histopathologic features of the macular portion of an acral melanoma showing the parallel ridge pattern on dermoscopy. (A) Melanocytes arranged as solitary units are mainly observed in the crista profunda intermedia (asterisks), although a few melanocytes are also detected in the crista profunda limitans (arrows) (hematoxylin-eosin stain). (B) Melanin granules in the cornified layer are mostly derived from melanocytes in the crista profunda intermedia (Fontana-Masson stain). They are detected as broad columns under the surface ridges (blue bars). Melanin granules are mostly absent in the cornified layer under the surface furrow, corresponding to the underlying crista profunda limitans (arrows). This distribution corresponds well to the dermoscopic parallel ridge pattern. Reproduced with permissiomn from: Saida T, Koga H, Goto Y, Uhara H. Characteristic distribution of melanin columns in the cornified layer of acquired acral nevus: An important clue for histopathologic differentiation from early acral melanoma. Am J Dermatopathol 2011; 33:468. DOI: 10.1097/DAD.0b013e318201ac8f. Copyright © 2011 International Society of Dermatopathology. Unauthorized reproduction of this material is prohibited. Graphic 89623 Version 8.0

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Schematic representation of the dermoscopic patterns of melanocytic lesions located on the palms and soles

The parallel furrow, lattice-like, and fibrillar patterns are major dermoscopic patterns seen in acquired melanocytic nevus of the palms and soles, whereas the parallel ridge pattern is the most sensitive and specific dermoscopic pattern detected in acral melanoma. Reproduced with permission from: Saida T. Textbook of Dermoscopy, Nankodo Co. Ltd, Tokyo, 2011. Copyright © 2011 Toshiaki Saida, MD, PhD. Graphic 89396 Version 2.0

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Dermoscopic images of variants of the parallel furrow pattern in acquired melanocytic nevi of palms and soles

In the parallel furrow pattern, parallel pigmented lines are detected along the furrows of the skin markings. Variants of this pattern include: (A) single solid line variant, (B) double solid line variant, (C) single dotted line variant, and (D) double dotted line variant. Graphic 89403 Version 1.0

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Combination of the parallel furrow pattern and other benign dermoscopic patterns in acquired melanocytic nevi of the palms and soles

(A) In this lesion, the parallel furrow pattern is associated with the lattice-like pattern in the center of the lesion. (B) The parallel furrow pattern shows transition to the fibrillar pattern on the right side of this lesion. Reproduced with permission from: John Wiley & Sons, Inc. Saida T, Koga H, Uhara H. Key points in dermoscopic differentiation between early acral melanoma and acral nevus. J Dermatol 2011; 38:25. Copyright © 2011 Japanese Dermatological Association. All rights reserved. Graphic 89405 Version 5.0

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Combination of the three major dermoscopic patterns in melanocytic nevi of the palms and soles

In this nevus, the three major benign dermoscopic patterns, the parallel furrow (blue circle), fibrillar (dashed red circle), and lattice-like pattern (dotted green circle), are detected. Note that they are arranged in an orderly fashion. Inset: clinical photograph. Reproduced with permission from: Saida T, Koga H. Dermoscopic patterns of acral melanocytic nevi: Their variations, changes, and significance. Arch Dermatol 2007; 143:1423. Copyright © 2007 American Medical Association. All rights reserved. Graphic 89404 Version 9.0

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Dermoscopic image of an acquired melanocytic nevus on the palm: The lattice-like pattern

On dermoscopic examination, this acquired melanocytic nevus on the palm shows a pigment distribution that forms linear lines along and across the surface furrows in a lattice-like fashion. Graphic 89450 Version 1.0

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Dermoscopic image of an acquired melanocytic nevus on the sole: The fibrillar pattern

In this regular fibrillar pattern, the starting points of the fibrils align on the lines corresponding to the surface furrows (arrows). Graphic 89451 Version 1.0

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Dermoscopic parallel furrow pattern and fibrillar pattern

Because of the oblique arrangement of the cornified layer, the parallel furrow pattern sometimes shows features of fibrillar pattern. If the fibrils do not reach the neighboring furrow (A), the pattern is classified as parallel furrow pattern. If the fibrils reach or cross the neighboring furrow (B) or cover at least the whole width of one surface ridge, the pattern is classified as fibrillar. Graphic 89452 Version 1.0

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Oblique-view dermoscopy of the fibrillar pattern in an acral melanocytic nevus

This melanocytic nevus of the sole shows the regular fibrillar pattern on the ordinary dermoscopy (A). The green lines correspond to the furrows of the skin marking visualized by the furrow ink test. Oblique view dermoscopy using a noncontact dermatoscope changes the fibrillar pattern to the parallel furrow pattern, dotted line variant (B). Graphic 90127 Version 2.0

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Dermoscopic features of regular and irregular fibrillar pattern

In the regular fibrillar pattern of benign nevi (A), the overall arrangement of the fibrils is mostly symmetric and the starting points of the fibrils align on straight lines corresponding to the surface furrows. In contrast, in the irregular fibrillar pattern seen in melanoma (B), the fibrils are variable in color and thickness and are arranged in a disorderly, haphazard fashion. Their starting points do not align on a straight line. Graphic 89455 Version 1.0

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Minor dermoscopic patterns seen in acquired melanocytic nevi of palms and soles

(A) Globular pattern. (B) Acral reticular pattern. Graphic 89457 Version 1.0

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Minor dermoscopic patterns seen in acquired melanocytic nevi of palms and soles: Globulo-streaklike pattern

Globulo-streak-like pattern seen in two small acquired melanocytic nevi (arrows) affecting the arch areas. Graphic 90125 Version 2.0

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Dermoscopy of acral melanocytic lesions: Transition pattern

On dermoscopy, this nevus located on the inner aspect of the right heel shows the parallel furrow pattern in the lower portion and the reticular pattern in the upper portion. This pattern is characteristic of melanocytic nevi of the glabrous/nonglabrous skin transition zone. Inset: clinical photograph. Graphic 90126 Version 2.0

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Dermoscopic features of congenital nevi of the palms and soles: The crista dotted pattern

In the crista dotted pattern, brown globules are regularly distributed on the surface ridges. The globules correspond to nevus cell nests surrounding the distal portion of the eccrine ducts, which open in the center of the ridges. Graphic 89466 Version 1.0

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Dermoscopic features of congenital nevi of palms and soles: The peas-in-a-pod pattern

The peas-in-a-pod, commonly detected in congenital nevus on the palms and soles, is regarded as a combination of the parallel furrow pattern and crista dotted pattern. Graphic 89467 Version 1.0

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Dermoscopic features of a congenital plantar nevus

In this plantar congenital nevus, the dermoscopic pattern is similar to the parallel ridge pattern. However, the color is grayish and the pigmented bands are segmented, resembling the crista dotted pattern. These findings help in differentiating this pattern from the classic parallel ridge pattern seen in melanoma. Subtle features of the parallel furrow pattern, which is typical of acquired acral melanocytic nevi, are detected on the left side of this lesion. Graphic 89468 Version 2.0

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Dermoscopic features of congenital melanocytic nevus on the palms and soles: The parallel furrow pattern

In this plantar congenital nevus, the typical parallel furrow pattern is associated with a grayishbrown background pigmentation. The gray tone reflects the melanin granules in the dermis derived from the prominent intradermal component of congenital nevi. Graphic 89464 Version 1.0

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Clinical and histopathologic features of a melanocytic nevus located on the foot

Melanocytic nevus located in the fourth interdigital space of the right foot of a 23-year-old woman. This brownish-black macule, 5 mm in diameter, shows virtually no irregularity in shape or color. Reproduced with permission from: Saida T, Kawachi S, Koga H. Anatomic transitions and the histopathologic features of melanocytic nevi. Arch Dermatol 2008; 144:1232. Copyright © 2008 American Medical Association. All rights reserved. Graphic 90128 Version 12.0

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Dermoscopic features of an acral melanocytic nevus located in the transition zone between glabrous and nonglabrous skin

In this nevus located on the side of a toe, a densely arranged reticular or branched pigmentation is observed. Inset: clinical photo. Note that the histopathological features of melanocytic nevi located on the transition zone between glabrous and nonglabrous skin often mimic those of melanoma, showing prominent proliferation of solitary melanocytes within the epidermis. Courtesy of Akemi Ishida-Yamamoto, MD, PhD Graphic 89469 Version 2.0 Histologic features of melanocytic nevi of the glabrous/nonglabrous skin transition zone

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Clinical and histopathologic features of a melanocytic nevus located on a transition area (the fourth interdigital area of the right foot) of a 23-year-old woman. (A-C) In all of the histopathologic photographs (hematoxylin-eosin), we see that melanocytes proliferate mainly as solitary units within the epidermis, and many of them are situated above the dermoepidermal junction, mimicking histopathologic features of melanoma in situ. However, overall distribution of melanocytes within the lesion is mostly symmetrical and orderly. The nuclei of melanocytes are relatively large but not hyperchromatic; instead, they are vesicular. In addition, there is virtually no inflammatory cell infiltrate in the dermis. The original magnifications are x12, x38, and x84 for panels A, B, and C, respectively. Reproduced with permission from: Saida T, Kawachi S, Koga H. Anatomic transitions and the histopathologic features of melanocytic nevi. Arch Dermatol 2008; 144:1232. Copyright © 2008 American Medical Association. All rights reserved. Graphic 91380 Version 11.0

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Dermoscopic features of advanced melanoma of the sole

There is an ulcerated nodule on the right, surrounded by a blue white veil (star). The parallel ridge pattern (square) as well as the irregular fibrillar pattern (circle) are also detected. Reproduced with permission from: John Wiley & Sons, Inc. Saida T, Koga H, Uhara H. Key points in dermoscopic differentiation between early acral melanoma and acral nevus. J Dermatol 2011; 38:25. Copyright © 2011 Japanese Dermatological Association. All rights reserved. Graphic 89402 Version 5.0

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Parallel ridge pattern seen on dermoscopic examination of melanoma of palms and soles

The parallel ridge pattern represents band-like pigmentation on the ridges of the skin markings. In this melanoma in situ (A), the pattern covers almost all the lesion. In an early invasive melanoma of the sole (B), the parallel ridge pattern is detected only in the lower portion of the lesion (circle) and irregular diffuse pigmentation is observed in the upper portion. Graphic 89397 Version 1.0

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Dermoscopic features of macular areas of melanoma on the sole

In the macular areas of this advanced melanoma, the parallel ridge pattern is detected focally (red rectangle). An irregular fibrillar pattern (blue circle) and the parallel furrow pattern (green rounded rectangle) are also focally detected. Graphic 89398 Version 1.0

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Dermoscopic image of irregular diffuse pigmentation in a melanoma on the sole

In this advanced melanoma, irregular diffuse, structureless pigmentation of variable shades from tan to brownish black, predominates. Hints of the parallel ridge pattern also can be recognized. Graphic 89400 Version 1.0

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Clinical image of atypical melanosis of the foot

A 45 x 25 mm brownish macule with irregular shape and color on the volar aspect of the great toe. Graphic 90136 Version 2.0

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Dermoscopic image of atypical melanosis of the foot

On dermoscopic examination, atypical melanosis of the foot shows a typical parallel ridge pattern. Graphic 90137 Version 2.0

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Histopathologic characteristic of atypical melanosis of the foot

The melanocytes in the crista profunda intermedia are slightly increased in number. Eccrine ducts run through the epidermal rete ridges. Graphic 90138 Version 2.0

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The 3-step dermoscopic algorithm for the diagnosis and management of acquired melanocytic lesions of the palms and soles

Reproduced with permission from: John Wiley & Sons, Inc. Saida T, Koga H, Uhara H. Key points in dermoscopic differentiation between early acral melanoma and acral nevus. J Dermatol 2011; 38:25. Copyright © 2011 Japanese Dermatological Association. All rights reserved. Graphic 89477 Version 6.0

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Acral melanocytic lesion with equivocal dermoscopic features

A brown macule 6.5 mm in maximum diameter is present on the right fifth toe of a 63-year-old woman. On dermoscopic examination, the lesion does not show any typical/regular patterns. Graphic 90139 Version 2.0

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The furrow ink test: Parallel furrow pattern

In this acral lesion, the pigmented lines correspond to the furrows of the skin markings. The parallel furrow pattern is typical of acquired acral nevi. Graphic 90140 Version 2.0

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The furrow ink test: Parallel ridge pattern

In this acral melanocytic lesion, the band-like pigmentation is detected between the furrows, on the ridges of the skin markings. The parallel ridge pattern is typical of acral melanoma. Graphic 90141 Version 2.0

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Black heel (calcaneal petechiae)

The black specks on the heel result from intradermal hemorrhage due to trauma (eg, friction against shoes during vigorous sports). Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 89487 Version 3.0

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Black heel (calcaneal petechiae)

Aggregated black specks on the heel resulting from intraepidermal hemorrhage caused by shearforce injuries (eg, during vigorous sports). Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 89488 Version 3.0

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Dermoscopic features of the "black heel"

The "black heel" results from the formation of tiny petechiae in the superficial skin tissue of the heel caused in most cases by friction with tight, ill-fitted sport shoes. Reddish to black, globular pigmentation on the ridges (the pebbles on the ridges) is characteristic. Inset: clinical photograph. Graphic 89473 Version 2.0

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Dermoscopic features of superficial hematoma in the plantar skin

On dermoscopy, a superficial hematoma in the plantar skin shows a pigment distribution reminiscent of the parallel ridge pattern. However, the reddish tone and demarcation of the lesion and the presence of reddish black globules are helpful in differentiating hematomas from melanocytic lesions. Graphic 89474 Version 1.0

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Dermoscopic features of pigmentation induced by 5-fluorouracil

The drug-induced light brown pigmentation is accentuated on the surface ridges, resembling the parallel ridge pattern. This pigmentation can be differentiated from melanoma based upon the presence of multiple brown macules bilaterally on the palms and soles and history of drug intake. Graphic 89475 Version 1.0

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Peutz-Jeghers syndrome

Multiple pigmented macules are present on the lips. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 55335 Version 4.0

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Peutz-Jeghers syndrome

Multiple hyperpigmented macules on the dorsum of the hand of a patient with Peutz-Jeghers syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 89493 Version 2.0

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Cutaneous hyperpigmentation in Peutz-Jeghers syndrome

Multiple hyperpigmented macules on the volar aspect of the thumb in a patient with Peutz-Jeghers syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 89492 Version 3.0

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Volar melanotic macule

The picture shows one of several light-brown macules noted on the soles of a middle-aged Japanese man. The macule has regular borders and even pigmentation. On dermoscopy, it shows a typical parallel ridge pattern. Graphic 90143 Version 2.0

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Tinea nigra

A well-dermarcated brown patch on the palm of a three-year-old boy with tinea nigra. The patch had been slowly expanding for six months. A potassium hydroxide preparation revealed grayish brown branching hyphae typical of tinea nigra which is caused by a dermatiaceous fungus Phaeoannellomyces werneckii. Copyright © Samuel Freire da Silva, MD, Dermatlas; http://www.dermatlas.org. Graphic 89558 Version 3.0

Contributor Disclosures Toshiaki Saida, MD, PhDNothing to discloseHiroshi Koga, MDNothing to discloseHensin Tsao, MD, PhDGrant/Research/Clinical Trial Support: Relay Therapeutics; Asana BioSciences [Melanoma (Dual BRAF/PI3K inhibitor, ERK 1/2 inhibitor)]. Consultant/Advisory Boards: Epiphany Dermatology [Basal cell carcinoma, melanoma, nevi, skin cancer screening]; World Care Clinical; Ortho Dermatologics [Melanoma (Imaging services)]. Consultant/Advisory Boards (Spouse): Ortho Dermatologics [Melanoma].Rosamaria Corona, MD, DScNothing to disclose Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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Patch testing - UpToDate uptodate.com/contents/patch-testing/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 03, 2019.

INTRODUCTION

Patch testing is an essential investigation to identify

specific allergens in allergic contact dermatitis (ACD) or, in some cases, to make the diagnosis of ACD. Patch testing is based upon the principle that in sensitized individuals, primed antigen-specific T lymphocytes of the Th1 phenotype circulate throughout the body and are able to recreate a delayed-type hypersensitivity reaction when nonirritating concentrations of the antigen are applied to normal skin. This topic will discuss indications, techniques, and interpretation of patch testing. The basic mechanisms, clinical manifestations, diagnosis, and management of ACD are discussed separately. (See "Basic mechanisms and pathophysiology of allergic contact dermatitis" and "Clinical features and diagnosis of allergic contact dermatitis" and "Management of allergic contact dermatitis".)

INDICATIONS FOR PATCH TESTING Indications for patch testing may include:

●Persistent eczematous eruptions when contact allergy is suspected [1] ●Any chronic dermatitis, especially when involving the hands, feet, face, or eyelids ●Eczematous dermatitis in individuals involved in high-risk occupations for contact dermatitis (eg, health care workers, dental assistants, cosmetologists, machinists, or rubber and plastic workers)

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●Dermatitis of unknown etiology ●Worsening of a previously stable dermatitis Patch testing also may be indicated when allergic contact dermatitis (ACD) is suspected as a complication of: ●Atopic dermatitis ●Stasis dermatitis ●Seborrheic dermatitis ●Nummular eczema ●Asteatotic eczema ●Psoriasis

SELECTION OF ALLERGENS

Observational studies

have identified more than 4350 chemicals as contact allergens with varying potential to cause allergic contact dermatitis (ACD) [2]. However, a high proportion of ACD are caused by a relatively small number of allergens commonly found in the environment.

Standard (baseline) series of allergens — Standard (baseline) or screening series of contact allergens, which are designed to include the most common sensitizers responsible for ACD in a given region, are recommended as the initial battery for patients undergoing patch testing. The standard series are revised on a regular basis, as new allergens are identified as a cause of ACD. There are several baseline series throughout the world, including the North American Contact Dermatitis Group and the European standard series of approximately 35 allergens (determined by consensus of the European Society of Contact Dermatitis and the European Environmental and Contact Dermatitis Research Group). Details on the standard series most commonly used can be found at www.dermnetnz.org/dermatitis/standard-patch.html. The American Contact Dermatitis Society (ACDS) (www.contactderm.org) has developed a recommended core series of 80 allergens divided into eight panels [3]. The thin-layer rapid-use epicutaneous (TRUE) test, which includes 35 allergens and one control, is a commercially available ready-to-use test widely used in basic standard patch testing among dermatologists and allergists. Although it is easy to apply, it may have lower sensitivity than other standard series [4].

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Additional series of patch testing — Supplemental series of patch tests suitable for specific exposures, including workplace exposures, are available to complement the standard series (eg, hairdressers, dental, or cosmetic series). The patient's clinical presentation and history help to determine whether testing with supplemental series and/or products provided by the patient is necessary [5]. (See "Clinical features and diagnosis of allergic contact dermatitis", section on 'History'.)

Individualized patch testing — In the event that a standard series and supplemental series do not identify an offending antigen, patients may be patch tested with their own products. As a general rule, when patch testing patients with their own products, it is acceptable to use products that are left on the skin (eg, lotions, creams). However, products that typically are rinsed off the skin (eg, soap) should not be patch tested; when left on the skin these products may act as irritants. Rinse-off products may be tested with open testing. (See 'Open test' below.) Specific allergens can also be customized [6].

PATCH TEST PROCEDURE Preparing the patient — Patients need to be informed that patch testing is a time consuming process that requires at least three visits during a specified week. Patients should avoid showering, exercising, and extremes of heat and humidity, and should be alerted that positive reactions can result in itching and discomfort. Patch testing is usually performed on the back. If the back is excessively hairy it may be difficult to achieve adequate skin contact with the patches. To avoid irritation it is advisable to clip the hair from the back one or two days before patch testing.

Effect of systemic immunosuppression — The effect of systemic immunosuppression on the accuracy of patch testing has not been well established. Potent topical corticosteroids applied to the test site or oral corticosteroids ideally should be discontinued at least two weeks before patch testing [7,8]. Topical treatment with potent corticosteroids or systemic treatment with corticosteroids or other immunosuppressant drugs may cause weak or negative reactions [1,7]. Studies on poison ivy, which usually induces strong positive reactions, have indicated that it may be acceptable to perform patch testing with doses of prednisone up to 20 mg per day. However, this practice may be suboptimal for allergens that are weaker than poison ivy, and generally should be discouraged [9,10]. In two small studies, positive patch test reactions were seen in patients taking prednisone, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil, infliximab, adalimumab, and etanercept [11,12]. An additional study found no difference in the prevalence or intensity of positive patch test reactions in psoriasis patients on etanercept, infliximab,

85

adalimumab, and ustekinumab [13]. A small case series and a few case reports suggest a variable and potentially allergen-specific effect of dupilumab on patch testing results [14-16]. This suggests that it may be preferable to patch test patients prior to the initiation of dupilumab.

Effect of oral antihistamines — Oral antihistamines may be continued during patch testing, as they have minimal if any effect on the mechanisms of delayed hypersensitivity. Since a positive patch test reaction is not a histamine mediated process, there is no pathophysiologic rationale to discontinue antihistamines prior to patch testing.

Effect of ultraviolet radiation — Patients should avoid irradiation from both artificial and natural (sunlight) sources of ultraviolet (UV) radiation before patch testing. Irradiation with UVB can reduce the number of antigen presenting cells in the skin and the intensity of patch test reactions. Patch testing should be deferred in heavily tanned patients, and a minimum of four weeks after significant sun exposure should be allowed before patch testing.

Patch test site — The optimal site for patch testing is the upper back. The outer aspect of the upper arms is an alternative. Placing patches on other skin areas may result in a higher degree of false-negative results. If the skin is oily, gentle degreasing can be performed with ethanol or another mild solvent. The sites of patch application are then marked with a suitable marker to identify the test sites. Patch testing should be performed on intact skin without dermatitis to minimize the risk of nonspecific inflammatory responses with numerous false-positive tests ("angry back" syndrome). (See 'The "angry back"' below.)

Types of tests Closed test — The most commonly accepted technique for patch testing involves the application of test allergens under occlusion onto the skin of the upper back for two days. Allergens are applied in standard amounts to aluminum or synthetic material chambers mounted on nonocclusive tape strips. Commercially available patch test units are described in the table (table 1).

Open test — Open test may be used to test products with a potential to create irritation on the skin, which include paints, soluble oils, soaps, glues, and other cleansing agents. Unlike traditional patch testing, the area is kept open. After 30 minutes the materials are gently removed and readings are performed in a delayed fashion similar to closed patch testing. If the reaction is negative but contact allergy is still suspected, closed patch testing with single ingredients in appropriate concentration and vehicle should be performed.

Semi-open test — The semi-open or semi-occlusive test is used for products with a slight irritant potential, including [17,18]:

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●Pharmaceutical products – Products containing antiseptic agents such as mercurial compounds (eg, phenylmercuriborate), quaternary ammonium salts such as benzalkonium chloride and iodine; antiseptics containing emulsifiers such as lauraminoxyde and nonoxynol; products containing solvents such as propylene glycol in high concentrations; creams based on the emulsifier sodium laurylsulfate. ●Cosmetic products – Products containing emulsifiers, solvents, or other potentially irritant substances such as mascara, nail lacquers, hair dyes, shampoos, permanent-wave solutions, liquid soaps, and peels. ●Household and industrial products – Paints, resins, varnish, glue, ink, wax, and soluble oils (after having verified that the pH is >3 and 2 cm in diameter. These lesions may be isolated or grouped and may or may not have surface changes (picture 18A-B). The differential diagnosis of tumors and nodules is shown in the table (table 5). (See "Overview of benign lesions of the skin".) ●Telangiectasia is a dilated superficial blood vessel (picture 19). ●Purpura are red-purple lesions that do not blanch under pressure, resulting from the extravasation of blood from cutaneous vessels into the skin. Purpuric lesions can be macular or raised (palpable purpura) (picture 20).

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●Pustules are small, circumscribed skin papules containing purulent material (picture 21A-B). The differential diagnosis of pustules is shown in the table (table 6). ●Vesicles are small (1 cm in diameter) vesicles. The differential diagnosis of vesicles and bullae is shown in the table (table 7). ●Wheals are irregularly shaped, elevated, edematous skin areas that may be erythematous or paler than surrounding skin (picture 3A-C). The borders of a wheal are well demarcated but not stable; they may move to adjacent, uninvolved areas over periods of hours. ●Scale is flakes on the skin surface formed by desiccated, thin plates of cornified epidermal cells (picture 23A-B). ●Atrophy is a depression from the surface of the skin caused by underlying loss of epidermal or dermal substance (picture 24A-B). ●Hyperpigmentation is increased skin pigment (picture 7A-B); hypopigmentation is decreased skin pigment (picture 25). Depigmentation is total loss of skin pigment (picture 26).

Secondary lesions — Secondary lesions of the skin represent evolved changes from the skin disorder, due to secondary external forces, such as scratching, picking, infection, or healing. Examples include: ●Excoriation describes superficial, often linear skin erosion caused by scratching (picture 27A-B). ●Lichenification is dry, leathery thickening of the skin with exaggerated skin markings secondary to chronic inflammation caused by scratching or other irritation (picture 2B-E). ●Edema is swelling due to accumulation of water in tissue (picture 28). ●Scale describes superficial epidermal cells that are dead and cast off from the skin (picture 29). ●Crust is dried exudate of serum, blood, sebum, or purulent material on the surface of the skin, a "scab" (picture 30). ●Fissure is a deep skin split extending into the dermis (picture 31). ●Erosion is a superficial, focal loss of part of the epidermis (picture 32A-B). Ulceration is focal loss of the epidermis extending into the dermis. Lesions may heal with scarring (picture 33). The differential diagnosis of erosions and ulcers is shown in the table (table 8). ●Scar is fibrous tissue that replaces normal dermal or subcutaneous tissue after skin injury (picture 34).

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Lesion distribution — The location of one or multiple skin lesions and the arrangement of multiple lesions in relation to each other can suggest a particular diagnosis. Initial differential diagnoses based on typical distributions of common skin dermatoses are summarized in the table (table 9) and shown graphically in the figures (figure 1A-B). Common arrangements of lesions are: ●Clustered, as seen in herpes simplex infections (picture 22) ●Grouped, as seen in dermatitis herpetiformis (picture 35A-B) and granuloma annulare (picture 36) ●Linear, as seen in contact dermatitis (picture 37 and picture 38) and morphea (picture 39A-B) ●Zosteriform, as seen in herpes zoster infection (picture 40A-C) and metastatic breast carcinoma ●Coalescing or confluent, as seen in psoriasis and viral exanthems (picture 41) Certain dermatologic conditions have a predilection for particular parts of the body and are seen in distinct demographic groups. As an example, tinea capitis is a common scalp eruption in children but is rare in adults. In contrast, tinea pedis is seen frequently in adults but rarely in children. Thus, when a child presents with foot lesions, diagnoses in addition to tinea must be considered, including atopic dermatitis, scabies, drug eruptions, and contact dermatitis. An adult with a scalp eruption is likely to have seborrheic dermatitis, psoriasis, or allergic contact dermatitis. That said, it is important to keep an open mind and broad differential diagnosis in all patients to avoid missing atypical presentations.

SUMMARY ●The initial approach to the patient presenting with a skin problem requires a detailed history of the current skin complaint and a full body skin examination (figure 1A-B). In some cases, the patient's general medical history may be relevant to the diagnosis of skin disorders. (See 'Introduction' above.) ●Key questions for the patient include the time of onset, duration, location, evolution, and symptoms of the rash or lesion. Additional information on family history, occupational exposures, comorbidities, medications, and social or psychologic factors may be helpful. (See 'History' above.) ●The physical examination of a patient with a skin complaint includes visual inspection and palpation of the skin and sometimes additional examination aided by a Wood's lamp or a dermatoscope. (See 'Physical examination' above.) ●The morphology, arrangement, and distribution of the lesions are cardinal features to be identified by visual inspection and palpation. In many cases, the location of one or multiple skin lesions and the arrangement of multiple lesions in relation to each other can suggest a particular diagnosis

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(table 9 and figure 1A-B). (See 'Lesion morphology and distribution' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like

to acknowledge Adam O Goldstein, MD, MPH, and Beth G Goldstein, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Subscription and License Agreement. Topic 6838 Version 18.0

GRAPHICS

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Common disorders encountered during the physical examination of skin, front view

Reproduced with permission from Fitzpatrick TB, Bernhard JD, Copley TG. In: Dermatology in General Medicine, Freedberg IN, Eisin AZ, Wolff K, et al. (Eds), 5th ed, McGraw-Hill 1999. Copyright © 1999 The McGraw-Hill Companies, Inc. Graphic 61227 Version 3.0

118

Common disorders encountered during the physical examination of skin, back view

Reproduced with permission from: Fitzpatrick TB, Bernhard JD, Copley TG. In: Dermatology in General Medicine, Freeberg IN, Eisin AZ, Wolff K, et al. (Eds), 5th ed, McGraw-Hill 1999. Copyright © 1999 The McGraw-Hill Companies, Inc. Graphic 52494 Version 4.0

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Fitzpatrick skin phototypes

Skin type

Unexposed skin color

Reaction to sun exposure*

I

White

Always burns, never tans

II

White

Always burns, minimal tan

III

White to olive

Burns minimally, gradually tans

IV

Light brown

Burns minimally, tans well

V

Brown

Very rarely burns, tans profusely

VI

Dark brown to black

Never burns, tans deeply

Note: Slight variations on the definitions of the phototypes appear in the literature. * After the first one hour of sun exposure on untanned skin on the first day of spring. Graphic 60541 Version 4.0

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Papulopustular rosacea

Inflammatory papules are present on the nose. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 63008 Version 5.0

121

Atopic dermatitis

Atopic dermatitis involving the sides of the neck. Note the scaling and characteristic reticular pigmentation. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 102395 Version 3.0

122

Atopic dermatitis

Hyperpigmented, slightly scaly patches and lichenified plaques are present in the popliteal fossae of this patient with atopic dermatitis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 68215 Version 6.0

123

Urticaria

A well-circumscribed plaque, slightly lighter-than-normal skin is visible on the neck of this patient with urticaria. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 101336 Version 3.0

124

Urticaria

Large, well-circumscribed plaques on the chest of this patient with urticaria. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 101337 Version 3.0

125

Henoch-Schönlein purpura

Purpuric lesions are clearly visible on the plantar surface but less obvious on the lower leg in this patient with Henoch-Schönlein purpura. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 101339 Version 4.0

126

Xerosis (dry skin)

Reduced skin shininess and ashy appearance in this patient with extreme skin dryness. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 101381 Version 3.0

127

Postinflammatory hypopigmentation in a patient with psoriasis

Macular hypopigmented lesions are present on the back of this patient after resolution of plaque psoriasis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 101382 Version 4.0

128

Postinflammatory hyperpigmentation and scarring in acne vulgaris

Multiple hyperpigmented macules and scars on the lower face of a woman with acne vulgaris. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 58817 Version 6.0

129

Acne keloidalis nuchae

Mild acne keloidalis nuchae. Multiple small, follicular papules on the posterior scalp and posterior upper neck. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 97613 Version 3.0

130

Pseudofolliculitis barbae

Tight, curly hairs that have been sharpened by shaving penetrate the skin on the chin and neck. Inflammatory papules and pustules that resemble acne are evident. Reproduced with permission from: Goodheart HP, MD. Goodheart's Photoguide of Common Skin Disorders, 2nd ed. Lippincott Williams & Wilkins, Philadelphia 2003. Copyright ©2003 Lippincott Williams & Wilkins. Graphic 69365 Version 4.0

131

Pseudofolliculitis barbae

Hyperpigmented papules and small pustules are present on the mandible and neck. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 51138 Version 6.0

132

Pseudofolliculitis barbae

Numerous erythematous and hyperpigmented papules are present on the beard area in this patient with pseudofolliculitis barbae. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 63934 Version 5.0

133

Central centrifugal cicatricial alopecia

Inflammatory central centrifugal cicatricial alopecia demonstrating hair loss on the crown of the scalp, inflamed papules, pustules, and scarring. Graphic 91651 Version 2.0

134

Central centrifugal cicatricial alopecia

Severe central centrifugal cicatricial alopecia demonstrating hypopigmentation, hyperpigmentation, and extensive scarring. Graphic 91652 Version 2.0

135

Central centrifugal cicatricial alopecia

Reduced hair density on the crown of the scalp in a patient with early central centrifugal cicatricial alopecia. Graphic 91649 Version 2.0

136

Dissecting cellulitis of the scalp

Fluctuant nodules and areas of scarring alopecia on the scalp. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 75929 Version 6.0

137

Dissecting cellulitis of the scalp

Multiple alopecic nodules and plaques with crusting at sites of drainage. Graphic 91508 Version 3.0

138

Traction alopecia Hair loss on the anterior scalp is evident in this patient with traction alopecia. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 60331 Version 5.0

139

Traction alopecia

Loss of the frontal hairline is evident in this patient with traction alopecia. Traction alopecia may result from tightly braided hairstyles. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 82515 Version 6.0

140

Dermatosis papulosa nigra

Numerous hyperpigmented papules on the cheek and periocular region of this patient with dermatosis papulosa nigra. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 100131 Version 3.0

141

Dermatosis papulosa nigra

Multiple hyperpigmented papules are present on the face of this patient with dermatosis papulosa nigra. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 73398 Version 7.0

142

Keloids

Keloids presenting as firm, smooth nodules on the ear. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 96383 Version 3.0

143

Multiple small, pigmented seborrheic keratoses of the face (dermatosis papulosa nigra)

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 66252 Version 5.0

144

Keloids from acne

Firm papules and nodules on the posterior shoulder. Reproduced with permission from: Stedman's Medical Dictionary. Copyright © 2008 Lippincott Williams & Wilkins. Graphic 61382 Version 6.0

145

Keloids

Patient with large, spontaneous keloids on the upper back. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 97537 Version 3.0

146

Clinical and dermoscopic image of lichen planus-like keratosis

(A) Lichen planus-like keratosis, also called lichenoid keratosis, presenting as a solitary, gray to brown papule or plaque on the face. (B) On dermoscopy, coarse, large, and partially confluent gray dots are seen. Graphic 96329 Version 2.0 Clinical and dermoscopic images of Merkel cell carcinoma

(A) Merkel cell carcinoma presenting as a red nodule with scaling on the cheek of this patient. Note the background sun-damaged skin. (B) Dermoscopy shows a polymorphous, vascular pattern composed of linear vessels over a pink background. White scales are also present. Graphic 102595 Version 2.0

147

Vitiligo

Depigmented macular lesions in a patient with vitiligo. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 101356 Version 3.0

148

Viral exanthem

Multiple erythematous macules are present on the skin of this patient with a viral exanthem. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 58169 Version 8.0

149

Solar lentigines presenting as brown macules on the dorsum of the hand

Multiple brown macules are present on the dorsal hand. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 61452 Version 7.0

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Differential diagnosis of macules

Erythematous macules

Hyperpigmented macules

Drug eruption

Nevi

Viral exanthem

Fixed drug eruption

Secondary syphilis

Postinflammatory

Rheumatic fever

Ephelis (freckle)

Photodistributed macules

Lentigo

Drugs

Schamberg's purpura

Dermatomyositis

Nevus

Lupus erythematosus

Mongolian spot

Porphyria cutanea tarda

Purpura

Polymorphous light eruption

Stasis dermatitis

Hypopigmented macules

Melasma

Postinflammatory

Melanoma

Tinea versicolor

Ochronosis

Vitiligo

Mastocytosis

Halo nevus

Café-au-lait spot

Sarcoidosis Tuberous sclerosis Cutaneous T cell lymphoma Leprosy Graphic 61066 Version 3.0 Differential diagnosis of papules

Isolated papules

Papular eruptions

h d

151

Acrochordon

Acne rosacea

Actinic keratosis

Acne vulgaris

Angiofibroma

Appendageal tumors (usually benign)

Appendageal tumors (benign or malignant)

Arthropod bite

Bacillary angiomatosis

Bacillary angiomatosis

Basal cell carcinoma

Dermatomyositis

Chondrodermatitis nodularis helicis

Drug eruption

Dermatofibroma

Eczematous dermatitis

Fungal infections (early)

Flat warts

Hemangioma

Folliculitis

Keratoacanthoma

Granuloma annulare

Melanoma

Keratosis pilaris

Milia

Lichen nitidus

Molluscum contagiosum

Lichen planus

Neurofibroma

Lichen sclerosus

Nevus

Lupus erythematosus

Pyogenic granuloma

Lymphoma

Sebaceous hyperplasia

Miliaria

Seborrheic keratosis

Molluscum contagiosum

Squamous cell carcinoma

Neurofibromatosis

Venous lake

Pediculosis corporis

Wart

Perioral dermatitis Pityriasis rosea Polymorphous light eruption Psoriasis Sarcoidosis

152

Sarcoma Scabies Syphilis Urticaria Vasculitis Viral exanthem Xanthoma Graphic 61037 Version 2.0 Plaque psoriasis

An erythematous plaque with coarse scale is present on the knee of this patient with psoriasis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 54581 Version 7.0

153

Chronic plaque psoriasis

Multiple large plaques with silver scale on the back. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 99437 Version 3.0

154

Differential diagnosis of plaques

Acanthosis nigricans

Lymphoma (cutaneous T cell)

Candidiasis

Morphea

Cellulitis

Myxedema

Deep fungal infections

Necrobiosis lipoidica diabeticorum

Dermatomyositis

Paget's disease

Diaper dermatitis

Pityriasis rosea

Eczematous dermatitis

Psoriasis

Erythrasma

Sarcoidosis

Tinea infections

Seborrheic dermatitis

Granuloma annulare

Sweet's syndrome

Ichthyosis

Syphilis

Lichen planus

Tinea versicolor

Lichen sclerosus

Vasculitis

Lupus erythematosus

Xanthelasma

Lyme disease Graphic 68549 Version 2.0

155

Erythema nodosum

Multiple erythematous nodules on the lower leg. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 108925 Version 3.0

156

Multiple lipomas

Nodules are present on the arm of this patient with multiple lipomas. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 61498 Version 7.0

157

Differential diagnosis of nodules and tumors

Acrochordon

Lymphoma (cutaneous)

Angioma

Melanoma

Appendageal tumors

Metastatic carcinoma

Basal cell carcinoma

Neurofibroma

Callus/clavus

Nevus

Chondrodermatitis nodularis helicis

Prurigo nodularis

Dermatofibroma

Pyogenic granuloma

Dermatofibrosarcoma

Seborrheic keratosis

Erythema nodosum

Squamous cell carcinoma

Hidradenitis suppurativa

Syphilis

Histiocytosis

Tuberous sclerosis

Inclusion cyst

Venous lake

Kaposi's sarcoma

Wart

Keloid

Xanthoma

Lipoma Graphic 70150 Version 2.0

158

Telangiectasias

Multiple telangiectasias are present on the nose. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 71614 Version 6.0

159

Henoch-Schönlein purpura

Palpable, purpuric lesions on the legs of a child with Henoch-Schönlein purpura. Courtesy of Moise L Levy, MD. Graphic 102281 Version 2.0

160

Inflammatory acne

Erythematous papules and pustules. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 70809 Version 6.0

161

Folliculitis

Small, inflammatory papules and pustules are present in this patient with folliculitis. Erythema is difficult to appreciate due to dark skin pigmentation. Postinflammatory hyperpigmentation is also present. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 62930 Version 5.0

162

Differential diagnosis of pustules

Acne vulgaris Arthropod bite (fire ants) Drug eruption Eosinophilic folliculitis Erythema toxicum neonatorum Folliculitis Fungal or yeast infections (especially tinea capitis and Majocchi's granuloma) Furunculosis Gonorrhea (disseminated) Herpes simplex/zoster Impetigo Keratosis pilaris Neonatal pustulosis Pseudofolliculitis barbae Pustular psoriasis Pyoderma gangrenosum Rosacea/perioral dermatitis Syphilis Varicella Graphic 56796 Version 3.0

163

Herpes simplex infection

Grouped vesicles on erythematous background are characteristic of recurrent herpes simplex infection. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 115618 Version 2.0

164

Differential diagnosis of vesicles and bullae

Bullous disease in diabetes

Herpes zoster

Bullous pemphigoid

Id reaction

Burn

Impetigo

Cellulitis

Insect bite reaction

Congenital syphilis

Lichen planus

Contact dermatitis

Lupus erythematosus (bullous)

Dermatitis herpetiformis

Pemphigus vulgaris/foliaceus

Eczema (especially hand/foot)

Porphyria cutanea tarda

Epidermolysis bullosa

Scabies

Erythema multiforme

Staphylococcal scalded skin

Fixed drug eruption

Streptococcal toxic shock

Fungal infections (especially tinea pedis)

Toxic epidermal necrolysis

Hand, foot, and mouth disease

Varicella

Herpes gestationis

Vasculitis

Herpes simplex Graphic 78295 Version 3.0

165

Urticaria Skin-colored wheals are present. Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd Edition. Philadelphia: Lippincott Williams & Wilkins, 2003. Copyright © 2003 Lippincott Williams & Wilkins. Graphic 50151 Version 2.0

166

Chronic plaque psoriasis

Annular psoriasis plaque. Graphic 113142 Version 1.0

167

Chronic plaque psoriasis

Thick scale on the temporal scalp. Graphic 113138 Version 1.0

168

Extragenital lichen sclerosus

Multiple white, atrophic plaques are present on the chest. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 60332 Version 5.0

169

Extragenital lichen sclerosus

Atrophic plaques with mottled hyperpigmentation are present on the shoulder and arm. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 51592 Version 5.0

170

Lichenoid drug eruption (drug-induced lichen planus)

Hyperpigmentation following the resolution of lichenoid drug eruption. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 83771 Version 9.0

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Pityriasis alba Hypopigmented macules are present on the face of this young girl with pityriasis alba. Copyright © Nicole Sorensen, RN, Dermatlas; http://www.dermatlas.org. Graphic 60866 Version 7.0

Segmental vitiligo Segmental vitiligo: patches of depigmentation on the anterior trunk. Reproduced with permission from: Stedman's Medical Dictionary. Copyright ©2008 Lippincott Williams & Wilkins. Graphic 72369 Version 3.0

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Excoriations

Linear excoriations (secondary to scratching) are present. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 73387 Version 6.0

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Factitial dermatitis

Excoriated lesions and postinflammatory hyperpigmentation in a patient with factitial dermatitis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 101359 Version 3.0

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Lichenification

Thickened skin with accentuated skin lines is present in this patient who chronically rubbed and scratched this area. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 80745 Version 7.0

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Adult atopic dermatitis

Chronic atopic dermatitis with lichenification (skin thickening and enhancement of skin markings) of the knee flexures in a 22-year-old woman. Copyright © Monica Standish, RN, Dermatlas; http://www.dermatlas.org. Graphic 64525 Version 4.0

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Adult chronic atopic dermatitis

Lichenified, hyperpigmented plaque in the elbow flexure of a 35-year-old woman with atopic dermatitis. Copyright © Yusoff Saifuzzaman, MD, Dermatlas; http://www.dermatlas.org. Graphic 55375 Version 5.0

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Angioedema of the lips

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 57090 Version 7.0 Scale

Actinic keratosis. Scale overlies erythematous macules. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 68198 Version 8.0

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Impetigo

Crusted lesions in a patient with impetigo. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 82281 Version 5.0

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Hyperkeratotic hand eczema

Chronic, hyperkeratotic, and fissured hand eczema in a 69-year-old man. Reproduced with permission from: Diepgen TL, Yihune G, et al. Dermatology Online Atlas. Published online at: www.dermis.net. Copyright © 1996-2015 DermIS. All rights reserved. Graphic 95750 Version 2.0

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Erosions

Multiple shallow erosions are present in areas of sloughed skin in this patient with toxic epidermal necrolysis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 57242 Version 7.0

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Toxic epidermal necrolysis

Multiple bullae and areas of denuded epidermis are present. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 59418 Version 9.0 Pyoderma gangrenosum Peristomal pyoderma gangrenosum is caused by an inflammatory process that produces severe and painful skin ulcerations. Courtesy of Dorothy B Doughty, MN, RN, CWOCN, FAAN. Graphic 72285 Version 2.0

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Differential diagnosis of erosions and ulcers

Mouth

Genital

Other

Aphthae

Balanitis

Basal cell carcinoma

Avitaminosis

Candidiasis

Bullous pemphigoid

Burn

Chancroid

Ecthyma

Candidiasis

Diaper dermatitis

Erythema multiforme

Epidermolysis bullosa

Erythema multiforme

Ischemia

Erythema multiforme

Fixed drug eruption

Necrobiosis lipoidica

Hand, foot, and mouth disease

Fungal infections (tinea cruris)

Pemphigus vulgaris

Herpangina

Herpes simplex

Herpes simplex

Intertrigo

Lichen planus

Lichen planus

Lupus erythematosus

Lichen sclerosus

Squamous cell carcinoma

Pemphigus vulgaris

Lymphogranuloma venereum

Stasis ulcer

Perlèche

Squamous cell carcinoma

Toxic epidermal necrosis

Toxic epidermal necrolysis

Syphilis

Porphyria cutanea tarda Pyoderma gangrenosum Spider bite

Graphic 74110 Version 3.0

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Dissecting cellulitis of the scalp

Extensive scarring in a patient with dissecting cellulitis of the scalp. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 81039 Version 5.0 Distribution of common skin dermatoses

Flexural distribution

Mouth

Acanthosis nigricans

Mucous cysts

Atopic dermatitis

Leukoplakia

Bullous pemphigoid

Fordyce spots

Extensor distribution

Pyogenic granuloma

Psoriasis

Skin cancers

Atopic dermatitis (infants)

Kaposi's sarcoma

Dermatitis herpetiformis

Axillae

Xanthomas

Acanthosis nigricans

Feet/hands

Hidradenitis suppurativa

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Feet/hands

Hidradenitis suppurativa

Eczema

Impetigo

Tinea infections and "id" reactions

Hailey-Hailey disease

Erythema multiforme

Acrochordon

Wrists/ankles

Folliculitis

Lichen planus

Erythrasma

Scabies

Contact dermatitis

Contact dermatitis

Buttocks/anal

Eczema

Folliculitis

Photodistributed

Psoriasis

Lupus erythematosus

Hidradenitis suppurativa

Photodrug eruption

Lichen sclerosus et atrophicus

Dermatomyositis

Streptococcal cellulitis

Pellagra

Kawasaki disease

Porphyria cutanea tarda

Scalp

Polymorphous light eruption

Seborrhea Contact dermatitis Tinea capitis and kerion Discoid lupus Psoriasis

Graphic 59080 Version 4.0

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Dermatitis herpetiformis Multiple inflammatory papules and vesicles are present near the elbow. Courtesy of Scott Florell, MD, Department of Dermatology, University of Utah. Graphic 86768 Version 3.0

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Dermatitis herpetiformis

Erythematous papules and vesicles are present on the knee. Graphic 86749 Version 2.0

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Disseminated granuloma annulare

This 60-year-old patient with disseminated granuloma annulare presented with hundreds of erythematous papules and plaques on the medial arms, medial thighs, and buttocks. None of the lesions showed central clearing. Graphic 51459 Version 2.0

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Acute irritant contact dermatitis

Paederus dermatitis. Acute contact dermatitis may occur after accidental exposure to an insect belonging to the genus Paederus, common in the tropical regions. The insect does not sting or bite, but accidental crushing may release its hemolymph that contains pederin, a potent vesicant. (A) Well-defined, erythematous patches with central hyperpigmentation and vesicles in a kissing lesion fashion. (B) Well-defined, linear, erythematous patch with central vesicles and pustules. (A) Courtesy of Kulthanan K Siriraj Hospital, Mahidol University, Bangkok, Thailand. (B) Courtesy of Wanitphakdeedecha R Siriraj Hospital, Mahidol University, Bangkok, Thailand. Graphic 61579 Version 3.0

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Berloque dermatitis This adolescent developed hyperpigmented streaks from a photosensitizer in his sunscreen. After several days of erythema, the red patches became dark brown. Copyright © Kosman Sadek Zikry, MD, Dermatlas; http://www.dermatlas.org. Graphic 81457 Version 7.0

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Linear morphea

A shiny, sclerotic, hyperpigmented plaque is present in a linear distribution on the arm. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 51218 Version 5.0

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Linear morphea

Linear morphea in a child presenting as a midline band of skin atrophy and hyperpigmentation on the forehead and scalp. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 115807 Version 2.0

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Herpes zoster

Courtesy of Vaibhav Parekh, MD, MBA. Graphic 65213 Version 1.0

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Herpes zoster

Grouped vesicles and underlying erythema are present in a dermatomal distribution. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 58282 Version 5.0

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Herpes zoster

Courtesy of Vaibhav Parekh, MD, MBA. Graphic 52440 Version 1.0

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Atypical hand, foot, and mouth disease caused by coxsackievirus A6 in adults

Dermatologic and mucosal manifestations of hand, foot, and mouth disease among military personnel, demonstrating: (A) Extensive and confluent purpuric and hemorrhagic crusted papules and plaques on the foot and anterior shin. (B) Erythematous papules and erosions on the palate. (C) Grouped purpuric papules on the hand. (D) Similar lesions with extensive involvement of the extensor aspects of the upper extremities — September 18, 2015. Reproduced from: Banta J, Lenz B, Pawlak M, et al. Notes from the Field: Outbreak of Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6 Among Basic Military Trainees - Texas, 2015. MMWR Morb Mortal Wkly Rep 2016; 65:678. Graphic 108969 Version 1.0

Contributor Disclosures Cheryl A Armstrong, MDNothing to discloseRobert P Dellavalle, MD, PhD, MSPHEquity Ownership/Stock Options: Altus Labs [Itch, eczema]. Grant/Research/Clinical Trial Support: Pfizer

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[Patient decision aids, inflammatory and immune-mediated skin disease]. Consultant/Advisory Boards: Altus Labs [Itch, eczema]; ParaPRO [Scabies, lice]. Other Financial Interest: Journal of Investigative Dermatology; Journal of the American Academy of Dermatology [Stipends]; Cochrane Council meetings [Expense reimbursement].Moise L Levy, MDGrant/Research/Clinical Trial Support: Galderma [Atopic dermatitis (Investigational drug)]; Janssen Pharmaceutica [Psoriasis (Investigational drug)]; Pfizer [Atopic dermatitis (Investigational drug)]. Consultant/Advisory Boards: Cassiopea [Pediatric and adolescent acne]; Regeneron Pharmaceuticals [Atopic dermatitis (Dupilumab)]; UCB [Psoriasis (Certolizumab pegol)]. Patent Holder: Incontinentia pigmenti (NEMO gene mutations). Other Financial Interest: Novan [Data safety monitoring board for molluscum contagiosum trial (Investigational drug)].Rosamaria Corona, MD, DScNothing to disclose Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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Approach to the patient with a scalp disorder uptodate.com/contents/approach-to-the-patient-with-a-scalp-disorder/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Apr 17, 2019.

INTRODUCTION

Disorders of the scalp can result from a wide variety of

inflammatory, infectious, parasitic, neoplastic, and idiopathic dermatologic or systemic disorders. Often, the patient history and physical examination significantly narrow the differential diagnosis. This topic discusses the clinical assessment of patients with scalp disorders and reviews multiple conditions that present with visible changes on the scalp. To aid with diagnosis, the disorders are organized according to important clinical features. The evaluation of hair loss, a clinical finding that occurs in some scalp disorders, is reviewed separately. (See "Evaluation and diagnosis of hair loss".)

PATIENT ASSESSMENT

The patient history and physical

examination are often sufficient for identifying the most likely cause of a scalp eruption. In the remainder of cases, this information helps to narrow the differential diagnosis. Relevant information from the patient history may include: ●Age of onset (eg, birth, infancy, childhood, or adulthood)

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●Duration ●Associated symptoms (eg, pruritus, pain, or systemic symptoms) ●Perceived inciting or exacerbating factors ●Personal history of skin disorders ●Hair and scalp care practices ●Occurrence of a similar condition in family members or cohabitants The physical examination should include a thorough examination of the scalp. The clinician should note the presence of characteristic physical features such as scale, erythema, papules, nodules, pustules, blisters, erosions, and alopecia, as such features help to elucidate the most likely etiology. Because some disorders affecting the scalp also affect other areas of the skin, performance of a full skin examination is valuable. Often, examination of the scalp is challenging because of hair covering the scalp area. Use of an additional light source is helpful and hair should be physically parted to allow for examination as much of the scalp area as possible. In cases in which uncertainty about the diagnosis remains after the clinical evaluation, a scalp biopsy may aid with diagnosis. Depending on the suspected disorder and the size and shape of the involved area, a shave, punch, or excisional biopsy may be indicated. In particular, biopsies of some hair loss disorders can be difficult to interpret. Examination of the specimen by a dermatopathologist is often helpful in these cases. (See "Skin biopsy techniques" and "Evaluation and diagnosis of hair loss", section on 'Scalp biopsies'.) The text below organizes disorders that commonly affect the scalp according to key clinical findings. Of note, some disorders may exhibit features from more than one of the listed categories.

SCALY PATCHES AND PLAQUES

Scaly

patches or plaques on the scalp are typically an indicator of scalp inflammation. Concomitant erythema is often present. In children, tinea capitis, seborrheic dermatitis, and atopic dermatitis are common causes of scaly patches or plaques on the scalp. Seborrheic dermatitis, psoriasis, and allergic contact dermatitis are common causes in adults. Focal areas of erythema with overlying hyperkeratosis may represent actinic keratoses, particularly when found in middle-aged and older adults. Of note, inflammatory conditions of the scalp may result in hair loss. In most cases, the associated hair loss is reversible. Permanent hair loss (cicatricial alopecia) can occur in inflammatory conditions that lead to irreversible damage to hair follicles, such as discoid lupus erythematosus and lichen planopilaris, forms of primary cicatricial alopecia (see 'Cicatricial alopecia' below). Untreated tinea capitis may also eventually cause permanent alopecia [1].

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Most of the conditions described below can be diagnosed based upon recognition of classic clinical findings, with skin biopsy reserved for unclear or atypical presentations. The need for additional testing is indicated for disorders in which this is often helpful or necessary.

Common disorders Tinea capitis — Tinea capitis is a dermatophyte infection that is a common cause of scaling scalp eruptions in children and an infrequent cause of scalp eruptions in adults. Trichophyton and Microsporum species are the most frequent causative organisms [2]. Tinea capitis presents as scaly patches or plaques with or without inflammation (picture 1A-B). Circular areas of scale and alopecia are common and hair breakage at follicular orifices can lead to the appearance of numerous dark-colored dots within the affected area. Posterior cervical adenopathy is common [2,3]. A potassium hydroxide (KOH) preparation or fungal culture from scale or a hair shaft in an involved area is useful for confirming the diagnosis (picture 2). (See "Officebased dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.) Kerion is a manifestation of an acute, local inflammatory response to tinea capitis. Kerion presents as a deep-seated boggy plaque with pustules (picture 3). (See 'Kerion' below.)

Seborrheic dermatitis — Seborrheic dermatitis is common in infants and adults. In infants, seborrheic dermatitis most frequently presents as an accumulation of yellowish, greasy scales on the scalp, a presentation often referred to as "cradle cap" (picture 4). Infants may also develop facial involvement or retroauricular involvement manifesting as erythematous patches or plaques with fine, greasy scale. Truncal, diaper-area, and intertriginous involvement are additional presentations (picture 5A-B). (See "Cradle cap and seborrheic dermatitis in infants".) Of note, infants with Langerhans cell histiocytosis may present with seborrheic dermatitis-like eruptions with predilection for the scalp, trunk, or diaper areas (picture 6A-C). In Langerhans cell histiocytosis petechiae are often present. (See 'Langerhans cell histiocytosis' below.) Seborrheic dermatitis in adolescents and adults is typically found on the face (particularly eyebrows and nasolabial folds), scalp, upper trunk, and postauricular areas (picture 7A-D) [4]. Patients develop erythematous patches or plaques with overlying fine, greasy scale. In mild cases (ie, dandruff), erythema may be minimal or absent. Pruritus may be present. (See "Seborrheic dermatitis in adolescents and adults".)

Atopic dermatitis — Atopic dermatitis in infants often involves the face and scalp, presenting with erythematous, scaly patches and crusts (picture 8). Extensor surfaces are an additional common site of involvement (picture 9). The diaper-area is usually spared.

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Scalp involvement is less common in older children and adults; a flexural distribution, particularly in the antecubital and popliteal fossae, is common in this population (picture 10). Erythematous patches, excoriated papules, lichenified plaques, and marked pruritus are common features. However, scalp involvement may occur, particularly in severe cases. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

Psoriasis — Psoriasis of the scalp tends to appear as erythematous plaques with overlying silvery scale (picture 11). Pruritus may be nonexistent to severe. Other manifestations of psoriasis may be present elsewhere, such as on extensor surfaces, elbows, knees, sacrum, or nails (eg, pitting, onycholysis, oil spots) (picture 12A-E). A family history of psoriasis is often present. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

Allergic contact dermatitis — Allergic contact dermatitis usually presents with erythematous, scaly patches or plaques on the scalp (picture 13). Severe cases may exhibit blistering, serous drainage, erosions, and crusting. Pruritus is usually significant. Use of hair care products is a common culprit. Patch testing is used to evaluate for the inciting antigen. (See "Clinical features and diagnosis of allergic contact dermatitis", section on 'Clinical features' and "Common allergens in allergic contact dermatitis", section on 'Hair care products'.)

Actinic keratosis — Actinic keratoses may appear on the scalp as single or multiple erythematous macules or small patches with overlying scale (picture 14). Adults with scalp hair loss, light skin color, and a history of significant sun exposure are most susceptible. The diameter of actinic keratoses usually ranges from a few millimeters to 2 cm. (See "Epidemiology, natural history, and diagnosis of actinic keratosis", section on 'Clinical features'.) A small proportion of actinic keratoses progress to cutaneous squamous cell carcinoma. Size greater than 1 cm, induration, ulceration, tenderness, and rapid growth are among the signs that suggest a biopsy may be indicated to rule out squamous cell carcinoma. (See "Epidemiology, natural history, and diagnosis of actinic keratosis", section on 'Biopsy'.)

Less common disorders Pityriasis amiantacea — Pityriasis amiantacea is an uncommon scalp condition characterized by the accumulation of thick scale that adheres tightly to the scalp and hair (picture 15). Involvement may be localized or widespread. The etiology is uncertain; it has been proposed that the disorder may be a reaction pattern observed in various scalp diseases (eg, psoriasis, seborrheic dermatitis, tinea capitis, or atopic dermatitis) [5]. Secondary bacterial infection may occur. The diagnosis of pityriasis amiantacea is made based upon the classic clinical appearance. A full skin examination aids in identifying an associated skin disorder. A KOH preparation or fungal culture is indicated if the clinical findings suggest tinea capitis.

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Pemphigus foliaceus — Pemphigus foliaceus is an autoimmune blistering disorder in which superficial blistering results in erythematous patches or plaques with erosions, crusts, and scale (picture 16A-B). The scalp, face, and trunk are common sites of involvement. Pain or burning sensations may be present. The diagnosis of pemphigus foliaceus is confirmed based upon clinical, histologic, and immunopathologic findings [6]. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pemphigus foliaceus' and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Diagnosis'.)

Dermatomyositis — Dermatomyositis of the scalp usually presents as a pruritic eruption characterized by diffuse erythema with scale and atrophy (picture 17) [7,8]. Other cutaneous findings of dermatomyositis, such as a poikilodermatous eruption on the chest and extremities, Gottron papules on the dorsal hands, or a violaceous heliotrope eruption on the face are often present (picture 18A-E) [7]. Muscle involvement is also usually present. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".) The diagnosis of dermatomyositis is usually based upon recognition of the characteristic skin findings, muscle weakness, and laboratory evidence of myositis. Skin biopsy may be helpful for ruling out other skin disorders, particularly when muscle involvement is absent. (See "Cutaneous dermatomyositis in adults: Overview and initial management", section on 'Patient evaluation'.)

Langerhans cell histiocytosis — Langerhans cell histiocytosis (LCH) is a rare disorder of histiocytes that can affect multiple organs. Both children and adults can develop LCH. Skin involvement in LCH is most likely to manifest on the scalp, groin, trunk, and face (picture 6A-C). Patients may develop scaly or crusted erythematous to brown papules and thin plaques or other skin manifestations. Petechiae are often present within involved areas. Hypopigmentation may occur in patients with dark skin. A skin biopsy demonstrating Langerhans cells with kidney-shaped nuclei and positive staining for CD1a and langerin confirms the diagnosis [9]. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

PLAQUES WITHOUT SCALE

Nevus sebaceous,

syringocystadenoma papilliferum, alopecia mucinosa, and cutaneous B-cell lymphoma are examples of skin conditions that can manifest as non-scaly plaques on the scalp. Nevus sebaceous can often be diagnosed based upon clinical examination due to its characteristic yellow-orange color. Skin biopsy is necessary to confirm a diagnosis of the other disorders.

Nevus sebaceous — Nevus sebaceous is a benign cutaneous hamartoma that typically first presents at birth or in early childhood and commonly occurs on the scalp. Affected patients exhibit a solitary, yellow-orange or tan, oval or linear hairless plaque (picture 19). In patients

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with dark skin, nevus sebaceous may be a dark brown color (picture 20). (See "Nevus sebaceus and nevus sebaceus syndrome".) Nevus sebaceous typically becomes more prominent with age. As children enter early puberty, nevus sebaceous tends to become thicker, verrucous, or nodular (picture 21). Nevus sebaceous may also occur as a feature of nevus sebaceous syndrome (also known as Schimmelpenning syndrome). In nevus sebaceous syndrome, nevus sebaceous is often extensive and patients have associated cerebral, ocular, or skeletal defects [10]. (See "Nevus sebaceus and nevus sebaceus syndrome".)

Syringocystadenoma papilliferum — Syringocystadenoma papilliferum is an uncommon benign adnexal neoplasm with apocrine differentiation that has a predilection for the scalp. Syringocystadenoma papilliferum usually first appears at birth or in childhood and manifests as a single papule, multiple papules, or plaque (picture 22). Syringocystadenoma papilliferum may arise independently or within a preexisting nevus sebaceous [11]. The color of syringocystadenoma papilliferum is typically pink or red. At puberty the neoplasm grows in size and may take on a verrucous appearance. (See "Cutaneous adnexal tumors", section on 'Syringocystadenoma papilliferum'.)

Alopecia mucinosa — Alopecia mucinosa (also known as follicular mucinosis) is usually characterized by an erythematous or skin-colored indurated plaque with alopecia on the face or scalp (picture 23A-B). Follicular papules may be present. Alopecia mucinosa may be idiopathic or associated with mycosis fungoides [12].

Cutaneous B-cell lymphoma — Cutaneous B-cell lymphoma can present as solitary or multiple erythematous, red-brown, or violaceous papules, plaques, or nodules (picture 24). The head is a common site for the primary cutaneous follicle center lymphoma subtype of cutaneous B-cell lymphoma. A skin biopsy is necessary for diagnosis. (See "Primary cutaneous follicle center lymphoma".)

PAPULES AND NODULES

Nodular growths on the scalp

may be a manifestation of cysts, benign cellular proliferation, or malignancy. Of the diagnoses reviewed below, pilar cyst, acne keloidalis nuchae, and juvenile xanthogranuloma can often be diagnosed clinically. A skin biopsy is recommended for the diagnosis of the other disorders.

Pilar cyst — Pilar cysts (also known as trichilemmal cysts) present as smooth, mobile, skin-colored nodules on the scalp (picture 25A-B). A punctum is usually absent. Spontaneous rupture may result in prominent inflammation. (See "Overview of benign lesions of the skin", section

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on 'Pilar (trichilemmal) cysts'.)

Acne keloidalis nuchae — Acne keloidalis nuchae is a common form of cicatricial (scarring) alopecia that primarily affects the occipital scalp. Males of African origin with Afro-textured hair are the population most commonly affected. Patients present with inflamed papules, pustules, and smooth dome-shaped keloid-like papules on the posterior scalp (picture 26). The condition may lead to the formation of large keloid-like plaques or nodules (picture 27A-B). (See "Acne keloidalis nuchae".)

Dermoid cyst — Dermoid cysts are slow-growing, benign, subcutaneous nodules that develop along embryonic fusion planes and result from an abnormality during fetal development. The cysts are lined by stratified squamous epithelium and contain other cutaneous structures (eg, hair follicles, sweat glands, and sebaceous glands) [13]. Dermoid cysts most frequently are found periorbitally, but may also appear on the scalp and other areas [14]. Patients usually present in infancy or childhood with a firm nodule (typically 0.5 to 5 cm) that is fixed to the underlying bone or freely mobile (picture 28) [15]. Midline dermoid cysts may have intracranial extension. (See "Skin nodules in newborns and infants", section on 'Dermoid cysts and sinuses'.)

Juvenile xanthogranuloma — Juvenile xanthogranuloma is a nonLangerhans cell histiocytosis that becomes evident at birth or in early childhood [16]. Patients usually have a 0.5 to 2 cm solitary reddish or yellowish papule or nodule on the head, neck, or upper trunk (picture 29). Multiple lesions may also occur (picture 30). Spontaneous resolution usually occurs within a few years. (See "Juvenile xanthogranuloma (JXG)".)

Cylindroma — Cylindromas are uncommon benign adnexal tumors that have a predilection for the face and scalp of adults. Cylindromas usually occur as red-blue or blue, slowgrowing solitary papules or nodules that range from a few millimeters to a few centimeters in diameter (picture 31). Multiple cylindromas are features of familial cylindromatosis or BrookeSpiegler syndrome (picture 32) [17]. (See "Cutaneous adnexal tumors", section on 'Cylindroma and spiradenoma'.)

Angiolymphoid hyperplasia with eosinophilia — Angiolymphoid hyperplasia with eosinophilia (ALHE, also known as epithelioid hemangioma) is an uncommon benign vascular neoplasm that typically occurs in adults. ALHE usually presents as a group of several red-brown or violaceous papules or small nodules in a localized area on the skin (picture 33) [18]. ALHE usually occurs on the head or neck, and the ears are a particularly common location. A skin biopsy is necessary for diagnosis.

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Skin cancer — Various forms of skin cancer may present as papules or nodules on the scalp. Non-healing or recurrent ulceration, skin induration, and progressive growth should raise suspicion for malignancy. Patients may develop basal cell carcinoma and squamous cell carcinoma, the most common forms of skin cancer, as well as a wide variety of less common cutaneous malignancies that can occur on the head. Examples include Merkel cell carcinoma, which often presents as a rapidly growing skin-colored or blue-red nodule (picture 34), and angiosarcoma, which often presents as bluish to violaceous nodules, macules, or patches with or without ulceration (picture 35) [19]. A biopsy is indicated to confirm the diagnosis of skin cancer. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma".)

Metastatic carcinoma — The scalp is a common site for cutaneous metastases of internal malignancy. Metastatic carcinoma often presents as a firm skin-colored, red, violaceous, or hyperpigmented nodule; however, other presentations, such as patches or plaques, also occur [20,21]. Ulceration may be present. A biopsy demonstrates features of the primary malignancy.

PUSTULES

Pustular eruptions on the scalp may occur as a result of infectious or

noninfectious inflammatory disorders. Recognition of the associated clinical features is important for narrowing the differential diagnosis.

Folliculitis — Folliculitis is an inflammatory process of the hair follicles that most frequently occurs as a result of the invasion of microorganisms into the follicle. Patients develop inflamed follicular papules and pustules (picture 36A-B). Bacterial culture of pustules often reveals Staphylococcus aureus infection. There are also fungal and viral forms of folliculitis. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris" and "Dermatophyte (tinea) infections", section on 'Majocchi's granuloma'.)

Kerion — Kerion is a complication of severe tinea capitis that results from an intense inflammatory reaction to the infection (picture 3). Patients develop a boggy plaque that is often studded by pustules. Purulent drainage may be present.  

Dissecting cellulitis of the scalp — Dissecting cellulitis of the scalp is an uncommon form of cicatricial alopecia that presents with follicular papules, pustules, fluctuant nodules, and abscesses on the scalp (picture 37). Patients may develop permanent alopecia, scarring, and sinus tract formation. Dissecting cellulitis of the scalp most frequently occurs in young men of African descent, but is not exclusive to this population [22]. (See "Dissecting cellulitis of the scalp".)

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Folliculitis decalvans — Folliculitis decalvans is a form of cicatricial alopecia that presents with inflamed papules and pustules on the scalp and scarring alopecia (picture 38A-B). Pustules and papules are usually located at the periphery of areas of alopecia. Tufting of hairs (multiple hairs emerging from a single follicular orifice) is an additional common feature [23]. (See "Folliculitis decalvans".)

Acne keloidalis nuchae — Pustules are a common feature of acne keloidalis, a form of scarring alopecia distinguished by the development of dome-shaped keloid-like papules and keloid-like plaques on the posterior scalp. (See 'Acne keloidalis nuchae' above and "Acne keloidalis nuchae".)

Erosive pustular dermatosis of the scalp — Erosive pustular dermatosis of the scalp is a rare disorder characterized by the development of sterile pustules, erosions, and crusted plaques on the scalp that lead to scarring (picture 39) [24]. Erosive pustular dermatosis of the scalp may occur after scalp trauma or scalp surgery. The condition primarily affects older adults.

BLISTERS AND EROSIONS

Allergic contact dermatitis,

herpes zoster, and autoimmune blistering disease are examples of disorders that may cause blistering eruptions on the scalp.

Allergic contact dermatitis — Severe allergic contact dermatitis may present with erythematous patches or plaques with vesiculation or bulla formation (picture 40). Pruritus is often intense. The diagnosis may be made clinically. Patch testing is used to identify a causative allergen. (See 'Allergic contact dermatitis' above.)

Herpes zoster — Herpes zoster presents as a dermatomal eruption with localized erythema and grouped vesicles that evolve to form erosions, pustules, and crusts (picture 41A-B). Patients usually have unilateral symptoms of burning, aching, stinging, or throbbing. Symptoms can be severe. The diagnosis is usually made clinically; however, laboratory tests are available to confirm the diagnosis. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)

Autoimmune blistering diseases — Autoimmune blistering diseases, such as pemphigus foliaceus, dermatitis herpetiformis, and certain types of pemphigoid, have a predilection for the scalp. Histopathologic examination and immunofluorescence studies are used for diagnosis. Key clinical features of these diagnoses include:

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●Pemphigus foliaceus – Multiple erythematous patches or plaques with superficial erosions, crusts, or scale on the scalp, face, or upper trunk (picture 16A-B) (see "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pemphigus foliaceus') ●Dermatitis herpetiformis – Intensely pruritic papules, vesicles, erosions, and excoriations with a predilection for the elbows, forearms, knees, scalp, back, and buttocks (picture 42) (see "Dermatitis herpetiformis") ●Mucous membrane pemphigoid with skin involvement – Mucous membrane blistering and erosions; erythematous plaques with bullae on the scalp, face, or upper trunk that often heal with scarring (see "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Mucous membrane pemphigoid') ●Brunsting-Perry pemphigoid –Bullae on the scalp, face, or upper trunk that heal with scarring (picture 43) (see "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Brunsting-Perry pemphigoid')

THICKENED SCALP

Thickening of the scalp is an uncommon

clinical finding that can occur in patients with cutis verticis gyrata and lipedematous scalp.

Cutis verticis gyrata — Cutis verticis gyrata is a rare disorder in which extensive soft tissue proliferation results in an undulating appearance of the scalp that resembles the surface of the cerebral cortex (picture 44). The scalp is soft to palpation. Cutis verticis gyrata is classified as primary essential, primary nonessential, or secondary. Primary essential cutis verticis gyrata occurs in isolation, whereas the primary nonessential form is associated with neurologic or ophthalmologic abnormalities. The most common presentation of cutis verticis gyrata is primary nonessential cutis verticis gyrata occurring in association with mental retardation [25]. Secondary cutis verticis gyrata results from neoplastic or inflammatory scalp conditions, genetic disorders, or systemic diseases (eg, acromegaly, myxedema, amyloidosis) [25]. (See "Cutis verticis gyrata".)

Lipedematous scalp — Lipedematous scalp is a rare condition characterized by thickening of the subcutaneous tissue of the scalp [26]. The condition results in a soft, spongy, or doughy quality detected during palpation. Patients may have associated symptoms of pain, paresthesias, headache, burning sensations, tenderness, or pruritus. The term lipedematous alopecia has been used to refer to similar clinical findings accompanied by alopecia.

CICATRICIAL ALOPECIA

Cicatricial (scarring) alopecia is a

permanent form of hair loss that occurs as a result of irreversible damage to hair follicles. Cicatricial alopecia should be suspected when patients exhibit hair loss that is accompanied by a loss of

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visible follicular ostia. There are multiple forms of cicatricial alopecia, each of which exhibits additional characteristic clinical features. The major subtypes of cicatricial alopecia are listed below with their associated clinical findings. ●Discoid lupus erythematosus – Well-demarcated inflammatory plaques with follicular plugging that develop into atrophic, dyspigmented scars (picture 45A-D) (see "Overview of cutaneous lupus erythematosus", section on 'Discoid lupus erythematosus') ●Lichen planopilaris – Perifollicular erythema and hyperkeratosis (picture 46) (see "Lichen planopilaris") ●Central centrifugal cicatricial alopecia – Centrifugal progression of alopecia on the central scalp (picture 47A-B); primarily affects women of African descent (see "Central centrifugal cicatricial alopecia") ●Folliculitis decalvans – Papules, pustules, and tufted folliculitis (multiple hairs emerging from a single inflamed follicle), particularly at the periphery of patches of alopecia (picture 38A-B) (see "Folliculitis decalvans") ●Dissecting cellulitis of the scalp – Papules, pustules, fluctuant nodules, and abscesses (picture 37) (see 'Dissecting cellulitis of the scalp' above and "Dissecting cellulitis of the scalp") ●Acne keloidalis nuchae – Papules pustules, dome-shaped keloid-like papules, and keloid-like plaques on the occipital scalp (picture 26) (see 'Acne keloidalis nuchae' above and "Acne keloidalis nuchae") Performance of a scalp biopsy is usually recommended to confirm the diagnosis of cicatricial alopecia. An exception is acne keloidalis nuchae, for which the distinctive clinical features (location on posterior scalp and keloid-like papules) often negates the need for a biopsy diagnosis. Additional subtypes of cicatricial alopecia and the evaluation and diagnosis of patients with cicatricial alopecia are reviewed in detail separately. (See "Evaluation and diagnosis of hair loss".)

MARKED PRURITUS

The presence of pruritus can be a useful

clue for diagnosis. Scalp pruritus may be the most prominent scalp manifestation of pediculosis capitis and is a common feature of several other scalp diseases.

Pediculosis capitis — Pediculosis capitis (head lice) is a common cause of scalp pruritus in children, but may also occur in adults. Affected patients often present with pruritus of the scalp and excoriations without an identifiable eruption. Close examination will reveal nits (lice eggs) firmly attached to hair shafts and lice (picture 48). Cervical adenopathy may be present. (See "Pediculosis capitis".)

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Other disorders — Allergic contact dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis, dermatomyositis, and dermatitis herpetiformis are examples of additional scalp disorders that frequently present with pruritus. Scabies, another pruritic disorder, typically spares the scalp but may involve the scalp in young infants and immunocompromised patients (picture 49A-B). (See "Scabies: Epidemiology, clinical features, and diagnosis", section on 'Clinical manifestations'.)

CHILDREN

Many of the disorders described above can develop in children.

Seborrheic dermatitis and atopic dermatitis are common scalp conditions in infants. In children, the differential diagnosis for scalp eruptions often includes tinea capitis, pediculosis capitis, allergic contact dermatitis, and psoriasis. Nevus sebaceous, juvenile xanthogranuloma, syringocystadenoma papilliferum, and Langerhans cells histiocytosis are uncommon conditions that often initially present in children. Scalp disorders in the newborn infant are reviewed separately. (See "Skin lesions in the newborn and infant".)

SUMMARY AND RECOMMENDATIONS ●A wide variety of disorders may present with cutaneous changes on the scalp. The patient history and physical examination are important tools for diagnosis. The recognition of certain clinical features significantly narrows the differential diagnosis. (See 'Scaly patches and plaques' above and 'Plaques without scale' above and 'Papules and nodules' above and 'Pustules' above and 'Blisters and erosions' above and 'Thickened scalp' above and 'Cicatricial alopecia' above and 'Marked pruritus' above.) ●Many scalp conditions can be diagnosed based upon information obtained from the clinical evaluation alone. If the diagnosis remains uncertain, a skin biopsy is often useful. Depending on the clinical scenario, select laboratory studies may also be of value. (See 'Patient assessment' above.)

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Approach to the patient with an intertriginous skin disorder uptodate.com/contents/approach-to-the-patient-with-an-intertriginous-skin-disorder/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Oct 18, 2018.

INTRODUCTION

Intertriginous skin disorders are a diverse group of

diseases that may occur as a manifestation of a variety of cutaneous and systemic diseases. The differential diagnosis includes a broad list of inflammatory, infectious, genetic, and other disorders, which often can be differentiated based upon clinical features. Diagnostic techniques, such as a potassium hydroxide preparation, Wood's lamp examination, culture, or skin biopsy, may also be useful. The evaluation of intertriginous skin eruptions will be reviewed here. Intertrigo, one of the most common intertriginous skin disorders, is reviewed in detail separately. (See "Intertrigo".)

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DEFINITION

Intertriginous skin, also known as skin folds, are sites in which

opposing skin surfaces come into contact while at rest, resulting in chronic skin occlusion. The primary intertriginous skin areas include the groin folds, axillae, and gluteal cleft. Body habitus may contribute to additional intertriginous sites, such as inframammary skin and abdominal folds.  

PATIENT ASSESSMENT

The diagnosis of an intertriginous

skin disorder begins with review of the patient history and a physical examination. Helpful historical information may include: ●Patient age ●Associated symptoms ●Duration ●Clinical course (eg, chronic, episodic) ●Family history ●Medication exposure ●Comorbidities ●Response to prior therapies The physical examination provides the foundation for the differential diagnosis. A complete skin examination should be performed, including careful examination of all intertriginous sites, the remaining skin, and nails. Important features to assess include: ●Distribution ●Lesion morphology (papules, pustules, plaques, erosions, scale, etc) (see 'Morphology' below) ●Concomitant abnormalities of nonintertriginous skin and nails that suggest specific diseases (see 'Associated physical findings' below) Additional testing is indicated when the diagnosis remains uncertain based upon the history and physical examination or testing is necessary to confirm a presumed diagnosis. Examples of commonly performed tests include: ●Potassium hydroxide preparation of disorders with scale to detect superficial fungal infections (see "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation')

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●Wood's lamp examination of red to brown patches with fine or absent scale to detect erythrasma (see "Office-based dermatologic diagnostic procedures", section on 'Wood's lamp examination (black light)') ●Bacterial culture of pustular or blistering eruptions to detect infections and determine the causative organism Skin biopsies are not usually necessary and are generally reserved for patients with an uncertain diagnosis or for whom pathologic examination is required to confirm the suspected diagnosis. The preferred type of biopsy to perform depends upon the differential diagnosis. A shave biopsy is adequate for evaluation of disorders with pathology primarily involving the epidermis and the superficial dermis; punch biopsies allow for examination of the epidermis and full thickness of the dermis. Direct immunofluorescence is indicated if the differential diagnosis includes an autoimmune blistering disorder, such as pemphigus vegetans. (See "Skin biopsy techniques", section on 'Biopsy techniques' and "Approach to the patient with cutaneous blisters", section on 'Skin biopsy'.)

MORPHOLOGY

Careful evaluation of the morphology of intertriginous skin

disorders helps to narrow the differential diagnosis. Disorders characterized by erythematous patches or plaques, hyperpigmentation, pustules, blisters, erosions, ulceration, papules, verrucous or hyperkeratotic features, and nodules are reviewed below.

Erythematous patches or plaques — A wide variety of disorders may result in inflamed patches or plaques on intertriginous skin. Of note, erythema may be subtle in individuals with highly pigmented skin.

Common disorders — Careful examination for the presence of scale can facilitate diagnosis. Erythrasma, pityriasis rosea, seborrheic dermatitis, and tinea cruris may have associated scale, though scale generally is less prominent on intertriginous skin and may be absent. Scale is typically absent in intertrigo and inverse psoriasis.

Scale sometimes present ●Erythrasma – Erythrasma is a superficial corynebacterial infection that can present with erythematous to brown, well-defined patches or thin plaques in the skin folds (picture 1A-B). Fine scale and wrinkling often gives the skin a "cigarette paper" appearance. Affected areas may be asymptomatic or associated with mild pruritus. Examination with a Wood’s lamp demonstrating coral red fluorescence or a Gram stain demonstrating gram-positive filaments and rods confirms the diagnosis (picture 2). (See "Erythrasma" and "Office-based dermatologic diagnostic procedures", section on 'Wood's lamp examination (black light)'.)

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●Pityriasis rosea – Occasionally, pityriasis rosea can present as well-defined, dull pink to brown papules and plaques in the groin and axillae rather than the classic presentation (picture 3A-B). Onset is sudden, often beginning with an initial, larger herald patch. The fine, peripheral scale seen in classic pityriasis rosea plaques may be present or absent. Lesions are asymptomatic or minimally pruritic. Spontaneous resolution usually occurs within several weeks [1]. (See "Pityriasis rosea".) ●Seborrheic dermatitis – Involvement of the groin, axillae, and inframammary creases may occur in seborrheic dermatitis in infants and adults, manifesting as well-demarcated, moist, erythematous patches or plaques, often with associated greasy scale (picture 4A-C). Involvement of the scalp, facial creases, or postauricular creases usually accompanies intertriginous involvement, assisting with diagnosis [2]. (See "Seborrheic dermatitis in adolescents and adults" and "Cradle cap and seborrheic dermatitis in infants".) ●Tinea cruris – Tinea cruris is a superficial dermatophyte fungal infection of the groin skin folds and may extend to the lower abdomen, proximal thighs, and buttocks. Erythematous patches or plaques with peripheral scale are characteristic, but scale may also be minimal or absent (picture 5A-B). Tan or reddish-brown hyperpigmentation may also be seen centrally. Mild pruritus is common, and there is often concomitant tinea pedis or onychomycosis. The diagnosis can be confirmed with a potassium hydroxide preparation of scale that reveals large, branching hyphae (picture 6). (See "Dermatophyte (tinea) infections".)

Scale typically absent ●Intertrigo – Intertrigo is a common intertriginous dermatitis that usually results from friction and moisture within skin folds. Intertrigo appears as moist, dull red to red-brown patches or thin plaques (picture 7A-B). Pruritus is common and pain may occur if fissuring or erosion is present. Debilitation, infancy, and obesity are risk factors for intertrigo [3]. The diagnosis is made based upon the distribution limited to sites of friction and moisture and the exclusion of other disorders. (See "Intertrigo".) Candidal or bacterial infections may be inciting or exacerbating factors. Features suggestive of candidal intertrigo are beefy red plaques with satellite papules and pustules (picture 8) (see 'Pustules' below). Often, satellite lesions demonstrate a collarette of scale. A potassium hydroxide preparation from the scale or pustule can be used to confirm candidal infection. Streptococcal intertrigo due to beta-hemolytic streptococcus usually presents with brightly erythematous patches and intense itching or burning (picture 9A-B) [4,5]. A bacterial culture confirms the diagnosis. (See 'Pustules' below and "Intertrigo".) ●Psoriasis – Inverse psoriasis presents as well-demarcated, erythematous plaques in the groin, the axillae, or inframammary creases (picture 10A-B). Unlike many other areas involved with psoriasis, thick scaling in inverse psoriasis is uncommon. Often, the surface of intertriginous lesions of psoriasis have a shiny appearance due to maceration. The presence of psoriatic involvement in other skin areas, such elbows and knees, or psoriatic nail abnormalities (eg, nail pits, oil spots, and distal onycholysis) can help distinguish inverse psoriasis. In addition, patients may have a family

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history of psoriasis. (See "Treatment of psoriasis in adults", section on 'Intertriginous psoriasis' and "Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Inverse (intertriginous) psoriasis' and "Nail psoriasis".)

Less common disorders — Examples of less common disorders that may manifest with erythematous patches or plaques include extramammary Paget disease, Langerhans cell histiocytosis, lichen planus, symmetric drug-related intertriginous and flexural exanthema, and unilateral laterothoracic exanthem: ●Extramammary Paget disease – Extramammary Paget disease may present as well-demarcated, erythematous plaques on genital or perianal skin or the perineum. The plaques may exhibit crusting, erosions, lichenification, or a verrucous surface (picture 11A-B). Pruritus is common. The diagnosis should be suspected when patients fail to respond to treatment for a presumed diagnosis as expected. A biopsy is necessary to confirm the diagnosis. (See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment", section on 'Paget disease of the vulva'.) ●Langerhans cell histiocytosis – Langerhans cell histiocytosis is a potentially life-threatening disorder that can present in infancy or early childhood with red-orange or yellow-brown papules, plaques, erosions, and petechiae on the scalp, groin, or intertriginous regions (picture 12). A skin biopsy is necessary to confirm the diagnosis. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".) ●Lichen planus – Inverse lichen planus, also referred to as lichen planus pigmentosus inversus, is a rare, pruritic dermatosis that affects the axillae and groin. Affected patients develop asymptomatic or mildly pruritic, discrete, erythematous to violaceous patches and plaques that follow skin cleavage lines (picture 13). Hyperpigmentation is a striking feature. Middle-aged adults are most commonly affected. Classic lichen planus on areas such as the shins and wrists may also be present. Mucosal involvement is generally absent [6]. A skin biopsy reveals a band-like infiltrate of lymphocytes at the base of an atrophic epidermis. Pigment incontinence is a prominent histologic feature. (See "Lichen planus".) ●Symmetric drug-related intertriginous and flexural exanthema –Symmetric drug-related intertriginous and flexural exanthema is a medication reaction that presents as well-demarcated, erythematous patches affecting at least one flexural area. The onset is acute, and there is history of recent exposure to one of a wide variety of potential inciting medications. The diagnosis is made based on history, clinical suspicion, and improvement upon stopping the offending medication. (See "Drug eruptions", section on 'Symmetrical drug-related intertriginous and flexural exanthema'.) ●Unilateral laterothoracic exanthem – Unilateral laterothoracic exanthem is a viral exanthema that typically occurs in young children. It generally begins as a unilateral, morbilliform exanthema in or adjacent to one axilla and may also begin in the groin (picture 14). Mild pruritus is common. Progression to the other side of the body often occurs. The diagnosis is made based upon the clinical appearance. Complete resolution within five weeks is expected [7]. (See "Atypical exanthems in children", section on 'Unilateral laterothoracic exanthem'.)

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Hyperpigmentation — Examples of disorders of intertriginous sites with hyperpigmentation as a primary feature include acanthosis nigricans, confluent and reticulated papillomatosis, and Dowling-Degos disease. Hyperpigmentation may also occur as a secondary effect of any cutaneous inflammatory disorder (postinflammatory hyperpigmentation), particularly in individuals with moderately to highly pigmented skin (see 'Erythematous patches or plaques' above): ●Acanthosis nigricans – Acanthosis nigricans is a common disorder that usually presents as velvety, brownish, asymptomatic plaques on the neck and/or intertriginous skin (picture 15A-B). The disorder is associated with obesity and insulin resistance [8]. Rarely, acanthosis nigricans is associated with malignancy. The physical examination is usually sufficient for diagnosis. (See "Acanthosis nigricans".) ●Confluent and reticulated papillomatosis – Confluent and reticulated papillomatosis (CARP) presents as erythematous to dark brown, net-like patches involving the trunk, neck, and axillae (picture 16A-B). CARP typically occurs in young adults and is asymptomatic in most patients. The diagnosis usually can be made based upon the physical findings and the exclusion of tinea versicolor with a potassium hydroxide preparation. (See "Confluent and reticulated papillomatosis".) ●Dowling-Degos disease – Dowling-Degos disease (reticulate pigmented anomaly of flexures) is a rare autosomal dominant disease that typically presents in adulthood as reticular hyperpigmentation involving the intertriginous skin, neck, and inner aspects of the arms and thighs (picture 17). Pruritus is common. The diagnosis is made based upon the clinical appearance and a skin biopsy demonstrating increased pigment in the basal layer of the epidermis and finger-like rete ridges with thinning of the suprapapillary epithelium. Galli-Galli disease is an autosomal dominant disorder that is considered an allelic variant of Dowling-Degos disease that has similar clinical and histologic features but also exhibits suprabasal acantholysis. (See "Congenital and inherited hyperpigmentation disorders", section on 'Dowling-Degos disease'.)

Pustules — Cutaneous disorders with intertriginous pustules as a common feature include amicrobial pustulosis of the folds, folliculitis, candidal intertrigo, pemphigus vegetans, and subcorneal pustular dermatosis: ●Amicrobial pustulosis of the folds – Amicrobial pustulosis of the folds is rare and occurs most often in young women and in association with autoimmune diseases. Patients develop recurrent eruptions of follicular and nonfollicular sterile pustules that exhibit a predilection for intertriginous skin, scalp, and periorificial areas on the head (mouth, nostrils, ear canals). The diagnosis is based upon the clinical findings as well as the exclusion of infection and other disorders. (See "Neutrophilic dermatoses", section on 'Amicrobial pustulosis of the folds'.) ●Bacterial folliculitis – Bacterial folliculitis presents with multiple follicular pustules and erythematous papules. Pruritus is common. Staphylococcus aureus is a frequent causative organism. The diagnosis usually can be made based upon the physical examination. (See "Infectious folliculitis", section on 'Bacterial folliculitis'.)

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●Candidal intertrigo – Candidal intertrigo is an intertriginous fungal skin infection caused primarily by Candida albicans [9]. The typical manifestations consist of beefy red plaques with delicate, peripheral pustules (picture 8). The pustules may present as superficial erosions due to their fragile nature. Itching and burning are frequent symptoms. A potassium hydroxide preparation demonstrating yeast, hyphae, and pseudohyphae confirms the diagnosis (picture 18). (See "Intertrigo" and "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.) ●Pemphigus vegetans – Pemphigus vegetans is a variant of pemphigus that may present with vegetative plaques on intertriginous skin (picture 19). Pustules may precede the development of the vegetative plaques (picture 20). Pemphigus vegetans is reviewed below. (See 'Verrucous or hyperkeratotic papules or plaques' below.) ●Subcorneal pustular dermatosis – Subcorneal pustular dermatosis is a rare disorder that presents as an extensive eruption of fragile, sterile pustules favoring intertriginous areas, such as the groin and axillae (picture 21). An annular or serpiginous distribution is common. There is significant clinical overlap between subcorneal pustular dermatosis and variants of immunoglobulin A (IgA) pemphigus [10]. IgA pemphigus is less likely to involve intertriginous skin, and a skin biopsy with direct immunofluorescence helps to distinguish between these diagnoses. (See "Subcorneal pustular dermatosis" and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'IgA pemphigus'.)

Blisters, erosions, or ulcers — Intertriginous erosions can be prominent in bullous impetigo and Hailey-Hailey disease and may also occur as secondary lesions in other disorders, such as Langerhans cell histiocytosis and pustular diseases. Ulcers may occur in the setting of metastatic Crohn disease or sexually transmitted diseases: ●Bullous impetigo –Bullous impetigo is a cutaneous infection caused by S. aureus strains that produce an exfoliative toxin, resulting in superficial blisters. Intact blisters are rare, as they are often denuded by friction. The more common findings are superficial erosions associated with background erythema and golden or "honey" crusts (picture 22A-B). The face, extremities, groin, axillae, and neck are common sites [11]. The diagnosis can be made based upon the clinical appearance and confirmed with Gram stain and culture. (See "Impetigo".) ●Hailey-Hailey disease – Hailey-Hailey disease (benign familial pemphigus) is a rare autosomal dominant, intraepidermal blistering disorder that presents as painful blisters, erosions, and maceration in intertriginous areas (picture 23A-B) [12]. Onset usually occurs after puberty. Skin biopsy confirms the diagnosis and demonstrates acantholysis of the epidermis. (See "Hailey-Hailey disease (benign familial pemphigus)".) ●Metastatic Crohn disease – Metastatic Crohn disease may present as deep, jagged ulcerations in the inguinal creases, often with associated genital swelling (picture 24) [13]. Skin lesions may occur before or after development of gastrointestinal disease. A punch biopsy reveals noncaseating granulomas in the dermis.

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Various sexually transmitted infectious diseases may cause ulcers in the genital region or groin. This differential diagnosis is reviewed separately. (See "Approach to the patient with genital ulcers".)

Discrete papules — Discrete papules on intertriginous skin occur in patients with acrochordons, Fox-Fordyce disease, and pseudoxanthoma elasticum: ●Acrochordons – Acrochordons, also known as skin tags, are benign skin growths that appear as soft, pedunculated papules and most often occur on the axillae, neck, groin, and inframammary regions (picture 25A-B). The diagnosis typically can be made based upon the clinical appearance. (See "Overview of benign lesions of the skin", section on 'Acrochordon (skin tag)'.) ●Fox-Fordyce disease – Fox-Fordyce disease (apocrine miliaria) is an inflammatory disease that predominantly occurs in young adult women. It typically presents as pruritic papules in the axillary vaults, although it has been reported on other areas rich in apocrine glands, such as the areola and the vulva. Occlusion of the apoeccrine sweat ducts is thought to cause the eruption (picture 26A-B) [14]. The diagnosis can usually be made based upon the clinical appearance. (See "Fox-Fordyce disease (apocrine miliaria)".) ●Pseudoxanthoma elasticum – Pseudoxanthoma elasticum is an autosomal recessive disease that results in abnormal elastic tissue [15-17]. The classic cutaneous findings are collections of yellow papules in flexural areas, such as the sides of the neck, antecubital fossae, axillae, and groin (picture 27) [18]. The papules are asymptomatic and may be detected incidentally. Skin biopsy confirms the diagnosis. Patients with pseudoxanthoma elasticum are at risk for cardiovascular and ocular complications. (See "The genodermatoses: An overview", section on 'Pseudoxanthoma elasticum'.)

Verrucous or hyperkeratotic papules or plaques — Verrucous or hyperkeratotic papules or plaques on intertriginous skin may be indicative of condylomata acuminata, condylomata lata, granular parakeratosis, or pemphigus vegetans: ●Condylomata acuminata – Condylomata acuminata, caused by human papilloma virus infection, may present as soft, verrucous plaques on the external genitalia, perianal skin, perineum, groin, or lower abdomen (picture 28A-C). The physical examination is usually sufficient for diagnosis. A skin biopsy can confirm the diagnosis when the diagnosis is uncertain. (See "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis".) ●Condylomata lata – Condylomata lata are a manifestation of secondary syphilis characterized by the development of moist, warty plaques on perianal, perivaginal, or inguinal skin (picture 29). Condylomata lata contain large numbers of spirochetes and are highly infectious. The diagnosis is usually made through serologic testing for syphilis. A skin biopsy can be useful for differentiating condylomata lata from other skin lesions. Dark field microscopy and polymerase chain reaction diagnostic tests may be available in specialized centers. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients".)

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●Granular parakeratosis –Granular parakeratosis presents as pink to brown, hyperkeratotic papules that coalesce into plaques (picture 30A-B). The disorder most commonly affects the axillae of women but may also occur in other intertriginous areas and in men or children [19,20]. Pruritus is common. A biopsy can confirm the diagnosis. The name of this disorder reflects the histologic pattern observed on skin biopsy [21]. (See "Granular parakeratosis".) ●Pemphigus vegetans – Pemphigus vegetans is an immunobullous disease and a variant of pemphigus vulgaris. It can present as macerated, warty plaques involving intertriginous areas (picture 19) [22]. Blisters and erosions may not be evident. A skin biopsy with direct immunofluorescence can confirm the diagnosis. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".) ●Seborrheic keratoses – Seborrheic keratoses are common, benign epidermal tumors that typically arise during adulthood. Characteristic clinical features are well-demarcated, hyperpigmented, round or oval papules or plaques with a verrucous surface and stuck-on appearance (picture 31A-B). In addition, seborrheic keratoses have visible keratin plugs. Common intertriginous locations for seborrheic keratoses are the inframammary skin and abdominal folds. (See "Overview of benign lesions of the skin", section on 'Seborrheic keratosis'.)

Nodules — Cutaneous nodules on intertriginous skin may occur in patients with furunculosis or hidradenitis suppurativa: ●Furunculosis – Furuncles, also known as boils, are perifollicular, cutaneous abscesses that occur in sites of hair follicles. S. aureus infection is the most common cause. Furuncles appear as painful, inflamed nodules that may be fluctuant and may drain purulent material. (See "Cellulitis and skin abscess: Clinical manifestations and diagnosis", section on 'Skin abscess'.) ●Hidradenitis suppurativa –Hidradenitis suppurativa is a chronic inflammatory disorder that is characterized by recurrent, inflamed nodules, abscesses, and comedones on intertriginous skin (picture 32). The disease may progress to sinus tract formation and severe, rope-like scarring. The axillae, groin, and inframammary areas are among the most common sites of involvement. The patient history and physical findings support the diagnosis. (See "Hidradenitis suppurativa: Pathogenesis, clinical features, and diagnosis".)

AGE

Review of the typical age distribution of specific disorders may help to narrow the

differential diagnosis. The disorders often responsible for intertriginous eruptions in infants and children are listed below. These disorders are not exclusive to children and may also occur in adolescents and adults.

Infants — Intertriginous disorders often in the differential diagnosis for infants include: ●Bullous impetigo

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●Intertrigo ●Langerhans cell histiocytosis ●Seborrheic dermatitis ●Psoriasis

Prepubertal children — Intertriginous disorders often in the differential diagnosis for prepubertal children include: ●Acanthosis nigricans ●Bullous impetigo ●Condylomata acuminata ●Pityriasis rosea ●Psoriasis ●Unilateral thoracic exanthem

SYMPTOMS

Associated symptoms, such as pruritus and pain, may help to

narrow the differential diagnosis.

Pruritus — Prominent pruritus may occur in association with: ●Bacterial folliculitis ●Dowling-Degos disease ●Extramammary Paget disease ●Fox-Fordyce disease ●Granular parakeratosis ●Intertrigo ●Tinea cruris

Pain — Pain is a common symptom in patients with: ●Metastatic Crohn disease

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●Furunculosis ●Hailey-Hailey disease ●Hidradenitis suppurativa ●Intertrigo with fissuring ●Pemphigus vegetans

FAMILY HISTORY

Patients with psoriasis and autosomal dominant

disorders, such as Dowling-Degos disease and Hailey-Hailey disease, may report similar symptoms in family members, assisting with diagnosis.

OTHER HISTORY

Information regarding the clinical course, medication

exposure, and response to previous treatments may facilitate diagnosis. For example, an acute onset is typical of bacterial folliculitis, bullous impetigo, furunculosis, and symmetric drug-related intertriginous and flexural exanthemata, in contrast to the chronic and relapsing course that characterizes hidradenitis suppurativa, subcorneal pustular dermatosis, amicrobial pustulosis of the folds, and other disorders. The medication exposure history may indicate susceptibility to intertriginous infections due to immunosuppression or exposure to drugs associated with symmetric drug-related intertriginous and flexural exanthemata. Failure to respond to topical corticosteroids or other therapies as expected may result in a shift in the presumed diagnosis, such as from psoriasis to extramammary Paget disease.

ASSOCIATED PHYSICAL FINDINGS

An

examination for additional physical findings can help to support a diagnosis.

Skin abnormalities — Knowledge of current or prior characteristic nonintertriginous skin lesions may be helpful. Examples include: ●Lichen planus – Violaceous, polygonal, intensely pruritic papules or plaques on the extremities, particularly wrists and ankles ●Pityriasis rosea – Numerous oval, erythematous plaques with peripheral collarettes of scale, often following the initial appearance of a larger, similar "herald patch" ●Psoriasis – Erythematous plaques with thick, silvery scale on the scalp, trunk, or extremities ●Seborrheic dermatitis – Greasy scale involving the scalp, nasolabial folds, eyebrows, or postauricular skin

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●Syphilis – History of painless chancre, diffuse macular or papular eruption including palms and soles, or alopecia

Nail abnormalities — Nail abnormalities may occur in association with certain intertriginous skin disorders. Examples include: ●Hailey-Hailey disease – Longitudinal white bands ●Lichen planus – Longitudinal ridging, nail plate thinning, longitudinal fissuring, trachyonychia, erythema of the lunula, hyperpigmentation, onycholysis (see "Overview of nail disorders", section on 'Lichen planus') ●Psoriasis – Pitting, oil drop discoloration, onycholysis, subungual hyperkeratosis, nail plate crumbling, other findings (see "Nail psoriasis")

SUMMARY AND RECOMMENDATIONS ●Intertriginous skin areas are sites in which opposing skin areas come into contact while at rest leading to chronic skin occlusion. Examples include the axillae, groin folds, and gluteal cleft. The presence of additional intertriginous areas, such as inframammary skin and abdominal folds, is dependent on body habitus. (See 'Definition' above.) ●Intertriginous skin disorders are a diverse group of inflammatory, infectious, genetic, and other disorders and exhibit a wide variety of clinical features. Many intertriginous disorders can be diagnosed based upon the patient history and physical examination. When this is insufficient, tests such as potassium hydroxide preparation, Wood’s lamp examination, culture, and skin biopsy may help with diagnosis. (See 'Patient assessment' above.) ●Important diagnostic information may include the patient age, associated symptoms, and family history. The physical examination should include an assessment of the distribution and morphology of the intertriginous skin disorder. In addition, examination of the entire skin surface and nails should be performed to identify other findings suggestive of specific diseases. (See 'Morphology' above and 'Age' above and 'Symptoms' above and 'Family history' above and 'Associated physical findings' above.)

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Approach to the patient with annular skin lesions uptodate.com/contents/approach-to-the-patient-with-annular-skin-lesions/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Dec 13, 2019.

INTRODUCTION

A wide variety of cutaneous and systemic disorders

present with annular (ring-like) skin lesions (table 1). The careful assessment of lesion characteristics and accompanying clinical features is valuable for narrowing the differential diagnosis.   Diagnostic clues for the identification of disorders that present with annular lesions will be reviewed here. Greater detail on many of the disorders discussed below is available elsewhere in UpToDate.

DEFINITION

Annular skin lesions are figurate lesions characterized by a ring-like

morphology. Although plaques represent the most common presentation of annular lesions, lesions may also be macular, nodular, or composed of grouped papules, vesicles, or pustules. Additional terms that are frequently used to describe the characteristics of annular lesions include: ●Arcuate – Consists of arc-shaped lesions that represent incompletely formed annular lesions (picture 1).

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●Polycyclic – Exhibits multiple coalescing arcuate or annular lesions (picture 2A-B). ●Target/targetoid – Demonstrates a dusky red center surrounded by a zone of pallor, which in turn is surrounded by a peripheral erythematous ring (a characteristic feature of erythema multiforme) (picture 3A-B). ●Atypical target – Lacks full criteria for target lesions; only two zones of color change are present (picture 4).

PATIENT ASSESSMENT

The identification of the underlying

diagnosis in patients with annular lesions begins with the assessment of several factors. The clinician should consider the following points during the skin examination: ●What are additional physical characteristics of the lesions? ●Are the lesions stationary, expanding, or migratory? ●Where are the lesions located? ●Are there associated systemic or cutaneous signs or symptoms? If the diagnosis is not apparent after these questions have been answered, additional studies may be considered (see 'Diagnostic tests' below). A table of disorders that may present with annular features and their clinical and pathologic features is provided (table 1). In some disorders, such as tinea corporis and erythema annulare centrifugum, annular lesions represent the most common clinical presentation. In contrast, other disorders may demonstrate annular lesions only as an occasional or incidental feature. For example, annular lesions are not a classic feature of psoriasis, nummular dermatitis, seborrheic dermatitis, secondary syphilis, sarcoidosis, mycosis fungoides, or malignant skin tumors, but occasionally occur in the context of these diseases. A distinct annular variant of lichen planus has been reported [1]. The concomitant detection of features that are more typical of a particular skin disease can be of value in the diagnosis of annular lesions in conditions in which this morphology is not common. As an example, the identification of classic psoriatic plaques on the scalp or signs of psoriatic nail disease may lead to the inclusion of psoriasis into the differential diagnosis for a scaly and erythematous annular lesion.

Lesion characteristics Color — Lesion color can be useful for narrowing the differential diagnosis. The vast majority of annular lesions represent inflammatory processes, and thus, manifest with blanchable cutaneous erythema. Of note, in patients with dark skin pigmentation, this erythema may be difficult to appreciate.

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Acute inflammatory lesions often present with bright erythema (picture 5A-C). In contrast, erythema tends to be muted in lesions of granuloma annulare, a disorder characterized by annular plaques that persist for months to years (picture 6A-C). Lesion color may also be influenced by disorder-specific characteristics. Lesions of acute or chronic urticaria characteristically have a pink color that results from the combination of dermal edema and vascular dilation (picture 7A-B). Moreover, a dusky red to violaceous color, which is often seen in the setting of epidermal necrosis, is a common feature in lesions of erythema multiforme (picture 3B). (See "Granuloma annulare", section on 'Clinical features' and "New-onset urticaria", section on 'Clinical manifestations' and "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.) The color of lesions may shift with lesion age. As acute inflammatory lesions resolve, erythema may become less prominent. Postinflammatory hyperpigmentation, when present, may be the only remnant of resolved lesions.

Scale — The presence, absence, and quality of scale are key diagnostic features for several annular dermatoses. When a rim of fine scale is present, the clinician should take note of whether it is "leading" (present at the advancing edge), or "trailing" (present more centrally): ●Leading scale – The prototypical annular inflammatory skin lesion with leading scale is the dermatophyte infection tinea corporis (picture 5A, 5D). Single or multiple lesions may be present. ●Trailing scale – Trailing scale is most commonly seen in pityriasis rosea and superficial erythema annulare centrifugum. •Pityriasis rosea – Patients with pityriasis rosea typically present with numerous oval erythematous thin plaques on the trunk and proximal extremities. The long axis of the oval is arranged along lines of skin tension. On the back, this classically results in a "Christmas tree-like" distribution. The scale is typically described as a collarette (picture 8). A larger, oval, erythematous plaque (herald patch) occurs as the initial sign of disease in 50 percent or more of patients. (See "Pityriasis rosea".) •Superficial erythema annulare centrifugum – Erythema annulare centrifugum is an inflammatory reactive disorder that occurs in both superficial and deep forms. Patients present with single or multiple annular or arcuate erythematous plaques on the face, neck, trunk, or extremities. Trailing scale is a characteristic feature of the superficial form (picture 5B, 5E). In contrast, scale is typically absent in the deep variant of the disease. The cause of the disorder is often unknown; infections and medications are among the possible triggers [2]. (See "Erythema annulare centrifugum".) In addition, a very thin, palpable rim of ribbon-like scale known as a cornoid lamella is a pathognomonic feature of lesions of porokeratosis (picture 9A-B). These lesions also have a distinct histopathologic appearance (picture 10). The absence of scale is a relevant feature for granuloma annulare, distinguishing these lesions from the more prevalent diagnosis of tinea corporis.

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Granuloma annulare presents as single or multiple papules or plaques that exhibit a dull, erythematous color and tend to be slightly firm and smooth to palpation (picture 6A-C). (See "Porokeratosis" and "Granuloma annulare".)

Vesicles or pustules — Linear IgA dermatosis is an autoimmune subepidermal blistering disorder that may be triggered by medications (particularly vancomycin) [3]. It classically presents with annular clusters of tense vesicles and bullae in a "string of jewels" pattern (picture 11). In the early stages of the condition, the vesicles may be tiny, few in number, and located on an annular erythematous, edematous base. Linear IgA dermatosis may be idiopathic or drug-induced. When it occurs in children, the term chronic bullous dermatosis of childhood is also used to describe this condition. (See "Linear IgA bullous dermatosis".) Flaccid pustules coalescing into annular, polycyclic, or serpiginous configurations are typical of subcorneal pustular dermatosis (also known as Sneddon-Wilkinson disease) (picture 12A-B). Intertriginous areas, skin flexures, and the abdomen are preferred sites of involvement. (See "Subcorneal pustular dermatosis".) Neutrophilic figurate erythema typically begins with a target-like, erythematous papule that expands to an annular, erythematous patch with vesicles or purpura. It has histologic features similar to other neutrophilic dermatoses with a lesser degree of inflammation [4].

Purpura — Purpura results from the extravasation of erythrocytes from cutaneous vessels. Examples of disorders that characteristically present with purpuric annular lesions include: ●Purpura annularis telangiectodes of Majocchi – Purpura annularis telangiectodes of Majocchi is a subtype of pigmented purpuric dermatosis [5]. Patients present with symmetric, asymptomatic eruptions of pinpoint nonblanchable red to red-brown macules that coalesce to form annular patches (picture 13). The most common site of involvement is the lower extremity. Mycosis fungoides (a form of cutaneous T cell lymphoma) can present with lesions with similar features and should be considered in the differential diagnosis in patients with extensive or chronic involvement. (See "Pigmented purpuric dermatoses (capillaritis)", section on 'Purpura annularis telangiectodes (Majocchi's disease)'.) ●Acute hemorrhagic edema of infancy –Acute hemorrhagic edema of infancy is a benign small vessel vasculitis that is characterized by edematous urticarial plaques that progress to purpuric plaques that often have a targetoid appearance (picture 14) [6]. Lesions are primarily distributed on the head, genitals, and distal extremities. Fever may be present, but patients typically do not appear toxic. Children under the age of two represent the population that is usually affected. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis", section on 'Differential diagnosis'.) ●Immunoglobulin A vasculitis (Henoch-Schönlein purpura) – Immunoglobulin A vasculitis (HenochSchönlein purpura) is an IgA-mediated small vessel vasculitis that occurs in children and adults. Cutaneous features include symmetric palpable purpura that are predominantly distributed in

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dependent regions (picture 15). Some lesions may have an annular appearance. Systemic involvement can occur, including renal failure. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".) ●Traumatic purpura – Trauma may lead to annular purpuric or ecchymotic lesions on the skin. Skin injury sustained during participation in paintball, a sport that involves shooting nonlethal capsules at other players, is a classic example. Teenagers are common participants in this activity. The impact of the paintball capsule on the skin typically results in an annular purpuric lesion that persists for one to two weeks (picture 16). Suction purpura from the Chinese practice of "cupping" or romantic liaisons may be annular. In general, the diagnosis of traumatic purpura is facilitated by the patient history. ●Urticarial vasculitis – Urticarial vasculitis is another disorder in which purpura may occur in the setting of annular lesions. (See 'Symptoms' below.) ●Dependent purpura in annular inflammatory disorders – Purpura on the lower legs or other dependent areas are common secondary occurrences in nonpurpuric inflammatory disorders. The purpura develop as a result of vascular leakage. This is particularly common in serum sickness-like eruptions in children (picture 5G) (see 'Expanding lesions' below). The most prominent purpura are usually located in areas with the highest hydrostatic forces (eg, lower legs), as blood extravasation is most likely to occur in those sites.

Symptoms — Most annular eruptions are either asymptomatic or mildly to moderately pruritic, and knowledge of associated symptoms may be useful for supporting the diagnosis of specific diseases. A less commonly observed feature that occurs fairly frequently in urticarial vasculitis is the presence of burning or painful sensations in addition to pruritus. Lesions of urticarial vasculitis often look identical to classic urticaria (edematous pink wheals), but frequently persist beyond 24 hours and may be associated with residual bruising or hyperpigmentation (picture 17A-B) [7]. Such features should prompt consideration for urticarial vasculitis in patients who present with urticarial lesions. Urticarial vasculitis may occur in association with autoimmune diseases, medications, injections, and malignancy. (See "Urticarial vasculitis".)

Lesion progression — Several disorders are characterized by transient or migratory features, and asking patients about lesion expansion, lesion migration, and lesion time course can be useful for diagnosis.

Expanding lesions — Outward spread of individual annular lesions is commonly noted in tinea corporis, granuloma annulare, erythema chronicum migrans, and erythema annulare centrifugum. Lesions progressively advance into areas of previously uninvolved tissue, resulting in a progressive increase in size.

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●Tinea corporis – Lesions of tinea corporis expand slowly over the course of weeks as the fungal infection spreads outward, often leaving central clearing (picture 5A, 5D). (See "Dermatophyte (tinea) infections", section on 'Tinea corporis'.) ●Erythema migrans – The hallmark feature of early localized Lyme disease is erythema migrans. A set of concentric erythematous rings appears 7 to 14 days after tick detachment and progressively enlarges to form a lesion that is usually at least 5 cm in diameter (picture 18A-B). Lesions may demonstrate a "bulls-eye" appearance, and last approximately four weeks if untreated [8]. In patients with early disseminated Lyme disease, multiple annular lesions may be present (picture 19). (See "Clinical manifestations of Lyme disease in adults".) The clinical appearance of erythema migrans is indistinguishable from that of the skin findings of southern tick-associated rash illness (STARI); however, the different endemic areas of the vectors assist with diagnosis. (See "Southern tick-associated rash illness (STARI)".) ●Granuloma annulare – In contrast to the fairly rapid outward spread of erythema migrans, lesions of granuloma annulare expand slowly over the course of weeks to months. Solitary or multiple annular plaques with a firm border are seen (picture 6A-C). Lesions are commonly found on distal extremities. (See "Granuloma annulare".) ●Erythema annulare centrifugum – The annular erythematous scaly or nonscaly plaques of erythema annulare centrifugum tend to expand over the course of days to weeks (picture 5B, 5E). (See 'Scale' above.) ●Serum sickness-like reactions – Serum sickness-like reactions occur due to a variety of medications (most commonly antibiotics [6]) and are most frequently seen in children. Symptoms begin one to three weeks after initiation of the offending agent. (See "Serum sickness and serum sickness-like reactions".) Patients with serum sickness-like reactions usually present with urticarial lesions that start in the flexures and then become generalized (picture 5C, 5F-G). These eruptions are frequently initially mistaken for acute urticaria, but in contrast to acute urticaria, individual lesions remain for greater than 24 hours. The skin lesions typically gradually expand, leaving central clearing or central faint purpura, which are usually most evident on the abdomen or lower legs. Affected patients commonly also develop fever, arthralgias, and erythematous and edematous hands and feet. ●Erythema gyratum repens – Erythema gyratum repens is a rare, often paraneoplastic eruption characterized by concentric polycyclic, annular, and circinate red plaques that give a characteristic "wood grain" appearance (picture 20A-C). (See "Cutaneous manifestations of internal malignancy", section on 'Erythema gyratum repens'.) ●Erythema papulatum centrifugum (EPC) – EPC, also known as erythema papulosa semicircularis recidivans, is an annular, eczematous eruption that primarily has been described in Japanese and Chinese males. Patients present with tiny, grouped papules on the trunk that spontaneously resolve but frequently relapse. EPC is characterized by histologic evidence of perieccrine inflammation [9].

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Migratory lesions — Transient lesions are characteristic of urticaria and erythema marginatum. ●Urticaria – Although an outbreak of urticaria may last days to weeks or more, a hallmark feature of urticaria is that the individual erythematous, edematous plaques last less than 24 hours (picture 7AC). Marking a few lesions with a pen can be useful for confirming the transient nature in patients with numerous lesions. (See "New-onset urticaria" and "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".) ●Urticaria multiforme (acute annular urticaria) – Urticaria multiforme, also known as acute annular urticaria, is a self-limited urticarial hypersensitivity eruption that primarily occurs in infants and very young children [10,11]. Lesions appear on the face, trunk, and extremities as annular erythematous plaques with central clearing or dusky blue centers. Unlike serum sickness-like reactions and erythema multiforme, the duration of individual lesions does not exceed 24 hours. Myalgias and arthralgias are absent. Pruritus is typically present. Other associated findings may include angioedema of the face or acral areas, dermatographism, and low-grade fever. Viral or bacterial infections, antibiotics, and vaccinations have been proposed as potential triggers. The disorder is treated with antihistamines and discontinuation of a triggering medication, if present. ●Erythema marginatum – The migratory, polycyclic, and nonpruritic erythematous plaques of erythema marginatum typically migrate within minutes to hours(picture 2A, 2C). These annular lesions tend to have a thin border and often display arciform, polycyclic, and other incompletely formed annular lesions. Erythema marginatum occurs in association with rheumatic fever due to group A streptococcal infection. (See "Acute rheumatic fever: Clinical manifestations and diagnosis".) ●Eosinophilic annular erythema – Eosinophilic annular erythema is a rare disorder that presents with recurrent, annular or gyrate, often asymptomatic erythematous plaques on the trunk and extremities [12-14]. Both children and adults may be affected. A hypersensitivity reaction to an unknown antigen has been proposed as an inciting factor for eosinophilic annular erythema; however, the cause of the condition remains unknown [12]. Histopathologic examination of lesional tissue typically reveals a dense perivascular and interstitial lymphocytic infiltrate with many eosinophils. Although some authors have proposed that eosinophilic annular erythema may be a subtype of eosinophilic cellulitis (Wells syndrome) [13,15], the relationship between these disorders remains unclear. Responses to antimalarials or systemic glucocorticoids have been reported; however, the condition also may spontaneously resolve over months to years [12]. (See "Eosinophil biology and causes of eosinophilia", section on 'Disorders with eosinophilic involvement of specific organs'.)

Lesion location — The location of annular skin lesions can offer clues for diagnosis. Disorders that frequently present with photodistributed, acral, or genital lesions are reviewed below.

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Photodistributed — Photoexacerbated dermatoses tend to occur on sites that are not typically covered by clothing or other adornments such as the balding scalp, forehead, dorsal nose, zygomatic cheeks, posterolateral neck, upper chest, extensor upper extremities, and shins. On the face, the shadow areas of the orbital rim, chin, and nasolabial folds are often spared. ●Lupus erythematosus – Lupus erythematosus is the most common cause of annular lesions in a photodistributed arrangement. Subacute cutaneous lupus erythematosus, tumid lupus erythematosus, and neonatal lupus erythematosus may present with such features. •Subacute cutaneous lupus erythematosus – Subacute cutaneous lupus erythematosus often presents with annular erythematous scaly plaques (picture 21) [16]. Scaling at the borders of lesions is common. The neck, upper trunk, and arms are typical sites of involvement. (See "Overview of cutaneous lupus erythematosus", section on 'Subacute cutaneous lupus erythematosus'.) •Lupus erythematosus tumidus – Lupus erythematosus tumidus features smooth, raised, fixed erythematous plaques (picture 22). Lesions may be annular with central clearing or solid plaques. Scale is uncommon. •Neonatal lupus erythematosus – Neonatal lupus erythematosus is a self-limited condition that results from transplacental transmission of maternal SSA/Ro, SSB/La, or U1RNP antibodies. These infants present with annular, scaly red plaques on the face, arms, or trunk that are triggered by ultraviolet light (picture 23). Diagnosis should prompt evaluation for cardiac manifestations. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".) ●Actinic lichen planus –Photodistributed annular lesions are also a common manifestation of actinic lichen planus (lichen planus actinicus), an idiopathic condition that most commonly occurs in dark-skinned young adults in subtropical climates [1]. Individuals of Middle-Eastern descent appear to be most susceptible. Patients present with annular hyperpigmented plaques (picture 24AB). ●Annular elastolytic giant cell granuloma – Annular elastolytic giant cell granuloma is characterized by annular red plaques with raised borders and an atrophic center and is typically found on sunexposed skin (picture 25A-B). It closely resembles granuloma annulare and can be differentiated histopathologically. (See "Granuloma annulare", section on 'Differential diagnosis'.)

Acral — The palms and soles are often spared in generalized eruptions such as urticaria. In contrast, the target or atypical target lesions of erythema multiforme have a predilection for these and other acral sites. Target lesions of erythema multiforme classically demonstrate a dusky red center, surrounded by a zone of pallor, which is in turn surrounded by a peripheral erythematous ring (picture 3A-C). Patients often have a history of oral or genital herpes simplex virus infection. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".) The dorsal hands and feet are common sites for the nonscaly, erythematous plaques of granuloma annulare (picture 6A-C). (See "Granuloma annulare".)

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Genital ●Erythema multiforme – Erythema multiforme may involve the genitals with either typical target lesions or atypical target lesions that do not include all three color zones (picture 26) (see 'Definition' above). Approximately 20 percent of patients with recurrent erythema multiforme have genital involvement [17]. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".) ●Circinate balanitis – Circinate balanitis associated with reactive arthritis is characterized by serpiginous lesions on the glans penis that may take on an arcuate or annular appearance (picture 27A-B). Conjunctivitis, urethritis, and palmoplantar hyperkeratosis (keratoderma blennorrhagicum) are additional features of reactive arthritis. (See "Reactive arthritis".) ●Annular lichen planus – Annular lichen planus may involve the male genitalia or other body sites (picture 28A-B) [18].

Intertriginous — Intertriginous eruptions localize to the flexures (neck, axilla, inguinal folds, inframammary folds, and gluteal cleft). ●Annular lichenoid dermatitis of youth – Annular lichenoid dermatitis of youth typically features smooth, annular, red plaques on the groin or flanks in young people. The histopathology reveals a lichenoid infiltrate with apoptotic cells in the tips of the rete ridges with a polyclonal infiltrate [19]. ●Subcorneal pustular dermatosis – Subcorneal pustular dermatosis is characterized by asymptomatic, chronic, recurrent crops of small pustules in annular, arcuate, or serpiginous configurations in intertriginous regions. (See "Subcorneal pustular dermatosis".) ●Interstitial granulomatous dermatitis – Interstitial granulomatous dermatitis (IGD) is a granuloma annulare-like disorder associated with systemic disease, such as autoimmune diseases, infections, and malignancy. Classically, IGD is characterized by linear, "cord-like" eruptions on the trunk. Other variants are recognized, including an annular form that may occur on the proximal limbs or intertriginous areas [20].

FEBRILE PATIENTS

Several diagnoses should be considered in

febrile patients with annular skin lesions. ●Acute febrile neutrophilic dermatosis (Sweet syndrome) – Patients with acute febrile neutrophilic dermatosis present with an abrupt onset of red, well-demarcated, tender, and often annular plaques accompanied by fever and leukocytosis (picture 29A-B). The cutaneous lesions often demonstrate an edematous, almost vesicular (pseudovesicular) appearance, and are typically located on the upper body. Associated factors include inflammatory bowel disease, malignancy, infections, and medications [21]. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)

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●Serum sickness-like reaction –Patients with serum sickness-like reactions frequently present with fever. (See 'Expanding lesions' above.) The possibility of the following disorders also should be considered in febrile children: ●Acute hemorrhagic edema of infancy – This disorder presents as annular purpuric edematous plaques in young children (picture 14). (See 'Purpura' above.) ●Kawasaki disease – Kawasaki disease is a self-limited vasculitis of childhood that presents with fever, conjunctivitis, mucositis, acral edema, lymphadenopathy, and an exanthematous skin eruption. Occasionally, the cutaneous eruption of Kawasaki disease manifests as an annular or targetoid eruption (picture 30) [22]. (See "Kawasaki disease: Clinical features and diagnosis".) ●CANDLE syndrome – Chronic atypical neutrophilic disorder with lipodystrophy and elevated temperature (CANDLE) syndrome is an autoinflammatory disorder due to mutations in PSMB8. Patients typically present with early-onset fever and generalized, annular violaceous plaques as well as other systemic findings associated with chronic inflammation [23]. (See "Periodic fever syndromes and other autoinflammatory diseases: An overview", section on 'Chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature'.)

DIAGNOSTIC TESTS

If after a careful history (including a

thorough chronologic drug history) and physical examination, the diagnosis of an annular skin eruption remains unclear, select diagnostic studies may be helpful (table 1). As noted above, circling lesions with a pen or marker can be useful for identifying the migratory nature of certain disorders. (See 'Migratory lesions' above.) Examples of scenarios in which additional studies can be of value are below: ●Scaly annular eruption – Potassium hydroxide preparation (KOH) is instrumental in diagnosing or ruling out tinea corporis (picture 31). (See "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.) ●Photodistributed annular eruption – Antinuclear antibody (ANA) testing and skin biopsy can be useful for confirming a diagnosis of cutaneous lupus erythematosus. (See "Overview of cutaneous lupus erythematosus".) ●Target or atypical target lesions – Herpes simplex virus (HSV) is a common trigger of erythema multiforme. If lesions suspicious for active HSV infection are present in a patient with erythema multiforme, the performance of Tzanck smears, direct fluorescent antibody preparations, viral cultures, or PCR studies on specimens taken from the site of suspected HSV infection may be used to confirm the presence of the virus. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Diagnosis'.)

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●Migratory, serpiginous eruption – In patients with symptoms or signs suggestive for rheumatic fever, throat cultures, rapid streptococcal antigen tests, and antistreptolysin O antibody titers are confirmatory tests for streptococcal pharyngitis, the most common inciting factor for acute rheumatic fever. (See "Acute rheumatic fever: Clinical manifestations and diagnosis", section on 'Diagnosis'.) Other laboratory tests may be performed based upon suspicion of the underlying disorder.

Skin biopsy — Skin biopsy is always an option when the diagnosis is uncertain. It is most useful when the disorders being considered have different histopathologic findings (table 1). A 4 mm punch biopsy from the active edge of an annular lesion is generally preferred over a shave biopsy, as it allows for evaluation of the full thickness of the epidermis and dermis. (See "Skin biopsy techniques", section on 'Punch biopsy'.)

EMPIRICAL DIAGNOSIS OF TINEA CORPORIS

If performing a KOH is not feasible prior to treatment in a patient who

presents with lesions suspicious for tinea corporis, empirical therapy with a topical antifungal agent with activity against dermatophytes (eg, azole antifungals, ciclopirox, or terbinafine) is reasonable, due to the relatively high prevalence of tinea corporis and the low risk for adverse effects of topical agents. Combination products containing antifungal agents and potent corticosteroids (eg, betamethasone dipropionate with clotrimazole, Lotrisone) should be avoided, as the corticosteroid component may exacerbate tinea and cause cutaneous atrophy. A recurrence or a failure of presumed tinea corporis to resolve after treatment may indicate inadequate treatment, reinfection (from autoinoculation or an external source), or an incorrect diagnosis. (See "Dermatophyte (tinea) infections", section on 'Tinea corporis'.)

INDICATIONS FOR REFERRAL

Urgent

dermatologic consultation should be performed if the underlying diagnosis is uncertain in systemically ill patients with inflammatory annular lesions. The acute illness or an underlying systemic disorder may be associated with significant morbidity (eg, immunoglobulin A vasculitis [Henoch-Schönlein purpura], acute rheumatic fever, systemic lupus erythematosus, etc). Infants with annular eruptions should have prompt dermatology referral because of the potential for morbidity even in the absence of obvious signs of systemic illness. As examples, untreated neonatal lupus and immunoglobulin A vasculitis (Henoch-Schönlein purpura) may have serious long-term sequelae.

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INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topic (see "Patient education: Granuloma annulare (The Basics)")

SUMMARY AND RECOMMENDATIONS ●Annular skin lesions are characterized by a ring-like morphology. Annular lesions are common in skin disease, and occur in the setting of a variety of disorders (table 1). (See 'Definition' above.) ●The identification of associated clinical features is often useful for the diagnosis of annular lesions. Physical characteristics such as lesion color and the presence or absence of scale, vesicles, or pustules can be quickly assessed. Other factors to consider include the course of lesion progression, lesion location, and associated cutaneous or systemic symptoms. (See 'Patient assessment' above.) ●If the diagnosis remains uncertain after the patient history and physical examination, diagnostic studies such as potassium hydroxide (KOH) preparations to evaluate for tinea corporis, skin biopsies, and select laboratory studies based upon clinical suspicion of the underlying diagnosis can be useful. (See 'Diagnostic tests' above.) ●Whenever feasible the diagnosis of tinea corporis should be confirmed with a KOH preparation prior to treatment. If it is not possible to perform a KOH preparation, empirical treatment with a topical antifungal agent may be prescribed. Combined antifungal and potent corticosteroid agents should not be used. (See 'Empirical diagnosis of tinea corporis' above.) ●Serious systemic disorders may present with inflammatory annular lesions. Urgent dermatologic consultation should be obtained if the diagnosis remains uncertain in patients who are systemically ill. (See 'Indications for referral' above.)

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Approach to the patient with cutaneous blisters uptodate.com/contents/approach-to-the-patient-with-cutaneous-blisters/print

Approach to the patient with cutaneous blisters Authors: Christopher Hull, MD John J Zone, MD Section Editor: Erik Stratman, MD Deputy Editor: Abena O Ofori, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jul 30, 2019.

INTRODUCTION

Cutaneous blisters occur in a wide variety of clinical

settings, including autoimmune disorders, drug reactions, infections, genetic disorders, and physical injury. The ability to narrow the differential diagnosis for patients with blistering skin lesions is essential for the prompt recognition of life-threatening disorders and the appropriate management of other blistering diseases (algorithm 1). The clinical approach to the diagnosis of disorders that present with cutaneous blisters and a summary of common investigative tests used to assist with diagnosis is discussed here. Blistering disorders in the newborn infant and specific blistering disorders are discussed in greater detail separately. (See "Vesicular, pustular, and bullous lesions in the newborn and infant".)

DEFINITION

Blistering skin disorders are characterized by the presence of fluid-

filled lesions on the skin that occur as a result of a loss of adhesion between cells within the epidermis (acantholysis), edema between epidermal cells (spongiosis), or disassociation of the epidermis and dermis. Pathologic events that may lead to the formation of blisters include the following: ●Disruption of cellular or extracellular adhesion molecules (eg, autoimmune blistering disorders, congenital epidermolysis bullosa) ●Epidermal cell injury or death (eg, toxic epidermal necrolysis, erythema multiforme) ●Accumulation of excessive edema (spongiosis) within the epidermis (eg, contact dermatitis, acute and chronic vesicular palmoplantar dermatitis)

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●Traumatic injury (eg, friction or coma blisters) Specific terms are used to describe cutaneous blisters based upon lesion size. Vesicles are usually designated as lesions that are less than 1 cm in diameter (picture 1A). In contrast, bullae are classified as lesions that are greater than 1 cm in size (picture 2). The watery clear fluid content of vesicles and bullae distinguishes these lesions from pustules, which contain thicker, yellow-white purulent material (see "Approach to the patient with pustular skin lesions"). Although the clear fluid contents of vesicles and bullae may develop a more turbid quality over time, the watery quality is retained and such lesions are still easily distinguished from pustules. In cases in which blister formation is associated with damage to the blood vessels in the dermis, red blood cells may enter the blister cavity, resulting in red-colored blister fluid. The term "hemorrhagic blister" is used to refer to such lesions. Blisters may occur at a variety of histologic locations within the skin. The location in which blisters form is often useful for diagnosis and can be determined via histopathologic examination (table 1). The general categories used to describe the location of blister formation include [1]: ●Intracorneal or subcorneal – Cleavage plane within the stratum corneum or immediately beneath the stratum corneum (eg, pemphigus foliaceus, staphylococcal scalded skin syndrome) (picture 3) ●Intraepidermal – Cleavage plane within the malpighian layer of the epidermis, excluding subcorneal and suprabasilar disorders (eg, contact dermatitis, viral infections) (picture 4A-B) ●Suprabasilar – Cleavage plane within the epidermis with only an intact basal layer (picture 5A) (eg, pemphigus vulgaris, paraneoplastic pemphigus) ●Subepidermal – Cleavage plane within or below the basement membrane zone (picture 5B) (eg, bullous pemphigoid, porphyria cutanea tarda) The clinical features of a blistering disorder often correlate with the histopathologic subtype. Whereas subcorneal blistering disorders tend to present with extremely fragile blisters that quickly evolve to scale, erosions, and desquamation, slightly less fragile flaccid vesicles or bullae are characteristic of intraepidermal or suprabasilar blisters. Lastly, tense bullae are typically seen in subepidermal blistering disorders due to the relatively greater proportion of epidermis overlying the blister cavity.

LIFE-THREATENING EMERGENCIES

Several blistering disorders represent potentially life-

threatening emergencies, warranting the need for early diagnosis and therapy. These include:

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●Toxic epidermal necrolysis – Widespread sloughing of skin and severe mucositis in this disorder are associated with risk for sepsis (picture 6A-C). (See 'Generalized blisters with systemic illness' below.) ●Staphylococcal scalded skin syndrome – A high mortality rate occurs in adults with this disorder (picture 7A-B). (See 'Generalized blisters with systemic illness' below.) ●Disseminated herpes simplex or herpes zoster infection in immunocompromised patients – May result in life-threatening internal complications (picture 8). (See 'Generalized blisters with systemic illness' below.) ●Purpura fulminans – Although retiform purpura are the primary feature of purpura fulminans, associated necrotic bullae may also be present (picture 9). (See "Approach to the patient with retiform (angulated) purpura", section on 'Recognition of life-threatening emergencies'.)

PATIENT ASSESSMENT

Blistering skin lesions can present

a diagnostic challenge since the differential diagnosis is vast. The recognition of the distribution of the lesions is a useful clinical tool to begin to narrow the differential diagnosis (algorithm 1). A thorough patient history, the identification of additional clinical features, and pathologic and laboratory studies are often of additional value. Examples of questions that may be useful during the assessment of the patient with cutaneous blisters include: ●Where are the lesions located (generalized, localized, specific sites)? ●Are mucous membranes involved? ●What is the size and configuration of blisters? ●If bullae are present, are they flaccid or tense? ●What is the patient's age? ●Does the patient have a history of exposure to a new medication?

Lesion distribution — The identification of cutaneous blisters as generalized, localized, or associated with mucous membrane involvement can offer valuable clues for diagnosis (table 2A-C).

Generalized distribution

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Generalized blisters with systemic illness — Acute or chronic signs or symptoms of systemic illness are frequent features of several disorders that present with generalized blisters. ●Stevens-Johnson syndrome and toxic epidermal necrolysis – Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) are acute, severe disorders characterized by epidermal sloughing of the skin and mucous membranes. These conditions most commonly occur as a result of exposure to an inciting medication [2]. Following a brief prodromal period of fever and flu-like symptoms, patients develop painful erythematous and purpuric macules or areas of diffuse macular erythema that progress to vesicles, bullae, and skin sloughing (picture 6A-D). The extent of body surface area involvement differentiates Stevens-Johnson syndrome (30 percent). Skin biopsies of fully developed lesions demonstrate epidermal-dermal separation and fullthickness epidermal necrosis. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".) ●Staphylococcal scalded skin syndrome – Staphylococcal scalded syndrome occurs as a reaction to toxin released by Staphylococcus aureus, and most commonly occurs in infants, young children, and adults with renal failure [3]. Fever, malaise, and skin tenderness typically precede the eruption. The fragile subcorneal bullae often demonstrate the appearance of wrinkled skin with subsequent desquamation (picture 7A-C). Examination of a frozen tissue specimen of sloughed epidermis can be used to rapidly distinguish staphylococcal scalded skin from the epidermal sloughing of toxic epidermal necrolysis. Frozen sections taken from staphylococcal scalded skin syndrome demonstrate cleavage at the granular layer, whereas full-thickness epidermal necrosis and cleavage at the dermal-epidermal junction characterize toxic epidermal necrolysis. The site of the primary staphylococcal infection also should be identified. (See "Staphylococcal scalded skin syndrome".) ●Varicella zoster virus infection – Varicella (chicken pox) is a disorder that most frequently occurs in children who are not vaccinated against the disease. Patients experience a prodrome of fever and malaise followed by the development of a generalized eruption of 1 to 3 mm intraepidermal or subepidermal vesicles surrounded by erythema. These lesions are often described as "dew drops on a rose petal," and subsequently evolve to form pustules and crusts (picture 1A-B). (See "Clinical features of varicella-zoster virus infection: Chickenpox".) ●Disseminated herpes zoster – Disseminated herpes zoster can occur in immunocompromised patients. Unlike classic herpes zoster, the vesicular lesions are not restricted to a dermatome (picture 8). Disseminated herpes zoster may also result in life-threatening infection including pneumonia, hepatitis, encephalitis, or other organ involvement. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Special considerations in immunocompromised hosts'.) ●Disseminated herpes simplex virus –Immunocompromised patients and patients with a compromised skin barrier (eg, atopic dermatitis, Darier disease) may develop widespread vesicles, pustules, and crusts due to herpes simplex virus infection. The term eczema herpeticum is used to

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describe this occurrence in patients with atopic dermatitis (picture 10A-B). (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection".) ●Sweet syndrome (acute febrile neutrophilic dermatosis) –Although edematous, erythematous plaques with a pseudovesicular quality are most characteristic of Sweet syndrome, the plaques occasionally exhibit frank vesicle or bulla formation (picture 11A-B). The plaques are most frequently found on the upper body; fever and leukocytosis are also typically present. Sweet syndrome may occur in the setting of malignancy, infection, drug exposure, autoimmune disease, or inflammatory bowel disease. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".) ●Bullous systemic lupus erythematosus – Bullous systemic lupus erythematosus presents as widespread, tense, subepidermal bullae in patients with systemic lupus erythematosus. The skin lesions may resemble bullous pemphigoid or dermatitis herpetiformis (picture 12) [4]. Antibodies against type VII collagen have been associated with this disease. (See "Bullous systemic lupus erythematosus".) ●Paraneoplastic pemphigus – Paraneoplastic pemphigus is an uncommon mucocutaneous suprabasilar or subepidermal blistering disorder that occurs in the setting of malignancy. Stomatitis is characteristically severe (picture 13), but the morphology of skin lesions is variable [5]. In some cases, the skin lesions may resemble blisters of pemphigus vulgaris or erythema multiforme (picture 14A-B). Non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Castleman's disease are the conditions most commonly associated with this disorder [5]. Serologic testing reveals reactivity with multiple antigens, including desmoplakins, desmogleins, and bullous pemphigoid antigen 1 (BPAg1, BP230) [6,7]. (See "Paraneoplastic pemphigus".)

Other generalized blistering disorders — Examples of generalized blistering disorders that are not necessarily associated with systemic illness are listed below. ●Miliaria crystallina –Miliaria crystallina results from the obstruction of the ducts of eccrine sweat glands and usually occurs in the setting of excessive warmth. The fragile intracorneal or subcorneal 1 mm vesicles typically occur on the face and trunk (picture 15). (See "Miliaria".) ●Bullous impetigo –Subcorneal vesicles and bullae containing clear or yellow fluid on the face, trunk, perineum, or extremities characterize bullous impetigo, a disorder that most frequently occurs in neonates and children (picture 16). The bullae rupture easily, leaving erosions with a collarette of scale. (See "Impetigo", section on 'Bullous impetigo'.) ●Pemphigus – The formation of flaccid bullae that quickly evolve to erosions are typical of pemphigus vulgaris (picture 17) [8]. Mucous membrane vesicles and erosions are a frequent associated finding (picture 18A-B). The level of blister formation in pemphigus vulgaris is suprabasilar. By contrast, the most prominent feature of pemphigus foliaceus, a subcorneal blistering disorder, is erythematous plaques with overlying scale or crust (picture 19A-B). These patients do not develop mucosal blisters. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)

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●Bullous pemphigoid – Bullous pemphigoid is a subepidermal blistering disorder that most commonly occurs in older adults (picture 20A-B) [9]. The classic skin lesions are urticarial plaques and tense bullae on the trunk and extremities. Intense pruritus is common, and lesions typically do not scar. Localized forms of bullous pemphigoid may also occur [10]. Bullous pemphigoid patients may also develop mucosal involvement. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".) ●Pemphigoid gestationis – Pemphigoid gestationis is a subepidermal blistering disorder that occurs during pregnancy or in the immediate postpartum period. Urticarial plaques and vesicles typically begin around the umbilicus prior to spreading elsewhere with large bulla formation (picture 21A-C). (See "Dermatoses of pregnancy", section on 'Pemphigoid gestationis'.) ●Linear IgA bullous dermatosis – Linear IgA bullous dermatosis is a subepidermal blistering disorder associated with the deposition of IgA at the basement membrane zone of skin and mucosal tissues [11]. This disorder may occur as a primary autoimmune disease or as a drug reaction. The cutaneous bullae often have a distinctive grouped appearance that resembles a cluster of jewels (picture 22). The term chronic bullous disease of childhood is used to refer to this disorder in children. (See "Linear IgA bullous dermatosis".) ●Dermatitis herpetiformis – Dermatitis herpetiformis is a cutaneous manifestation of gluten sensitivity that presents with grouped vesicles and excoriated papules with a predilection for the extensor extremities, scalp, and buttocks (picture 23) [12,13]. The lesions of this subepidermal blistering disorder are intensely pruritic. (See "Dermatitis herpetiformis".) ●Epidermolysis bullosa – Congenital epidermolysis bullosa is a rare genetic disorder that consists of multiple variants. Depending on the type of epidermolysis bullosa, lesions may be intraepidermal or subepidermal, localized or generalized, and detected as early as birth or not until adulthood (picture 24). (See "Epidemiology, pathogenesis, classification, and clinical features of epidermolysis bullosa".) ●Epidermolysis bullosa acquisita – Epidermolysis bullosa acquisita is a rare, acquired subepidermal blistering disorder that may affect both skin and mucous membranes (picture 25). Tense bullae, scarring, and milia formation are common associated features. Antibodies against type VII collagen are pathogenic in this disease and can be measured in serum [14]. (See "Epidermolysis bullosa acquisita".)

Localized distribution — The recognition that blisters are primarily located in certain body locations, such as dependent areas, acral areas, or sun-exposed skin may assist with diagnosis (table 2B and algorithm 1). In addition, a linear distribution of skin lesions suggests the possibility of an external insult as the cause of blistering.

Dependent areas

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●Coma blisters – Coma blisters are tense, subepidermal bullae that have been reported to occur in sites of pressure in comatose patients. These lesions have been associated with exposure to drugs (eg, opiates, tricyclic antidepressants, antipsychotics) and a variety of medical conditions, such as chronic renal failure, diabetic ketoacidosis, hyperparathyroidism, and neurologic disease [15]. Erythematous or ecchymotic patches or plaques may precede the development of bullous lesions. The blisters spontaneously resolve within two to four weeks [15]. ●Bullous disease of diabetes (bullosis diabeticorum) – Bullous disease of diabetes is a term used to describe the abrupt development of noninflammatory, tense, subepidermal bullae in patients with diabetes in sites of otherwise normal-appearing skin (picture 2) [16]. Lesions most commonly occur on the feet or lower legs and may be up to several centimeters in diameter. The bullae spontaneously resolve over the course of a few weeks. The term bullous diabeticorum has also been used to refer to this disorder. ●Bullous leukocytoclastic vasculitis –Hemorrhagic vesicles or bullae may occur among the purpuric macules, papules, or plaques of cutaneous leukocytoclastic vasculitis (picture 26). Necrosis of the skin overlying areas of small vessel vasculitis leads to the development of these subepidermal bullous lesions. (See "Evaluation of adults with cutaneous lesions of vasculitis".) ●Edema (stasis) blisters – Bullae may form in areas of edema. These asymptomatic lesions often occur on the lower legs and resolve upon resolution of the cause of edema (picture 27) [15]. There is little published information on edema blisters, and it is not definitively known whether the majority of these blisters are subepidermal or intraepidermal. (See "Stasis dermatitis", section on 'Clinical presentation'.)

Hands or feet ●Acute palmoplantar (dyshidrotic) eczema – Intensely pruritic vesicles or bullae on the hands or feet are consistent with this disorder (picture 28A-B). The palms, soles, and sides of the digits are typical sites for involvement. Spongiotic intraepidermal vesicles are present on histopathologic examination. (See "Acute palmoplantar eczema (dyshidrotic eczema)".) ●Dermatophytosis –Blistering tinea pedis is most often associated with Trichophyton mentagrophytes or Epidermophyton floccosum infection [17]. The associated intraepidermal spongiotic vesicles and bullae are often present on the soles or between the toes (picture 29). In addition, dermatophytid reactions (autoeczematization or id reactions that occur in the setting of dermatophyte infection) may result in vesicular eruptions on the hands (picture 30). (See "Dermatophyte (tinea) infections", section on 'Tinea pedis' and "Dermatophyte (tinea) infections", section on 'Dermatophytid (id) reactions'.) ●Friction blister –Friction blisters are intraepidermal blisters that result from trauma-induced separation within the epidermis. They most frequently occur on the heels and soles of the feet due to friction from shoes during walking or running. The possibility of epidermolysis bullosa simplex should be considered in patients with frequent and excessive blistering. (See "Friction blisters".)

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●Sucking blisters – Blisters on the hands or feet due to intrauterine sucking may be detected in neonates (picture 31A-B). ●Erythema multiforme – The acral extremities are a site of predilection for lesions of erythema multiforme, a disorder that most commonly occurs in association with herpes simplex virus infection. The classic dusky erythematous target lesions of erythema multiforme may exhibit a central subepidermal blister (picture 32). Mucosal involvement is also frequently present (picture 33A-B). (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.) ●Localized epidermolysis bullosa simplex – Localized epidermolysis bullosa simplex (formerly known as the Weber-Cockayne variant of epidermolysis bullosa simplex) is a rare autosomal dominant genetic disorder in which intraepidermal blisters form in sites of friction or trauma. The hands and feet are frequently affected (picture 34A-B). (See "Epidemiology, pathogenesis, classification, and clinical features of epidermolysis bullosa", section on 'EBS, localized'.)

Photodistributed ●Polymorphous light eruption – Polymorphous light eruption is a fairly common disorder that usually develops within hours of sun exposure. Although the most common manifestations are pruritic erythematous papules or plaques, vesicles or bullae may also occur as a manifestation of extensive dermal edema (picture 35). (See "Polymorphous light eruption".) ●Porphyria cutanea tarda – Photosensitivity is a key feature of porphyria cutanea tarda, an inherited or acquired metabolic disorder that may present with the formation of predominantly noninflammatory vesicles and bullae (picture 36A-B). Sun-exposed areas are typically affected. The dorsal hands and forearms are common sites of involvement, and crusts, scars, and milia are often present. Other cutaneous features of porphyria cutanea tarda include hyperpigmentation, hypertrichosis, and localized sclerodermoid plaques [18]. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical features'.) ●Pseudoporphyria – Although pseudoporphyria presents with clinical and histopathologic features that resemble porphyria cutanea tarda, abnormalities of porphyrin metabolism are absent. Like porphyria cutanea tarda, subepidermal bullae, crusts, and scarring on the dorsal hands are common clinical findings (picture 37). A number of medications have been associated with this condition [19]. (See "Pseudoporphyria".) ●Sunburn and phototoxic reactions –Severe sunburns can result in blister formation on the skin (picture 38). Phototoxic eruptions, which usually occur due to sun exposure after ingestion of a photosensitizing drug, resemble sunburns and can also present with blistering. (See "Sunburn" and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)

Dermatomal

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●Herpes zoster – Herpes zoster (shingles) presents with a grouped eruption of painful intraepidermal vesicles in a dermatomal distribution (picture 39A-B). In immunocompromised patients, disseminated lesions may occur. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)

Linear distribution ●Contact dermatitis – Intensely pruritic dermatitis and intraepidermal spongiotic bullae often develop in patients with severe contact dermatitis, such as can occur after exposure to poison ivy (picture 40). Lesions develop in sites of contact of the inciting substance with the skin. A linear distribution is common. (See "Clinical features and diagnosis of allergic contact dermatitis".) ●Phytophotodermatitis –Erythema, edema, and vesiculation occurring in a linear or odd configuration may develop after topical exposure to certain of plant-derived substances (eg, lemons, limes, celery, wild parsnip, or parsley) followed by sun exposure (picture 41A-B) [20]. The term "berloque dermatitis" has been used to refer to lesions secondary to natural oil of bergamot in products used on the skin. Significant postinflammatory hyperpigmentation after resolution of the acute process is common. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phytophotodermatitis'.)

Other localized blistering disorders ●Herpes simplex virus – A localized eruption composed of grouped, small, often umbilicated vesicles or vesicopustules is characteristic of herpes simplex virus infection (picture 42A-B). The lips, genitals, and buttocks are common sites of involvement. Primary infections tend to be most severe and can be accompanied by lymphadenopathy and flu-like symptoms. Extensive lesions may occur in patients with atopic dermatitis, a condition referred to as eczema herpeticum (also referred to as Kaposi's varicelliform eruption). (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection" and "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection".) ●Bullous arthropod bite – Occasionally, vesicles and bullae occur at sites of arthropod bites (picture 43A-B). (See "Insect and other arthropod bites".) ●Fixed drug eruption –Central bullae may appear in lesions of fixed drug eruptions, which present as single or multiple dusky erythematous to violaceous round plaques (picture 44). The lips, genitalia, face, and acral areas are common sites of involvement. The lesions tend to heal with significant postinflammatory hyperpigmentation and typically recur in the same sites with subsequent drug exposure. (See "Fixed drug eruption".) ●Transient acantholytic dermatosis (Grover's disease) –Transient acantholytic dermatosis is a disorder that is most commonly detected in middle-aged Caucasian men. Pruritic, erythematous papules and papulovesicles are typically localized to the trunk (picture 45). Acantholysis and dyskeratosis are evident on histopathologic examination of papulovesicular lesions. (See "Grover's disease (transient and persistent acantholytic dermatosis)".)

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●Hailey-Hailey disease – Hailey-Hailey disease is an uncommon genetic disorder that presents with fragile acantholytic blisters that quickly evolve to erosions that are primarily localized to the neck and intertriginous areas (picture 46A-C). Erythematous vegetative plaques develop in involved areas as the disease progresses. (See "Hailey-Hailey disease (benign familial pemphigus)".) ●Bullous pyoderma gangrenosum –Atypical variants of pyoderma gangrenosum may present with subepidermal bullae in conjunction with superficial ulcers (picture 47). (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.)

Mucous membrane involvement — Many blistering eruptions may also have mucosal involvement. When blistering disorders involve the mucous membranes, frank vesicles and bullae often are not seen. Rather, mucosal inflammation or erosions tend to be the predominant clinical finding. The following disorders are examples of blistering diseases that may present with both cutaneous and mucosal findings (table 2C): ●Mucous membrane pemphigoid –Mucous membrane pemphigoid (MMP) is defined as a diverse group of blistering disorders characterized by mucous membranes as the primary site of involvement. Inflamed, eroded, or scarred mucosa may be present (picture 48A-E). Cutaneous blisters accompany the mucosal lesions in some patients. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".) ●Pemphigus vulgaris (see 'Other generalized blistering disorders' above) ●Paraneoplastic pemphigus (see 'Generalized blisters with systemic illness' above) ●Bullous pemphigoid (see 'Other generalized blistering disorders' above) ●Linear IgA bullous dermatosis (see 'Other generalized blistering disorders' above) ●Epidermolysis bullosa acquisita (see 'Other generalized blistering disorders' above) ●Erythema multiforme (see 'Hands or feet' above) ●Stevens-Johnson syndrome and toxic epidermolytic necrolysis (see 'Generalized blisters with systemic illness' above) ●Herpes simplex virus infection (see 'Other localized blistering disorders' above)

Additional clinical features — In addition to the recognition of the distribution of cutaneous blisters, knowledge of the patient's age, blister characteristics, and the patient's drug history may help to narrow the differential diagnosis.

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Patient age — Although patient age cannot be used to definitively exclude most blistering disorders, this information may provide additional clues for diagnosis. ●Neonates – In neonates, blistering lesions can occur due to intrauterine or postpartum exposure to infections or trauma, congenital disorders, miliaria crystallina, or other disorders. The differential diagnosis for neonates with cutaneous blisters is reviewed separately. (See "Vesicular, pustular, and bullous lesions in the newborn and infant".) ●Young children – Disorders such as bullous impetigo and staphylococcal scalded skin occur with greater frequency in infants and young children than in other age populations. ●Older adults – Pemphigus and pemphigoid occur with greater frequency in older adults than in younger individuals.

Blister configuration — Grouped blisters are characteristic of herpes simplex virus infection (picture 39A), herpes zoster (picture 39B), dermatitis herpetiformis (picture 23), and linear IgA bullous dermatosis. An annular configuration is often present in linear IgA bullous dermatosis (picture 22) and a linear arrangement of bullous lesions suggests the possibility of contact dermatitis or phytophotodermatitis.

Blister size — Small vesicles are the primary lesions in miliaria crystallina, acute palmoplantar eczema, herpes simplex virus or varicella zoster virus infection, and dermatitis herpetiformis.

Blister quality — Tense blisters are a characteristic feature of subepidermal blistering disorders, such as bullous pemphigoid, pemphigoid gestationis, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, and porphyria cutanea tarda. More flaccid blisters are typically seen in conditions in which the level of bulla formation is more superficial.

History of drug exposure — Drug exposure is frequently associated with fixed drug eruptions, pseudoporphyria, Stevens-Johnson syndrome, toxic epidermal necrolysis, and linear IgA dermatosis (table 3). Occasionally, erythema multiforme, pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, and mucous membrane pemphigoid are linked to an inciting pharmacologic agent.

Nikolsky sign — The Nikolsky (or Nikolskiy) sign is a clinical finding that describes the elicitation of skin blistering as a result of gentle mechanical pressure on the skin. Depending on the clinical scenario, a positive Nikolsky sign may be observed at the edge of an existing lesion, in an area of normal-appearing skin, or in both locations [21].

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The Nikolsky sign is often cited as a feature of the acantholytic, suprabasilar blistering disorder pemphigus vulgaris; however, the absence of this finding does not rule out this diagnosis. In addition, the Nikolsky sign has been detected in multiple blistering diseases with divergent modes of blister formation and levels of blister cleavage, including among them toxic epidermal necrolysis, staphylococcal scalded skin syndrome, and a subset of patients with bullous pemphigoid [21]. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Clinical features'.)

DIAGNOSTIC TESTS

Many blistering disorders share clinical

features, and diagnostic tests are essential in differentiating these conditions and making an accurate diagnosis. The principle tests utilized in the evaluation of blistering diseases include light microscopy, direct immunofluorescence, indirect immunofluorescence, antigen-specific serologic testing, and microbiologic studies. The selection of the most appropriate studies to order is patientspecific and based upon the suspected diagnoses.

Skin biopsy — A skin biopsy with or without direct immunofluorescence studies is often the first step in the evaluation of patients with an unknown skin blistering disorder.

Light microscopy — Examination of a skin biopsy with light microscopy is useful for identifying the histopathologic features that characterize specific disorders. Light microscopy can detect the level of blister formation, the type of inflammatory cell infiltrate, the presence of dyskeratotic cells, and histopathologic features suggestive of infection (picture 5A-B). Specimens for light microscopic examination are usually obtained from lesional tissue. If small vesicles are present, removal of an entire lesion is preferred. For larger lesions, the specimen should be obtained from the edge of a blister; the specimen should contain both portions of the blister and intact skin. Punch biopsies are most frequently utilized for the evaluation of blistering lesions, as they allow for evaluation of the full thickness of the epidermis and dermis, which can be useful in cases in which dermal findings may offer additional clues for diagnosis. A deep shave biopsy that extends into the reticular dermis can also be utilized, but may result in a larger, scoop-like scar. Specimens for light microscopy can be placed in formalin for preservation. (See "Skin biopsy techniques", section on 'Punch biopsy' and "Skin biopsy techniques", section on 'Shave biopsy'.)

Direct immunofluorescence — Direct immunofluorescence is a technique that allows for the detection of antibody or complement deposition within the skin. Direct immunofluorescence studies are typically utilized when an autoimmune blistering disorder is suspected. The recognition of the pattern and location of antibody binding can offer valuable insight for diagnosis. For example, intercellular antibody deposition in the epidermis characterizes pemphigus vulgaris and pemphigus foliaceus, whereas linear antibody deposition along the basement membrane zone is detected in bullous pemphigoid (picture 49A-C).

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The specimen should be taken from normal-appearing skin adjacent to the blister, which is referred to as a perilesional biopsy. A biopsy of lesional skin is more likely to result in false negative results because of destruction of the immunoreactants by the inflammatory process. Tissue obtained for direct immunofluorescence should not be placed in formalin; rather, Michel's medium or Zeus medium can be used for preservation. Fresh specimens also may be sent to the laboratory, provided they are kept moist with saline, and processing within 24 hours is feasible. The basic procedure for direct immunofluorescence is as follows [22]: ●Cut sections from the specimen are placed on microscope slides ●A solution containing antisera against IgG, IgA, IgM, complement factor C3, and fibrinogen conjugated to fluorescent dye is incubated with the sections ●The sections are subsequently washed and mounted for examination utilizing an epifluorescence microscope

Serologic tests — Indirect immunofluorescence studies and antigen-specific serologic testing may be useful for the evaluation of autoimmune blistering disorders.

Indirect immunofluorescence — Indirect immunofluorescence can be used to detect antibodies within the circulation. In this technique, the presence of antibodies in the patient's serum that are capable of binding to components of an epithelial specimen that is not from the patient is assessed (picture 50). Similar to direct immunofluorescence, this test is typically utilized to aid in the diagnosis of autoimmune blistering disease. The basic procedure for indirect immunofluorescence is as follows [22]: ●Blood is drawn from the patients and centrifuged to separate serum ●The selected substrate (eg, monkey esophagus, guinea pig esophagus, rat bladder, or human skin depending upon the suspected diagnosis) is incubated with progressive dilutions of patient serum ●The tissue is incubated with antibodies conjugated to a fluorescent dye that are directed against the antibodies bound to the substrate ●The slides are washed, mounted, and examined utilizing an epifluorescent microscope ●Results are reported as the limiting dilution in which specific fluorescence is detected

Antigen-specific serologic testing — If the target of circulating antibodies associated with specific autoimmune blistering diseases is known, antigen-specific testing can be used to detect the presence of antibodies in serum. Enzyme-linked immunosorbent assay (ELISA) is the most common test utilized and is frequently employed in disorders such as bullous pemphigoid, pemphigoid gestationis, and pemphigus vulgaris. Other antigen-specific

247

serologic tests, such as immunoblotting and immunohistochemistry, have also been utilized for the diagnosis of autoimmune blistering diseases. These tests are more labor-intensive than ELISA, but may be the only way to definitively identify epidermolysis bullosa acquisita and laminin-332 pemphigoid. These disorders may be associated with inflammatory bowel disease or malignancy, respectively.

Basement membrane zone-split skin technique — Tissue specimens with an artificially induced cleavage zone between the epidermis and dermis (known as basement membrane zone-split skin or salt-split skin) are utilized to obtain more precise information on the localization of antibody binding within the basement membrane zone in direct and indirect immunofluorescence studies [22]. Incubation of the skin substrate in a 1 M sodium chloride (NaCl) or ethylenediaminetetraacetic acid (EDTA) solution induces separation at the level of the lamina lucida. The location of antibody binding to the epidermal (roof) or dermal (floor) side of the split can be used to further narrow the differential diagnosis (picture 51). (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Laboratory tests'.)

Microbiologic studies — If infection is suspected, microbiologic tests can be useful for diagnosis. A potassium hydroxide (KOH) preparation is a quick diagnostic test for bullous tinea pedis (picture 52). In addition, bacterial cultures of the blister site may aid in the diagnosis of bullous impetigo, and in staphylococcal scalded skin syndrome, culture of the potential sites of the primary staphylococcal infection can be of value. In patients with suspected herpes simplex virus or varicella zoster virus infection, studies such as Tzanck smear (picture 53), viral culture, polymerase chain reaction, and direct fluorescent antibody testing may be used to confirm a diagnosis. (See "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation' and "Office-based dermatologic diagnostic procedures", section on 'Tzanck smear'.)

INDICATIONS FOR REFERRAL

Referral to a

dermatologist is indicated if an autoimmune blistering disease is suspected, if the cause of blistering is unknown, or if the disease continues to progress despite appropriate treatment. Patients with suspected toxic epidermal necrolysis require immediate transfer to an experienced burn unit. Patients with staphylococcal scalded skin syndrome require hospital admission for intravenous antibiotic therapy. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae" and "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Staphylococcal scalded skin syndrome'.)

INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best

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for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topics (see "Patient education: Blisters (The Basics)")

SUMMARY AND RECOMMENDATIONS ●A wide variety of disorders can result in the formation of blisters on the skin. Autoimmune disorders, drug reactions, infections, genetic disorders, and traumatic injury are among the potential causes of cutaneous blistering. (See 'Introduction' above and 'Definition' above.) ●Cutaneous blisters may occur at various sites within the skin (table 1). Blisters that form within the epidermis tend to be more fragile and flaccid than the tense blisters that are typically associated with subepidermal blistering diseases. (See 'Definition' above.) ●Life-threatening cutaneous blistering disorders include toxic epidermal necrolysis, staphylococcal scalded skin syndrome, disseminated herpes simplex virus infection, disseminated herpes zoster, and purpura fulminans. Identification of these disorders should be prompt to reduce the risk of fatal complications. (See 'Life-threatening emergencies' above.) ●The distribution of cutaneous blisters is often useful for narrowing the differential diagnosis (table 2A-C and algorithm 1). Blistering conditions may be divided in to generalized or localized disorders, and additional features such as the patient's age, blister characteristics, and the patient's drug history may also offer clues for diagnosis (table 3). (See 'Patient assessment' above.) ●Diagnostic tests commonly utilized in the evaluation of blistering skin disorders include light microscopy, direct and indirect immunofluorescence studies, antigen-specific serologic studies, and microbiologic tests. The specific disorders considered in the differential diagnosis determine the selection of the most appropriate test(s). (See 'Diagnostic tests' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 13684 Version 19.0

GRAPHICS

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Approach to the differential diagnosis of cutaneous blisters

HSV: herpes simplex virus; LCV: leukocytoclastic vasculitis; IgA: immunoglobulin A; VZV: varicella zoster virus. Graphic 103314 Version 3.0

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Varicella

A vesicle on an erythematous base is present. Varicella lesions are often described as resembling a "dew drop on a rose petal." Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 72210 Version 3.0

251

Bullous disease of diabetes (bullosis diabeticorum)

A noninflammatory bulla is present on the lower leg in this patient with bullosis diabeticorum. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 57569 Version 6.0 Histopathologic sites of blister formation in blistering disorders

Intracorneal/subcorneal

Intraepidermal

Suprabasilar

Subepidermal

Staphylococcal scalded skin syndrome

Varicella zoster virus infection*

Paraneoplastic pemphigus*

Miliaria crystallina

Herpes simplex virus infection*

Pemphigus vulgaris

StevensJohnson syndrome

Bullous impetigo IgG/IgA pemphigus foliaceus Subcorneal pustular dermatosis

Epidermolysis bullosa simplex Acute palmoplantar (dyshidrotic) eczema Autoeczematization (id) reaction Friction blister

Transient acantholytic dermatosis (Grover's disease) Hailey-Hailey disease Darier's disease

Sweet's syndrome Bullous systemic lupus erythematosus Bullous pemphigoid Pemphigus gestationis Linear IgA

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Polymorphous light eruption Contact dermatitis

Linear IgA bullous dermatosis Dermatitis herpetiformis Junctional epidermolysis bullosa Dystrophic epidermolysis bullosa Epidermolysis bullosa acquisita Coma blister Bullous disease of diabetes Bullous leukocytoclastic vasculitis Erythema multiforme Porphyria cutanea tarda Phototoxic reaction Arthropod bite¶ Fixed drug eruption Bullous pyoderma gangrenosum Mucous membrane pemphigoid

IgG: immunoglobulin G; IgA: immunoglobulin A.

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* May also be subepidermal. ¶ May also be intraepidermal. Graphic 74129 Version 4.0 Pemphigus foliaceus

Blister formation within the superficial granular layer in pemphigus foliaceus. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 57313 Version 4.0

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Allergic contact dermatitis

Epidermal spongiosis and spongiotic vesicles are present in this biopsy taken from a patient with poison ivy. Infiltrating lymphocytes are apparent in the epidermis. Reproduced with permission from: Rubin E, Farber JL. Pathology, 3rd Edition. Philadelphia: Lippincott Williams & Wilkins, 1999. Copyright © 1999 Lippincott Williams & Wilkins. Graphic 82841 Version 2.0

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Varicella

This photomicrograph of the skin from a patient with varicella shows an intraepidermal vesicle. Multinucleated giant cells and nuclear inclusions are present. Reproduced with permission from: Rubin E, Farber JL. Pathology, 3rd Edition. Philadelphia: Lippincott Williams & Wilkins, 1999. Copyright © 1999 Lippincott Williams & Wilkins. Graphic 82840 Version 1.0

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Pemphigus vulgaris

Histology-stained section of a skin biopsy specimen from a blister in a patient with pemphigus vulgaris demonstrates characteristic loss of cohesion between epidermal keratinocytes (acantholysis) above an intact basement membrane zone. Courtesy of Beth G Goldstein, MD, and Adam O Goldstein, MD. Graphic 60749 Version 4.0

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Bullous pemphigoid

This hematoxylin and eosin stain of a skin tissue biopsy specimen from the edge of an established lesion of bullous pemphigoid demonstrates a subepidermal blister with an edematous papillary dermis as its base. The roof of the blister consists of the intact epidermis, including the stratum basalis. Eosinophil-rich inflammatory cells, fibrin, and tissue fluid fill the blister. Reproduced with permission from: Rubin E, Farber JL. Pathology, 3rd ed, Lippincott Williams & Wilkins, Philadelphia 1999. Copyright ©1999 Lippincott Williams & Wilkins. Graphic 66267 Version 4.0

258

Cutaneous changes of Stevens-Johnson syndrome (SJS)

Generalized eruption of lesions that initially had a target-like appearance but then became confluent, brightly erythematous, and bullous. The patient had extensive mucous membrane involvement and tracheobronchitis. Reproduced with permission from: Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. In: Color Atlas and Synopsis of Clinical Dermatology: Common and Serious Diseases, 3rd edition, Fitzpatrick TB, Johnson RA, Wolff K, et al (Eds), McGraw-Hill, New York 1997. Copyright © 1997 McGraw-Hill. Graphic 67632 Version 18.0

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Toxic epidermal necrolysis

Diffuse erythema and large areas of denuded epidermis are present. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 68458 Version 7.0

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Toxic epidermal necrolysis

Multiple bullae and areas of denuded epidermis are present. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 59418 Version 9.0

261

Staphylococcal scalded skin syndrome

A wrinkled appearance to the skin, bullae, and desquamation are present in this patient with staphylococcal scalded skin syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 80198 Version 3.0

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Staphylococcal scalded skin syndrome

Diffuse erythema and desquamation are present in this child with staphylococcal scalded skin syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 72261 Version 6.0

263

Disseminated herpes zoster

The multiple vesicles and crusts of herpes zoster are not limited to a dermatome. Reproduced with permission from: Herbert A Hochman, MD. Originally published in Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd Edition. Philadelphia: Lippincott Williams & Wilkins, 2003. Graphic 77688 Version 1.0

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Purpura fulminans

A large, retiform, purpuric lesion is present on the leg. Purpura fulminans is characterized by the presence of extensive purpura. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 57103 Version 5.0 Examples of generalized cutaneous blistering disorders

Disorder

Clinical features

Pathology

Laboratory findings

Bullous pemphigoid

Tense bullae, urticarial papules and plaques; mucous membrane involvement in up to 30 percent of cases

H&E: subepidermal blister with eosinophils; DIF: linear basement membrane zone deposition of IgG and C3

IIF: IgG anti-BP antigen 180 and 230

Pemphigus vulgaris

Flaccid vesicles and erosions on skin and mucous membranes, desquamative gingivitis; scalp involvement

H&E: intraepidermal blister formation, acantholysis; DIF: intercellular epidermal IgG deposition involving lower epidermis

IIF: intercellular IgG staining of skin substrate, anti-desmoglein 3 IgG

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involvement common Pemphigus foliaceus

Flaccid vesicles and erosions; no mucous membrane involvement

H&E: intraepidermal vesicle and acantholysis (blister is subcorneal); DIF: intercellular IgG deposition in upper epidermis

IIF: intercellular IgG staining of skin substrate; anti-desmoglein 1 IgG

StevensJohnson syndrome and toxic epidermal necrolysis

Exudative erosions of lips, oral mucosa, eyes, genital mucosa; targetoid papulovesicles of skin, skin sloughing, and skin pain

H&E: vacuolar interface dermatitis or epidermal necrosis

None

Paraneoplastic pemphigus

Targetoid papulovesicles, erythema multiforme-like cutaneous lesions; exudative erosions of lips, oral mucosal, eyes, genital mucosa

H&E: mixed histology with overlapping features of pemphigus vulgaris, erythema multiforme, and lichen planus; DIF: staining of transitional epithelium (rodent bladder)

IIF: antibodies to multiple antigens (desmoplakins, desmogleins, bullous pemphigoid antigen 1, etc)

Dermatitis herpetiformis

Grouped papulovesicles on elbows, knees, buttocks, scalp; intense pruritus

H&E: subepidermal blister with neutrophils in dermal papillae; DIF: IgA in dermal papillae

Elevation of serum IgA antiepidermal transglutaminase antibodies

Disseminated HSV/VZV

Fever, hepatitis, CNS involvement; grouped and scattered monomorphic vesicles

Intraepidermal blister; ballooning of keratinocyte cytoplasm and margination of chromatin to form intranuclear inclusion bodies; mixed inflammatory infiltrate

Viral culture, Tzanck smear, DFA, PCR

Linear IgA bullous dermatosis

Annular or arcuate vesicles and bullae; can have mucous membrane involvement

H&E: subepidermal blister with predominance of neutrophils; DIF: linear IgA along basement membrane zone

IIF: circulating IgA antibasement membrane antibodies

Epidermolysis bullosa i i

Tense blisters and erosions with i d ili

H&E: subepidermal blisters with mixed inflammatory i fil f hil

 

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acquisita

scarring and milia

infiltrate of neutrophils, eosinophils, lymphocytes; DIF: broad, linear IgG along the basement membrane zone; in salt-split skin, IgG stains dermal side

Staphylococcal scalded skin syndrome

Widespread erythema, flaccid bullae, erosions, desquamation of skin

H&E: subcorneal blister (split within the granular cell layer)

Toxin-mediated condition; culture often negative at sites of blistering

Bullous systemic lupus erythematosus

Other skin findings of SLE: nail fold telangiectasias, malar erythema, discoid or subacute cutaneous lupus

H&E: similar to dermatitis herpetiformis; DIF: mixed features similar to bullous pemphigoid and lupus

Antinuclear antibody test

H&E: hematoxylin and eosin pathology stain; DIF: direct immunofluorescence; IIF: indirect immunofluorescence; IgG: immunoglobulin G; IgA: immunoglobulin A; HSV: herpes simplex virus; VZV: varicella zoster virus; CNS: central nervous system; DFA: direct fluorescent antibody test; PCR: polymerase chain reaction; SLE: systemic lupus erythematosus. Graphic 60255 Version 2.0 Select examples of localized cutaneous blistering disorders

Disorder

Clinical features

Diagnostic tests

Dermatitis

Linear configuration if contact dermatitis.

H&E: spongiosis

Bullous tinea pedis

Vesicles on soles of feet or between the toes.

KOH examination demonstrating hyphae or positive fungal culture

Fixed drug eruption

Dusky violaceous patch, hemorrhagic bulla; may recur at same location with future drug exposures.

History

Erythema multiforme

Targetoid papules on extremities and acral locations; hemorrhagic vesicles/bullae; intermittent recurrences usually associated with HSV infection.

H&E: vacuolar interface dermatitis; positive confirmation of concurrent HSV outbreak

Friction

Most commonly seen on soles of feet or

History

267

H&E: lichenoid or interface dermatitis

blisters

palms of hands at sites of friction.

Coma blisters

Tense blisters at sites of pressure in comatose patients.

History

Bullous insect bites

Intense pruritus and erythematous papules.

History

Bullous disease of diabetes (bullous diabeticorum)

Tense blisters found predominately on lower extremities. Lack of erythema or inflammation. Rare manifestation of diabetes.

H&E: pauci-inflammatory subepidermal blister

Grover's (transient acantholytic dermatosis)

Keratotic eroded papules and vesicles on the abdomen, chest, back. Male predominance. Often worsens with heat, exercise, hospitalization.

H&E: dyskeratosis and acantholysis

H&E: intraepidermal blister

H&E: subepidermal blister and eccrine gland necrosis

DIF: negative

DIF: negative

H&E: hematoxylin and eosin pathology stain; DIF: direct immunofluorescence; KOH: potassium hydroxide; HSV: herpes simplex virus. Graphic 82490 Version 2.0 Blistering disorders with mucous membrane involvement

Disorder

Associated conditions

Clinical features

Pathology

Laboratory findings

Herpes simplex virus (HSV)

None

Recurrent, grouped vesicles; most commonly found on lips or genitalia

H&E: intraepidermal blister; ballooning of keratinocyte cytoplasm and margination of chromatin to form intranuclear inclusion bodies; mixed inflammatory infiltrate

Viral culture, Tzanck smear, HSV DFA, PCR

268

Erythema multiforme

HSV or Mycoplasma pneumoniae infection, occasionally drug exposure

Mucosal erythema and erosions, most frequently involving oral cavity; target lesions on skin

H&E: vacuolar interface dermatitis, necrotic keratinocytes, subepidermal clefts and vesiculation

HSV testing on active lesions, serology, or biopsy specimen; testing for M. pneumoniae infection

Pemphigus vulgaris

None

Vesicles, erosions and desquamative gingivitis

H&E: intraepidermal vesicle, acantholysis

IIF: intercellular IgG staining of skin substrate, IgG antidesmoglein 3

DIF: intercellular epidermal IgG deposition Mucous membrane pemphigoid*

Reflects a diverse group of subepidermal blistering disorders with mucous membranes as the primary site of involvement

Vesicles and erosions, desquamative gingivitis; can have ocular involvement and symblepharon

H&E: subepidermal blisters; inflammatory infiltrate and DIF findings vary with subtype

IIF: varies with subtype

StevensJohnson syndrome and toxic epidermal necrolysis

Medication, Mycoplasma infection

Exudative erosions of lips, oral mucosa, eyes, genital mucosa; targetoid papulovesicles of skin, skin sloughing, skin pain

H&E: vacuolar interface dermatitis or epidermal necrosis

None

Paraneoplastic pemphigus

Underlying malignancy

Targetoid papulovesicles; erythema multiforme-like cutaneous lesions; exudative

H&E: mixed histology; overlapping features of pemphigus vulgaris, erythema multiforme, and

IIF: intercellular IgG deposition on transitional epithelium (rodent bladder)

269

erosions of lips, oral mucosal, eyes, genital mucosa

lichen planus DIF: intercellular IgG deposition; basement membrane zone IgG deposition also may be present

HSV: herpes simplex virus; H&E: hematoxylin and eosin pathology stain; DFA: direct fluorescent antibody; PCR: polymerase chain reaction; DIF: direct immunofluorescence; IgG: immunoglobulin G; IIF: indirect immunofluorescence. * Skin-predominant forms of bullous pemphigoid, linear IgA bullous dermatosis, and epidermolysis bullosa acquisita may also present with mucosal involvement. Graphic 67630 Version 2.0 Stevens-Johnson syndrome (SJS)

Multiple erosions and crusts are present on the lips of this patient with SJS. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 68682 Version 6.0

270

Staphylococcal scalded skin syndrome

Perioral crusting is present in this child with staphylococcal scalded skin syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 50249 Version 5.0

271

Chickenpox (varicella-zoster infection)

Numerous vesicles, some of which are hemorrhagic, on the face of a child with chickenpox. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 94664 Version 3.0

272

Eczema herpeticum Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 62779 Version 5.0

273

Eczema herpeticum

Hemorrhagic crusts and vesicles due to herpes simplex virus infection are present on the hand of this infant with underlying atopic dermatitis. Reproduced with permission from: Fleisher GR, Ludwig S, Baskin MN. Atlas of Pediatric Emergency Medicine, Lippincott Williams & Wilkins, Philadelphia 2004. Copyright © 2004 Lippincott Williams & Wilkins. Graphic 74838 Version 4.0

274

Sweet syndrome

Vesicles and inflammatory papules and plaques are present in this patient with Sweet syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 50526 Version 3.0

275

Sweet syndrome

Vesiculation is present in this inflammatory plaque of Sweet syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 62314 Version 3.0

276

Bullous lupus

Multiple blisters in a young woman with bullous systemic lupus erythematosus. Courtesy of Samuel L Moschella, MD. Graphic 66048 Version 2.0 Paraneoplastic pemphigus An erosive mucositis in a patient with paraneoplastic pemphigus associated with Castleman's tumor; mucous membrane and cutaneous lesions cleared with tumor removal. Copyright © Chris Ha, MD, Dermatlas; http://www.dermatlas.org. Graphic 59594 Version 9.0

277

Paraneoplastic pemphigus

Vesicles and flaccid bullae are present on the skin. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 67265 Version 6.0

278

Paraneoplastic pemphigus

Bullae, erosions, and crusts are present on the skin. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 79192 Version 4.0

279

Miliaria crystallina

Multiple small vesicles on the skin. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 76069 Version 3.0

280

Bullous impetigo

Vesicles and pustules that easily rupture and evolve to erosions and crusts are characteristic of bullous impetigo.  Graphic 63992 Version 4.0

281

Pemphigus vulgaris

Flaccid bullae and erosions on the skin of a patient with pemphigus vulgaris. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 53425 Version 7.0

282

Pemphigus vulgaris - oral lesions

Multiple erosions on the palate in a patient with pemphigus vulgaris. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 57924 Version 6.0

283

Pemphigus vulgaris

Erosions on the tongue and lips are present in this patient with pemphigus vulgaris. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 77462 Version 5.0

284

Pemphigus foliaceus Pemphigus foliaceus lesions exhibit erythema, scaling, and crusting. The face and scalp are often the initial sites of involvement. Reproduced with permission from: Stedman's Medical Dictionary. Copyright © 2008 Lippincott Williams & Wilkins. Graphic 54341 Version 2.0

285

Pemphigus foliaceus

Pemphigus foliaceus is characterized by erythema, scaling, and crusting that first appears on the face and scalp, and later involves the chest and back. Reproduced with permission from: Bystryn J, Ruldolph J. Pemphigus. Lancet 2005; 266:61. Copyright © 2005 Nicholas Soter, MD. Reproduced in Lancet with permission from: the New York University Department of Dermatology. Graphic 72419 Version 4.0

286

Bullous pemphigoid

Multiple tense bullae arising on erythematous plaques, ruptured bullae, and erosions in and around skin of the axilla. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 78910 Version 3.0

287

Bullous pemphigoid

Multiple erythematous plaques, bullae, erosions, and crusts on the trunk and extremity skin. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 72866 Version 5.0

288

Pemphigoid gestationis

Periumbilical erythematous papules, vesicles, erosions, and crusts are present in this patient with pemphigoid gestationis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 78383 Version 7.0

289

Pemphigoid gestationis

Widespread erythematous plaques, bullae, and erosions are present on this patient with extensive disease. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 52776 Version 7.0

290

Pemphigoid gestationis

Multiple tense bullae on skin. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 72690 Version 6.0

291

Linear IgA bullous dermatosis

Tense bullae, erosions, and crusts, often in a pattern described as "clusters of jewels" or "strings of pearls," on skin of a patient with linear IgA bullous dermatosis. IgA: immunoglobulin A. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 56434 Version 9.0

292

Dermatitis herpetiformis

Vesicles, bullae, erosions, and crusts on elbow skin. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 78315 Version 5.0

293

Dystrophic epidermolysis bullosa

Multiple bullae and erosions are present in this infant with dystrophic epidermolysis bullosa. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 68938 Version 3.0

294

Epidermolysis bullosa acquisita

Tense bullae, erosions, and crusts on skin of a patient with epidermolysis bullosa acquisita. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 62505 Version 6.0

295

Bullous cutaneous small vessel vasculitis

Vesicles overlying purpuric macules are present on the lower leg. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 57440 Version 5.0

296

Stasis dermatitis

A bulla is present within an area of stasis dermatitis on the lower leg. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 78581 Version 2.0

297

Dyshidrotic eczema

Small vesicles (arrows) are visible on the lateral fingers. Reproduced with permission from: Goodheart HP. Goodheart's photoguide to common skin disorders, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2003. Copyright © 2003 Lippincott Williams & Wilkins. Graphic 55722 Version 2.0

298

Dyshidrotic eczema with large bullae

Large bullae resulting from coalescence of vesicles on the palms of a patient with severe dyshidrotic eczema. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 83007 Version 8.0

299

Acute tinea pedis

The medial aspect of the left great toe demonstrates erythematous, papulovesicular lesions caused by Trichophyton mentagrophytes. Courtesy of John T Crissey, MD. Graphic 54214 Version 3.0

300

Autoeczematization (id reaction)

Numerous pinpoint vesicles are present on the hand. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 52664 Version 5.0

301

Sucking blister

A blister is present on the thumb of this neonate. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 67302 Version 3.0

302

Intrauterine sucking lesions Intrauterine sucking lesions can be seen in the dorsum of the fingers, hand, or radial aspect of the wrist of newborn infants. The lesions may appear as ruptured (pictured above) or intact vesicles. They can be multiple, unilateral, or bilateral. Rarely, they may have a hemorrhagic component. Courtesy of Gerardo A Cabrera-Meza, MD. Graphic 78479 Version 3.0

303

Target lesions of erythema multiforme

Target lesions with central bullae are present on the hand. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 79955 Version 8.0

304

Erythema multiforme

Erosions are present on the penis of this patient with erythema multiforme. A target-like lesion is present on the distal glans. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 75314 Version 6.0

305

Erythema multiforme Hemorrhagic crusting and mucosal erosions involving the lips and tongue in a patient with erythema multiforme. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 58969 Version 7.0

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Epidermolysis bullosa simplex

Bullae are present on the hands of this infant with epidermolysis bullosa simplex. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 59364 Version 4.0

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Epidermolysis bullosa simplex

Multiple erosions and bullae are present on the foot of this child with epidermolysis bullosa simplex. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 73201 Version 5.0

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Polymorphous light eruption

This photo shows a 35-year-old woman with a symmetrical papulovesicular eruption on the forearms. Lesions were also present on the neck and lower legs. Copyright © Eric Ehrsam, MD, Dermatlas; http://www.dermatlas.org. Graphic 64270 Version 7.0

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Porphyria cutanea tarda

Vesicles and erosions are visible on the dorsum of the hand in a patient with porphyria cutanea tarda related to underlying hepatitis C virus infection. Courtesy of Jean-François Dufour, MD. Graphic 74528 Version 1.0

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Porphyria cutanea tarda

Macular erythema, erosions, crusts, and scars are present on the hands of this patient with porphyria cutanea tarda. Reproduced with permission from: Stedman's Medical Dictionary. Copyright © 2008 Lippincott Williams & Wilkins. Graphic 78547 Version 2.0

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Pseudoporphyria

Vesiculation and crusting are present on the dorsal hand. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 80856 Version 3.0

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Sunburn

Erythema, edema, and bullae are present on this child with a severe sunburn. Reproduced with permission from: Fleisher GR, Ludwig S, Baskin MN. Atlas of Pediatric Emergency Medicine, Lippincott Williams & Wilkins, Philadelphia 2004. Copyright © 2004 Lippincott Williams & Wilkins. Graphic 52112 Version 2.0

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Vesicles of herpes zoster

Multiple vesicles are present in this patient with herpes zoster. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 81443 Version 6.0

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Herpes zoster

Grouped vesicles and underlying erythema are present in a dermatomal distribution. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 58282 Version 5.0

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Poison ivy allergic contact dermatitis

Large bullae on the hand of a child with acute allergic contact dermatitis from poison ivy. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 101005 Version 3.0

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Phytophotodermatitis

After making lemonade during an outdoor excursion trip, this 38-year-old female presented with erythematous linear and angulated patches and crusts on the face. Copyright © Shahbaz A Janjua, MD, Dermatlas; http://www.dermatlas.org. Graphic 57871 Version 5.0

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Berloque dermatitis This adolescent developed hyperpigmented streaks from a photosensitizer in his sunscreen. After several days of erythema, the red patches became dark brown. Copyright © Kosman Sadek Zikry, MD, Dermatlas; http://www.dermatlas.org. Graphic 81457 Version 7.0

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Female genital herpes simplex virus Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 58485 Version 4.0

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Herpes simplex labialis

Grouped vesicles are evident on the lower vermilion border. Reproduced with permission from: Bickley LS, Szilagyi P. Bates' Guide to Physical Examination and History Taking, Eighth Edition. Philadelphia: Lippincott Williams & Wilkins, 2003. Copyright © 2003 Lippincott Williams & Wilkins. Graphic 73975 Version 4.0

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Bullous arthropod bite

Multiple erythematous papules consistent with arthropod bites are present on the foot. An intact, fluid-filled bulla is present at the site of one lesion. Graphic 52794 Version 2.0

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Bullous arthropod (insect) bite

A bulla is present in the site of an insect bite. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 60230 Version 3.0

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Fixed drug eruption

Multiple violaceous, round plaques are present on the skin. A central bulla is present in one lesion. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 67733 Version 3.0

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Grover's disease

Typical appearance of scattered pruritic, erythematous papules and papulovesicles on the trunk. Courtesy of Whitney High, MD. Graphic 76504 Version 2.0

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Vulvar Hailey-Hailey disease

A large, erythematous plaque with multiple superficial erosions involving the vulvar and groin area in a patient with Hailey-Hailey disease. Courtesy of Lynne J Margesson, MD. Graphic 80862 Version 6.0

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Hailey-Hailey disease Typical axillary plaque of Hailey-Hailey disease, showing superficial erosions and crusts. Graphic 61689 Version 3.0

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Perianal Hailey-Hailey disease Large, erythematous, and crusty perianal plaque in a patient with Hailey-Hailey disease. Graphic 74552 Version 6.0

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Bullous pyoderma gangrenosum

Three large hemorrhagic bullae on the dorsum of the hand and fingers. The bulla on the index finger has ruptured, resulting in a large erosion with an irregular, raised, pustular border and a purulent hemorrhagic exudate. Reproduced with permission from: Fitzpatrick TB, Johnson RA, Wolff K, et al. Color atlas and synopsis of clinical dermatology, 3rd ed, McGraw-Hill, New York 1997. Copyright © 1997 McGrawHill. Graphic 55967 Version 3.0

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Mucous membrane pemphigoid

Irregular erosions and a blister on the mucosal surface of the lip. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 52208 Version 5.0

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Mucous membrane pemphigoid

Mucosal erosions on the gingiva and palate. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 63997 Version 6.0

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Mucous membrane pemphigoid

Erosions are present on the genital mucosa. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 75723 Version 4.0

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Stage 3 ocular cicatricial pemphigoid

Note the symblepharon bridging between the eyeball and the eyelid. Graphic 54207 Version 1.0

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Cicatricial pemphigoid

Erosions are present on the gingiva in this patient with cicatricial pemphigoid. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 77654 Version 5.0

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Bullous drug eruptions

Drug eruption

Clinical features

Common medications

Linear IgA bullous dermatosis

Annular erythema and blisters ("crown of jewels").

Vancomycin, penicillin, cephalosporins, ACE inhibitors, NSAIDs

Pseudoporphyria

Photodistributed blisters on dorsal hands, forearms, face. Similar clinical presentation as porphyria cutanea tarda (with negative porphyrin studies).

NSAIDs, tetracyclines, furosemide

Fixed drug eruption

Dusky, violaceous patch. Hemorrhagic vesicle or bulla. History of recurrences at same location with medication usage.

Sulfonamides, NSAIDs, tetracyclines

StevensJohnson syndrome, toxic epidermal necrolysis

Widespread, dusky erythema with epidermal detachment and flaccid blisters. Prominent mucosal involvement.

Antibiotics, anticonvulsants, allopurinol, dapsone, NSAIDs

IgA: immunoglobulin A; ACE: angiotensin-converting enzyme; NSAID: nonsteroidal anti-inflammatory drug. Graphic 55836 Version 2.0

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Pemphigus vulgaris direct immunofluorescence

An intercellular pattern of IgG antibody binding is evident on direct immunofluorescence in this specimen from a patient with pemphigus vulgaris. Courtesy of Kristin M Leiferman, MD, Immunodermatology Laboratory, Department of Dermatology, University of Utah, Salt Lake City, Utah. Graphic 82837 Version 2.0

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Pemphigus foliaceus direct immunofluorescence

Intercellular antibody binding is evident within the upper epidermis in this direct immunofluorescence specimen from a patient with pemphigus foliaceus. Courtesy of Kristin M Leiferman, MD, Immunodermatology Laboratory, Department of Dermatology, University of Utah, Salt Lake City, Utah. Graphic 82838 Version 2.0

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Direct immunofluorescence of bullous pemphigoid

Direct immunofluorescence discloses linear deposits of IgG and C3 along the dermoepidermal junction. Ultrastructurally, these antibodies and complement are present in the lamina lucida. Reproduced with permission from: Rubin E, Farber JL. Pathology, 3rd ed, Lippincott Williams & Wilkins, Philadelphia 1999. Copyright ©1999 Lippincott Williams & Wilkins. Graphic 53466 Version 3.0

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Pemphigus vulgaris indirect immunofluorescence

Pemphigus vulgaris. Indirect immunofluorescence performed on monkey esophagus demonstrates intercellular IgG antibody deposition. Courtesy of Kristin M Leiferman, MD, Immunodermatology Laboratory, Department of Dermatology, University of Utah, Salt Lake City, Utah. Graphic 82839 Version 2.0

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Serum IgG basement membrane zone antibodies localizing to the epidermal side of split skin substrate in bullous pemphigoid by indirect immunofluorescence microscopy

Linear IgG antibody staining on the epidermal side of basement membrane zone-split skin substrate characteristic of bullous pemphigoid. This pattern also is referred to as staining the roof of the blister. Courtesy of Kristin M Leiferman, MD, Immunodermatology Laboratory, Department of Dermatology, University of Utah, Salt Lake City, Utah. Graphic 82836 Version 6.0

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Dermatophyte potassium hydroxide preparation

Septate hyphae are visible on a background of squamous cells in this potassium hydroxide preparation taken from a lesion of tinea corporis. Potassium hydroxide preparations from tinea pedis and tinea cruris have a similar appearance. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 60102 Version 6.0 Tzanck preparation This Tzanck preparation of a specimen from a patient with herpes simplex virus infection demonstrates a multinucleated giant cell. Graphic 79784 Version 2.0

Contributor Disclosures

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Christopher Hull, MDNothing to discloseJohn J Zone, MDNothing to discloseErik Stratman, MDNothing to discloseAbena O Ofori, MDNothing to disclose Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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Approach to the patient with facial erythema uptodate.com/contents/approach-to-the-patient-with-facial-erythema/print

Approach to the patient with facial erythema Author: Mark V Dahl, MD Section Editor: Erik Stratman, MD Deputy Editor: Abena O Ofori, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Mar 16, 2020.

INTRODUCTION

Facial erythema (facial redness), a clinical finding most

noticeable in fair-skinned individuals, occurs as a result of cutaneous blood vessel dilation and increased blood flow to the skin. Although transient facial erythema is often observed as a normal, neurologically mediated response to strong emotion, exercise, or heat exposure, inflammation and a variety of medical conditions can lead to longer-lasting and symptomatic or cosmetically distressing facial erythema. Examples of disorders that may present with diffuse or localized facial erythema and the evaluation of patients with this clinical finding will be reviewed here. More detailed information on flushing and many of the other disorders associated with facial erythema is available separately. (See "Approach to flushing in adults" and 'Etiology' below.)

ETIOLOGY

A variety of factors, including primary skin diseases, external insults,

and systemic illness may cause facial redness. Knowledge of the distinctive characteristics of these disorders is helpful for diagnosis.

Primary inflammatory skin diseases ●Rosacea –The erythematotelangiectatic subtype of rosacea is characterized by centrofacial erythema and telangiectasias (picture 1A-B) [1-3]. Affected patients also often exhibit flushing and sensitivity of facial skin. The patient history and physical findings are usually sufficient for the diagnosis of this disorder. Other rosacea subtypes may also demonstrate these clinical features. (See "Rosacea: Pathogenesis, clinical features, and diagnosis".)

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●Perioral dermatitis – Perioral dermatitis (also known as periorificial dermatitis) presents with multiple small, erythematous, inflammatory papules clustered around the mouth, nose, or eyes (picture 2). Fine scale is also often present, but the rash is characteristically more red and bumpy than red and scaly. In patients with perioral lesions, the skin immediately adjacent to the vermillion border of the lip is classically spared. Perioral dermatitis most frequently affects young women; occasionally, the disorder occurs in children. (See "Perioral (periorificial) dermatitis".) ●Seborrheic dermatitis – Erythema accompanied by greasy, yellow-white scale is a characteristic feature of seborrheic dermatitis in adults. In patients with dark skin, the scale may have a gray or brown hue. Involvement of the face typically manifests in the nasolabial folds, eyebrows, glabella, and lateral nasal areas (picture 3A-B). Other potential sites of involvement include the scalp, ears, chest, axillae, and groin. The diagnosis of seborrheic dermatitis is usually made based upon the clinical findings [4,5]. (See "Seborrheic dermatitis in adolescents and adults".) ●Atopic dermatitis – Facial involvement of atopic dermatitis is common in infants (picture 4A-C) but may also occur in older children and adults (picture 5A-B). Intensely pruritic, erythematous patches or plaques with accompanying scale, exudate, excoriations, or lichenification are often seen. The presence of a chronic, very pruritic, dermatitic skin disorder with lichenification in a typical distribution (eg, flexures in adults, cheeks in infants) suggests the possibility of atopic dermatitis [6]. Patients may also exhibit an extra skin fold beneath the bilateral lower eyelids that is known as a Dennie-Morgan fold (picture 6). An uncommon variant is photosensitive atopic dermatitis, which occurs predominantly in atopic skin exposed to ultraviolet light [7]. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".) ●Psoriasis – The clinical findings in facial psoriasis may be more subtle than the classic thick plaques with silver scale that are typical of lesions in other body areas (picture 7A-B). In some patients, lesions closely resemble the erythematous patches and finer scale of seborrheic dermatitis. The detection of lesions consistent with the classic presentation of psoriasis elsewhere on the body is helpful for diagnosis. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

Disorders due to external insults ●Irritant contact dermatitis – Contact with skin care products, cosmetics, or other substances that contain irritants may result in facial eruptions with features of eczematous dermatitis. The dermatitis may be diffuse or localized depending on the sites of contact. The facial folds and the delicate skin of the eyelids are particularly susceptible to more severe involvement. Unlike allergic contact dermatitis, which is typically associated with intense pruritus, patients with irritant contact dermatitis tend to complain of burning or prickling sensations [8]. The patient history is critical for identifying this diagnosis. (See "Irritant contact dermatitis in adults".)

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●Allergic contact dermatitis – Delayed hypersensitivity reactions to external substances that contact the skin can cause acute, intense inflammatory reactions characterized by bright erythema, scale, and exudate (picture 8A-B) [8]. Other times, the dermatitis is only mildly inflamed and chronic. Patch testing can be useful for identifying the causative antigenic substance. (See "Clinical features and diagnosis of allergic contact dermatitis" and "Patch testing".)

Photosensitive disorders ●Sunburn – The appearance of confluent, erythematous patches following sun exposure is a classic feature of sunburn. Pruritus or pain may also be present. In severe cases, edema and blistering can occur. Desquamation commonly occurs during healing. (See "Sunburn".) ●Polymorphous light eruption (PMLE) – Often colloquially referred to as sun poisoning or sun allergy, PMLE may present with a wide variety of clinical manifestations [9,10]. Erythematous patches, papules, vesicles, or plaques may occur within hours to days after sun exposure (picture 9). PMLE is particularly likely to occur in early spring, as patient tolerance to sunlight tends to rise with increasing exposure. (See "Polymorphous light eruption".) ●Phototoxic and photoallergic eruptions – Phototoxic eruptions are sunburn-like reactions induced by the ingestion or application of photosensitizing substances (picture 10) [11-14]. The photosensitizing agent decreases the amount of ultraviolet light exposure required to elicit this reaction. Severe eruptions with blistering and edema may occur. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.) Photoallergic reactions are characterized by pruritic, eczematous eruptions in sun-exposed areas (picture 11) [11-13]. Topical, rather than ingested, agents are the most frequent causes of photoallergic reactions [15]. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.) ●Photodamage – The formation of numerous telangiectasias and a ruddy complexion secondary to chronic sun exposure is a common cause of facial redness [16]. Sun-protected areas of the face are relatively spared. Patients may have accompanying poikiloderma of Civatte, a disorder characterized by mottled pigmentation and telangiectasias on the lateral neck (picture 12). (See "Photoaging", section on 'Clinical features'.) ●Acute cutaneous lupus erythematosus, dermatomyositis, and lupus tumidus erythematosus [17]. (See 'Systemic disorders' below and 'Localized inflammatory infiltrates' below.)

Systemic disorders ●Lupus erythematosus – Patients with systemic lupus erythematosus may develop acute cutaneous lupus erythematosus, which often manifests as persistent, violaceous erythema on the malar area of the face (picture 13) [18,19]. This clinical finding is often referred to as a "butterfly rash." The prominent telangiectasias of rosacea are not a feature of acute cutaneous lupus

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erythematosus. The presence of signs or symptoms of systemic lupus erythematosus suggests this diagnosis. (See "Overview of cutaneous lupus erythematosus", section on 'Acute cutaneous lupus erythematosus' and "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.) Patients with subacute cutaneous lupus erythematosus have a photosensitive form of lupus erythematosus. Erythematous, annular or nummular, scaling, psoriasiform plaques usually appear on the trunk, but the face may be involved. The inner edge of annular plaques often shows fine white, trailing scales. Patients are otherwise usually healthy but some may have arthritis or other findings of systemic lupus erythematosus. (See "Overview of cutaneous lupus erythematosus", section on 'Subacute cutaneous lupus erythematosus'.) ●Dermatomyositis – A classic sign of dermatomyositis is the "heliotrope eruption," a violaceous and often edematous eruption that occurs on the eyelids and periorbital skin (picture 14A-B). Patients may or may not have accompanying proximal muscle weakness. The detection of other cutaneous signs of dermatomyositis, such as Gottron papules and periungual telangiectasias, raises suspicion for this diagnosis. In addition, the possibility of an underlying malignancy must be considered in adults with dermatomyositis. (See "Clinical manifestations of dermatomyositis and polymyositis in adults" and "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations".)

Infectious disorders ●Viral infections – Erythema infectiosum is a viral disease caused by parvovirus B19 that most commonly occurs in children [20]. A common feature of this disorder is the appearance of red patches on the cheeks that resemble facial skin after a slap on the face (picture 15). Nonspecific constitutional symptoms, such as fever, coryza, headache, or gastrointestinal distress, usually precede the cutaneous findings. A reticulated eruption on the trunk and extremities frequently appears one to two days after the facial lesions. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Erythema infectiosum'.) Morbilliform or confluent facial redness may also occur as early features of other viral infections, such as measles or rubella; other body sites are typically also involved (picture 16A-B). (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention" and "Rubella".) ●Erysipelas – Erysipelas is a superficial form of cellulitis that usually results from infection with beta-hemolytic streptococci [21]. Patients typically present with the acute development of an erythematous, warm, edematous, and well-defined plaque (picture 17). Fever and lymphadenopathy often accompany the cutaneous symptoms. (See "Cellulitis and skin abscess: Clinical manifestations and diagnosis".)

Localized inflammatory infiltrates 345

●Lupus tumidus erythematosus – Also known as tumid lupus erythematosus, lupus tumidus erythematosus is an uncommon disorder that presents with erythematous plaques in sun-exposed areas, such as the face, neck, upper trunk, and upper extremities, and scale is typically absent (picture 18) [22,23]. The vast majority of patients do not have associated systemic lupus. The performance of a biopsy assists with diagnosis. (See "Overview of cutaneous lupus erythematosus", section on 'Lupus erythematosus tumidus'.) ●Jessner's lymphocytic infiltrate – This idiopathic disorder most commonly manifests as erythematous, asymptomatic, often annular plaques on the face, neck, or upper trunk (picture 19A-B) [24,25]. A skin biopsy is useful for diagnosis. Jessner's lymphocytic infiltrate shares clinical and histopathologic features with lupus tumidus erythematous. The relationship between these disorders remains unclear [25]. ●Granuloma faciale –Granuloma faciale usually presents as a solitary, red-brown, asymptomatic, round plaque with follicular prominence on the face (picture 20) [26]. The histopathologic finding of a normal-appearing thin zone in the papillary dermis (Grenz zone) above a dense inflammatory dermal infiltrate containing eosinophils, lymphocytes, neutrophils, and plasma cells is characteristic of this diagnosis. The disorder is most common in Caucasian men [26]. (See "Granuloma faciale".) ●Cutaneous lymphoid hyperplasia (lymphocytoma cutis) – Cutaneous lymphoid hyperplasia occurs as a result of antigenic stimulation in the skin leading to lymphocyte proliferation. The specific cause of the disorder is often unknown, but insect bites and infections, including Lyme disease, have been linked to some cases [27,28]. Patients typically present with a red-brown to violaceous nodule or plaque. A skin biopsy is necessary for diagnosis. (See "Clinical manifestations of Lyme disease in adults", section on 'Borrelial lymphocytoma'.) ●Tinea faciei –Infections with dermatophytic fungi can mimic other acute and chronic facial skin diseases depending upon the nature of the infecting organism and the intensity of the host's defense reaction. In general, facial fungal infections tend to be unilateral; sharply marginated; occasionally annular, scaling, or weeping; and slowly enlarging plaques (picture 21) [29]. Potassium hydroxide examination of scale or culture confirms the clinical diagnosis. If lesions have been treated with a topical corticosteroid, they typically seem to improve as inflammation is reduced (tinea incognito) but recur when treatments are stopped. (See "Dermatophyte (tinea) infections", section on 'Tinea faciei'.)

Other ●Flushing –Flushing is characterized by the sudden and transient appearance of facial erythema. The etiology and clinical manifestations of flushing are discussed separately [30]. (See "Approach to flushing in adults".) ●Ruddy complexion – Generalized redness of the skin may occur as a normal feature in some individuals with fair skin (eg, Fitzpatrick skin phototype I or II (table 1)). Unlike erythematotelangiectatic rosacea, redness is not limited to the central face.

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●Keratosis pilaris rubra – Keratosis pilaris rubra faciei is most common in children, adolescents, and young adults with fair complexions. Triangular, erythematous patches are present on the bilateral cheeks (picture 22). Follicular keratotic papules are located within the areas of redness, giving the skin a rough texture [31]. Clinical examination is usually sufficient for diagnosis. ●Topical corticosteroid withdrawal –Some patients develop a red face from prolonged use of moderate- to high-potency topical corticosteroids on the face. Symptoms of burning or stinging develop within several days after applications are stopped or reduced. Diagnostic difficulties arise from the inability to clearly distinguish the redness from topical corticosteroid withdrawal from the redness due to exacerbation of the underlying dermatosis. Features suggesting topical corticosteroid withdrawal include the appearance of generalized redness of the face within four days of withdrawal and symptoms of pain, especially burning sensations [32]. ●Burning face syndrome (facial erythrodysesthesia) – Painful or burning sensations are associated with facial erythema due to mild dilation of blood vessels. Some patients have rosacea, while others seem to have a neuropathic pain syndrome [33].

PATIENT ASSESSMENT

The first step for narrowing the

differential diagnosis of facial erythema is the performance of a thorough patient history and skin examination. The recognition of associated symptoms, exacerbating factors, lesion time course, and subtle clinical features of the affected area are often valuable for diagnosis. In addition, the performance of a full skin examination may yield additional skin findings that suggest an underlying cutaneous or systemic disorder. The clinician should consider the following points during the patient evaluation: ●What are the physical characteristics of the eruption? •Diffuse and symmetrical without scale – ruddy complexion, flushing •Diffuse and symmetrical with scale – irritant contact dermatitis, airborne allergic contact dermatitis, atopic dermatitis in infants •Symmetrical, central face or cheeks without scale – rosacea, erythema infectiosum, keratosis pilaris rubra faciei •Symmetrical, central face with scale – seborrheic dermatitis, atopic dermatitis, psoriasis •Photodistributed – sunburn; polymorphous light eruption; phototoxic reaction; photoallergic reaction; photodamage; acute, subacute, and discoid cutaneous lupus erythematosus; dermatomyositis; lupus erythematosus tumidus •Localized plaques or patches – erysipelas, lupus tumidus erythematosus, cutaneous lymphoid hyperplasia, Jessner's lymphocytic infiltrate, granuloma faciale

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•Presence of telangiectasias – photodamage, rosacea ●Are there associated symptoms? •Prominent pruritus – allergic contact dermatitis, atopic dermatitis, photoallergic reaction •Painful or burning sensations – sunburn, irritant contact dermatitis, phototoxicity, erysipelas, rosacea •Sick patient – lupus erythematosus, systemic infection, drug eruption ●How long has the eruption been present; how long do symptoms last? •Acute – allergic contact dermatitis, atopic dermatitis flare, erythema infectiosum and other viral infections, sunburn, phototoxic reaction, photoallergic reaction •Transient – flushing ●Has the patient applied any products to the skin that could cause an irritant or allergic reaction? •Allergic contact dermatitis, irritant contact dermatitis, photoallergic reaction ●Is the eruption exacerbated by sun exposure? •Sunburn, phototoxic reaction, photoallergic reaction, cutaneous lupus erythematosus, dermatomyositis, lupus tumidus erythematosus ●Is the patient ingesting any photosensitizing medications or supplements? •Phototoxic reaction, occasionally photoallergic reactions ●Are other body sites involved, and in what distribution? •Psoriasis, atopic dermatitis, seborrheic dermatitis, viral exanthems, drug eruptions, photodermatoses, erythroderma, other disorders

DIAGNOSTIC TESTS

The workup of patients with facial redness is

dependent upon the disorders suspected as a result of the clinical assessment. Diagnostic tests that can be useful for the evaluation of select patients include: ●Patch testing ●Skin biopsy ●Directed serologic studies (eg, investigative tests for autoimmune disease)

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Patch testing — Patch testing can be useful for identifying the causative allergen in patients with contact dermatitis. The procedure is most appropriate for patients in whom an allergic contact dermatitis is strongly suspected (eg, history of contact with a potential allergen, paroxysmal nature of eruptions, or severe pruritus) or in patients with persistent, pruritic, eczematous facial eruptions without another identifiable cause. (See "Patch testing".) The results of patch testing must be interpreted carefully since a positive patch test result does not definitively indicate that a specific allergen is the cause of dermatitis. A thorough patient interview prior to patch testing and reevaluation following the elimination of the identified allergen are essential for confirming the relevance of patch test results.

Biopsy — Skin biopsies are not necessary in most patients with facial erythema, as a thorough clinical history and skin examination often yields the diagnosis. However, in cases in which the diagnosis remains uncertain and the disorders being considered have distinctive histopathologic findings, skin biopsies can be of value. Punch biopsies are typically performed for the evaluation of facial dermatoses as they allow for the evaluation of the full thickness of the epidermis and dermis through the removal of a relatively small skin sample. We most commonly perform 3 mm punch biopsies when evaluating inflammatory facial dermatoses. Larger punch biopsies are typically avoided to minimize scarring, and smaller biopsies may increase the risk for inconclusive histopathologic results. (See "Skin biopsy techniques", section on 'Punch biopsy'.) If multiple sites are acceptable for biopsy, a site that minimizes cosmetic disfigurement should be selected.

Serology and other tests — Serologic studies and other investigative tests may be useful in the diagnostic workup of patients with facial redness related to systemic disorders such as acute cutaneous lupus erythematosus, dermatomyositis, or certain infections. The selection of studies is based upon the clinical suspicion for specific underlying disorders. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Childhoodonset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Diagnosis' and "Juvenile dermatomyositis and polymyositis: Diagnosis" and "Clinical manifestations of dermatomyositis and polymyositis in adults".)

TOPICAL CORTICOSTEROID USE

The

treatment of facial erythema should be selected based upon the measures appropriate for the specific underlying disorder. For corticosteroid-responsive inflammatory dermatoses, low-potency agents (eg, hydrocortisone 1% or 2.5%) are most frequently employed to minimize risk for the induction of acneiform eruptions and cutaneous atrophy that may lead to telangiectasias and a red hue to the skin (table 2).

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With the exception of specific disorders in which higher-potency topical corticosteroids are required (eg, discoid lupus erythematosus), the use of medium- or high-potency topical corticosteroids for inflammatory facial dermatoses generally is not recommended. Facial dermatoses requiring treatment with medium- or high-potency topical corticosteroids are best managed by a dermatologist. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

INDICATIONS FOR REFERRAL

Evaluation by a

dermatologist is appropriate for patients with facial redness of unknown cause or that fails to respond as expected to therapy. Facial biopsies and patch testing are best performed by clinicians trained in these procedures. (See 'Patch testing' above and 'Biopsy' above.)

SUMMARY AND RECOMMENDATIONS ●Facial redness is a common cutaneous finding that may occur as a normal feature or as a consequence of cutaneous or systemic disorders. Examples of conditions that may lead to facial redness include inflammatory skin disease, photosensitive disorders, autoimmune disorders, vascular reactions, and infections. (See 'Etiology' above.) ●The evaluation of the patient with facial redness begins with a thorough patient history and whole body skin examination. Details such as the features of cutaneous lesions, symptoms, duration of the eruption, and exacerbating factors should be assessed. (See 'Patient assessment' above.) ●Although the diagnosis of disorders of facial erythema can commonly be made based upon the patient history and clinical examination, patch testing, skin biopsy, or laboratory studies may be beneficial in select patients. Antinuclear antibody testing is not indicated in all patients with facial redness. (See 'Diagnostic tests' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 13686 Version 12.0

GRAPHICS

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Rosacea

Centrofacial redness with telangiectasias in rosacea. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 77020 Version 6.0

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Rosacea Erythema and telangiectasias on the cheek. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 56083 Version 6.0

352

Perioral dermatitis

Small, acne-like papules and scale are typically present in perioral dermatitis. The skin nearest to the mouth is characteristically spared. Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd ed. Lippincott Williams & Wilkins, Philadelphia 2003. Copyright ©2003 Lippincott Williams & Wilkins. Graphic 73779 Version 3.0 Seborrheic dermatitis Facial redness and scale involving the nasolabial folds and central face. Reproduced with permission from: Goodheart HP. Goodheart's photoguide of common skin disorders, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2003. Copyright © 2003 Lippincott Williams & Wilkins. Graphic 56410 Version 4.0

353

Facial seborrheic dermatitis

Intense erythema and scaling involving the central face and nasolabial folds. Graphic 59104 Version 4.0 Atopic dermatitis - infantile Hyperpigmented, lichenified patches are present on the face of this infant with atopic dermatitis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 77386 Version 11.0

354

Atopic dermatitis: Infantile Confluent erythema, microvesiculation, scaling, and crusting on the face, with similar involvement (to a lesser degree) on the trunk and arms. Reproduced with permission from: Fitzpatrick TB, Johnson RA, Wolff K, et al (Eds). Color Atlas and Synopsis of Clinical Dermatology, 3rd ed, McGraw-Hill, New York, 1997. Copyright © McGraw-Hill. Graphic 77457 Version 6.0

355

Atopic dermatitis: Infantile Confluent erythema, microvesiculation, papules, crust, and scale on the face of an infant. Reproduced with permission from: Fitzpatrick TB, Johnson RA, Wolff K, et al (Eds), Color Atlas and Synopsis of Clinical Dermatology, 3rd ed, McGraw-Hill, New York 1997. Copyright © McGraw-Hill. Graphic 56461 Version 5.0

356

Atopic dermatitis

Erythema and scale on the periocular skin in atopic dermatitis. The pruritus associated with eyelid involvement can be severe. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 75681 Version 5.0

357

Atopic dermatitis

Slightly lichenified dermatitic plaques are present on the face. Erythema is subtle in this darkskinned patient. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 56815 Version 4.0

358

Dennie-Morgan fold in atopic dermatitis

An extra skin fold is present under the eyes in this patient with facial atopic dermatitis. Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2003. Graphic 62145 Version 2.0

359

Psoriasis

On the face, the appearance of psoriasis is often more eczematous than papulosquamous. Most patients with facial psoriasis also have extensive generalized psoriasis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 79191 Version 5.0

360

Psoriasis

Erythematous, scaly plaques are present on the face. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 68576 Version 4.0

361

Allergic contact dermatitis

An intense, inflammatory eruption is present on the face. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 67215 Version 5.0

362

Allergic contact dermatitis

Acute allergic contact dermatitis is severely pruritic. Skin often weeps. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 82705 Version 5.0

363

Polymorphous light eruption

This 12-year-old girl developed a pruritic eruption that consisted of discrete and coalescing erythematous papules on the face. The lesions were photodistributed and appeared within hours after intense sun exposure in the spring. Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org. Graphic 51455 Version 6.0

364

Phototoxic eruption

Diffuse, sunburn-like erythema is present on the face and ears. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 69140 Version 9.0

365

Photoallergic eruption

This 45-year-old woman developed an acute, well-demarcated, erythematous plaque with vesicles after topical application of ketoprofen gel followed by sun exposure. The patient wore socks, which protected the foot from the sun, creating the line of demarcation that is visible in the image. Copyright © Eric Ehrsam, MD, Dermatlas; http://www.dermatlas.org. Graphic 63557 Version 8.0

366

Poikiloderma of Civatte

Chronic sun damage is associated with the development of poikiloderma of Civatte, which typically presents as redness, telangiectasias, and mottled hyperpigmentation on the lateral neck. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 81779 Version 6.0

367

Acute cutaneous lupus erythematosus

Malar erythema and subtle edema are present in this patient with systemic lupus erythematosus. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 75781 Version 5.0

368

Heliotrope eruption in dermatomyositis

Violaceous erythema is present on the periorbital skin in this patient with dermatomyositis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 56879 Version 5.0

369

Heliotrope eruption in dermatomyositis

Violaceous erythema and edema are present on the upper eyelid in this patient with dermatomyositis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 68649 Version 8.0

370

Erythema infectiosum

Redness appears acutely on one or both cheeks ("slapped cheek" appearance). The redness may be reticulated. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 52251 Version 7.0

371

Measles

Numerous erythematous macules are present on the face and trunk. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 61958 Version 5.0

372

Measles

Numerous erythematous macules are present on the face. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 73806 Version 4.0

373

Erysipelas

Erysipelas lesions are raised above the level of surrounding skin, and there is a clear line of demarcation between involved and uninvolved tissue. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 67112 Version 6.0

374

Lupus erythematosus tumidus

Inflammatory plaques consistent with lupus erythematousus tumidus (tumid lupus erythematosus) are present on the face. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 71792 Version 4.0

375

Jessner's lymphocytic infiltration of the skin

Annular, erythematous plaques are present on the face. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 76268 Version 5.0

376

Jessner's lymphocytic infiltration of the skin

An erythematous, round plaque is present on the lateral forehead. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 62419 Version 5.0

377

Granuloma faciale

A red-brown plaque is present on the face. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 50769 Version 4.0

378

Tinea faciei

An erythematous, oval plaque and pustules on the face. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 78234 Version 7.0

379

Fitzpatrick skin phototypes

Skin type

Unexposed skin color

Reaction to sun exposure*

I

White

Always burns, never tans

II

White

Always burns, minimal tan

III

White to olive

Burns minimally, gradually tans

IV

Light brown

Burns minimally, tans well

V

Brown

Very rarely burns, tans profusely

VI

Dark brown to black

Never burns, tans deeply

Note: Slight variations on the definitions of the phototypes appear in the literature. * After the first one hour of sun exposure on untanned skin on the first day of spring. Graphic 60541 Version 4.0

380

Keratosis pilaris rubra faciei

Multiple small, follicularly-based, rough, keratotic papules are present on the cheeks. As shown here, background erythema may also be present in patients with this condition. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 77270 Version 5.0 Comparison of representative topical corticosteroid preparations (classified according to the US system)

Potency group*

Corticosteroid

Vehicle type/form

Brand names (United States)

Available strength(s), percent (except as noted)

Superhigh potency (group 1)

Betamethasone dipropionate, augmented

Gel, lotion, ointment (optimized)

Diprolene

0.05

Clobetasol propionate

Cream, gel, ointment, solution (scalp)

Temovate

0.05

Cream, emollient base

Temovate E

0.05

381

emollient base

High potency (group 2)

Lotion, shampoo, spray aerosol

Clobex

0.05

Foam aerosol

Olux-E, Tovet

0.05

Solution (scalp)

Cormax

0.05

Diflucortolone valerate (not available in United States)

Ointment, oily cream

Nerisone Forte (United Kingdom, others)

0.3

Fluocinonide

Cream

Vanos

0.1

Flurandrenolide

Tape (roll)

Cordran

4 mcg/cm2

Halobetasol propionate

Cream, lotion, ointment

Ultravate

0.05

Amcinonide

Ointment

Cyclocort¶, Amcort¶

0.1

Betamethasone dipropionate

Ointment

Diprosone¶

0.05

Cream, augmented formulation (AF)

Diprolene AF

0.05

Clobetasol propionate

Cream

Impoyz

0.025

Desoximetasone

Cream, ointment, spray

Topicort

0.25

Gel

Topicort

0.05

Ointment

ApexiCon¶, Florone¶

0.05

Cream, emollient

ApexiCon E

0.05

Fluocinonide

Cream, gel, ointment, solution

Lidex¶

0.05

Halcinonide

Cream, ointment

Halog

0.1

H l b t

L ti

B h li

0 01

Diflorasone diacetate

l

382

High potency (group 3)

Medium potency (group 4)

Halobetasol propionate

Lotion

Bryhali

0.01

Amcinonide

Cream

Cyclocort¶, Amcort¶

0.1

Lotion

Amcort¶

0.1

Betamethasone dipropionate

Cream, hydrophilic emollient

Diprosone¶

0.05

Betamethasone valerate

Ointment

Valisone¶

0.1

Foam

Luxiq

0.12

Desoximetasone

Cream

Topicort LP¶

0.05

Diflorasone diacetate

Cream

Florone¶

0.05

Diflucortolone valerate (not available in United States)

Cream, oily cream, ointment

Nerisone (Canada, United Kingdom, others)

0.1

Fluocinonide

Cream aqueous emollient

Lidex-E¶

0.05

Fluticasone propionate

Ointment

Cutivate

0.005

Mometasone furoate

Ointment

Elocon

0.1

Triamcinolone acetonide

Cream, ointment

Aristocort HP¶, Kenalog¶, Triderm

0.5

Betamethasone dipropionate

Spray

Sernivo

0.05

Clocortolone pivalate

Cream

Cloderm

0.1

Fluocinolone acetonide

Ointment

Synalar¶

0.025

Flurandrenolide

Ointment

Cordran

0.05

Hydrocortisone valerate

Ointment

Westcort

0.2

Mometasone furoate

Cream, lotion, ointment, solution

Elocon¶

0.1

383

Cream

Kenalog¶, Triderm

0.1

Ointment

Kenalog¶

0.1

Ointment

Trianex

0.05

Aerosol spray

Kenalog

0.2 mg per 2 second spray

Dental paste

Oralone

0.1

Betamethasone dipropionate

Lotion

Diprosone¶

0.05

Betamethasone valerate

Cream

Beta-Val, Valisone¶

0.1

Desonide

Ointment

DesOwen, Tridesilon¶

0.05

Gel

Desonate

0.05

Fluocinolone acetonide

Cream

Synalar¶

0.025

Flurandrenolide

Cream, lotion

Cordran

0.05

Fluticasone propionate

Cream, lotion

Cutivate

0.05

Hydrocortisone butyrate

Cream, lotion, ointment, solution

Locoid, Locoid Lipocream

0.1

Hydrocortisone probutate

Cream

Pandel

0.1

Hydrocortisone valerate

Cream

Westcort¶

0.2

Prednicarbate

Cream (emollient), ointment

Dermatop

0.1

Triamcinolone acetonide

Lotion

Kenalog¶

0.1

Ointment

Kenalog¶

0.025

Alclometasone dipropionate

Cream, ointment

Aclovate

0.05

Triamcinolone acetonide

Lowermid potency (group 5)

Low potency

384

potency (group 6)

dipropionate

ointment

Betamethasone valerate

Lotion

Beta-Val¶, Valisone¶

0.1

Desonide

Cream

DesOwen, Tridesilon¶

0.05

Lotion

DesOwen, LoKara

0.05

Foam

Verdeso

0.05

Cream, solution

Synalar¶

0.01

Shampoo

Capex

0.01

OilΔ

Derma-Smoothe/FS Body, DermaSmoothe/FS Scalp

0.01

Triamcinolone acetonide

Cream, lotion

Kenalog¶, Aristocort¶

0.025

Hydrocortisone (base, ≥2%)

Cream, ointment

Hytone, Nutracort¶

2.5

Lotion

Hytone, Ala Scalp, Scalacort

2

Solution

Texacort

2.5

Ointment

Cortaid, Cortizone 10, Hytone, Nutracort

1

Cream

Cortaid¶, Cortizone 10, Hytone, Synacort

1

Gel

Cortizone 10

1

Lotion

Aquanil HC, SarnolHC, Cortizone 10

1

Spray

Cortaid

1

Solution

Cortaid, Noble, Scalp Relief

1

Cream, ointment

Cortaid

0.5

Cream

MiCort-HC

2.5

Fluocinolone acetonide

Least potent (group 7)

Hydrocortisone (base, 3 to 4 seconds) may be present. Prolonged pallor with leg elevation to 45° for 1 minute (Buerger's test) supports vascular compromise. Peripheral dry gangrene may occur with disease progression. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Clinical features'.) ●Diagnosis – Peripheral arterial disease should be confirmed with ankle-brachial index (ABI) testing. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Diagnosis of lower extremity PAD'.)

Neuropathy — Diabetic neuropathy is responsible for the vast majority of neuropathic ulcers. Diabetic patients may have up to a 25 percent lifetime risk of developing a foot ulcer. Other causes of peripheral neuropathy (eg, spinal cord disorders [injury or spina bifida], tabes dorsalis, alcohol abuse, nutritional deficiencies, and autoimmune diseases) may result in similar ulcerations. ●Clinical features – Neuropathic ulcers are painless and occur over pressure points on the foot or heel (table 2). Ulcers have a punched-out morphology and typically occur within a thick callus (picture 4). Associated clinical findings of diabetic neuropathy include claw toes, neuropathic (Charcot) arthropathy, and reduced sweating resulting in dry, scaly feet (picture 5). (See "Evaluation of the diabetic foot", section on 'Inspection'.)

460

●Diagnosis –Sensory examination confirms decreased sensation in the involved areas. Ulcers can become deep, and underlying osteomyelitis should be considered when ulcers do not heal with offloading therapies. (See "Management of diabetic foot ulcers".)

LESS COMMON CAUSES

There are multiple less common

causes of leg ulcers, including physical injury, infection, vasculopathy, pyoderma gangrenosum (PG), panniculitis, malignancy, medications, and brown-recluse spider envenomation (table 1).

Physical injury — Physical injury to the skin may cause ulceration. Ulcers may result from pressure, thermal injury (burns or cold injury), radiation exposure, iatrogenic injury, or factitial (self-induced) injury. Of note, traumatic ulcers on the lower legs can demonstrate prolonged healing in older individuals and patients with underlying venous hypertension or arterial insufficiency. ●Clinical features – Ulcer features vary depending on the inciting injury. In particular, pressure ulcers often occur in sites overlying bony prominences; on the lower extremity, the heels are common sites [4]. The appearance of pressure ulcers ranges from shallow open ulcers to deep ulcers that expose bone, tendon, or muscle (picture 6 and figure 1). (See "Clinical staging and management of pressure-induced skin and soft tissue injury" and "Assessment and classification of burn injury".) ●Diagnosis – With the exception of factitial ulcers, diagnosis is largely straightforward and relies on historical evidence of skin trauma.

Infection — Primary infectious ulcers may result from bacterial, fungal, spirochete, or protozoal infections, either by direct inoculation or systemic spread. Staphylococcal and streptococcal skin infections are common bacterial infections that may result in ulceration. Cutaneous ulcers also may result from atypical mycobacterial infections, late-stage syphilis (gummas) (picture 7), deep fungal infections (eg, coccidioidomycosis, blastomycosis, histoplasmosis), and protozoal infections (eg, leishmaniasis (picture 8)). These infections most commonly, but not exclusively, occur in immunosuppressed patients. ●Clinical features – Clinical features vary according to the type of infection. Furuncles secondary to methicillin-resistant Staphylococcus aureus (MRSA) may progress to form larger abscesses, cellulitis, or ulcerative, necrotic plaques. Ecthyma, a form of nonbullous impetigo caused by Streptococcus pyogenes (with frequent contamination with S. aureus), produces punched-out shallow ulcers with a purulent necrotic crust and surrounding erythema (picture 9). Ecthyma gangrenosum, a Pseudomonas aeruginosa infection characterized by bacterial invasion of the media and adventitia of arteries and veins, results in the rapid development of gangrenous ulcers with black eschar (picture 10). Ecthyma gangrenosum usually occurs in immunocompromised patients. (See "Impetigo" and "Pseudomonas aeruginosa skin and soft tissue infections", section on 'Ecthyma Gangrenosum'.)

461

●Diagnosis – The diagnosis of infectious ulcers requires identification of the causative organism via swab cultures for aerobic bacteria or tissue culture for bacteria, fungi, and atypical mycobacteria. For tissue culture, incisional or punch biopsies should be obtained from the edge of the ulcer, placed on a sterile gauze pad moistened with non-bacteriostatic saline, and sent for culture in a sterile urine cup. In addition, ulcer edge tissue should be sent for histopathologic examination, including special stains for infectious organisms, since this may yield a more rapid diagnosis than culture. Culture can take up to six weeks for certain mycobacteria and fungi. In addition, secondary bacterial infection can complicate chronic ulcers caused by venous insufficiency, arterial insufficiency, neuropathic disease, or other etiologies. Clinical signs such as exacerbations of erythema, warmth, edema, and exudate warrant investigation for secondary infection. (See "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities" and "Infectious complications of pressure-induced skin and soft tissue injury".)

Vasculopathy — Vasculopathic disorders can cause lower extremity ulcers by means of inflammatory processes that cause destruction of blood vessel walls (vasculitis) or vessel occlusion leading to ischemia.

Vasculitis — Vasculitis of small or medium-sized cutaneous blood vessels can result in leg ulcers. Small-vessel vasculitis can be idiopathic or a consequence of infections, drugs, mixed cryoglobulinemia, autoimmune disorders (eg, systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome), or malignancies (particularly hematologic malignancies). Inflammation of both small and medium-sized cutaneous blood vessels is associated with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides, including granulomatosis with polyangiitis (formerly Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), and microscopic polyangiitis. Inflammation of medium-sized blood vessels occurs in cutaneous and systemic polyarteritis nodosa. (See "Evaluation of adults with cutaneous lesions of vasculitis".) ●Clinical features – The characteristic clinical finding of cutaneous small-vessel vasculitis is palpable purpura. Palpable purpura may develop an overlying necrotic vesicle or bulla that becomes ulcerative. Subcutaneous nodules, necrotic ulcerations, retiform purpura, and livedo racemosa are features of medium-sized vessel involvement. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'When to suspect cutaneous vasculitis'.) ●Diagnosis – A diagnosis of vasculitis requires a skin biopsy that reaches the subcutis. In cutaneous small-vessel vasculitis, biopsy of an early but palpable lesion is most informative [5]. Biopsies demonstrate leukocytoclastic vasculitis (infiltration of postcapillary venules by neutrophils undergoing degranulation and fragmentation) and fibrinoid necrosis of the involved vessels. Similar changes occur in vasculitis of medium-sized vessels involving the small arteries in the deep reticular dermis and fat. Performance of direct immunofluorescence studies to identify immunoglobulin or complement deposits is an important component of the evaluation of cutaneous vasculitis. (See "Evaluation of adults with cutaneous lesions of vasculitis".)

462

Livedoid vasculopathy — Livedoid vasculopathy (LV) is a chronic, painful, ulcerative skin condition, most common in young and middle-aged women [6]. While the pathogenesis of LV is not clearly understood, hypercoagulable states and impaired fibrinolysis have been implicated [7]. (See "Livedoid vasculopathy".) ●Clinical features – LV is characterized by crusted, painful, stellate, shallow ulcerations that are slow to heal (picture 11). The disease is often bilateral, involving the skin around the ankle and dorsal foot. The ulcers heal with white, atrophic, stellate scars with telangiectasia, known as atrophie blanche. The terms atrophie blanche and livedoid vasculopathy have been used interchangeably in older literature; however, atrophie blanche is now recognized as a healing pattern that can occur as a result of both LV and chronic venous insufficiency. (See "Livedoid vasculopathy", section on 'Clinical features'.) ●Diagnosis – A skin biopsy is used to confirm the diagnosis. Characteristic findings are hyaline thrombi in the mid and upper dermal blood vessels with fibrinoid changes in vessel walls. Further evaluation for hypercoagulable states, paraproteinemias, cryoprecipitable proteins (cryoglobulins or cryofibrinogen), and collagen vascular disease may be helpful as indicated by history and physical examination. (See "Livedoid vasculopathy", section on 'Diagnosis'.)

Thromboangiitis obliterans — Thromboangiitis obliterans (TAO, Buerger's disease) is a vaso-occlusive inflammatory vasculopathy affecting small and medium-sized arteries, veins, and nerves of the extremities. The pathophysiology of TAO is characterized by inflammatory thrombi occluding vessels, with sparing of the vessel walls. A rare disorder, TAO most commonly affects young to middle-aged male smokers. Exposure to tobacco is considered essential to initiation and progression of the disorder. (See "Thromboangiitis obliterans (Buerger's disease)".) ●Clinical features – The legs are affected more often than the arms. Affected individuals present with ischemic symptoms of the extremities, which may progress to digital gangrene and ulcerations (picture 12A-B). Raynaud phenomenon and superficial thrombophlebitis are other common features [8]. (See "Thromboangiitis obliterans (Buerger's disease)", section on 'Clinical features'.) ●Diagnosis – TAO is a clinical diagnosis requiring a compatible history (including tobacco use), physical findings, and diagnostic changes on angiography. Angiography demonstrates involvement of the small and medium-sized arteries, segmental occlusions, and "corkscrew"-shaped collateral vessels around areas of occlusion (image 1). (See "Thromboangiitis obliterans (Buerger's disease)", section on 'Diagnosis'.)

Microvascular occlusion disorders — Occlusion of small cutaneous blood vessels may occur by multiple mechanisms, such as platelet plugging (eg, thrombocythemia, heparin-induced necrosis), cryoagglutination (eg, cryoglobulinemia, cryofibrinogenemia), bacterial infection (eg, ecthyma gangrenosum), embolism (eg, cholesterol emboli, oxalosis), coagulopathies (eg, antiphospholipid syndrome, protein C or S deficiency, warfarin necrosis), and calciphylaxis [9].

463

The clinical features vary with etiology. Overall, cutaneous ulcerations resulting from microvascular occlusion typically are very painful and retiform purpura are a common associated finding (picture 13A-B). The approach to diagnosis is also dependent on the etiology; histologic examination often is useful. Examples of clinical and histologic findings of specific microvascular occlusion disorders include: ●Cryoglobulinemia (type I) and cryofibrinogenemia – Patients with type I cryoglobulinemia or cryofibrinogenemia may exhibit retiform acral purpura or skin necrosis leading to ulceration (picture 14). Involvement of other acral sites including ears and nose may also occur, especially with cryoglobulinemia. Livedo reticularis, the Raynaud phenomenon, and acral cyanosis are additional common clinical findings. Histopathologic examination of early sites of involvement reveals bland hyaline thrombi or red cell occlusion of superficial dermal blood vessels. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Type I cryoglobulinemia' and "Cryofibrinogenemia".) ●Cholesterol emboli – An abrupt onset of widespread livedo reticularis plus distal retiform purpura is strongly suggestive of cholesterol emboli (more common) or oxalate emboli (rare). Peripheral gangrene and ulcerations occur in a subset of patients [10]. (See "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".) Cholesterol embolization is most common in men over age 50 with atherosclerotic disease. Cholesterol emboli may occur spontaneously, but are more commonly seen within hours to days of arterial catheterization. Thrombolytic therapy and starting anticoagulation therapy (warfarin blue toe syndrome) have also been implicated, but a causal relationship is not well established. Fullthickness punch or incisional biopsies to fat in sites of retiform purpura may demonstrate characteristic elongated clefts in deep dermal arterioles. ●Oxalosis – Oxalate embolism can occur in patients with primary hyperoxaluria. Patients develop hyperoxalemia and hyperoxaluria leading to recurrent urolithiasis that begins in childhood and subsequent progression to renal failure. Skin manifestations of oxalosis present after the onset of renal failure and include acrocyanosis, livedo reticularis, and cutaneous necrosis. Histopathologic examination reveals birefringent yellow-brown crystals within and around vessels in the deep dermis or fat. (See "Primary hyperoxaluria".) ●Calciphylaxis – Calciphylaxis, also referred to as calcific uremic arteriolopathy, presents with painful indurated reticulate purpuric plaques that progress to necrosis and ulceration (picture 13A, 13C). Calciphylaxis is most commonly seen in patients with renal failure, often in the setting of diabetes. Prognosis is poor [11]. (See "Calciphylaxis (calcific uremic arteriolopathy)".) Biopsies of involved skin must include the subcutaneous tissue; calcium deposits are found in the media of blood vessels in the fat. Perieccrine calcium deposition may be a highly specific but not sensitive finding in calciphylaxis [12]. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Diagnosis'.)

464

Sickle cell disease — Leg ulcers can occur as a complication of sickle cell disease. The ulcers most commonly occur on the medial and lateral malleoli and are usually painful and intractable [13,14]. The mechanism for ulcer development is not fully understood but may involve impaired blood flow, endothelial dysfunction, thrombosis, inflammation, and delayed healing [15]. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Leg ulcers'.)

Pyoderma gangrenosum — Pyoderma gangrenosum (PG) is a neutrophilic dermatosis often associated with an underlying systemic disorder, such as inflammatory bowel disease, arthritis, or hematologic disease (eg, acute and chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, IgA monoclonal gammopathy) [16]. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis", section on 'Associated disorders'.) ●Clinical features – PG classically presents as single or multiple rapidly progressive painful leg ulcers with necrotic borders and surrounding erythema (picture 15A-B). The initial clinical finding is a pustule, which then develops an overlying necrotic bulla that ulcerates with purulent drainage. The lower leg is a common site of involvement [17]. PG may exhibit pathergy, the induction or worsening of PG in sites of trauma. In its acute phase, PG may be accompanied by systemic symptoms or signs, such as fever and leukocytosis. In addition to the classic form, there are bullous, pustular, superficial granulomatous, and peristomal variants. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.) ●Diagnosis – PG is a diagnosis of exclusion, since there are no specific clinical, pathologic, or laboratory findings. Biopsies of an acute PG ulcer may demonstrate a neutrophilic infiltrate in the dermis, often with a surrounding mononuclear cell infiltrate. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis", section on 'Diagnosis'.)

Panniculitis — Panniculitides are disorders characterized by inflammation of the subcutaneous fat. Panniculitides associated with lower extremity ulcers include erythema induratum (nodular vasculitis) and panniculitis caused by alpha-1-antitrypsin deficiency or pancreatic disease. (See "Panniculitis: Recognition and diagnosis".) ●Erythema induratum – Erythema induratum typically occurs in young or middle-aged women and involves the lower legs, especially the posterior calves. The disorder presents with tender subcutaneous nodules and plaques that may ulcerate and drain (picture 16A-B). Biopsy demonstrates a mixed septal and lobular inflammatory cell infiltrate with vasculitis in most cases. Erythema induratum was classically described as a tuberculid associated with M. tuberculosis; however, erythema induratum may also be idiopathic or associated with other infections or drugs. (See "Cutaneous manifestations of tuberculosis", section on 'Erythema induratum of Bazin'.)

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●Alpha-1-antitrypsin deficiency –Alpha-1-antitrypsin deficiency produces a neutrophil panniculitis in a small subset of patients [18]. Patients develop tender erythematous or purpuric nodules and plaques on the lower trunk and extremities. The nodules and plaques may ulcerate, drain an oily discharge, and heal with scarring. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Skin disease'.) Biopsies of early alpha-1-antitrypsin deficiency panniculitis demonstrate a neutrophilic infiltrate of the fat followed by necrosis and destruction of fat lobules. Diagnosis is confirmed by serum evaluation of alpha-1-antitrypsin activity and genotype analysis. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".) ●Pancreatic panniculitis – Suppurative panniculitis is a rare complication of benign or malignant pancreatic disease [19]. Subcutaneous painful nodules develop on the lower extremities and trunk and may drain an oily material (picture 17). Systemic symptoms may include fever, abdominal pain, and arthritis; ascites and pleural effusions may also be present. Histopathologic examination of pancreatic panniculitis demonstrates septal and lobular inflammation, plus the diagnostic changes of fat necrosis and characteristic "ghost cells" and saponification of the fat. (See "Panniculitis: Recognition and diagnosis".)

Malignancy — Leg ulcers may arise as a feature of a primary cancer or as a result of malignant transformation of a chronic ulcer. Various cutaneous malignancies can cause ulcers. In a prospective study of 154 chronic leg ulcers in 144 patients that were diagnosed as venous ulcers but failed to respond to three months of standard treatment, biopsies revealed skin cancer in 16 ulcers (10 percent) [20]. Of the 16 malignant ulcers, there were 9 squamous cell carcinomas, 5 basal cell carcinomas, 1 melanoma, and 1 leiomyosarcoma. Cutaneous lymphomas (both B and T cell) and Kaposi's sarcoma may also cause leg ulcerations. Malignant ulcers often are not recognized immediately. Primary malignant ulcers may be assumed to result from other causes of ulceration, and malignant transformation of a chronic ulcer may become apparent only after an ulcer fails to respond as expected to treatment. Diagnosis is dependent upon histologic confirmation of malignancy. Ulcers that are enlarging or failing to heal despite treatment, occurring in scars, or with exophytic or irregular wound edges probably warrant biopsy to rule out malignancy, but a standard of care has not been determined in large studies.

Drugs — Drugs associated with the development of leg ulcers include warfarin, heparin, and hydroxyurea. ●Warfarin– Warfarin skin necrosis is a microvascular occlusion syndrome that begins two to five days after beginning warfarin without concomitant heparin therapy and results from a transient hypercoagulable state [21,22]. Pain is the initial symptom, followed by erythema, which then becomes hemorrhagic and necrotic (picture 18A-B). Retiform purpura may be adjacent to sites of skin necrosis. Warfarin-induced skin necrosis is more common in women than men and is most

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likely to occur in fatty areas, such as breasts, hips, buttocks, and thighs. A biopsy of involved skin demonstrates bland thrombi in dermal blood vessels. (See "Protein C deficiency", section on 'Warfarin-induced skin necrosis'.) ●Heparin – Heparin-induced thrombocytopenia is a thrombotic complication of heparin therapy resulting from the production of autoantibodies against platelet factor 4 in complex with heparin. Patients with heparin-induced thrombocytopenia may develop microvascular occlusion resulting in skin necrosis at sites of heparin injection or other sites, such as the distal extremities or nose (picture 19). The initial manifestation is erythema that evolves to purpura, hemorrhage, and necrosis. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".) ●Hydroxyurea–Hydroxyurea-related leg ulcers may occur in patients receiving chronic hydroxyurea therapy. The ulcers are clinically similar to ulcers of livedoid vasculopathy: painful, fibrous, persistent ulcers with surrounding atrophie blanche changes, typically near the malleoli or on the anterior lower leg [23]. The mechanism for ulcer development may involve drug-induced cytologic damage [23].

Brown recluse spider bite — Loxosceles reclusa envenomation is a rare cause of dermonecrotic lesions resulting in painful leg ulcers. The venom contains sphingomyelinase D, which may be responsible for neutrophil activation and skin necrosis (necrotic arachnidism). (See "Bites of recluse spiders".) ●Clinical features – The actual bite is often minimally painful; however, it is followed by the appearance of a tender erythematous plaque. The plaque develops central pallor followed by painful blistering and/or necrosis in about 40 percent of cases (picture 20A-B) [24]. (See "Bites of recluse spiders", section on 'Clinical manifestations of bites'.) ●Diagnosis – The diagnosis is based upon witnessing the spider bite and correct identification of the spider. Most ulcers suspected to be caused by spider bites are actually due to infection or pyoderma gangrenosum. In the absence of a witnessed bite and identification of the spider, other etiologies should be considered. (See "Bites of recluse spiders", section on 'Diagnosis'.)

PATIENT EVALUATION

The evaluation of patients with leg

ulcers begins with a clinical evaluation aimed at narrowing the differential diagnosis. Given that the vast majority of ulcers are caused by venous insufficiency, arterial insufficiency, or neuropathy, the initial goal should be to identify patients with these conditions. Alternative diagnoses should be considered when patients have features that are not consistent with these etiologies or fail to respond to appropriate treatments.

History — Key aspects of the patient history that should raise suspicion for venous, arterial, or neuropathic ulcers are reviewed in a table (table 2). Additional information that may aid in identifying other causes includes:

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●History of trauma at ulcer site (traumatic ulcers, pyoderma gangrenosum [PG]) ●Severe pain (ulcers due to arterial insufficiency, microvascular occlusion disorders, or PG) ●Rapid ulcer development (infectious ulcers, PG, brown recluse spider bite ulcer) ●Underlying thrombosis or coagulopathies (venous insufficiency ulcers, microvascular occlusion disorder ulcers, livedoid vasculopathy [LV]) ●Underlying autoimmune disease or hematologic disease (ulcers due to vasculitis, PG, LV) ●Other chronic disease (ulcers due to arterial insufficiency [atherosclerosis], diabetic neuropathy [diabetes], PG [inflammatory bowel disease, arthritis], panniculitides [pancreatitis, alpha-1-antitrypsin deficiency, tuberculosis]) ●Medication exposure (warfarin-, heparin-, or hydroxyurea-induced ulcers) ●Poor mobility (pressure ulcers) ●Smoking (ulcers due to thromboangiitis obliterans) In addition, the clinician should review prior ulcer treatments. A failure to respond to treatment may suggest an incorrect diagnosis or malignant ulcer. (See 'Malignancy' above.)

Physical examination — The physical examination serves to identify physical features of the ulcer (eg, location, size, shape) and associated cutaneous or non-cutaneous features that may aid in diagnosis. Findings that should raise suspicion for venous insufficiency, arterial insufficiency, and neuropathic ulcers are reviewed in a table (table 2). Because arterial insufficiency ulcers are common, routine palpation of pedal pulses is prudent. (See "Clinical assessment of chronic wounds", section on 'Vascular assessment'.) Additional physical examination findings that may help to narrow the differential diagnosis include: ●Palpable purpura (ulcers due to small or small- and medium-vessel vasculitis) ●Retiform purpura or livedo racemosa (ulcers due to microvascular occlusion disorders or mediumvessel vasculitis) ●Nodules (ulcer due to medium-vessel vasculitis or panniculitis) ●Predilection for high-fat areas (ulcers due to calciphylaxis or warfarin) ●Atrophie blanche (livedoid vasculopathy or venous insufficiency ulcers) ●Livedo reticularis (ulcers due to microvascular occlusion disorders) ●Oily drainage (ulcers due to pancreatic panniculitis or alpha-1-antitrypsin panniculitis)

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The physical examination should also include an assessment for clinical signs of secondary infection (eg, warmth, erythema, swelling, purulent drainage, malodor) or osteomyelitis (eg, visible bone, ability to probe to bone). (See "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities", section on 'Clinical manifestations' and "Osteomyelitis in adults: Clinical manifestations and diagnosis".)

Biopsy — Biopsies are not necessary for the diagnosis of most ulcers, but can be helpful when the diagnosis is unclear or ulcers fail to respond to therapy. Histopathologic examination may be particularly helpful when vasculitis, microvascular occlusion disorders, panniculitis, infection, or malignancy are in the differential diagnosis. In general, biopsies for diagnosis are performed from the edge of an ulcer. A punch biopsy to subcutaneous fat or a wedge biopsy from the ulcer edge are recommended. A biopsy from purpura or early necrosis at the ulcer edge may be particularly informative. A biopsy site may subsequently ulcerate in cases of PG (pathergy) and patients should be informed of this risk. Biopsies to provide tissue for culture are also useful for evaluating ulcers for primary or secondary infection. (See 'Infection' above.)

Additional tests — The need for serologic, radiologic, or microbiologic studies is determined by the disorders being considered. Such studies may be performed to confirm ulcer etiology or to evaluate for an associated underlying disease. (See 'Common causes' above and 'Less common causes' above.) Additional tests also may serve to evaluate for complications such as wound infection or osteomyelitis. However, routine wound swab cultures are not recommended in the absence of clinical signs of infection because bacterial colonization of ulcers is common [4]. (See 'Physical examination' above and "Clinical assessment of chronic wounds", section on 'Wound assessment' and "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

INDICATIONS FOR REFERRAL

Leg ulcers that do

not heal within three months of conservative wound care, are associated with livedo racemosa/reticularis or purpura, increase rapidly in size, or worsen with debridement should be referred to dermatology for further assessment. Classic venous ulcers or worsening arterial ulcers should be referred to vascular surgery.

SUMMARY AND RECOMMENDATIONS 469

●Leg ulcers are a common condition that can result in significant morbidity. The causes of leg ulcers are diverse (table 1). The most common causes are venous insufficiency, arterial insufficiency, and neuropathy. Physical injury, infection, vasculopathies, pyoderma gangrenosum (PG), panniculitis, malignancies, drugs, and spider bites are less common etiologies. (See 'Common causes' above and 'Less common causes' above.) ●Although the differential diagnosis of leg ulcers is broad, the high frequency of venous insufficiency, arterial insufficiency, and neuropathic ulcers warrant strong consideration of these etiologies during patient evaluation (table 2). If findings are not consistent with these etiologies, less common causes of leg ulcers should be considered. (See 'Patient evaluation' above.) ●Clinical findings that suggest venous insufficiency ulcers include location on the lower leg, particularly near the medial or lateral malleoli, and signs of chronic venous disease, such as edema, varicosities, hemosiderin deposition, or stasis dermatitis. Venous ulcers are usually shallow with irregular borders and overlying yellow, fibrinous exudate. (See 'Venous insufficiency' above.) ●Clinical findings that suggest arterial insufficiency ulcers are painful, well-demarcated ulcers with a "punched-out" appearance located on toes or pressure areas. Associated clinical findings may include a shiny appearance to the skin, local hair loss, diminished pulses, and dry gangrene. (See 'Arterial insufficiency' above.) ●Clinical findings that suggest neuropathic ulcers include painless, "punched-out" ulcers occurring over pressure points, usually on the foot or heel. A surrounding callus is common. Patients with diabetic neuropathy may also have claw toes, neuropathic (Charcot) arthropathy, and reduced sweating on the feet resulting in dry, scaly feet. (See 'Neuropathy' above.) ●Careful assessment of the patient history and physical findings is often helpful for identifying less common causes of leg ulcers. Historical information such as the time course of ulcer development, underlying disease, or medication exposure can be useful. Recognition of associated physical findings such as palpable purpura, retiform purpura, or nodules can also aid in diagnosis. (See 'Patient evaluation' above.) ●Biopsies are not necessary for the diagnosis of most ulcers, but can be helpful when the diagnosis is uncertain. In particular, histopathologic examination may be helpful when the differential diagnosis includes vasculitis, microvascular occlusion syndromes, panniculitis, or malignancy. Additional laboratory or radiologic studies may be helpful for confirming the cause of an ulcer or evaluating for a suspected infection or associated underlying disease. (See 'Patient evaluation' above.)

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Evaluation of adults with cutaneous lesions of vasculitis uptodate.com/contents/evaluation-of-adults-with-cutaneous-lesions-of-vasculitis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Oct 28, 2019.

INTRODUCTION

Cutaneous vasculitis comprises a diverse group of

conditions characterized by acute, relapsing, or chronic inflammatory damage to small or mediumsized blood vessels in the skin or subcutaneous tissue. Cutaneous vasculitis can occur as a feature of multiple disorders and exhibits a wide variety of clinical manifestations. Examples of clinical findings include petechiae, palpable purpura, hemorrhagic bullae, nodules, ulcers, livedo reticularis, livedo racemosa, and urticaria. Although cutaneous vasculitis can be a benign, transient condition, it may also be an indicator of underlying disease or systemic vasculitis. Careful assessment is essential for accurate diagnosis and optimal management. A typical initial evaluation includes a skin biopsy to confirm vasculitis, careful review of the patient history to assess for the etiology of vasculitis, and laboratory tests to assess for systemic involvement. When the cause of vasculitis is uncertain, additional tests may be helpful. The general approach to the evaluation of adults with cutaneous lesions suggestive of vasculitis will be reviewed here. Overview discussions of vasculitis in adults and children and in-depth discussions of specific forms of vasculitis are provided separately. (See "Overview of and approach to the vasculitides in adults" and "Vasculitis in children: Evaluation overview" and 'Types of cutaneous vasculitis' below.)

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TYPES OF CUTANEOUS VASCULITIS

The dermatologic addendum to the 2012 Revised International

Chapel Hill Consensus Conference Nomenclature of Vasculitides provides a framework for the classification of vasculitides affecting the skin [1]. Major groupings are based upon the size of vessels involved, propensity to affect other organs, and associated causes: ●Small vessel vasculitis (primarily affects dermal vessels [arterioles, capillaries, venules]): •Immune complex vasculitis: -Immunoglobulin A (IgA) vasculitis (Henoch-Schönlein purpura) (see "IgA vasculitis (HenochSchönlein purpura): Clinical manifestations and diagnosis") -Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis) (see "Urticarial vasculitis") -Cryoglobulinemic vasculitis (see "Overview of cryoglobulins and cryoglobulinemia") •Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis: -Microscopic polyangiitis (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis") -Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (see "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)") -Granulomatosis with polyangiitis (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis") ●Medium vessel vasculitis (primarily affects arteries in subcutaneous tissue): •Cutaneous polyarteritis nodosa (see "Cutaneous polyarteritis nodosa") •Polyarteritis nodosa (see "Clinical manifestations and diagnosis of polyarteritis nodosa in adults") ●Variable-vessel vasculitis (may affect any type of vessel): •Behçet disease (see "Clinical manifestations and diagnosis of Behçet syndrome") •Cogan's syndrome (see "Cogan's syndrome") ●Cutaneous single-organ vasculitis (skin-limited vasculitis that exhibits no association with systemic vasculitis):

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•Cutaneous immunoglobulin M (IgM)/immunoglobulin G (IgG) immune complex vasculitis (leukocytoclastic vasculitis with IgG/IgM deposits that does not fit into another defined immune complex vasculitis) •Nodular cutaneous vasculitis (erythema induratum of Bazin) (see "Erythema induratum (nodular vasculitis)") •Erythema elevatum diutinum (see "Erythema elevatum diutinum") Additional defined variants include vasculitis associated with systemic disease (eg, rheumatoid vasculitis, lupus vasculitis, etc) and vasculitis associated with a probable etiology (ie, associated with a specific drug, infection, sepsis, neoplasm, etc). Large vessel vasculitides, such as Takayasu arteritis and giant cell arteritis, typically do not affect vessels in the skin. Occasionally, giant cell arteritis results in cutaneous necrosis related to vascular compromise of vessels proximal to the skin [1]. Rarely, giant cell arteritis involves vessels in the panniculus [1]. Kawasaki disease, a form of medium vessel vasculitis, also does not typically involve vessels in the skin. (See "Overview of and approach to the vasculitides in adults", section on 'Major categories of vasculitis'.)

WHEN TO SUSPECT CUTANEOUS VASCULITIS

Suspicion for cutaneous vasculitis typically arises based upon the

detection of suggestive cutaneous findings.

Suggestive findings — Cutaneous vasculitis may exhibit a variety of morphologies, which usually correlate with the pathologic processes occurring in the skin [2-4]. Clinical features can include manifestations typical of small vessel involvement (eg, petechiae, palpable purpura, hemorrhagic bullae, superficial ulceration, urticaria) or medium vessel involvement (eg, subcutaneous nodules, deep ulcers, livedo reticularis, livedo racemosa). The skin lesions are often asymptomatic but may be associated with pruritus, burning sensations, or pain. Examination of the entire skin surface can be helpful for the assessment for cutaneous vasculitis. Cutaneous vasculitis most commonly occurs in a symmetrical distribution on the lower legs, dependent areas, or on areas of constrictive clothing due to increased hydrostatic pressure in these locations. ●Petechiae – Petechiae are nonblanchable and nonpalpable, pinpoint macules (less than a few millimeters in diameter) that result from capillary inflammation and red blood cell extravasation (picture 1) [2]. Petechiae are nonblanchable due to the presence of extravasated erythrocytes in the dermis due to damaged vessel walls. Diascopy (the application of pressure to a skin lesion with a glass slide) is a helpful technique for identifying nonblanchable lesions.

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●Palpable purpura – Brisk inflammation of venules and arterioles initially manifests as infiltrated, erythematous papules and plaques. These progress to raised, nonblanchable (purpuric) lesions as damage to vessel walls increases (picture 2A-B) [2]. As with petechiae, diascopy can be used to confirm nonblanchable lesions. ●Hemorrhagic bullae – Small vessel involvement in the dermis can result in necrosis of overlying skin with associated blisters and extravasation of red blood cells (picture 3) [2]. ●Subcutaneous nodules – Intense inflammation of medium-sized vessels (vessels with muscular walls in the deep dermis and subcutis) can lead to the formation of nodular lesions (picture 4). ●Ulceration or digital necrosis – Ulceration and tissue necrosis occur when vasculitis results in reduced vascular perfusion in the skin (picture 5A-B) [2]. Superficial ulcers can occur in patients with small vessel vasculitis; deep ulcers are usually the result of medium vessel disease [5]. ●Livedo reticularis and livedo racemosa – Livedo reticularis presents as a localized or widespread, patchy, reticulated, vascular network with a red-blue or violaceous hue (picture 6A-B). It results from compromise of blood flow in medium-sized vessels and can occur in the setting of vasculopathy due to vasospasm, hypercoagulable states, thrombosis, increased blood viscosity, or embolic phenomena, as well as in association with vasculitis. Livedo racemosa presents with a more abrupt and broken vascular pattern than livedo reticularis (picture 7). It is strongly associated with Sneddon syndrome, a nonvasculitic disorder characterized by livedoid skin lesions and cerebrovascular accidents, but may also occur as a manifestation of medium vessel vasculitis and other disorders [6]. ●Urticaria – Unlike nonvasculitic urticaria, lesions of urticarial vasculitis usually persist for more than 24 hours and are frequently associated with a burning sensation or pain, rather than pruritus. Lesions may contain purpuric areas and can resolve with hyperpigmentation (picture 8). (See "Urticarial vasculitis".)

Mimickers — The presence of a petechial or purpuric eruption does not always indicate vasculitis. Examples of other disorders that may present with these findings include [7,8]: ●Common vasculitis mimickers: •Pigmented purpuric dermatoses (eg, nonblanchable pinpoint macules, patches, or plaques, often on the lower legs) (picture 9) (see "Pigmented purpuric dermatoses (capillaritis)", section on 'Schamberg's disease (progressive pigmentary purpura)') •Macular purpura due to chronic sun exposure, glucocorticoid therapy, trauma, or anticoagulants (picture 10) •Inflammatory disorders on the lower extremities or other dependent sites (eg, hemorrhagic macules or papules due to stasis dermatitis or maculopapular drug eruptions) (picture 11A-B)

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•Arthropod bites (eg, bedbugs) (picture 12) ●Less common vasculitis mimickers: •Scurvy (perifollicular hemorrhage) (picture 13) (see "Overview of water-soluble vitamins", section on 'Deficiency') •Platelet deficiencies or dysfunction (petechiae or macular purpura) (picture 14) •Hypercoagulable and thrombotic disorders (noninflammatory retiform purpura) (picture 15A-B) (see "Approach to the patient with retiform (angulated) purpura") •Cholesterol emboli (noninflammatory retiform purpura, digital gangrene, livedo reticularis) (picture 16) (see "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)") •Septic emboli (petechiae on the distal extremities, noninflammatory retiform purpura) (picture 17) (see "Complications and outcome of infective endocarditis", section on 'Metastatic infection') •Systemic amyloidosis (periorbital and pinch purpura) (picture 18) (see "Cutaneous manifestations of amyloidosis") •Strongyloidiasis (periumbilical purpura) (see "Strongyloidiasis") •Purpura fulminans (sharply demarcated retiform purpura in the setting of disseminated intravascular coagulation or sepsis) (picture 19) (see "Disseminated intravascular coagulation (DIC) in adults: Evaluation and management" and "Clinical manifestations of meningococcal infection", section on 'Purpura fulminans') •Calciphylaxis (painful retiform purpura in adipose-rich areas, livedo reticularis) (see "Calciphylaxis (calcific uremic arteriolopathy)") In addition, livedoid vasculopathy (also known as atrophie blanche) may be confused with vasculitis. Livedoid vasculopathy presents with punched-out ulcers on the lower legs with surrounding livedo reticularis or livedo racemosa (picture 20). (See "Livedoid vasculopathy".)

PATIENT ASSESSMENT

The evaluation of patients with

cutaneous lesions of vasculitis focuses on confirming the presence of vasculitis, evaluating for extracutaneous involvement, and identifying the underlying cause. This typically involves consideration of a skin biopsy (or biopsies), careful review of the patient history and review of systems, and performance of select laboratory tests.

Skin biopsy to confirm vasculitis

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Indications for biopsy — A diagnosis of cutaneous vasculitis may be strongly suspected based upon the physical examination; however, a biopsy is necessary for a definitive diagnosis. In general, a skin biopsy for routine histopathologic examination should be performed whenever feasible. However, clinicians with expertise in the evaluation of cutaneous vasculitis may elect to delay a biopsy for patients with classic presentations of acute small vessel cutaneous vasculitis that have persisted for less than four weeks, have a clear removable or treatable inciting factor (eg, drug or infection), and exhibit no clinical or laboratory evidence of systemic involvement because many such cases resolve spontaneously within a few weeks. If the vasculitis fails to improve within four weeks (ie, new lesions developing or persistence of red or purple lesions), performance of a skin biopsy is indicated. Of note, residual, macular or patchy hyperpigmentation is common after resolution of vasculitis lesions. An additional skin biopsy for direct immunofluorescence (DIF) may be performed at the same time as the biopsy for routine histopathologic examination but is not always necessary. (See 'Direct immunofluorescence' below.)

Diagnostic criteria — A histologic diagnosis of cutaneous vasculitis is confirmed by the identification of findings that indicate an inflammatory process that results in damage to vessel walls [2,4]. Small vessels (venules and arterioles) require two out of three of the following criteria for a definitive diagnosis of vasculitis [9]: ●Angiocentric and/or angioinvasive inflammatory infiltrates ●Disruption and/or destruction of vessel walls by the inflammatory infiltrate ●Fibrinoid necrosis (fibrin deposition within the vessel wall or lumen; results from the accumulation and conversion of plasma proteins [2]) Medium-sized vessels (small arteries and veins) in the deep dermis and subcutaneous tissue require both of the following criteria to confirm vasculitis: ●Inflammatory infiltrate infiltrating the muscular vessel wall ●Fibrinoid necrosis

Additional supportive findings — Other histopathologic findings that support but are not diagnostic for vasculitis include the presence of extravasated erythrocytes, nuclear debris (leukocytoclasia), necrosis of eccrine glands, endothelial cell damage swelling or necrosis, and cutaneous ulceration, infarction, or necrosis [9]. Findings that suggest particular forms of vasculitis (eg, granulomas in granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis [Churg-Strauss syndrome] and interface dermatitis in vasculitis associated with lupus erythematosus or dermatomyositis) represent additional helpful information that can be

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gleaned from a biopsy. "Leukocytoclastic vasculitis" is a pathologic term that describes the microscopic findings of a neutrophilic small vessel vasculitis, a characteristic feature of multiple forms of cutaneous small vessel vasculitis.

Procedure — Optimizing the timing of the biopsy, biopsy depth, and biopsy location increases the likelihood of identifying diagnostic features.

Timing — The histologic characteristics of vasculitic lesions evolve quickly. Selection of a lesion that the patient estimates has been present for 24 to 48 hours for biopsy may optimize both the detection of vasculitis and assessment of the type of inflammatory infiltrate, a feature that can be helpful for diagnosis. Lesions that are between 24 and 48 hours old are the most likely to demonstrate diagnostic findings. Biopsies of leukocytoclastic vasculitis taken prior to 24 hours are likely to have some infiltration of neutrophils but often do not yet exhibit fibrinoid necrosis. Beyond 48 hours, the inflammatory infiltrate in leukocytoclastic vasculitis begins to shift from a neutrophilic infiltrate to lymphocytes and macrophages, and then eventually clears, leaving only evidence of fibrinoid necrosis. (See 'Diagnostic criteria' above and 'Additional supportive findings' above.)

Type of biopsy — The cutaneous features dictate the type of biopsy that should be performed. In general, shave biopsies should be avoided, as they prevent the evaluation of vessels in the mid-dermis and deep dermis. (See "Skin biopsy techniques", section on 'Biopsy techniques'.) The following principles are helpful for guiding the selection of the appropriate procedure: ●Cutaneous findings suggestive of involvement of the vessels in the superficial to mid-dermis (petechiae, palpable purpura, or urticarial papules or plaques) should be evaluated with a punch biopsy that is 4 mm in diameter or larger. This allows for evaluation of vessels throughout the dermis. ●Cutaneous findings suggestive of involvement of the vessels in the mid-dermis to the subcutaneous tissue (livedo racemosa, subcutaneous nodules, ulcers) require a large punch biopsy (8 to 10 mm) or wedge biopsy that includes the subcutaneous tissue.

Location — The cutaneous features determine the optimal location of the biopsy within the involved area. Biopsies of petechial lesions or palpable purpura can be taken from any site within the lesion. The ideal location of the biopsy differs in patients with livedo racemosa or ulcerations. In livedo racemosa, biopsy should be performed within the pale center of an erythematous ring [2]. This is where the responsible vessel is likely to be located. When ulceration is present, the biopsy should be taken from the edge of the ulcer, rather than the ulcer itself. A biopsy taken from the base of an ulcer can reveal purely incidental findings of vascular injury that resemble the histopathologic findings of vasculitis [9]. Biopsies of nodular lesions should be centered over a tender nodule.

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Biopsies of infarcted digits are generally low yield for evaluation for vasculitis, as the infarcted area is simply a manifestation of underlying vessel obstruction. Biopsies of livedo reticularis, a feature that may accompany vasculitis, demonstrate nonspecific histopathologic findings and are usually not indicated.

Direct immunofluorescence — Although an additional skin biopsy for direct immunofluorescence (DIF) is commonly performed at the same time as the biopsy for routine histopathologic examination in patients with findings suggestive of small vessel vasculitis, an immediate biopsy for DIF is not mandatory when small vessel vasculitis is acute (duration hallux > index finger > single digit > multiple digits) ●Extension of pigment to the proximal or lateral nail fold (Hutchison sign) or free edge of nail plate ●Family history of melanoma

Dermoscopic examination (onychoscopy) — Nail plate dermoscopy (onychoscopy) may help the clinician with at least minimal training in dermoscopy in recognizing benign lesions that do not require further histologic examination from lesions that require biopsy or regular follow-up. However, clinicians should be cognizant that dermoscopy is not a substitute for histopathologic diagnosis and that it is important to maintain a low threshold of suspicion for performing a biopsy for histopathologic examination: ●Melanonychia due to melanocytic activation appears as a gray background with thin, gray, regular, parallel lines (picture 12). In melanocyte activation caused by chronic trauma, tiny, dark red to brown spots corresponding to extravasation of blood may also be seen [1]. (See "Dermoscopy of nail pigmentations", section on 'Benign lesions'.) ●Nail lentigines generally appear as homogeneous, longitudinal, thin, gray or brown lines on a gray or light brown background; nail lentigines are more common in adults than in children. ●Nail nevi, which are more common in children than in adults, appear as a band of regular lines of light brown to black color on a brown background (picture 13 and picture 14) [16,23]. ●Dermoscopic features associated with nail melanoma include (picture 15A-B) [16,23,24]: •Brown background hue •Presence of irregular, longitudinal lines (in their color, spacing, thickness, and parallelism) •Micro-Hutchinson sign (pigmentation of the cuticle seen on dermoscopy but not with the naked eye)

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It is important to note that irregular lines that would be considered suspicious for melanoma in an adult can often be seen in children with nail matrix nevi (picture 16 and picture 17). (See "Dermoscopy of nail pigmentations", section on 'Benign lesions' and "Dermoscopy of nail pigmentations", section on 'Melanonychia in children'.) The dermoscopic evaluation and differential diagnosis of longitudinal melanonychia are discussed in greater detail separately (algorithm 2). (See "Dermoscopy of nail pigmentations", section on 'Differential diagnosis of nail pigmentations'.)

When to biopsy — In most patients presenting with stable longitudinal melanonychia involving multiple nails, a biopsy is not required to confirm the clinical diagnosis (algorithm 1). (See 'Melanonychia due to melanocytic activation' above.) In contrast, a clinician's threshold for biopsy should be low when examining a patient with a single digit longitudinal melanonychia, especially if (algorithm 1): ●Onset occurred in adulthood ●Lesion is located on the thumb, index finger, or big toenail ●Lesion shows clinical features that suggest melanoma (see 'Clinical features suspicious for nail melanoma' above) ●Lesion shows dermoscopic features suspicious for melanoma (see 'Dermoscopic examination (onychoscopy)' above) ●Lesion is rapidly enlarging In children, longitudinal melanonychia is in most cases due to a nevus of the nail matrix, while nail melanoma is exceedingly rare, with only a few cases reported in the literature [12,25,26]. Thus, some experts suggest to avoid nail matrix biopsy in children where possible, with the exception of cases in which the band enlarges and/or darkens rapidly or involves the whole nail [27]. The techniques for performing a nail matrix biopsy are described elsewhere. (See "Nail biopsy: Indications and techniques".)

Histopathologic diagnosis — Histopathologic examination is the gold standard for the diagnosis of longitudinal melanonychia. However, differentiating early melanoma of the nail matrix from benign melanocytic lesions may be challenging, even for the expert pathologist, as some features (eg, cellular atypia, pagetoid spread, nest formation) can be seen in lentigines, nevi, and in melanoma in situ: ●Melanocytic activation – Melanocytic activation is characterized by nonspecific, melanic pigmentation of the matrix epithelium without an increase in the number of melanocytes. The Fontana-Masson stain is helpful when the pigmentation is barely visible. There are some

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melanocytes with pigmented dendrites in the suprabasal layer of the proximal matrix and basal layer of the distal matrix and pigmented keratinocytes; a few melanophages can be seen in the superficial dermis [28,29]. Cytologic atypia is absent. ●Lentigo – Lentigo is characterized by a slight to moderate increase in the number of matrix melanocytes (10 to 31 per mm) that are individually aligned in the basal layer without confluence [28,29]. Cytologic atypia is absent or mild; pagetoid spread is rare or focal. The pigmentation is usually limited to the lower third of the nail epithelium but can be observed throughout its full thickness. Fontana-Masson staining shows fine granularity of the melanin pigment. ●Nevus – On microscopic examination, a melanocytic nevus of the nail matrix is characterized by hyperplasia of melanocytes with nest formation. A lentiginous pattern can be seen at the center of the lesion, along with a suprabasal pagetoid spread tendency, mild nuclear pleomorphism, and nail plate involvement [29]. Periungual pigmentation can also be observed. ●Melanoma – Melanoma in situ is characterized by an increased number of melanocytes in the basal cell layer (39 to 136 per mm), with a predominance of single melanocytes and a few nests [20,28]. Nuclear atypia and pagetoid spreading are present. Atypical melanocytes have large, hyperchromatic, pleomorphic nuclei; prominent nucleoli; increased mitoses; and long, branching dendrites [6]. A dermal lymphoid infiltrate is present. The detection of melanocytes in the nail plate corresponding to the matrix keratogenous zone is an important finding for malignancy [29]. Invasive melanoma is characterized by atypical melanocytes invading the dermis. The commonest histogenic subtype is acral lentiginous, followed by nodular and desmoplastic [28]. (See "Pathologic characteristics of melanoma", section on 'Acral lentiginous melanoma'.)

DIFFERENTIAL DIAGNOSIS

Several nonmelanic

pigmentations of the nail plate may be confused with longitudinal melanonychia. These include (see "Overview of nail disorders"): ●Subungual hematoma (picture 18) ●Exogenous discoloration ●Splinter hemorrhage (picture 19A-C) ●Fungal melanonychia (picture 20) ●Longitudinal erythronychia ●Onychopapilloma (picture 21) ●Pigmented onychomatricoma

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MANAGEMENT

Longitudinal melanonychia is in most cases a benign

condition. A wait-and-see approach with periodic clinical and, if available, dermoscopic monitoring may be appropriate in adults and children when clinical and dermoscopic features indicate a low risk of melanoma [2,13,30]. (See 'Monitoring' below.) Melanonychia should be excised when worrisome features suspicious for melanoma (eg, wide band, presence of the Hutchinson sign, or irregular dermoscopic features) are noted. Additional surgery is generally needed if the initial biopsy shows melanoma. Wide surgical excision of the entire nail apparatus with margin control is a conservative option for subungual melanoma in situ; digit amputation is the traditional surgical approach for invasive melanoma [31,32]. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites", section on 'Subungual'.) There is very limited evidence to guide the management of biopsied lesions displaying atypical melanocytic hyperplasia, especially in children [33,34]. Some experts suggest that adult patients with melanocytic hyperplasia with moderate to severe melanocytic atypia on biopsy should undergo complete resection with margin control [33]. In children, given the extreme rarity of subungual melanoma, clinical and dermoscopic surveillance for enlargement or changes may be reasonable [34].

MONITORING

There is no consensus on the frequency and modalities of

follow-up for pigmented nail bands. Some experts recommend clinical and dermoscopic examination every six months for lesions that have subtle, irregular features that do not require immediate biopsy [1,16]. Baseline medical photography of the nail in question, including dermoscopy photos when possible, can be very helpful when clinically monitoring over time the patient with longitudinal melanonychia.

SUMMARY AND RECOMMENDATIONS ●Longitudinal melanonychia, also called "melanonychia striata," describes a pigmented, brown to black, longitudinal streak of the nail plate resulting from increased melanin production and deposition within the nail plate. This may result from melanocytic activation, due to multiple causes, or from benign or malignant hyperplasia of melanocytes in the nail matrix (table 1). (See 'Introduction' above and 'Pathophysiology' above.) ●Longitudinal melanonychia presents with one or more pigmented bands running from the proximal nail fold to distal margin of the nail plate (picture 1):

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•Melanonychia due to melanocytic activation, also called "functional melanonychia," is the most common type of melanonychia seen in adult patients. It includes ethnic melanonychia, commonly seen in patients with darker skin tones, melanonychia due to repeated trauma (frictional melanonychia), and melanonychia associated with skin diseases, systemic diseases, or exposure to drugs. (See 'Melanonychia due to melanocytic activation' above.) •Melanonychia due to melanocytic hyperplasia includes benign lesions (lentigines and nevi of the nail matrix) and nail melanoma. Nail lentigines and nevi present as single-digit bands, 3 mm in width (picture 11) with variegated pigmentation or proximal widening (triangular shape) •Pre-existing longitudinal melanonychia that becomes darker or wider or demonstrates blurred, lateral borders •Longitudinal melanonychia associated with nail plate fissuring, splitting, or dystrophy (picture 9B) •Melanonychia extending to the nail folds (Hutchinson sign (picture 9C)) ●Longitudinal melanonychia is in most cases a benign condition. A wait-and-see approach with periodic clinical and dermoscopic monitoring may be appropriate in adults and children when clinical and dermoscopic features indicate a low risk of melanoma. Surgical excision of the entire lesion should be performed when there are worrisome features suspicious for melanoma. (See 'Management' above.) ●Additional surgery is needed following an initial biopsy showing melanoma. Wide surgical excision of the entire nail apparatus with margin control is a conservative treatment option for subungual melanoma in situ; digit amputation is the traditional approach for invasive melanoma. (See "Surgical

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management of primary cutaneous melanoma or melanoma at other unusual sites", section on 'Subungual'.)

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Erythroderma in adults - UpToDate uptodate.com/contents/erythroderma-in-adults/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Aug 26, 2019.

INTRODUCTION

Erythroderma (literally, "red skin"), also sometimes

called exfoliative dermatitis, is a severe and potentially life-threatening condition that presents with diffuse erythema and scaling involving all or most of the skin surface area (≥90 percent, in the most common definition). Erythroderma is a clinical sign and, as such, may be the clinical presentation of a wide range of cutaneous and systemic diseases (including psoriasis and atopic dermatitis), drug hypersensitivity reactions, and, more rarely, Sézary syndrome, a leukemic subtype of cutaneous T cell lymphoma. Although uncommon in pediatric patients, erythroderma may similarly be the clinical

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presentation of a wide range of acquired and inherited diseases. The differential diagnosis for erythroderma in pediatric patients includes infections, inflammatory skin diseases, ichthyoses, and congenital immunodeficiencies. This topic will discuss the clinical manifestations, diagnosis, and treatment of erythroderma in adults. Erythroderma in neonates and infants and Sézary syndrome are discussed separately. (See "Neonatal and infantile erythroderma" and "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

EPIDEMIOLOGY

Erythroderma is a rare condition. The annual incidence

has been estimated to be approximately 1 per 100,000 in the adult population [1]. In a retrospective study, erythroderma accounted for 13 in 100,000 patients presenting with skin diseases in China [2]. Erythroderma can occur at any age and in both sexes, but is more frequent in older adults (mean age 42 to 61 years) and in males [2-6]. Erythroderma is exceedingly rare in children; its prevalence is estimated to be approximately 0.1 percent in pediatric dermatology clinic populations [7,8].

ETIOLOGY

A wide range of cutaneous or systemic diseases can evolve to or cause

erythroderma (table 1): ●Exacerbation of a preexisting inflammatory dermatosis – The most common cause of erythroderma is the exacerbation of a preexisting inflammatory dermatosis, most often psoriasis or atopic dermatitis [3-6,9,10]. In patients with psoriasis, triggers of erythroderma include the abrupt discontinuation of systemic corticosteroids or other immunosuppressant therapy, systemic illnesses, phototherapy burns, medications (eg, lithium, antimalarials), or HIV infection [11]. ●Hypersensitivity drug reaction – A hypersensitivity drug reaction is the second most frequent cause of erythroderma (approximately 20 percent of cases). A wide variety of drugs have been reported to be associated with erythroderma, including penicillins, sulfonamides, carbamazepine, phenytoin, and allopurinol (table 2) [4,12]. Multiple patterns of drug reaction, from maculopapular/morbilliform eruption to drug reaction with eosinophilia and systemic symptoms to toxic epidermal necrolysis, may present with erythroderma. ●Uncommon causes – Uncommon causes of erythroderma include cutaneous T cell lymphoma and other hematologic and systemic malignancies, immunobullous diseases, connective tissue diseases, and infections (table 1). ●Idiopathic – In approximately 30 percent of cases of erythroderma, no underlying cause is identified and erythroderma is classified as idiopathic (sometimes called "red man syndrome," a term which is also used to describe an infusion reaction to vancomycin) [11,13,14].

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PATHOGENESIS

The pathogenesis of erythroderma is incompletely

understood. A complex interaction of cytokines (eg, interleukin-1, -2 and -8 and tumor necrosis factor), chemokines, and intercellular adhesion molecules is believed to play a role in the massive recruitment of inflammatory cells to the skin and elevated epidermal turnover. The increased mitotic rate and decreased transit time of epidermal cells through the skin layers results in exfoliation, with significant loss of proteins, amino acids, and nucleic acids through the skin. Increased circulating levels of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin) have been demonstrated in patients with erythroderma secondary to psoriasis or eczema and in patients with Sézary syndrome [15,16]. Immunohistochemical studies demonstrate a predominantly Th1 cytokine profile in the dermal infiltrates of patients with erythroderma associated with inflammatory dermatoses and a Th2 profile in the dermal infiltrates of patients with Sézary syndrome [17]. These findings suggest that different pathophysiologic mechanisms may lead to the relatively uniform clinical presentation of erythroderma.

CLINICAL MANIFESTATIONS Onset — Erythroderma may develop acutely over hours or days or evolve gradually over weeks to months. The onset is usually abrupt in drug hypersensitivity reactions. A morbilliform or urticarial eruption may first appear anywhere on the skin, then erythematous patches increase in size and coalesce into a generalized bright red erythema with occasional islands of sparing (picture 1A-B). Organ involvement (eg, hepatitis, nephritis, pneumonia) may occur in DRESS (drug reaction with eosinophilia and systemic symptoms). (See "Exanthematous (maculopapular) drug eruption" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".) Erythroderma from underlying cutaneous or systemic diseases usually develops more gradually. Erythematous patches may occur anywhere on the skin, enlarge and coalesce over hours to days to weeks to involve nearly the entire skin surface. Initially, the erythematous patches may have the characteristics of the underlying disease, but the specific features of the underlying diseases are often lost after erythroderma has fully developed.

Cutaneous signs and symptoms — By definition, over 90 percent of the skin is involved; the skin is red and warm to the touch (picture 1B). In light-skinned patients, the color of the skin varies from bright pink (characteristic of a drug reaction) to a dusky red (characteristic of chronic erythroderma from many causes). In patients with darker skin tones, these features may be more subtle. Most patients complain of severe skin pain or itching.

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Linear crusted erosions and secondary lichenification may result from rubbing and scratching in chronic erythroderma. On palpation, the skin may feel leathery and indurated. Scaling is a common feature, particularly in erythroderma that has been present for more than a week. Scales can be large, small, or bran-like, and are particularly abundant in patients with underlying psoriasis. Palmoplantar keratoderma (hyperkeratosis of the palms and soles) is most often associated with pityriasis rubra pilaris (picture 2A), but also may occur in patients with Sézary syndrome (picture 3). Nail pitting is characteristic of psoriasis (picture 4). Moist, crusted lesions on the face and upper trunk often precede the development of erythroderma in patients with pemphigus foliaceous (picture 5A-B). (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pemphigus foliaceus'.) Hair (eg, telogen effluvium, scaling of the scalp) and nail changes (paronychia, nail dystrophy, and onychomadesis [nail shedding]) may be present. Involvement of the eyelids manifests with blepharitis, epiphora (excessive tearing), and ectropion (eyelid eversion). These features may be particularly prominent in patients with chronic erythroderma secondary to Sézary syndrome. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Skin lesions'.)

Extracutaneous findings — Patients with erythroderma often appear uncomfortable, shiver, and complain of feeling cold. Constitutional symptoms (eg, malaise, fatigue, fever, or hypothermia) and signs of high output cardiac failure (eg, peripheral edema, tachycardia) also may be present. (See "Clinical manifestations, diagnosis, and management of high-output heart failure", section on 'Clinical manifestations'.) Lymphadenopathy and hepatomegaly or splenomegaly may be observed in chronic erythroderma. Lymph node biopsy often shows only the features of dermatopathic lymphadenopathy (a benign reactive lymph node enlargement), but may be diagnostic of lymphoma in patient with cutaneous T cell lymphoma (CTCL). (See "Clinical presentation and diagnosis of non-Hodgkin lymphoma", section on 'Lymph node and tissue biopsy'.)

Laboratory abnormalities — Nonspecific laboratory abnormalities may occur in patients with erythroderma due to various causes, including leukocytosis, anemia, and elevated erythrocyte sedimentation rate. Eosinophilia may be found in patients with DRESS. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on 'Laboratory abnormalities'.) Atypical lymphocytes with cerebriform nuclei (Sézary cells) are often observed in erythroderma regardless of cause. Counts of Sézary cells greater than 20 percent of the circulating peripheral blood lymphocytes are found in Sézary syndrome, a leukemic variant of cutaneous T cell lymphoma. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Peripheral blood'.)

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CLINICAL COURSE

Depending upon the cause, the erythema may

become generalized in hours to days, weeks, or months. Exfoliation typically begins two to six days after the onset of erythema, starts in flexural areas, and rapidly extends to the entire body surface. Scaling is particularly pronounced in patients with underlying psoriasis. Over weeks to months, hair and nail changes may occur. (See 'Cutaneous signs and symptoms' above.) The duration of erythroderma is highly variable. Erythroderma due to drug reactions usually resolves in two to six weeks after stopping the culprit drug. In patients with drug reaction with eosinophilia and systemic symptoms (DRESS), resolution of erythroderma may require many weeks to months. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".) Erythroderma due to underlying cutaneous or systemic diseases may persist for weeks, months, or years.

COMPLICATIONS

Erythroderma is relatively well tolerated by many

patients. However, some patients, particularly those at the extremes of age and patients with comorbidities, may experience complications. (See 'Hemodynamic and metabolic disturbances' below and 'Infection' below.)

Hemodynamic and metabolic disturbances — Profound disturbances in fluid and electrolyte regulation, thermoregulation, and metabolic balance occur with erythroderma. Increased skin perfusion leads to fluid loss by transpiration, and consequent electrolyte imbalance. Heat loss, hypothermia, and compensatory hypermetabolism associated with hyperthermia may occur. The shunting of the blood through the skin due to peripheral vasodilation may result in high-output cardiac failure, especially in older or compromised patients. (See "Causes and pathophysiology of high-output heart failure".) Exfoliation of the skin results in significant protein loss that may exceed 9 g/m2 body surface per day, particularly in patients with erythrodermic psoriasis [18]. The protein loss causes negative nitrogen balance, hypoalbuminemia, edema, and muscle wasting.

Infection — Inflammation, fissuring, and excoriation increase the susceptibility of the erythrodermic skin to bacterial colonization. Sepsis from Staphylococcus aureus, including methicillin-resistant S. aureus, has been reported in erythrodermic patients and is of particular concern in those who are HIV positive [19-22]. Widespread superinfection with herpes simplex virus (Kaposi varicelliform eruption) also has been reported in erythrodermic patients [23,24]. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia" and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Eczema herpeticum'.)

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DIAGNOSIS

The diagnosis of erythroderma is straightforward; it is made

clinically in a patient presenting with diffuse and generalized erythema and scaling involving 90 percent or more of the body surface area (picture 1A-B). Determining the cause of erythroderma is more difficult and requires meticulous clinical assessment and clinicopathologic correlation.

DETERMINATION OF UNDERLYING CAUSE

The underlying cause of erythroderma is often difficult to determine and may

remain elusive. In approximately one third of patients, the cause cannot be determined and erythroderma is classified as idiopathic. However, ongoing evaluation of patients with idiopathic erythroderma is important, since the underlying cause may become apparent over time [13,14]. The evaluation of the erythrodermic patient to determine the underlying cause involves a detailed history, physical examination, skin biopsies, and laboratory tests. Specific tests are performed based upon the suspected cause.

History — A detailed history is of key importance in establishing the cause of erythroderma. Important elements of history are: ●History of presenting illness – Onset of symptoms and course of erythroderma ●Past dermatologic and medical history – History of inflammatory skin disease (eg, psoriasis, atopic dermatitis), preexisting systemic diseases or neoplasia ●Medication history, including over-the-counter medications and supplements ●Family history of inflammatory skin diseases

Physical examination — Physical examination should include a complete examination of the skin, hair, nails, and mucosae for any sign of underlying skin disease. Lymph node and organ enlargement should be assessed. Clinical signs that are nonspecific but may be helpful in suggesting the cause of erythroderma include: ●Color of erythema – In light-skinned patients, the color of the erythema may be helpful in ascertaining the diagnosis. Salmon pink/orange color with islands of sparing is typical of pityriasis rubra pilaris (picture 1A) [25]. A deeper red color associated with exfoliation is associated with psoriasis or cutaneous T cell lymphoma (picture 1B).

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●Scaling – Severe scaling may indicate psoriasis. Crusted scales are seen in pemphigus foliaceus, whereas exfoliation of large skin sheets is seen in drug reactions. Scaling between the fingers or burrows involving the web spaces may indicate scabies. ●Bullae – The presence of bullae and the involvement of the mucous membranes may indicate immunobullous disease (eg, pemphigus, bullous pemphigoid). Moist, crusted lesions on the face and upper trunk often precede the development of erythroderma in patients with pemphigus foliaceous (picture 5A-B). (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pemphigus foliaceus'.) ●Keratoderma – Waxy keratoderma of palms and soles with an orange hue is characteristic of pityriasis rubra pilaris (picture 2A-B), but may also be observed in Sézary syndrome (picture 3). ●Nail abnormalities – Nail thickening, subungual hyperkeratosis, and splinter hemorrhages are found in psoriasis and pityriasis rubra pilaris (picture 6) [2,26,27]. The presence of nail pitting is a clue to the diagnosis of erythrodermic psoriasis (picture 4). ●Hair abnormalities – Diffuse alopecia is common in erythroderma from all causes but may be particularly prominent in Sézary syndrome (picture 7) [28]. ●Oral involvement – Oral mucositis is seen in most cases of erythroderma associated with immunobullous disease, Stevens-Johnson syndrome/toxic epidermal necrolysis, and graft-versushost disease. ●Eye involvement – Conjunctival involvement is frequently seen in erythroderma associated with immunobullous diseases, such as mucous membrane pemphigoid, and Stevens-Johnson syndrome/toxic epidermal necrolysis. Chronic conjunctivitis may be complicated by the development of trichiasis and symblepharon and may be associated with the development of sicca syndrome and corneal perforation. ●Genitourinary involvement – The genitourinary tract may be involved in erythroderma associated with mucous membrane pemphigoid or Stevens-Johnson syndrome/toxic epidermal necrolysis.

Skin biopsy and histopathologic examination — Multiple skin biopsies may be necessary to identify the cause of erythroderma. Skin samples are usually obtained by punch biopsy of multiple involved sites. (See "Skin biopsy techniques", section on 'Punch biopsy'.) The histopathology of erythroderma may reflect the underlying etiology. However, histology is more often unrevealing or nonspecific. Hyperkeratosis, acanthosis, spongiosis, and perivascular inflammatory infiltrate are frequent findings in erythroderma. The relative prominence of these features may vary with the stage of the disease and the severity of inflammation (table 3) [29-31]. More specific histopathologic changes may become apparent later in the course of the disease. Therefore, repeated skin biopsies over time may be needed to establish the diagnosis.

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As an example, in the initial phase of Sézary syndrome histology may show a nonspecific perivascular lymphocytic infiltrate without atypical lymphocytes and an overlying hyperplastic and parakeratotic epidermis (picture 8) [29]. At a later stage, the infiltrate may become increasingly pleomorphic and acquire specific diagnostic features, such as atypical cerebriform mononuclear cells and Pautrier microabscesses (picture 8). (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Light microscopic findings'.) Immunohistochemistry and T cell receptor gene rearrangement studies should be performed if atypical lymphocytes are identified in the inflammatory infiltrate by routine histologic examination. The demonstration of an immunophenotype of T cells lacking mature T cell antigens (CD3+, CD4+, CD7-) and the clonality of the T cell receptor gene rearrangement support the diagnosis of Sézary syndrome. The expression of the programmed death-1 (PD-1) may also be helpful in differentiating Sézary syndrome from erythroderma associated with inflammatory skin diseases. In one study PD-1 was expressed by over 50 percent of neoplastic CD4+ T cells in 23 of 25 biopsies from patients with Sézary syndrome and only in 4 of 30 biopsies from patients with erythroderma associated with inflammatory skin diseases [32]. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Immunophenotyping confirming T cell origin (CD3+, CD4+)' and "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Clonality of the T cell receptor (TCR) gene rearrangement'.) A predominance of CD8+ lymphocytes in the dermal infiltrate suggests chronic actinic dermatitis (actinic reticuloid). (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Chronic actinic dermatitis'.) Direct immunofluorescence should be performed if an immunobullous disease is suspected based upon the presence of intraepidermal bullae or subepidermal bullae or an urticarial appearance of the erythroderma. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Direct immunofluorescence' and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Direct immunofluorescence'.) In approximately 30 percent of cases, the histologic features of erythroderma remain nonspecific throughout its course and a precise diagnosis of the underlying condition cannot be made.

Laboratory and imaging tests — Laboratory testing is based upon the patient's medical history, clinical presentation, and suspected cause of erythroderma. The initial laboratory evaluation includes: ●Complete blood cell count and differential. Leukocytosis is common in all types of erythroderma. Eosinophilia >700/microL may be found in drug reaction with eosinophilia and systemic symptoms (DRESS). (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on 'Laboratory abnormalities'.) ●Routine biochemistry tests including electrolytes, glucose, serum albumin, LDH, liver and kidney function tests.

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●Examination of a peripheral blood smear for the presence of Sézary cells (atypical lymphocytes with cerebriform nuclei). Counts of Sézary cells >20 percent of examined lymphocytes suggest Sézary syndrome; counts 90 percent versus 20 percent in the vehicle group) [67]. Tacrolimus was more effective than hydrocortisone acetate and comparable in efficacy to hydrocortisone butyrate. Pimecrolimus was more effective than vehicle in the treatment of mild to moderate atopic dermatitis (33 percent of patients were clear or almost clear at three weeks versus 10 percent of those who used the vehicle) and in preventing flares. Pimecrolimus was less effective than betamethasone valerate, but its potency compared with hydrocortisone was not evaluated in any of the included trials. ●A subsequent meta-analysis of four randomized trials comparing tacrolimus with pimecrolimus for the treatment of atopic dermatitis including more than 1800 patients found that tacrolimus 0.1% ointment was more effective than pimecrolimus 1% cream after six weeks of therapy in adult patients (relative risk 0.58, 95% CI 0.46-0.72) [76]. In pediatric patients with moderate to severe eczema, tacrolimus 0.03% was superior to pimecrolimus 1% (relative risk 0.65, 95% CI 0.57-0.75). However, in the group of pediatric patients with mild to moderate eczema, there was no significant difference between tacrolimus 0.03% and 1% pimecrolimus. ●In a systematic review of 31 randomized trials, pimecrolimus was significantly better than vehicle in preventing flares at six months [77]. However, pimecrolimus was less effective than mediumpotency topical corticosteroids (triamcinolone acetonide 0.1% and betamethasone valerate 0.1%) and tacrolimus 0.1%.

Long-term safety concerns — Although the topical calcineurin inhibitors in controlled trials have appeared to be safe in adults and children [74,78-81], in 2005, based upon case reports, animal studies, and the known risks with systemic calcineurin inhibitors, the FDA issued warnings about a possible link between the topical calcineurin inhibitors and cancer [82] and, in 2006, placed a boxed warning on the prescribing information for these medications [83]. Issues of concern include: ●Animal studies in mice, rats, and monkeys have found an increased risk of lymphoma and skin cancers with topical or oral exposure to calcineurin inhibitors.

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●As of December 2004, the FDA had received 29 reports of cancers in adults and children treated with topical calcineurin inhibitors. Approximately half the cases were lymphomas, and the other half were cutaneous tumors. ●Between January 2004 and January 2009, the FDA received 46 reports of new cancer cases among children 0 to 16 years old who used topical pimecrolimus and/or topical tacrolimus (30 lymphomas/leukemias, 8 skin cancers, and 8 other cancers). However, no definite causal relationship has been established [84], and two case-control studies did not detect an increased risk of lymphoma among patients treated with topical calcineurin inhibitors [85,86]. The Pediatric Eczema Elective Registry (PEER) is an industry-sponsored, ongoing cohort study established in 2004, as part of the postmarketing commitments for the approval of pimecrolimus, to evaluate the risk of malignancy in children. Among 7500 children enrolled between 2004 and 2014, five malignancies (two leukemias, one osteosarcoma, and two lymphomas) were reported [87]. The standardized incidence ratio, based upon the age-standardized Surveillance, Epidemiology, and End Results Program population, was 1.2 (95% CI 0.5-2.8) for all malignancies, 2.9 (95% CI 0.7-11.7) for lymphoma, and 2.0 (95% CI 0.5-8.2) for leukemia. Although the excess risk of lymphoma and leukemia is not statistically significant, the authors acknowledge that the small sample size and the resulting wide confidence interval may not allow the exclusion of all risk. A subsequent meta-analysis did not find a statistically significant association between the use of topical calcineurin inhibitors and risk of lymphoma [88], although an included cohort study reported a fivefold increased risk of T cell lymphoma in patients exposed to topical tacrolimus (relative risk 5.44, 95% CI 2.51-11.79) [89]. Waiting for more reassuring data from larger studies, the following FDA recommendations seem reasonable precautions [90,91]: ●Use these agents only as second-line therapy in patients unresponsive to or intolerant of other treatments. ●Avoid the use of these agents in children younger than two years of age; clinical studies have found higher rates of upper respiratory infections in children younger than two years who were treated with pimecrolimus. ●Use these agents only for short periods of time and use the minimum amount necessary to control symptoms; avoid continuous use. ●Avoid the use of these agents in patients with compromised immune systems. Providers and patients will need to weigh the risks and benefits of topical calcineurin inhibitors in comparison with those of other therapies. In particular, calcineurin inhibitors may continue to have an important role in the management of atopic dermatitis in areas at high risk for skin atrophy when treated with corticosteroids (eg, face) [92].

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Off-label use in infants — Topical calcineurin inhibitors have been approved in the United States as second-line therapies for the short and intermittent treatment of mild to moderate atopic dermatitis in adults and children aged ≥2 years. However, they have been used off-label in children as first-line treatment for atopic dermatitis and in children 60 kg to ≤100 kg, 45 mg; for children >100 kg, 90 mg; ustekinumab is given at weeks 0, 4, then every 12 weeks ●

Efficacy – Published randomized trials have demonstrated efficacy and safety of etanercept, adalimumab, and ustekinumab. Brief summaries of these trials are provided below:

• Etanercept – In a 48-week trial in which 211 children with moderate to severe plaque psoriasis (ages 4 to 17 years) were randomly assigned to receive either etanercept (0.8 mg/kg [maximum dose 50 mg]) or placebo once weekly for 12 weeks, more children treated with etanercept achieved at least 75 percent improvement in the PASI score than children in the placebo group (57 versus 11 percent) at 12 weeks [36]. In addition, sustained efficacy of etanercept for pediatric psoriasis has been demonstrated through 96 weeks [38].

• Adalimumab – In a trial in which 114 children (ages 4 to 17 years) were randomly assigned to methotrexate (0.1 to 0.4 mg/kg per week) or one of two dose regimens of adalimumab (0.4 or 0.8 mg/kg every other week), more patients in the adalimumab 0.8 mg/kg dose group achieved 75 percent improvement in the PASI score than patients in the methotrexate group (58 versus 32 percent) after 16 weeks [23]. Sustained efficacy of adalimumab over 52 weeks in children aged 4 to 18 years has also been reported [39].

• Ustekinumab – In a trial in which 110 adolescents with moderate to severe plaque psoriasis (ages 12 to 17 years) were randomly assigned to one of two regimens of ustekinumab (standard dosing or half-standard dosing), adolescents who received standard or half-standard dosing were more likely to achieve at least 75 percent improvement in the PASI score than children treated with placebo (81, 78, and 11 percent, respectively) [27]. The efficacy and safety of other antipsoriatic biologic agents, including secukinumab, ixekizumab, brodalumab, and guselkumab, for pediatric psoriasis remains to be determined. ●

Adverse effects and precautions – The most common side effects of biologic agents are injection site reactions and upper respiratory tract infections. Although there is concern for increased risk of opportunistic infections and malignancies, serious adverse events are rare in children. In the randomized trial that compared adalimumab with methotrexate, rates of infection were similar among the treatment groups [23]. Increased risk of malignancy has not been documented in children treated with biologic agents for psoriasis. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".) Children treated with biologic agents should be screened for tuberculosis annually. In addition, live vaccines should be avoided during therapy.

Cyclosporine — Cyclosporine is generally reserved for severe and refractory psoriasis:

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Administration – Cyclosporine is typically given orally at a dose of 4 to 5 mg/kg per day in two divided doses. Improvement can be rapid, with marked improvement often occurring within the first month of treatment. Once the disease is controlled, the dose can be tapered as tolerated. The duration of treatment should be limited to less than one year because of toxicities, particularly hypertension, renal and hepatic injury, and future malignancies.



Efficacy – Although cyclosporine has a long history of use for adult psoriasis, data on use for pediatric plaque psoriasis are limited [40]. In a retrospective study of 38 children and adolescents with cyclosporine for plaque psoriasis (median daily dose 3.2 mg/kg, range 2 to 5 mg/kg), 15 (39 percent) achieved at least 75 percent improvement in the PASI score after 16 weeks [41]. Eight patients had to discontinue treatment due to side effects. (See "Treatment of psoriasis in adults", section on 'Systemic calcineurin inhibitors'.)



Adverse effects and precautions – Serious side effects of cyclosporine include nephrotoxicity, hypertension, hepatotoxicity, hyperlipidemia, metabolic abnormalities, and increased risk for infections and malignancy. Laboratory monitoring to detect side effects and blood pressure checks are required during treatment. Live vaccines and macrolide antibiotics, which increase cyclosporine levels, should be avoided during treatment.

Retinoids — Oral retinoids are accepted effective treatments for pustular, palmoplantar, and erythrodermic psoriasis but are generally considered less effective for plaque psoriasis than other systemic therapies [42,43]. Acitretin is the oral retinoid of choice for psoriasis. In our practice, we most often use acitretin for pustular psoriasis: ●

Administration – Acitretin is typically given at a dose of 0.5 to 1 mg/kg per day for plaque psoriasis and typically takes two to three months for efficacy. Improvement is usually evident within two to three months [1]. Upon achievement of a satisfactory response, dosing can be tapered to the lowest dose necessary to maintain improvement.



Efficacy – Efficacy data for pediatric plaque psoriasis are limited [40,44,45]. In a retrospective study of 154 children treated with systemic therapy for moderate to severe psoriasis, of the 78 children treated with acitretin for plaque psoriasis, 27 (35 percent) achieved at least 75 percent clearance of skin disease [45].



Adverse effects and precautions – The most common side effects are skin and mucosal membrane dryness and elevation of serum triglyceride levels. Laboratory monitoring for hematologic abnormalities, hepatotoxicity, and hyperlipidemia is necessary during treatment. Oral retinoids are teratogenic and pregnancy must be avoided for three years after cessation of acitretin.

Other therapies Fumaric acid esters — Fumaric acid esters are used for the treatment of psoriasis in Europe. Data from retrospective studies, case series, and case reports support efficacy in children [40]. One of the largest studies, a retrospective study of 127 children (ages 6 to 17 years) treated with fumaric acid esters for

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psoriasis (including 96 children with plaque psoriasis), found that disease severity improved during treatment [46]. An approximately 50 percent improvement in the mean PASI score occurred within the first three months of treatment. Gastrointestinal disorders and flushing were the most common side effects. In a separate case series of 14 children with recalcitrant plaque psoriasis, treatment with fumaric acid esters (maximum daily dose 180 to 1200 mg per day and mean treatment duration of 48.6 weeks, range 12 to 124 weeks) was associated with improvement in the PASI score in 9 children (64 percent) [47]. Lymphopenia is potential side effect of fumaric acid esters. Progressive multifocal leukoencephalopathy has been reported in lymphopenic patients who continued fumaric acid ester therapy [48-50]. Apremilast — Limited data suggest that apremilast, an oral phosphodiesterase 4 inhibitor, may be an option for chronic plaque psoriasis in children. A phase 2, open-label study in which 42 pediatric patients aged 6 to 17 years with moderate to severe plaque psoriasis received apremilast (20 or 30 mg given twice daily based upon weight and age) for two weeks, followed by a 48-week extension phase in which treatment was continued, found a mean improvement in the week 12 PASI score of 68 percent among adolescents (age 12 to 17 years) and 79 percent among children (age 6 to 11 years) [51]. The most common adverse events were nausea, headache, abdominal pain, nasopharyngitis, diarrhea, and vomiting. Of the 42 patients, 31 completed the treatment extension phase. Five patients had adverse events that led to temporary drug interruption, and two patients had adverse events that led to drug withdrawal. Other reasons for treatment cessation included study withdrawal by the patient (six patients), loss to follow-up (one patient), dissatisfaction with response to treatment (one patient), and patient-reported suicidal ideation (one patient). Of note, dose titration at the start of therapy, which is often utilized to reduce adverse events from apremilast in adults, was not performed. Additional study is necessary to confirm efficacy and safety of apremilast for plaque psoriasis in children. (See "Treatment of psoriasis in adults", section on 'Apremilast'.)

CHILDREN WITH PSORIATIC ARTHRITIS Appropriate management of psoriatic arthritis is important to minimize risk for poor outcomes and disability. Often, joint disease warrants systemic therapy that improves concomitant skin disease (eg, methotrexate or biologic tumor necrosis factor [TNF]-alpha inhibitors). (See "Psoriatic juvenile idiopathic arthritis: Management and prognosis".)

VERY YOUNG CHILDREN Although mild to moderate plaque psoriasis in children under the age of four years is likely to respond to the general approach described above, modifications are appropriate for this population. In general, less potent topical corticosteroids (groups 4 to 7) are preferred over higher-potency agents. For children in diapers, treatment of this area with topical corticosteroids should be monitored closely since the occlusive effect of

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the diaper may increase risk for cutaneous side effects (picture 1F). (See 'Face and intertriginous skin' above.) As with older children, the primary treatments for facial and intertriginous psoriasis are topical calcineurin inhibitors and low-potency topical corticosteroids. We prefer to use topical calcineurin inhibitors (tacrolimus 0.03% or pimecrolimus 1%) for facial and intertriginous psoriasis, particularly when continuous corticosteroid therapy is required for disease control or side effects from topical corticosteroid therapy have occurred. Safety concerns regarding the use of topical calcineurin inhibitors are reviewed separately. (See "Treatment of atopic dermatitis (eczema)", section on 'Long-term safety concerns' and "Treatment of atopic dermatitis (eczema)", section on 'Off-label use in infants'.) Topical vitamin D analogs and topical retinoids are rarely used in the treatment of infants because of the common side effect of skin irritation. Our approach to moderate to severe psoriasis in children under the age of four primarily consists of optimization of topical therapy. We typically avoid phototherapy and systemic therapies in this age group because of safety concerns with use in this population. However, use of these interventions is necessary in rare, refractory cases.

COMORBIDITIES Psoriasis is associated with a variety of comorbidities. Clinician awareness of these disease associations facilitates identification of children who may benefit from screening for associated disease [1,52]. (See "Psoriasis in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Comorbidities' and "Psoriasis in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Additional evaluation'.)

PROGNOSIS Psoriasis in children is typically chronic, but its course is unpredictable. Spontaneous remissions and exacerbations are common. Occasionally, alleviating conditions, such as sun exposure during the summer months, or triggers, including infections and trauma, can be identified. The available therapies provide satisfactory disease control for the majority of pediatric patients.

PATIENT SUPPORT The National Psoriasis Foundation is a useful informational and support resource for patients and their families.

SOCIETY GUIDELINE LINKS

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Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Psoriasis".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topics (see "Patient education: Psoriasis (The Basics)" and "Patient education: Psoriatic arthritis in children (The Basics)")



Beyond the Basics topics (see "Patient education: Psoriasis (Beyond the Basics)" and "Patient education: Psoriatic arthritis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS ●

Psoriasis is an immune-mediated disease that occurs in children and adults. Chronic plaque psoriasis is the most common type of psoriasis in children (picture 1A-B). (See 'Introduction' above and "Psoriasis in children: Epidemiology, clinical manifestations, and diagnosis".)



Many of the treatments used for children and adults with psoriasis are similar; however, efficacy and safety data in children are more limited. (See 'Introduction' above.)



Disease severity influences the therapeutic approach to plaque psoriasis (algorithm 1). For children with mild to moderate plaque psoriasis (psoriasis involving less than 10 percent of the body surface area), we recommend topical agents as initial therapy rather than systemic therapy or phototherapy (Grade 1B). Topical corticosteroids are the mainstay of treatment. Topical calcineurin inhibitors and topical vitamin D analogs are additional common treatments. Tazarotene, tar, and anthralin are less frequently used topical treatments. (See 'Mild to moderate plaque psoriasis in children at least four years of age' above.)



Modification of the approach to topical treatment of psoriasis is helpful for optimizing treatment of psoriasis on the face, intertriginous skin, and scalp (picture 1C-D). Topical calcineurin inhibitors are commonly used as first-line agents for the treatment of facial and intertriginous psoriasis because of

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increased risk for topical corticosteroid-induced skin atrophy in these areas. For scalp psoriasis, it is important to select drug vehicles that the child and/or caregivers find acceptable for use in the hair. (See 'Special sites' above.) ●

Children with moderate to severe plaque psoriasis (psoriasis involving more than 10 percent of the body surface area that cannot be successfully treated with topical therapy) often require systemic therapy or phototherapy (algorithm 1). Our typical first-line treatment choices for children at least four years of age are methotrexate, narrowband ultraviolet B (UVB) phototherapy, or the biologic agent etanercept. Adalimumab and ustekinumab are additional biologic agents that have demonstrated efficacy for psoriasis in children. Cyclosporine, oral retinoids, and fumaric acid esters (not available in the United States) also have been used for the treatment of pediatric psoriasis. (See 'Moderate to severe plaque psoriasis in children at least four years of age' above.)



Modifications to the approach to treatment are indicated for the treatment of very young children. (See 'Very young children' above.) Use of UpToDate is subject to the Subscription and License Agreement.

Topic 112983 Version 8.0

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GRAPHICS Chronic plaque psoriasis

Clusters of small plaques on the knees. Graphic 113134 Version 1.0

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Chronic plaque psoriasis

Thick, well-demarcated plaques of psoriasis on the lower legs of an obese adolescent girl. Graphic 113135 Version 1.0

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Inverse psoriasis

Inverse psoriasis involving the axillae in a child. Graphic 113323 Version 1.0

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Chronic plaque psoriasis

Thick scale on the temporal scalp. Graphic 113138 Version 1.0

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Chronic plaque psoriasis

Characteristic areas of psoriasis involvement on the periphery of the scalp, postauricular area, conchal area of the ear, and neck. Graphic 113139 Version 1.0

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Psoriasis

Erythematous plaques in the diaper area in an infant with psoriasis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 99441 Version 3.0

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Initial management of psoriasis in children

* Refer to UpToDate topics on the management of psoriatic juvenile idiopathic arthritis. ¶ Topical therapy is often inadequate for children with moderate to severe disease; however, we typically attempt topical therapy prior to initiating phototherapy or systemic therapy to identify those children who can be sufficiently managed with topical therapy. Δ All listed treatments are reasonable first-line choices. Selection among these agents is dependent upon factors such as patient age, disease severity, comorbidities, tolerance of risks and side effects, and prior treatment history. Refer to UpToDate topics on the management of plaque psoriasis in children for additional information on treatment selection. Alternative systemic therapies include acitretin, cyclosporine, and fumaric acid esters. ◊ Phototherapy and systemic therapy are generally avoided in children under the age of four due to safety concerns. However, use of these interventions may be necessary in rare, refractory cases. § Refer to UpToDate table on topical corticosteroids. ¥ Topical calcineurin inhibitors are preferred over topical corticosteroids for long-term therapy. ‡ Often, patients find medications in shampoos, foams, solutions, gels, sprays, or oils preferable for application to the scalp. The vehicle options should be discussed with the child or caregiver to identify the most acceptable regimen. Graphic 115504 Version 1.0

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Comparison of representative topical corticosteroid preparations (classified according to the US system)

Potency group* Super-high potency (group 1)

High potency (group 2)

Corticosteroid

Brand names (United States)

Available strength(s), percent (except as noted)

Betamethasone dipropionate, augmented

Gel, lotion, ointment (optimized)

Diprolene

0.05

Clobetasol propionate

Cream, gel, ointment, solution (scalp)

Temovate

0.05

Cream, emollient base

Temovate E

0.05

Lotion, shampoo, spray aerosol

Clobex

0.05

Foam aerosol

Olux-E, Tovet

0.05

Solution (scalp)

Cormax

0.05

Diflucortolone valerate (not available in United States)

Ointment, oily cream

Nerisone Forte (United Kingdom, others)

0.3

Fluocinonide

Cream

Vanos

0.1

Flurandrenolide

Tape (roll)

Cordran

4 mcg/cm 2

Halobetasol propionate

Cream, lotion, ointment

Ultravate

0.05

Ointment

Cyclocort ¶, Amcort ¶

0.1

Betamethasone dipropionate

Ointment

Diprosone ¶

0.05

Cream, augmented formulation (AF)

Diprolene AF

0.05

Clobetasol propionate

Cream

Impoyz

0.025

Desoximetasone

Cream, ointment, spray

Topicort

0.25

Gel

Topicort

0.05

Ointment

ApexiCon ¶, Florone ¶

0.05

Cream, emollient

ApexiCon E

0.05

Fluocinonide

Cream, gel, ointment, solution

Lidex ¶

0.05

Halcinonide

Cream, ointment

Halog

0.1

Halobetasol propionate

Lotion

Bryhali

0.01

Amcinonide

Cream

Cyclocort ¶, Amcort ¶

0.1

Lotion

Amcort ¶

0.1

Betamethasone dipropionate

Cream, hydrophilic emollient

Diprosone ¶

0.05

Betamethasone valerate

Ointment

Valisone ¶

0.1

Foam

Luxiq

0.12

Cream

Topicort LP ¶

0.05

Diflorasone diacetate

Cream

Florone ¶

0.05

Diflucortolone valerate (not available in United States)

Cream, oily cream, ointment

Nerisone (Canada, United Kingdom, others)

0.1

Fluocinonide

Cream aqueous emollient

Lidex-E ¶

0.05

Fluticasone propionate

Ointment

Cutivate

0.005

Mometasone furoate

Ointment

Elocon

0.1

Cream, ointment

Aristocort HP ¶, Kenalog ¶,

0.5

Amcinonide

Diflorasone diacetate

High potency (group 3)

Vehicle type/form

Desoximetasone

Triamcinolone acetonide

Triderm Medium potency (group 4)

Betamethasone dipropionate

Spray

Sernivo

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0.05

Clocortolone pivalate

Lower-mid potency (group 5)

Cream

Cloderm

0.1

Fluocinolone acetonide

Ointment

Synalar ¶

0.025

Flurandrenolide

Ointment

Cordran

0.05

Hydrocortisone valerate

Ointment

Westcort

0.2

Mometasone furoate

Cream, lotion, ointment, solution

Elocon ¶

0.1

Triamcinolone acetonide

Cream

Kenalog ¶, Triderm

0.1

Ointment

Kenalog ¶

0.1

Ointment

Trianex

0.05

Aerosol spray

Kenalog

0.2 mg per 2 second spray

Dental paste

Oralone

0.1

Betamethasone dipropionate

Lotion

Diprosone ¶

0.05

Betamethasone valerate

Cream

Beta-Val, Valisone ¶

0.1

Ointment

DesOwen, Tridesilon ¶

0.05

Gel

Desonate

0.05

Fluocinolone acetonide

Cream

Synalar ¶

0.025

Flurandrenolide

Cream, lotion

Cordran

0.05

Fluticasone propionate

Cream, lotion

Cutivate

0.05

Hydrocortisone butyrate

Cream, lotion, ointment, solution

Locoid, Locoid Lipocream

0.1

Hydrocortisone probutate

Cream

Pandel

0.1

Hydrocortisone valerate

Cream

Westcort ¶

0.2

Prednicarbate

Cream (emollient), ointment

Dermatop

0.1

Triamcinolone acetonide

Lotion

Kenalog ¶

0.1

Ointment

Kenalog ¶

0.025

Alclometasone dipropionate

Cream, ointment

Aclovate

0.05

Betamethasone valerate

Lotion

Beta-Val ¶, Valisone ¶

0.1

Desonide

Cream

DesOwen, Tridesilon ¶

0.05

Lotion

DesOwen, LoKara

0.05

Foam

Verdeso

0.05

Cream, solution

Synalar ¶

0.01

Shampoo

Capex

0.01

Oil Δ

Derma-Smoothe/FS Body, Derma-Smoothe/FS Scalp

0.01

Cream, lotion

Kenalog ¶, Aristocort ¶

0.025

Cream, ointment

Hytone, Nutracort ¶

2.5

Lotion

Hytone, Ala Scalp, Scalacort

2

Solution

Texacort

2.5

Ointment

Cortaid, Cortizone 10, Hytone, Nutracort

1

Cream

Cortaid ¶, Cortizone 10, Hytone, Synacort

1

Gel

Cortizone 10

1

Lotion

Aquanil HC, Sarnol-HC, Cortizone 10

1

Desonide

Low potency (group 6)

Fluocinolone acetonide

Triamcinolone acetonide Least potent (group 7)

Hydrocortisone (base, ≥2%)

Hydrocortisone (base, 24 hours, have bruising, are painful, or are accompanied by systemic symptoms (eg, fever) should raise a concern for vasculitis.

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• Urticarial vasculitis is a disorder characterized by urticarial lesions with vasculitic findings on skin biopsy (picture 5). The disorder may be systemic or limited to the skin. (See "Urticarial vasculitis".)

• Immunoglobulin A (IgA) vasculitis (Henoch-Schönlein purpura) is a systemic vasculitis with a prominent cutaneous component characterized by purpuric lesions, particularly involving the lower extremities. The skin lesions can be urticarial initially, although the development of systemic disease with arthralgias, abdominal pain, and renal involvement should prompt investigation for this condition. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis", section on 'Skin manifestations'.)

• Patients with lupus may also develop urticarial lesions that persist and become vasculitic. Skin biopsy may show evidence of vasculitis. (See "Overview of cutaneous lupus erythematosus".) ●

Malignancies – Urticaria may also be seen with malignancies, especially immunoglobulin M (IgM) and sometimes immunoglobulin G (IgG) paraproteinemias. The etiology is also unclear but may be due to complement-mediated pathways. In these cases, the urticaria is persistent and becomes chronic. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Unclear association with malignancy'.)

The urticaria associated with systemic disorders is usually recurrent, persistent, and relatively difficult to treat, so patients with these disorders typically present with chronic urticaria. Clinical features that can help distinguish these disorders from uncomplicated chronic urticaria are reviewed separately. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Differential diagnosis'.)

EVALUATION AND DIAGNOSIS Urticaria is diagnosed clinically, based upon a detailed history and physical examination confirming the presence of characteristic skin lesions [32-35]. Clinical history — The clinical history should determine the following: ●

Were there other signs and symptoms of a generalized allergic reaction or anaphylaxis? Patients may fail to report more subtle symptoms unless specifically asked. The clinician should ask about chest tightness or difficulty breathing, hoarse voice or throat tightness, nausea, vomiting, crampy abdominal pain, lightheadedness, and other symptoms of anaphylaxis (table 2). (See "Anaphylaxis: Emergency treatment".)

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Has the patient had hives previously in the past? Some children develop acute urticaria repeatedly with infections. Adults may develop urticaria following nonsteroidal antiinflammatory drug (NSAID) ingestion but may not recognize the association until it has occurred several times. Does the patient have other allergic disorders?



Were there any symptoms or signs to suggest an underlying systemic disorder? Specifically, has the patient recently had unexplained fever, weight loss, arthralgias, arthritis, or bone pain [36,37]? Diseases that may include hives as part of the clinical presentation are reviewed separately. (See 'Systemic disorders that may include urticaria' above.)



Is a possible etiology apparent from the patient's history (table 1)? (See 'Etiologies' above.)

• Was the patient in his/her usual state of health when the hives appeared or has the patient been ill recently with viral or bacterial infections? Has the patient experienced any recent health events, such as musculoskeletal injuries for which he/she was taking NSAIDs or new diagnoses requiring unfamiliar medications or treatments?

• The patient should be asked to review events in the hours before the urticaria appeared. What had the patient ingested (foods, beverages, candy)? Was the patient involved in exercise or physical exertion? Was the patient exposed to extremes of temperature or stung by an insect? The answers may reveal clues to allergic or physical causes of urticaria.

• Patients should be questioned about any new medications or supplements in the preceding days or weeks [38,39]. Were any medications taken in the hours before the urticaria appeared?

• Inquiries should be made about recent travel (and symptoms of parasitic infection) and sexual history. (See 'Infections' above.)

• A complete review of systems is valuable in the patient with new-onset urticaria. Physical examination — Lesions should be visualized directly in order to make the diagnosis with certainty, since the term "hives" is used nonspecifically by patients. If the patient has no lesions at the time of evaluation, showing patients photographs of urticaria and asking if their lesions look similar can be helpful, although the diagnosis will need to be confirmed at some point in the future (picture 2). Individual urticarial lesions usually appear and resolve completely within 24 hours. If the patient is unsure of the duration of the lesions, a lesion can be circled with a pen and time to resolution noted. Laboratory studies — Laboratory studies are typically normal in patients who lack any history or physical findings to suggest an underlying disease process [3].

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For patients presenting with new-onset urticaria (with or without angioedema) in whom the clinical history and physical exam do not suggest an underlying disorder or urticarial vasculitis, international, European, and British practice parameters state that laboratory testing is not indicated [40-42]. American practice parameters state that a limited evaluation "may be considered" in such patients, primarily for the purpose of detecting underlying disorders earlier in the one-third of patients in whom urticaria will prove persistent (ie, initial presentation of chronic urticaria) [43]. In this setting, complete blood count with differential, urinalysis, erythrocyte sedimentation rate, and liver function tests are suggested. However, the author's approach is to obtain these tests in patients with persistent symptoms.



In patients in whom a specific etiology is suspected, laboratory studies and further evaluation should be directed at establishing or excluding that cause. (See 'Etiologies' above.)

Tests for allergic causes — An allergic cause is possible if the clinical history reveals a specific trigger to which the patient was exposed shortly before the onset of symptoms (usually within one to two hours). If the history does suggest a possible allergy, serum tests for allergen-specific immunoglobulin E (IgE) antibodies are appropriate, if commercially available. For example, if a patient who does not normally eat seafood but did so at a special occasion develops hives within 10 minutes of eating a crab cake, it would be reasonable to obtain a crab-specific IgE test, particularly if there were no other new foods ingested and the patient is avoiding seafood for fear of a repeat reaction. However, the interpretation of allergy tests can require some expertise. A positive result is suggestive, although not diagnostic, of allergy, and a negative result does not exclude allergy. Because of this, we suggest that patients suspected of having an allergy be referred to an allergist/immunologist for further evaluation when possible. Skin tests with fresh food, which should be performed by an allergy specialist, is probably the most convenient, inexpensive, and sensitive way to detect food hypersensitivity. (See 'Referral' below and "Overview of in vitro allergy tests".)

DIFFERENTIAL DIAGNOSIS The conditions discussed in this section are those that may mimic various features of urticaria [44]. The presence or absence of pruritus is a helpful clinical feature that can be used to narrow the differential. Nonpruritic conditions — Nonpruritic conditions that may resemble acute urticaria include viral exanthems, the skin changes of auriculotemporal syndrome, and Sweet syndrome. ●

Viral exanthems – Viral exanthems are common in children and can occur with many different infections, including erythema infectiosum (fifth disease), Epstein-Barr virus, enteroviruses, and measles. However, viral exanthems are generally not pruritic and usually consist of

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erythematous maculopapular eruptions that persist for days. Fever is often present. The macules are relatively fixed compared with urticarial lesions, which continually change, with new lesions appearing as older lesions resolve. (See topic reviews on specific infections.) ●

Auriculotemporal syndrome – Auriculotemporal syndrome is a nonpruritic flushing and/or sweating of the skin over the cheeks or jawline (the areas supplied by the auriculotemporal nerve) that occurs transiently after eating and may be mistaken for urticaria associated with food allergy [45]. It can be seen in children or adults and may develop following damage to the nerve secondary to forceps delivery, viral infection, surgery, or other local trauma. Unilateral distribution is typical, although bilateral cases have been reported [46].



Sweet syndrome – Sweet syndrome is an uncommon disease characterized by recurrent episodes of painful, long-lasting inflammatory papules and plaques associated with fever, arthralgias, and peripheral leukocytosis. There may be a history of a febrile illness one to three weeks before the onset of skin lesions in some cases. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)

Pruritic conditions — Pruritic conditions that are more likely to be confused with urticaria are discussed here. An overview of the causes of pruritic dermatoses is found separately. (See "Pruritus: Etiology and patient evaluation".) ●

Atopic dermatitis – Atopic dermatitis is a common disorder that presents initially as intensely pruritic erythematous patches with papules and some scaling. In children, the face, scalp, extremities, or trunk are typically involved, while the diaper area is spared. In older children and adults, the flexural areas (neck, antecubital fossae, and popliteal fossae) are most commonly involved. Other sites include the face, wrists, and forearms (picture 7). Erythematous areas of involvement last for days or weeks and have ill-defined borders. Scaling and xerosis develop with time. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)



Contact dermatitis – Contact dermatitis refers to any dermatitis arising from direct skin exposure to a substance. The dermatitis may either be allergic or irritant-induced. The latter is more common. Contact dermatitis is an erythematous, papular dermatitis, often with areas of vesiculation (picture 8). It is distributed in the areas of direct contact. (See "Contact dermatitis in children" and "Irritant contact dermatitis in adults" and "Common allergens in allergic contact dermatitis".)



Drug eruptions – Drug eruptions, also called morbilliform or exanthematous drug eruptions, are cutaneous drug reactions that closely mimic viral exanthems but occur in association with a medication. These dermatoses may or may not be pruritic and begin as small macules and/or

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papules that become larger and confluent with time (picture 9). The individual lesions are persistent, unlike urticaria. (See "Drug eruptions".) ●

Insect bites – Insect bites produce individual lesions that persist for days in most cases (see "Insect and other arthropod bites"). However, the stings of some insects can cause true urticaria as part of a systemic allergic reaction. (See 'IgE-mediated allergic reactions' above.)



Bullous pemphigoid – In older adults, bullous pemphigoid may start with pruritus, with or without urticarial lesions. Blistering usually becomes evident eventually. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Bullous pemphigoid'.)



Erythema multiforme minor – Erythema multiforme minor is a syndrome characterized by erythematous, iris-shaped macules and vesiculobullous lesions with a target appearance (picture 10). The lesions may be painful or pruritic and distributed symmetrically on the extensor surfaces of the extremities (particularly the palms and soles). Individual lesions last several days, unlike urticaria. There may be accompanying fever and malaise. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)



Plant-induced reactions – Poison ivy and poison oak can present with urticaria-like lesions initially that evolve into vesicular lesions. (See "Poison ivy (Toxicodendron) dermatitis".)

TREATMENT Initial treatment of new-onset urticaria (with or without angioedema) should focus on the short-term relief of pruritus and angioedema, if present. Approximately two-thirds of cases of new-onset urticaria will be self-limited and resolve spontaneously. The literature on management of acute urticaria is sparse, probably because the condition is so often self-limited [47]. The agents discussed below have mostly been evaluated in the treatment of chronic urticaria, and in some cases, their use in acute urticaria is extrapolated from those studies, which are presented separately. (See "Chronic spontaneous urticaria: Standard management and patient education".) H1 antihistamines — H1 antihistamines may be divided into older, first-generation agents (eg, diphenhydramine, chlorpheniramine, hydroxyzine) and newer, second-generation agents (eg, cetirizine, loratadine, fexofenadine, others). Second-generation agents are preferred for both adults and children. Second-generation agents — The newer, second-generation H1 antihistamines are recommended as first-line therapy by published guidelines from both allergy and dermatology expert panels [48,49]. These drugs are minimally sedating, are essentially free of the anticholinergic effects that can

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complicate use of first-generation agents, have few significant drug-drug interactions, and require less frequent dosing compared with first-generation agents [50-54]. We know of no data demonstrating that any specific agent is more effective than another for the treatment of acute urticaria, although a few studies in patients with chronic urticaria suggest that cetirizine and levocetirizine may be modestly more effective than other agents. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'Agents and efficacy studies'.) Some patients require higher than standard doses (shown below in parentheses) for control of urticarial symptoms and may experience drowsiness at these higher doses. Caution is therefore warranted until effects upon the individual are understood. The higher doses may have better efficacy in some adults, although this has not been conclusively demonstrated. Studies of higherdose antihistamines for chronic urticaria are reviewed separately. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'H1 antihistamines'.) Treatment with H1 antihistamines results in clearance of the lesions in some patients, but in others, treatment may only achieve flattening of the lesions and reduction in pruritus, with persistence of erythematous macules. Patients in the latter group can begin to reduce medications after the erythematous lesions clear. Second-generation H1 antihistamines include the following: ●

Cetirizine – Cetirizine demonstrates a rapid onset of action and some mast cell-stabilizing activity. It can be mildly sedating, in a dose-dependent manner, although less so than firstgeneration agents. It is available in both intravenous (in some countries) and oral formulations, and the dosing is similar for either route of administration. Intravenous doses should be administered over one to two minutes. The standard oral or intravenous dose of 10 mg once daily is appropriate for adults and children aged 12 years and older (and may be increased to 10 mg twice daily in adults if needed). Children six years of age and older can receive 5 mg or 10 mg. The usual dose for children aged two to five years is 5 mg once daily. Smaller children aged six months to two years may be given 2.5 mg once daily (can be increased to 2.5 mg twice daily in children one year and older if needed). The maintenance dose for patients with significant renal and/or hepatic insufficiency should be reduced by one-half.



Levocetirizine – Levocetirizine is an active enantiomer of cetirizine that produces effects equivalent to cetirizine at about one-half of the dose. For adults and children 12 years and older, the standard dose is 5 mg once daily in the evening (or up to 5 mg twice daily in adults if needed) or 2.5 mg once daily in the evening for children aged 6 to 11 years. Levocetirizine is unlikely to be effective as an alternative for patients who did not have an adequate response to

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cetirizine, and its sedative effects are similar to those of other second-generation antihistamines [55]. Dose reductions are necessary in renal insufficiency. ●

Loratadine – Loratadine is a long-acting, selective H1 antihistamine. The standard dose is 10 mg once daily for ages six years and older, which is minimally sedating. It can be increased up to 10 mg twice daily in adults if needed. For children aged two to five years, the usual dose is 5 mg once daily. For patients with significant renal and/or hepatic insufficiency, the usual dose is administered every other day.



Desloratadine – Desloratadine is the major active metabolite of loratadine and produces effects equivalent to loratadine at about one-half the dose. For adults and children 12 years and older, the standard dose is 5 mg once daily (or up to 5 mg twice daily in adults if needed). For children aged 6 to 11 years, the dose is 2.5 mg once daily, and for those aged 1 to 5 years, the dose is 1.25 mg once daily. A lower dose of 1 mg once daily is approved in the United States for small children aged 6 months to 1 year. For patients with significant renal and/or hepatic insufficiency, the usual dose is administered every other day.



Fexofenadine – Fexofenadine is minimally sedating. The suggested dose is 180 mg daily for ages 12 years and older (or up to twice daily in adults if needed) or 30 mg twice daily for children aged 2 to 11 years. A lower dose of 15 mg twice daily is approved in the United States for small children aged six months to two years. For patients with significant renal insufficiency, the adult dose should be reduced to 60 mg once daily. It is best taken without food and specifically not with fruit juices.

There are additional nonsedating antihistamines that are available in many countries, although not in the United States: ●

Ebastine – Ebastine is a nonsedating antihistamine that is licensed for use in children older than 12 years of age and adults. The usual dose is 10 mg daily, but it can be doubled to 20 mg daily if needed, although not in patients with liver insufficiency. One study of patients with acute urticaria found that 20 mg of ebastine was similar in efficacy to 5 mg of levocetirizine and caused fewer adverse effects [56].



Bilastine – Bilastine is a nonsedating antihistamine with efficacy similar to cetirizine and higher than that of fexofenadine [57]. The initial dose is 20 mg daily for children older than 12 years of age and adults. Bioavailability is reduced approximately 30 percent by grapefruit juice, ketoconazole, or erythromycin, and it should not be taken with food. The drug minimally crosses the blood-brain barrier (because it is a zwitterion), does not cause somnolence, and is not affected by alcoholic beverages [58].

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Rupatadine – Rupatadine antagonizes both histamine and platelet-activating factor (PAF) receptors [59]. It is licensed at a dose of 10 mg daily for patients older than 12 years of age, although it is safe in patients older than 2 years of age [60]. As is the case for bilastine, the drug should not be taken with grapefruit juice, ketoconazole, or erythromycin, but (unlike bilastine) it is not affected by food.

First-generation agents — The first-generation antihistamines include diphenhydramine, chlorpheniramine, hydroxyzine, and others [61]. These agents are lipophilic and readily cross the blood-brain barrier, causing sedating and anticholinergic side effects that may be dose-limiting in some patients. Significant sedation and impairment of performance (eg, fine motor skills, driving skills, and reaction times) occur in more than 20 percent of patients [62]. Anticholinergic side effects include dry mouth, diplopia, blurred vision, urinary retention, or vaginal dryness. Patients should be warned specifically about these adverse effects. Despite these adverse effects, patients at low risk of complications (eg, young, healthy patients) may find a sedating H1 antihistamine at bedtime helpful, especially when combined with a nonsedating H1 antihistamine during the day. Some first-generation H1 antihistamines are available in parenteral preparations for use in patients in whom a more rapid onset of action is desired, such as those who have presented to the emergency department. Parenteral dosing of the first-generation agents is: ●

Diphenhydramine – The dose in adults is 25 to 50 mg given by slow intravenous (IV) administration or intramuscular (IM) injection every four to six hours as needed. Children may receive 0.5 to 1.25 mg/kg (up to 50 mg per dose) IV/IM every six hours as needed. OR



Hydroxyzine – The dose in adults is 25 to 50 mg deep IM administration in adults every four to six hours as needed. Do not administer intravenously. Children may receive 0.5 to 1 mg/kg (up to 50 mg per dose) IM every six hours as needed.

Pregnant and lactating women — Pregnant women may be treated initially with loratadine (10 mg once daily) or cetirizine (10 mg once daily). There are reassuring human data for each of these drugs in a large number of pregnant patients [63]. The first-generation agent chlorpheniramine, 4 mg orally every four to six hours, may also be safely used in pregnancy [64,65]. Safety issues surrounding the use of antihistamines in pregnancy are reviewed separately. (See "Recognition and management of allergic disease during pregnancy", section on 'Oral antihistamines'.) Lactating women may be treated with either cetirizine or loratadine (both are dosed at 10 mg once daily), which are minimally excreted in breast milk and should not cause sedation or poor feeding in the infant. (See "Pharmacotherapy of allergic rhinitis", section on 'Breastfeeding women'.)

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H2 antihistamines — There are very few data examining the use of H2 antihistamines for acute urticaria, but the practice is supported by one randomized trial of 91 adults presenting to an emergency department with acute allergic reactions [66]. Subjects received 50 mg IV diphenhydramine with either placebo or 50 mg IV ranitidine. At two hours, the number of patients in whom urticaria had resolved was statistically greater in the ranitidine group compared with the placebo group (25 of 29 and 13 of 24, respectively). Options for H2 antihistamines include nizatidine, famotidine, ranitidine (no longer available in the US), and cimetidine, although caution should be used with cimetidine, since it can increase levels of other drugs. (See "Antiulcer medications: Mechanism of action, pharmacology, and side effects".) Studies of the use of H2 antihistamines in chronic urticaria are conflicting and are reviewed elsewhere [67-69]. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'H2 antihistamines'.) Glucocorticoids — Glucocorticoids do not appear to be necessary for isolated urticaria. However, a brief course (ie, usually a week or less) of systemic glucocorticoids may be added to antihistamine therapy for patients with prominent angioedema or if symptoms persist beyond a few days. Glucocorticoids do not inhibit mast cell degranulation but may act by suppressing a variety of contributing inflammatory mechanisms. A small number of trials have examined the utility of glucocorticoids in the management of acute urticaria [70-72]. In the largest study, the addition of prednisone to levocetirizine did not speed resolution of acute urticaria. In this randomized trial, 100 adults presenting to the emergency department with urticaria of ≤24 hours duration without angioedema, anaphylaxis, or fever, were treated with the H1 antihistamine levocetirizine (5 mg once daily for five days) plus either placebo or prednisone (40 mg once daily for four days) and followed by phone for several days [72]. The primary endpoint was complete relief of itching two days after the start of therapy, and secondary endpoints included resolution of skin lesions, relapses, and adverse events. Most subjects had resolution of itch by day 2, with a slightly lower percentage itch-free in the prednisone group (79 versus 67 percent). Similarly, by day 2, skin lesions had resolved entirely in 78 and 70 percent of those in the placebo and prednisone groups, respectively. Thus, the addition of prednisone to levocetirizine did not speed resolution of acute urticaria. Between one-quarter and one-third of patients experienced relapse in both groups, generally within the first few days of therapy. Another smaller randomized trial found that glucocorticoids were helpful when added to antihistamines, although the antihistamine regimen used in that study (hydroxyzine 25 mg orally every four to eight hours) may have been more difficult to adhere to [70]. Our approach is to treat all patients with H1 antihistamines, adding H2 antihistamines for more severe symptoms and reserving oral glucocorticoids for those patients with prominent angioedema

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or persistent symptoms despite antihistamines. The optimal agent and dose have not been determined for acute urticaria, but we typically administer: ●

In adults – Prednisone 30 to 60 mg daily, with tapering of the dose over five to seven days



In children – Prednisolone 0.5 to 1 mg/kg/day (maximum 60 mg daily), with tapering of the dose over five to seven days

Antihistamine therapy should be continued during and after the course of glucocorticoids because some patients experience an exacerbation as the glucocorticoids are tapered or discontinued. If symptoms do not recur over several days after stopping glucocorticoids, then antihistamines can be discontinued also. For patients whose symptoms recur when medications are discontinued, antihistamines should be reinstituted and used at the lowest effective dose. Repeated courses of glucocorticoids should be avoided, as the risks of adverse effects outweigh the benefit for most patients. (See 'Referral' below.)

REFERRAL Patients who are suspected of having an allergic etiology causing new-onset urticaria, such as a food or medication allergy, should be referred to an allergy specialist who will equip them with epinephrine for self-injection when indicated. These issues are discussed in detail separately. (See "Anaphylaxis: Emergency treatment", section on 'Discharge care'.) It should be explained to patients that about one-third of cases of new-onset urticaria will prove persistent and that if they continue to have ongoing symptoms after several weeks, they should seek re-evaluation in a primary care setting. Patients with difficult-to-control symptoms may also be referred to a dermatology or allergy specialist.

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urticaria and angioedema (excluding hereditary angioedema)".)

INFORMATION FOR PATIENTS

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UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topic (see "Patient education: Hives (The Basics)")



Beyond the Basics topic (see "Patient education: Hives (urticaria) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS ●

Urticaria is common, affecting up to 20 percent of the population. Urticarial lesions are intensely pruritic, circumscribed, raised, erythematous plaques, often with central pallor. Morphology and size can vary (picture 2). Uncomplicated urticarial lesions are pruritic cutaneous plaques that develop over minutes to hours and resolve in hours without residual markings. (See 'Clinical manifestations' above and 'Epidemiology' above.)



Urticaria is classified as acute or chronic. Acute urticaria is defined as periodic outbreaks of urticarial lesions that resolve within six weeks, and two-thirds of all urticaria falls into this category. (See 'Categorization of urticaria' above.)



A presumptive trigger, such as common viral and bacterial infections, medications, food ingestion, or insect sting, can sometimes be identified for new-onset urticaria. (See 'Etiologies' above.)



Occasionally, urticaria may be the presenting feature of another systemic disorder, such as urticarial vasculitis, mastocytosis, or systemic lupus erythematous. There are specific clinical features that should prompt an evaluation for these conditions. (See 'Systemic disorders that may include urticaria' above.)



The diagnosis of urticaria is made clinically. A careful history should be performed to exclude possible anaphylaxis, identify a possible trigger, and determine if there are signs or symptoms to suggest urticarial vasculitis or an underlying systemic disorder. If the history does not suggest a

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specific trigger or underlying systemic illness, then laboratory tests are usually normal and not helpful. Some guidelines advocate obtaining a complete blood count with differential, urinalysis, erythrocyte sedimentation rate, and liver function tests at initial presentation, while others suggest testing only if symptoms persist. (See 'Evaluation and diagnosis' above.) ●

In patients with mild symptoms of new-onset urticaria, we suggest treatment with a nonsedating H1 antihistamine alone (Grade 2B). In patients at low risk of complications from anticholinergic side effects (ie, young, healthy patients), use of a sedating H1 antihistamine at bedtime and a nonsedating H1 antihistamine during the day is a reasonable alternative. (See 'H1 antihistamines' above.)



In patients with moderate-to-severe new-onset urticaria, we suggest adding an H2 antihistamine (Grade 2C). (See 'H2 antihistamines' above.)



In patients with prominent angioedema or persistent symptoms despite an H1 and H2 antihistamine, we suggest adding a brief course of oral glucocorticoids (Grade 2C). We typically administer prednisone (30 to 60 mg daily) in adults or prednisolone (0.5 to 1 mg/kg/day) in children, tapered over five to seven days. (See 'Glucocorticoids' above.)



Urticaria that persists beyond several weeks may represent the beginning of chronic urticaria, a disorder that is reviewed separately. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)

ACKNOWLEDGMENT The editorial staff at UpToDate would like to acknowledge Clifton O Bingham, III, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Subscription and License Agreement. Topic 8101 Version 29.0

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GRAPHICS Acute urticaria on the trunk

Graphic 78544 Version 2.0

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Urticaria - Multiple images

Multiple images of urticaria are shown. Urticarial lesions may be rounded (F) or irregular (A) in shape and uniform or mixed (G) in morphology. Individual lesions may be small (H) or large (D). Urticaria are raised plaques, although they may appear flattened in patients taking antihistamines (C). Although lesions are consistently erythematous, this may be difficult to appreciate on darkly pigmented skin (I). Some urticaria show central clearing (E). Panel B courtesy of Andrew Samel, MD. Panels C, F, G, and H reproduced with permission from: Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2003. Copyright © 2003 Lippincott Williams & Wilkins. Panel D courtesy of Lee T Nesbitt, Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995. Panel E reproduced with permission from: Fleisher GR, Ludwig S, Baskin MN. Atlas of Pediatric Emergency Medicine, Lippincott Williams & Wilkins, Philadelphia 2004. Copyright © 2004 Lippincott Williams & Wilkins. Panel I reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 90166 Version 6.0

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Identifiable causes of urticaria Infections Viral Parasitic Bacterial

IgE-mediated allergic cases Medications Insects Stinging (yellow jackets, bees, wasps, hornets, fire ants) Biting (Triatoma [kissing bugs])

Foods Blood products (urticarial transfusion reaction) Latex (contact or inhaled) Contact allergens (animal saliva, raw foods) Aeroallergens (rare) Food additives

Direct mast cell activation Narcotics/opiates Muscle relaxants (eg, succinylcholine) Radiocontrast agents Vancomycin

Physical stimuli Dermatographism Delayed pressure Cold Cholinergic Vibratory Aquagenic Solar Exertion/exercise

Miscellaneous mechanisms Nonsteroidal anti-inflammatory drugs Serum sickness Transfusion reactions (distinct from IgE-mediated reactions) Hormone-associated (progesterone) Stinging nettle IgE: immunoglobulin E. Graphic 54872 Version 3.0

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Symptoms and signs of anaphylaxis Skin Feeling of warmth, flushing (erythema), itching, urticaria, angioedema, and "hair standing on end" (pilor erection)

Oral Itching or tingling of lips, tongue, or palate Edema of lips, tongue, uvula, metallic taste

Respiratory Nose - Itching, congestion, rhinorrhea, and sneezing Laryngeal - Itching and "tightness" in the throat, dysphonia, hoarseness, stridor Lower airways - Shortness of breath (dyspnea), chest tightness, cough, wheezing, and cyanosis

Gastrointestinal Nausea, abdominal pain, vomiting, diarrhea, and dysphagia (difficulty swallowing)

Cardiovascular Feeling of faintness or dizziness; syncope, altered mental status, chest pain, palpitations, tachycardia, bradycardia or other dysrhythmia, hypotension, tunnel vision, difficulty hearing, urinary or fecal incontinence, and cardiac arrest

Neurologic Anxiety, apprehension, sense of impending doom, seizures, headache and confusion; young children may have sudden behavioral changes (cling, cry, become irritable, cease to play)

Ocular Periorbital itching, erythema and edema, tearing, and conjunctival erythema

Other Uterine cramps in women and girls Original figure modified for this publication. Simons FER. Anaphylaxis. J Allergy Clin Immunol 2010; 125:S161. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 66333 Version 15.0

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Symptoms and signs of anaphylaxis in infants* Anaphylaxis symptoms that infants cannot describe

Anaphylaxis signs that are potentially difficult to interpret in infants and why

Anaphylaxis signs in infants: Obvious but may be nonspecific

General Feeling of warmth, weakness, anxiety, apprehension, impending doom

Nonspecific behavioral changes, such as persistent crying, fussing, irritability, fright

 

Flushing (may also occur with fever, hyperthermia, or crying spells)

Rapid onset of hives (potentially difficult to discern in infants with acute atopic dermatitis; scratching and excoriations, as such, will be absent in young infants); angioedema (face, tongue, oropharynx)

Hoarseness, dysphonia (common after a crying spell); drooling, increased secretions (common in infants)

Rapid onset of coughing, choking, stridor, wheezing, dyspnea, apnea, cyanosis

Spitting up/regurgitation (common after feeds), loose stools (normal in infants, especially if breastfed); colicky abdominal pain

Sudden, profuse vomiting

Hypotension; measured with an appropriate size blood pressure cuff, low systolic blood pressure for infants is defined as less than 70 mmHg from age 1 month to 1 year and less than (70 mmHg + [2 x age in years]) in the first and second years of life; tachycardia, defined as greater than 120 to 130 beats per minute from the third month to second year of life inclusive; loss of bowel and bladder control (ubiquitous in infants)

Weak pulse, arrhythmia, diaphoresis/sweating, pallor, collapse/unconsciousness

Drowsiness, somnolence (common in infants after feeds)

Rapid onset of unresponsiveness, lethargy, or hypotonia; seizures

Skin/mucus membranes Itching of lips, tongue, palate, uvula, ears, throat, nose, eyes, and so forth; mouth-tingling or metallic taste

Respiratory Nasal congestion, throat tightness; chest tightness; shortness of breath

Gastrointestinal Dysphagia, nausea, abdominal pain/cramping

Cardiovascular Feeling faint, presyncope, dizziness, confusion, blurred vision, difficulty in hearing, palpitations

Central nervous system Headache

* More than one body system involved. From: Simons FER. Anaphylaxis in infants: Can recognition and management be improved? J Allergy Clin Immunol 2007; 120:537. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 64957 Version 7.0

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Urticarial drug eruption

Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd Edition. Philadelphia: Lippincott Williams & Wilkins, 2003. Copyright © 2003 Lippincott Williams & Wilkins. Graphic 75230 Version 3.0

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Urticarial vasculitis

Urticarial patch with central ecchymosis. Graphic 54877 Version 3.0

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Urticarial vasculitis

Annular patch with elevated borders. Graphic 66203 Version 2.0

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Urticarial vasculitis

Discrete and confluent urticarial patches with unusual annular and semi-annular features. Graphic 77924 Version 3.0

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Atopic dermatitis

Severe atopic dermatitis in a 12-year-old girl showing in the typical location of the popliteal fossae. Note the oozing of serous fluid from the most involved areas, plus the papular component and erythema. Courtesy of Scott Walsh, MD, FRPCP. Graphic 65407 Version 2.0

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Allergic contact dermatitis

Allergic contact dermatitis is characterized by an erythematous, papular dermatitis with indistinct margins, distributed in areas of exposure. Courtesy of James C Shaw, MD. Graphic 71913 Version 1.0

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Exanthematous (morbilliform) drug eruption

Drug-induced exanthems, such as this morbilliform eruption, often begin in dependent areas and generalize. Courtesy of Andrew Samel, MD. Graphic 70062 Version 5.0

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Erythema multiforme

Characteristic target lesions of the palm in erythema multiforme begin with a central vesicle. Courtesy of Nesbitt LT Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore 1995.

http://www.lww.com Graphic 74095 Version 6.0

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history Author: Sarbjit Saini, MD Section Editor: Jeffrey Callen, MD, FACP, FAAD Deputy Editor: Anna M Feldweg, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Apr 07, 2020.

INTRODUCTION Chronic spontaneous urticaria (CSU) is defined by the presence of recurrent urticaria (also called hives or wheals), angioedema, or both, for a period of six weeks or longer [1]. There are several theories regarding the pathogenesis of CSU, none of which have been conclusively established. CSU is a self-limited disorder in most patients, with an average duration of disease of two to five years, although active CSU significantly impairs quality of life [1]. The clinical manifestations, epidemiology, diagnosis, theories of pathogenesis, and natural history of CSU will be reviewed here. The management of CSU is discussed separately. (See "Chronic spontaneous urticaria: Standard management and patient education" and "Chronic spontaneous urticaria: Treatment of refractory symptoms".)

TERMINOLOGY The term "chronic spontaneous urticaria" (CSU) refers to patients with recurrent urticaria for six weeks or longer well, as those with both urticaria and angioedema. Note that in a 2017 international guideline, isolated idiopathic angioedema, without urticaria, was included in the definition of CSU for the first time, provided that other angioedema disorders (especially those mediated by bradykinin) have been excluded [1]. Therefore, CSU presents with an urticaria-predominant phenotype in approximately one-half of patients, a mixture of urticaria and angioedema in about 40 percent, and mainly angioedema in 10 percent. However, there are additional diagnostic considerations in patients

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with isolated angioedema, which are discussed in more detail separately. (See "An overview of angioedema: Clinical features, diagnosis, and management".) The term "spontaneous" is included to differentiate CSU from several forms of physical urticaria, which are hives triggered by physical stimuli, such as heat, cold, pressure applied to the skin, exercise, water, vibration, and sunlight. Physical urticaria is also called "inducible urticaria." Physical urticaria syndromes are discussed separately. (See "Physical (inducible) forms of urticaria".) Other terms for CSU include "chronic idiopathic urticaria" and the general term "chronic urticaria." We favor the term CSU over the others, although it is not as familiar to nonspecialists.

EPIDEMIOLOGY At any given time, CSU affects up to 1 percent of the general population in the United States, and the prevalence is believed to be similar in other countries [2-4]. Both children and adults can develop CSU, although it is more common in adults. Women are affected twice as often as men [3,5-11], and the condition typically begins in the third to fifth decades of life [3,7,10].

CLINICAL MANIFESTATIONS The clinical manifestations of CSU may be limited to the skin, although some patients report accompanying systemic symptoms. Cutaneous signs and symptoms Urticaria — Urticarial lesions (also called hives or wheals) have three typical features [1]: ●

An area of central swelling of various size, usually with surrounding erythema



An itching sensation



A fleeting time course for an individual lesion (usually 30 minutes to 24 hours) with the skin returning to normal without ecchymoses

Urticaria may be round, annular, or serpiginous (picture 1 and picture 2 and picture 3 and picture 4 and picture 5). Any area of the body may be affected. Areas in which clothing compresses the skin (ie, under waistbands) or the skin rubs together (axillae) are sometimes affected more extensively. Patients with intense pruritus may occasionally injure their skin by scratching, resulting in excoriations (superficial erosions and crusts). The lesions may appear flattened if the patient is currently taking H1 antihistamines.

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The pruritus of CSU may be severe enough to disrupt work, school, or sleep and is often most noticeable at night. Patients whose symptoms have resolved sometimes have difficulty describing urticarial lesions in a sufficiently detailed manner to assist in diagnosis. In this situation, showing patients photographs of urticaria and asking if the lesions looked similar can be helpful. Individual lesions usually appear, possibly enlarge or merge, and then resolve within 24 hours. If the patient is having difficulty estimating how long an individual lesion lasts, he/she can trace a newly developed lesion with a pen and monitor the time to resolution. Lesions lasting longer than 24 hours and those that are painful or burning in nature or leave residual bruising are suggestive of a vasculitic process. (See 'Differential diagnosis' below.) Angioedema — Angioedema, if present, is defined as episodic submucosal or subcutaneous swelling that is usually asymmetric in distribution and affects nondependent parts of the body, such as the lips, cheeks, periorbital areas of the face, extremities, and genitals [12]. It typically develops over minutes to hours and resolves gradually over one to three days, depending upon the initial severity. Affected areas typically feel slightly painful, numb, or tingling, rather than pruritic. In contrast, angioedema involving the throat, tongue, or lips, without urticaria, should prompt consideration of drug-induced angioedema (such as that seen with angiotensin-converting enzyme inhibitors), hereditary angioedema, or acquired C1 inhibitor deficiency. Episodic abdominal pain due to angioedema of the intestinal mucosa is another distinguishing feature of these disorders. (See "ACE inhibitor-induced angioedema" and "An overview of angioedema: Pathogenesis and causes".) Systemic symptoms — A subset of patients with CSU report systemic symptoms, including headache, fatigue, pain or swelling of joints, wheezing, flushing, gastrointestinal symptoms, and palpitations [13,14]. In a study of 155 CSU patients treated at a university allergy clinic, 103 reported systemic symptoms [13]. This subgroup had more severe and longer-lasting disease and significantly higher baseline tryptase levels, compared with CSU patients without systemic symptoms (5.1 versus 3.9 ng/mL, respectively). Although there was likely some referral bias in this study toward patients with more severe disease, clinicians should inquire about systemic symptoms in patients with CSU. Note that in patients with urticaria or angioedema accompanied by fever or objective evidence of joint inflammation, urticarial vasculitis should be considered. (See 'Differential diagnosis' below.)

ASSOCIATED CONDITIONS CSU is associated with various atopic and autoimmune disorders. There is a possible association with malignancies, although data are conflicting.

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Allergic diseases — Strong associations with atopic disorders, including food allergy, allergic rhinitis, chronic rhinosinusitis, atopic dermatitis, and asthma were demonstrated in a large cohort study of over 1 million Israeli adolescents [15]. These associations were not seen in the adult population, when studied by the same researchers. Instead, an association with autoimmune conditions was observed.   Autoimmune disorders — Various autoimmune conditions are more prevalent among patients with CSU [5,16-19]. In the largest study, the prevalence of autoimmune disorders in nearly 13,000 patients with CSU was compared with over 10,000 control patients [5]. The following autoimmune disorders were more prevalent in patients with CSU: thyroid disorders, celiac disease, Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes mellitus, with considerable variability between males and females. Antinuclear antibodies were also more prevalent than in the general population [5]. Among patients with CSU, an autoimmune disorder was more likely to be diagnosed in the decade after the onset of CSU, rather than before it. Thyroid disorders — In the larger study mentioned previously, hypothyroidism was diagnosed in 9.8 percent of CSU patients (versus 0.6 percent of controls) and hyperthyroidism in 2.6 percent (versus 0.5 percent of controls) [5]. A population-based Korean study found that individuals with autoimmune thyroid disease (Hashimoto thyroiditis and Graves' disease) had higher rates of CSU compared with controls (hazard ratio [HR] = 1.5, 95% CI 1.3-1.7) [20]. Thyroid autoantibodies, specifically thyroid peroxidase antibodies or antimicrosomal antibodies, are more prevalent among patients with CSU (12 to 30 percent), compared with members of the general population (5 to 10 percent) [6,21-23]. However, the presence of thyroid autoantibodies does not necessarily correlate with abnormal thyroid function, and the majority of patients with CSU who have demonstrable thyroid autoantibodies have normal thyroid function [22]. The role of these autoantibodies in CSU in patients with normal thyroid function is not clear. Their presence may simply reflect an underlying tendency to develop autoantibodies [18]. However, even in the absence of hypo- or hyperthyroidism, patients with thyroid autoantibodies are often poorly responsive to standard therapies for CSU and have more persistent disease [18]. The pathogenesis of autoimmune thyroid disease is reviewed elsewhere. (See "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)" and "Pathogenesis of Graves' disease".) Based upon the association between CSU and thyroid autoimmunity, several studies have examined the use of thyroid supplementation therapy in the treatment of CSU, with mixed results. These studies are reviewed elsewhere. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'Patients with thyroid autoantibodies'.)

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Unclear association with malignancy — The association between CSU (without vasculitis) and malignancy is unclear. Guidelines do not suggest that malignancy screening be performed in patients with CSU, unless indicated by specific abnormalities in the clinical history or physical exam or the presence of unintended weight loss [1,24,25]. Studies that support this approach include the following: ●

No increased risk of malignancy was found in a study of 1155 Swedish patients with CSU, in which subjects were followed by academic dermatologists for an average of 8.2 years [26]. The incidence of malignant cancer during the period of observation was compared with the expected number of cancers from the Swedish Cancer Registry, yielding a relative risk (RR) of 0.88 (95% CI 0.61-1.12).



In a systematic review of 6462 patients described in 29 studies, underlying diseases were detected as an underlying cause of CSU in only 105 patients (1.6 percent) [16]. Within this group, there were 60 cases of urticarial vasculitis, 17 patients with thyroid disease, 7 with lupus, and 16 with other connective tissue disorders. Three patients had a paraproteinemia, four had polycythemia vera, and five had various malignancies (breast cancer, acute myeloid leukemia, renal cell carcinoma, and two unidentified cancers). Therefore, few malignancies were detected in this review, and no one type of cancer predominated.

In contrast to the two studies above, a possible association was detected in a study of 12,720 Taiwanese patients with CSU [27]. In this cohort, subjects were identified as having CSU based upon the International Classification of Diseases (ICD)-9-CM code for urticaria, combined with use of an antihistamine for at least six months over a two-year period. Patients with coexisting allergic disorders that could require chronic antihistamines, patients receiving immunosuppressant drugs for any reason, and those with pre-existing malignancies, rheumatoid arthritis, lupus erythematosus, or Sjögren syndrome, were excluded. The rate of malignancies diagnosed in this cohort over an average follow-up period of five years was compared with expected rates obtained from the Taiwan National Cancer Registry. The standardized incidence ratio for patients with CSU was 2.2 (95% CI 2.0-2.4). However, information about possible confounders (eg, smoking and alcohol use) was not included, and patients may not have been systematically evaluated for signs or symptoms of underlying disorders. In addition, the authors noted that there was no diagnostic code for urticarial vasculitis, which is known to be associated with malignancy, so this diagnosis would not have been easily distinguished from simple CSU. Therefore, this study may have overestimated cancer risk, although the association warrants further evaluation. A case report and literature review described 26 patients in whom CSU preceded the diagnosis of a malignancy, usually by several months, and reported that treatment (ie, chemotherapy or surgical

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resection) led to resolution of the CSU in 88 percent of cases [28]. In three patients, return of urticaria signaled a recurrence of the malignancy. Until the association between chronic idiopathic urticaria and malignancy is better defined, it seems logical to continue to perform additional testing only if indicated by the patient's clinical history and physical exam.

EVALUATION AND DIAGNOSIS CSU is diagnosed clinically based upon the episodic and transient appearance of characteristic urticarial lesions, with or without angioedema, for a period of six weeks or longer. A detailed history and physical examination form the basis of the evaluation [1,29-32]. Several practice parameters have been published for the diagnosis of CSU [1,24,25,33,34]. The suggestions in this review are consistent with these, although some variation exists among guidelines. History — The clinical history is an important element of the evaluation. The history should include the signs and symptoms associated with the lesions, duration of individual lesions, and accompanying angioedema. If signs and symptoms are consistent with CSU, then questioning should focus on identifying a possible underlying cause and on ensuring that the patient does not have evidence of a more serious systemic disease. ●

To exclude a specific cause, clinicians should question patients about any newly administered drugs, including antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and hormonal therapies [35,36]. Inquiries should be made about recent travel, infections, changes in health status, other atopic conditions, sexual history, and complete review of systems. No external cause can be identified in 80 to 90 percent of adults and children with recurrent urticaria persisting longer than six weeks once these known causes are excluded [37-40]. The various identifiable causes of urticaria are discussed in more detail elsewhere. (See "New-onset urticaria".)



Patients should be thoroughly questioned about signs and symptoms of systemic disease, such as fever, weight loss, arthralgias, arthritis, cold or heat sensitivity, abdominal pain, and bone pain [17,41]. Occasionally, urticaria or urticarial vasculitis will be a presenting feature of an underlying systemic disorder, such as systemic lupus erythematosus. Systemic diseases that can present with urticaria accompanied by other signs and symptoms and disorders that involve urticarial vasculitis are reviewed in more detail separately. (See "New-onset urticaria", section on 'Systemic disorders that may include urticaria' and "Urticarial vasculitis", section on 'Associated conditions'.)

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Aggravating factors — Although not the sole cause of symptoms, certain factors aggravate CSU in a substantial subset of patients (table 1). These include: ●

Physical factors – Some patients with CSU have some flares that are triggered by physical stimuli. As an example, heat (hot showers, extreme humidity) is a common trigger for many CSU patients, and tight clothing or straps can also aggravate symptoms. In contrast, patients in whom physical factors are the main trigger for symptoms are more appropriately diagnosed as having a physical urticarial syndrome, such as cholinergic urticaria or delayed-pressure urticaria. Physical urticarias are reviewed separately. (See "Physical (inducible) forms of urticaria" and "Cold urticaria".)



Anti-inflammatory medications – NSAIDs worsen symptoms in 25 to 50 percent of patients with CSU [42].



Stress – Patients often report more severe symptoms during periods of physical or psychologic stress [43-50]. However, evidence that psychosocial factors are in some way causative is lacking [51].



Variations in dietary habits and alcohol – Although food allergy is a rare cause of CSU, some patients will report that variations in diet, particularly rich meals or spicy foods, will aggravate symptoms. Alcohol also aggravates symptoms in some. The interactions between diet and CSU are discussed separately. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'Dietary manipulations (controversial)'.)

Laboratory evaluation — Routine laboratory tests are unlikely to reveal abnormalities when the clinical history does not suggest an underlying allergic etiology or the presence of systemic disease [16,24,52-55]. Guidelines suggest initially obtaining a limited set of laboratories to screen for the systemic disorders that may involve urticaria [1,56-58]. The author and editors agree with limited testing and suggest the following: ●

A complete blood count with differential – This is usually normal in patients with CSU [59]. Eosinopenia (ie, an absolute eosinophil count of 12 years of age, 10 mg can be given initially.

• Doxepin (in adults) may be initiated at 10 or 25 mg given at bedtime. Doxepin is generally avoided in children 65 kg

Most patients require only one dose to treat symptoms adequately [63-66]. If symptoms are gradually improving after the initial dose, no further doses are needed. However, if symptoms continue to worsen after the initial dose, a second dose can be given after six hours, and a third dose can be given, if needed, after an additional six hours. A maximum of three doses within 24 hours is recommended. Efficacy studies — The "For Angioedema Subcutaneous Treatment" (FAST-1 and FAST-2) trials were randomized, multicenter, phase III trials, in which 130 adults with C1-INH deficiency were treated with icatibant for laryngeal, gastrointestinal, or cutaneous attacks of moderate-to-severe intensity [67]. FAST-1 compared icatibant with placebo, and FAST-2 compared icatibant with oral tranexamic acid (TA). The primary endpoint was median time to onset of symptom relief. FAST-1 did

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not demonstrate a clear benefit of icatibant over placebo (2 hours versus 4.2 hours), but FAST-2 did (2 hours with icatibant versus 11 hours with TA). In a pooled analysis of the two trials, significantly more patients receiving icatibant had symptom relief within four hours compared with placebo or TA (73 versus 45 and 29 percent, respectively) [68]. In addition, median time to near-complete symptom relief was significantly shorter with icatibant compared with placebo or TA (15, 21, and 36 hours, respectively). In a third trial, FAST-3, 83 patients were randomly assigned to receive icatibant or placebo for moderate-to-severe attacks at any location [69]. Icatibant significantly reduced median times to ≥50 percent reduction in symptom severity (2 versus 19.8 hours, primary endpoint), onset of primary symptom relief (1.5 versus 18.5 hours, secondary endpoint), or near-complete symptom relief (8 versus 36 hours) and provided a shorter time to initial symptom relief (0.8 versus 3.5 hours). For laryngeal attacks, median times to ≥50 percent reduction in symptom severity were 2.5 and 3.2 hours for icatibant and placebo, respectively. None of the patients receiving icatibant required rescue therapy before symptom relief occurred. A phase III study involved 32 children and adolescents with HAE, ranging in age from 2 to 18, who were treated with 0.4 mg/kg of icatibant [63]. Among 11 children and 11 adolescents treated for attacks, the median time to symptom relief was one hour. Adverse events occurred in nine subjects, were mild or moderate, and consisted predominantly of injection site reactions and gastrointestinal complaints. Adverse effects and precautions — Mild and transient pain at the injection site is the most common adverse reaction to icatibant. Other uncommon adverse effects include nausea, gastrointestinal colic, fever, asthenia, dizziness, increase in transaminases, and headache [70]. Icatibant should be used with caution in patients with acute ischemic heart disease or unstable angina, since antagonism of the bradykinin B2-receptor can reduce coronary blood flow in animal models, and patients with these comorbidities were excluded from clinical trials [71]. HAE attacks may relapse in 10 percent of cases [72]. Kallikrein inhibitor (United States only) — Ecallantide (Kalbitor [brand name]) is a genetically engineered recombinant plasma kallikrein inhibitor [73]. This drug blocks the production of bradykinin by inhibiting plasma kallikrein (figure 1) [59,74-78]. Ecallantide was approved by the FDA in 2009 for the treatment of acute attacks of HAE in patients 12 years of age or older [79]. It is only available in the United States [80]. Like pdC1-INH, ecallantide is a first-line acute therapy for laryngeal angioedema (following airway protection) and for gastrointestinal attacks. It is occasionally used for severe cutaneous attacks. However, clinical experience with ecallantide is more limited.

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Ecallantide should be administered by a clinician or a nurse, in a setting equipped to manage anaphylaxis as well as severe angioedema related to HAE. Anaphylaxis and allergic reactions were reported in 2 to 3 percent of patients in clinical trials. (See 'Efficacy studies and safety' below.) Ecallantide dosing and administration — Ecallantide is available in 1 mL vials of 10 mg each, and the adult dose is 30 mg. Injections should be given as three separate injections of 10 mg in the abdomen, upper arm, or thigh. The sites of injection should be anatomically distant from the area affected by the angioedema. A second dose of 30 mg may be administered if symptoms persist. Based on limited information, the second dose could be given as early as 1 hour and up to 24 hours after the first dose. Relapse has been reported in less than 3 percent of patients [81]. Efficacy studies and safety — The efficacy of ecallantide was assessed in two randomized trials: EDEMA3 [82] and EDEMA4 [80]. In an analysis of the pooled data from these studies, 143 subjects were treated with either ecallantide or placebo [83]. All types of attacks occurred (gastrointestinal, laryngeal, and cutaneous), with gastrointestinal attacks being the most common. Change from baseline mean symptom complex score at four hours after dosing was significantly greater in the ecallantide group compared with the placebo group (-0.97±0.78 and -0.47±0.71, respectively). The percentages of ecallantide- and placebo-treated patients with meaningful improvement at four hours were 70 and 38, respectively. Allergic reactions and anaphylaxis — The leading safety issue is a risk of allergic reactions and anaphylaxis, which have been reported in 3 to 4 percent of patients receiving it subcutaneously in the clinical trials [80,82,84]. For this reason, ecallantide should be administered in a supervised setting by a medically trained provider. Patients should be monitored carefully following administration because some symptoms of anaphylaxis overlap with those of HAE (ie, angioedema, throat discomfort), and recognition of an allergic reaction may be challenging. In the available reports, anaphylaxis presented within one hour of administration as flushing, urticaria, pruritus, rhinitis, chest discomfort, pharyngeal or laryngeal edema, wheezing, and/or hypotension. Anaphylaxis has not been reported with the first dose when the drug is given subcutaneously. All episodes have responded to epinephrine and other appropriate treatments with no fatalities [84]. Until more information is available, patients experiencing anaphylaxis or clear symptoms of hypersensitivity should not be given the drug again until evaluated by an allergy specialist. The mechanism responsible for these reactions has not been conclusively demonstrated, and the role of skin testing is not clear [84]. However, some patients with hypersensitivity reactions have tolerated the drug upon graded challenge [84].

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Other adverse effects of ecallantide are generally mild and include headache, nausea, fatigue, and diarrhea [80]. Injection site reactions are reported in 180° in clubbed nails and 160° in normal nails (figure 4). Clubbed fingers show the Schamroth sign, the obliteration of the diamond-shaped window normally visible when the dorsal surfaces of the terminal phalanges of corresponding fingers from opposite hands are placed together [158]. Digital clubbing can be acquired or hereditary: ●

Acquired bilateral clubbing is the most common form. It usually begins in the thumb and index fingers and is most often associated with pulmonary or cardiovascular diseases, including lung cancer, interstitial pulmonary fibrosis, lung abscess, pulmonary tuberculosis, pulmonary lymphoma, congestive heart failure, infective endocarditis, and cyanotic congenital heart disease [156]. Less frequently, digital clubbing may occur in patients with extrathoracic disease, including inflammatory bowel disease, liver cirrhosis, and gastrointestinal neoplasms. (See "Approach to the adult with interstitial lung disease: Clinical evaluation", section on 'Clubbing' and "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Extraintestinal manifestations' and "Malignancy and rheumatic disorders", section on 'Hypertrophic osteoarthropathy'.)



Acquired unilateral or single-digit clubbing is commonly related to nearby vascular lesions (such as a peripheral shunt, arteriovenous fistula, or aneurysm) but Pancoast tumors, lymphadenitis, or erythromelalgia can also cause unilateral clubbing [92,145]. Single nail involvement is typically traumatic but may be congenital. (See "Superior pulmonary sulcus (Pancoast) tumors".)



Isolated congenital digital clubbing (MIM #119900) is considered an incomplete form of primary hypertrophic osteoarthropathy (PHO) [159]. PHO is an autosomal recessive disorder due to mutations in the 15hydroxyprostaglandin dehydrogenase (HPGD) gene [160]. It presents in otherwise healthy children with clubbing, periostosis, and skin manifestations, including thickening of the skin of the face and scalp, coarsening of facial features, hyperhidrosis, and seborrhea.

Thyroid acropachy — Thyroid acropachy is a rare manifestation of Graves' disease characterized by digital clubbing, softtissue swelling of the hands and feet, and periosteal reaction with new bone formation (picture 54). It is almost always associated with thyroid dermopathy and exophthalmos and usually becomes apparent after the diagnosis and treatment of hyperthyroidism. (See "Overview of the clinical manifestations of hyperthyroidism in adults".) Half-and-half nails — Half-and-half nails (also termed "apparent leukonychia" or "Lindsay nails") are a manifestation of chronic renal insufficiency and uremia [32,33]. A half-and-half nail typically exhibits a red, pink, or brown; horizontal; distal

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band that occupies 20 to 60 percent of the total length of the nail [92,145,161]. The proximal portion of a half-and-half nail usually has a dull, white, ground-glass appearance due to underlying nail bed changes (picture 10). The nails may revert to normal following renal transplantation [162]. Half-and-half nails have also been reported in association with other systemic diseases (including Kawasaki disease, cirrhosis, Crohn disease, zinc deficiency, chemotherapy, Behçet disease, and pellagra) and drugs [22]. Koilonychia — Koilonychia, also called spoon nail, is the upward curving of the distal nail plate that results in a spoonshaped nail that could hold a drop of water on the surface (picture 55A-B). Koilonychia has been associated with iron deficiency and other systemic conditions in rare case reports; however, it is more commonly seen as an occupational change in nails and may be idiopathic. Ruling out iron deficiency anemia in someone with koilonychia is the only work-up necessary in this condition. (See "Iron deficiency in infants and children 85 percent). "Negative features" are: ●Symmetry of the pigmentation pattern ●Presence of only one color (black, gray, blue, red, dark brown, or tan) "Positive features" are: ●Blue-white veil ●Multiple brown dots ●Pseudopods ●Radial streaming ●Scar-like depigmentation ●Peripheral black dots/globules ●Broadened network ●Multiple blue/gray dots

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●Multiple (five to six) colors The presence of both negative features virtually excludes the diagnosis of melanoma. For all other lesions, the presence of any one of the positive features raises the suspicion for melanoma. Menzies method has a sensitivity of 85 to 92 percent and a specificity of 38 to 78 percent among examiners with various degrees of experience [5,7,11,30,33,35,36].

The seven-point check list — The seven-point checklist is based upon seven dermoscopic features frequently associated with melanoma (table 5) [10]: Major criteria: ●Atypical pigment network ●Blue-whitish veil ●Atypical vascular pattern Minor criteria: ●Irregular streaks ●Irregular dots/globules ●Irregular blotches ●Regression structures A score is calculated by summing points allotted as two points for each of the major three criteria and one point for each of the four minor criteria. A final score of three or more suggests melanoma [10]. The seven-point checklist has a sensitivity of 62 to 95 percent and a specificity of 35 to 97 percent among experts and non-experts [5,7,10,30-32,34,35,37]. The presence of any one of the criteria has been proposed as sufficient to warrant a biopsy in a revised version of this check list [37]. This revised seven-point checklist lowered the threshold for biopsy, using a total score of one instead of three as sufficient to warrant a biopsy. Although this revision increases the sensitivity of the criteria, the authors acknowledge that the most sensitive and specific method to diagnose melanoma requires supportive evidence based on clinical characteristics, follow-up, and the comparative approach [38].

CASH algorithm — CASH is an acronym for Color, Architectural disorder, Symmetry, and Homogeneity/Heterogeneity of dermoscopic structures (table 6) [11]. This method is based upon evaluating a pigmented lesion for the following: ●Presence of few versus many colors

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●Architectural order versus disorder ●Symmetry of shape and pattern versus asymmetry ●Homogeneity versus heterogeneity of dermoscopic structures The scoring system for the CASH algorithm is shown in a table (table 6). A total CASH score of eight or more is suspicious of melanoma (range 2 to 17) [11]. A score of eight was chosen as a threshold that optimizes sensitivity and specificity for individuals with all levels of experience. However, a lower threshold for lesion excision may be appropriate for novices. The CASH algorithm has a sensitivity of 87 to 98 percent and a specificity of 67 to 68 percent [11,39].

Pattern analysis — Pattern analysis is based upon the association of an image with a recognition template developed from previous experience (table 7) [40,41]. It therefore requires the knowledge and recognition of the global and local patterns of nevi and melanoma [9,42,43]. For experienced clinicians, pattern analysis is a sensitive and specific method, whereas for nonexperts, it may have a worse diagnostic accuracy than the unaided eye [31,44]. In analyzing a melanocytic lesion using the pattern analysis method, it should be determined whether or not the lesion manifests one of the global patterns encountered in nevi. In broad terms, benign lesions have an organized distribution of dermoscopic structures, one or a few colors, and a symmetric pattern. In contrast, melanomas often have a disorganized distribution of structures, multiple colors, and an asymmetric pattern (figure 7).

Nevi: Global and local features — Nevi tend to manifest 1 of the 10 following benign global patterns (figure 8): ●Reticular diffuse: A diffuse pigment network composed of lines that have minimal variation in their color and thickness. The holes of the network also appear relatively homogeneous in size. The network tends to fade toward the periphery. This pattern is commonly seen in melanocytic nevi with a prominent junctional component (ie, junctional nevi, superficial congenital nevi) (picture 11). ●Reticular patchy: A subclassification of reticular diffuse and represents a reticular network similar to that described above presenting in focal patches that are distributed in a symmetric and organized manner. The patches are separated by homogeneous structureless areas, which are of the same color or slightly darker than the background skin. This pattern is commonly seen in acquired melanocytic nevi and superficial congenital nevi (picture 12). ●Peripheral reticular with central hypopigmentation:Auniform network at the periphery of the lesion with a central homogeneous and hypopigmented structureless area. The structureless area has the same color, or slightly darker as compared to the background skin. This pattern is commonly seen in acquired melanocytic nevi, especially in individuals with fair skin (picture 13).

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●Peripheral reticular with central hyperpigmentation:A uniform network at the periphery of the lesion with a central homogeneous and hyperpigmented structureless area or blotch. This pattern is commonly seen in acquired melanocytic nevi, especially in individuals with darker skin (picture 14). ●Homogeneous pattern: A diffuse homogeneous structureless pattern in a stable and non-changing lesion. It may appear as gray-blue as seen in blue nevi, brown as seen in congenital nevi, or tan-pink as seen in acquired nevi in individuals with fair skin (picture 15). ●Peripheral reticular with central globules:Auniform network at the periphery of the lesion with central globules. This pattern is commonly seen in congenital nevi (picture 16). ●Peripheral globules with central network or homogeneous area, including the starburst pattern: The central component consists of a reticular or homogeneous pattern. The peripheral component can manifest in one of three ways: a single row of globules as seen in some actively growing nevi; more than one row of globules (ie, tiered globules) creating a starburst pattern as commonly seen in Spitz nevi; and streaks (classic starburst pattern) giving the appearance of an exploding star, as seen in Spitz/Reed nevi (picture 17). ●Globular pattern: Globules of similar shape, size, and color are distributed throughout the lesion. Globules may be large and angulated, creating a cobblestone pattern as seen in dermal nevi and some congenital nevi (picture 18). ●Two-component pattern: A combination of two patterns with one half of the lesion manifesting one pattern and the other half another pattern. The most common two-component pattern is the reticular-globular pattern (picture 19). ●Multicomponent pattern: A combination of three or more patterns distributed symmetrically in at least one axis (picture 20). Nevi on volar surfaces present a parallel furrow pattern, characterized by the presence of pigment along the sulci (furrows) of palms and soles (picture 21). (See "Dermoscopy of pigmented lesions of the palms and soles".) After determining whether or not the lesion adheres to 1 of the 10 benign global patterns, the observer proceeds to analyze the lesion's local features. A description of the typical and atypical variants of the local features with their diagnostic associations is provided in the table (table 7).

Melanoma: Global and local features — The melanoma specific structures are, by convention, termed atypical/irregular. Many of these atypical/irregular structures have a typical/regular counterpart that is associated with nevi (table 7). Global features of melanoma are: ●Deviation from the benign patterns and at least 1 of the 10 melanoma specific structures.

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●Multicomponent pattern: A combination of three or more patterns (eg, reticular, globular, and homogeneous), asymmetrically distributed in the lesion. It has also been defined as a lesion with three or more dermoscopic structures distributed asymmetrically. ●Nonspecific pattern: Lack of any recognizable global pattern of pigmentation. ●Volar skin patterns: Melanomas on palms and soles (ie, volar surfaces) can present with a multicomponent pattern, nonspecific pattern, or a parallel ridge pattern, which is characterized by the presence of pigment along the cristae (ridges) of palms or soles. (See "Dermoscopy of pigmented lesions of the palms and soles".) ●Facial skin patterns: Lesions on facial skin can present with a multicomponent pattern, nonspecific pattern, asymmetric follicular openings, perifollicular granularity, circle within a circle, angulated lines creating zigzag lines or coalescing to form polygons such as rhomboidal structures, and blotches obliterating follicular openings. Lesions displaying a multicomponent or nonspecific pattern are further examined for the following 10 melanoma specific structures (picture 22A-D): ●Atypical network, including angulated lines. ●Peripheral streaks (pseudopods and radial streaming). ●Negative network. ●Off-centered blotch. ●Atypical dots and/or globules. ●Regression structures, including granularity (also known as peppering), and scar-like areas. The presence of granularity and scar-like areas within the same lesion result in the appearance of a bluewhite coloration, usually overlying macular areas. ●Blue-white veil overlying raised areas. ●Atypical vascular structures. ●Shiny white lines (also known as crystalline structures). ●Tan peripheral structureless areas. The sensitivity, specificity, and predictive value of melanoma specific structures are provided in the table (table 9). A lesion is considered malignant if it deviates from the benign patterns, and has at least 1 of the 10 melanoma-specific structures. Lesions are considered suspicious if they have a benign pattern and reveal a melanoma specific structure, or if they do not adhere to one of the benign global patterns

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and lack a specific feature of melanoma.

DERMOSCOPY FROM A MANAGEMENT PERSPECTIVE

The primary

purpose of examining a skin lesion with a dermatoscope is to determine whether the lesion should be biopsied or not [45]. The decision to biopsy a suspicious lesion should be based upon the combination of clinical and dermoscopic examination of the lesion in question as well as surrounding lesions (comparative approach) and other relevant information, including history of change, associated symptoms, and personal and family history of melanoma and other skin cancers. In patients with multiple nevi, it is useful to identify the "signature nevus" pattern (the predominant type of nevus) as well as lesions that deviate from the predominant pattern ("ugly duckling" lesions), both clinically and dermoscopically [46,47]. A comparative dermoscopic approach to the patient with multiple nevi reduces the number of excisions of benign nevi [48]. (See "Melanoma: Clinical features and diagnosis", section on 'The "ugly duckling" sign'.) After a complete clinical and dermoscopic examination utilizing the two-step dermoscopy algorithm, a management decision can be rendered (algorithm 1). ●If the lesion is considered to be benign, the patient can be reassured, educated on the importance of self-skin examination, and instructed to return if changes are detected [49,50]. ●If the lesion is considered to be a melanoma, it should undergo excisional biopsy [51-54]. ●If the lesion is considered suspicious, there are two options: perform a biopsy or refer the patient to an expert clinician for further evaluation. The management decision will depend on several factors such as the pretest probability of the diagnosis of the lesion. For example, a lesion with a spitzoid morphology in a child is less likely to be a melanoma than a similar lesion in an adult. Based on the pretest probability, the clinician may be more likely to biopsy spitzoid lesions in adults than in children. Other factors that may influence the management decision include whether or not the lesion is an isolated lesion or one in a sea of many nevi, and whether or not the lesion is a clinical or dermoscopic outlier lesion. Lesions referred to an expert for further evaluation may be deemed benign, biopsied, or subjected to short-term monitoring. The rationale behind short-term monitoring is that stable lesions are biologically indolent and represent nevi, whereas changing lesions are biologically dynamic and may be atypical nevi or melanoma [55,56]. Short-term dermoscopic monitoring, which consists of comparing digital dermoscopic images of the same lesion taken approximately three to four months apart, should ideally be performed in specialized centers by experienced clinicians [55-57]. This type of monitoring is only suitable for

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macular (nonpalpable) lesions; suspicious or atypical nodular (palpable) lesions should be biopsied. Short-term dermoscopic monitoring is a safe and accepted approach to monitor these flat (nonpalpable) atypical lesions. In one study, 19 percent of 318 nevi showed a change during this time period (2.5 to 4.5 months) and 11 percent of those changing lesions were found to be early melanomas [55].

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dermoscopy".)

INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topics (see "Patient education: Seborrheic keratosis (The Basics)")

SUMMARY AND RECOMMENDATIONS ●The two-step dermoscopy algorithm forms the foundation of the dermoscopic evaluation of skin lesions. It is based upon the systematic search and recognition of specific dermoscopic structures to distinguish melanocytic and nonmelanocytic lesions, diagnose common benign and malignant nonmelanocytic lesions, and decide whether a melanocytic lesion is benign, suspicious, or malignant. (See "Overview of dermoscopy", section on 'Colors and structures'.) ●In the first step the observer decides whether a lesion is melanocytic or nonmelanocytic by looking for the presence or absence of specific features. (See 'Criteria for melanocytic lesions' above.) ●Nonmelanocytic lesions are further examined for the presence of features of dermatofibroma, basal cell carcinoma, squamous cell carcinoma, seborrheic keratosis, angioma, or other benign or malignant nonmelanocytic lesions. The possibility of a featureless or amelanotic melanoma should

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be kept in mind. (See 'Criteria for basal cell carcinoma' above and 'Criteria for seborrheic keratoses' above and 'Criteria for hemangioma/angioma and angiokeratoma' above and 'Vascular structures in skin lesions' above.) ●In the second step of the two-step algorithm, melanocytic lesions are further evaluated to differentiate benign nevi from suspicious lesions or melanoma. The decision whether to reassure the patient, monitor the lesion, or perform a biopsy is based upon this second step. (See 'Second step: Nevus versus suspicious lesion or melanoma' above.) ●The second step is performed using one of several algorithms. Clinicians with limited experience in dermoscopy may benefit from quantitative methods, such as the ABCD rule, Menzies method, and the seven-point checklist. These methods are relatively simple, accurate, and reproducible. (See 'ABCD rule of dermoscopy' above and 'Menzies method' above and 'The seven-point check list' above and 'CASH algorithm' above and 'Pattern analysis' above.) ●If a lesion is considered to be benign after a thorough clinical and dermoscopic examination, the patient can be reassured and educated on the importance of self-skin examination and instructed to return if changes occur. If the lesion is considered suspicious, there are two options: perform a biopsy or refer the patient to an expert clinician for further evaluation. Lesions referred to an expert for further evaluation may be deemed benign, biopsied, or subjected to short-term dermoscopic monitoring. (See 'Dermoscopy from a management perspective' above.) ●If the lesion is considered to be a melanoma, it should undergo excisional biopsy. (See "Melanoma: Clinical features and diagnosis", section on 'Biopsy'.)

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Dermoscopy of facial lesions - UpToDate uptodate.com/contents/dermoscopy-of-facial-lesions/print

Dermoscopy of facial lesions Authors: Iris Zalaudek, MD Danica Tiodorovic, PhD, MD Section Editor: Hensin Tsao, MD, PhD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jan 08, 2020.

INTRODUCTION

Dermoscopy is a noninvasive, in vivo technique used for

the examination of skin lesions. It is performed with a handheld instrument called a dermatoscope, which allows the visualization of subsurface skin structures in the epidermis, dermoepidermal junction, and upper dermis that are usually not visible to the naked eye. For clinicians who have been formally trained, dermoscopy significantly improves the diagnostic accuracy of pigmented and nonpigmented skin lesions [1,2]. However, the dermoscopic diagnosis of lesions located on the face may be challenging, due to the unique anatomic and histologic features of facial skin and their progressive changes caused by chronologic and photo-induced aging. This topic will review the dermoscopic features of benign and malignant facial lesions. The principles of dermoscopy and the dermoscopic evaluation of skin lesions, mucosal lesions, pigmented lesions of palms and soles, and nail pigmentations are discussed separately. Dermoscopic algorithms for skin cancer triage are also discussed separately. ●(See "Overview of dermoscopy".) ●(See "Dermoscopic evaluation of skin lesions".) ●(See "Dermoscopy of mucosal lesions".) ●(See "Dermoscopy of pigmented lesions of the palms and soles".) ●(See "Dermoscopy of nail pigmentations".) ●(See "Dermoscopic algorithms for skin cancer triage".)

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HISTOLOGIC FEATURES OF FACIAL SKIN The facial skin is characterized by a thin epidermis with an extremely thin stratum

corneum, nearly flat dermoepidermal junction, and a high density of large pilosebaceous units [3,4]. Continuous anatomic changes occur in its anatomy, due to intrinsic (chronologic) and extrinsic (photo-induced) aging [5]. The hallmark of sun-damaged skin is solar elastosis, characterized by the deposition in the upper dermis of a fibrillary material composed of elastin, fibronectin, and glycosaminoglycans. Other changes include epidermal atrophy, thinning of the spinous layer, flattening of the dermoepidermal junction with loss of rete ridges, and decreased collagen content (picture 1). (See "Photoaging".)

DERMOSCOPIC-PATHOLOGIC CORRELATION

While the pigment network is the dermoscopic hallmark of

melanocytic pigmented lesions located on the trunk and extremities, a true pigment network is rarely found on adult facial skin. The pigment network corresponds to epidermal melanin (either in melanocytes or keratinocytes) arranged along the elongated rete ridges. Thereby the tips of the rete ridges appear as network holes and the lateral borders as network lines (figure 1) [6,7]. Because of the histologic characteristics of facial skin (ie, flat dermoepidermal junction, absence of rete ridges, and high density of pilosebaceous units), pigmented lesions in this location exhibit distinctive dermoscopic patterns, which include: ●Pseudonetwork – Pigmented keratinocytes or melanocytes along the flattened dermoepidermal junction appear on dermoscopy as structureless diffuse brown pigmentation interrupted by numerous, variably broad and hypopigmented "holes," which correspond to hair follicles and sweat gland openings (figure 1). The combination of diffuse brown pigmentation and nonpigmented adnexal openings results in a distinctive dermoscopic feature known as "pseudonetwork," which is characteristic of facial melanocytic lesions (picture 2). ●Gray circles – Gray circles, also known as asymmetric pigmented hair follicles, correspond to pigmented melanocytes within the hair follicle (figure 2) [8,9]. The gray circles pattern is a unique dermoscopic feature of lentigo maligna (figure 2 and picture 3A). ●Yellow clods – The presence of keratotic plugs within the follicular structures enlarges the follicular openings and gives rise to variably large, partially confluent white to yellow clods (figure 2). Yellow clods are typically seen in pigmented actinic keratoses. Since the pseudonetwork is not specific of facial melanocytic lesions but can be seen also in nonmelanocytic pigmented lesions, additional criteria must be employed to differentiate melanocytic from nonmelanocytic lesions of the face [6,7,10].

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BENIGN MELANOCYTIC LESIONS Common nevus — In adults, the most common facial nevi are intradermal nevi of the Miescher type. They appear clinically as dome-shaped, usually nonpigmented or hypopigmented nodules with a smooth surface (picture 4). Terminal hairs are often present. On dermoscopy, Miescher nevi typically reveal comma-shaped or curved vessels and a structureless skin-colored to light brown background pigmentation. At times, residual brown globules (clods) or brown thick circles, mainly located around the hair follicles, can be seen (picture 5) [11,12]. In children, common facial nevi usually appear as flat, pigmented macules or papules, characterized dermoscopically by a pseudonetwork and small globules. The age-related difference in the morphologic appearance of facial nevi between children and adults has led to the concept that facial nevi may initially present as flat and pigmented macules and over time acquire the typical appearance of the intradermal nevus of Miescher [11,13].

Blue nevus — Blue nevi have a predilection for the head/neck area. They appear clinically as bluish macules or papules (picture 6A-B). The dermoscopic hallmark of blue nevus is a structureless blue pigmentation, although structureless color variegations of blue and white (whiteblue nevus) or blue and brown (brown-blue nevus) can be sometimes observed (picture 7). (See "Acquired melanocytic nevi (moles)", section on 'Blue nevi'.) It is important to remember that structureless blue color may be seen also in nodular melanoma, melanoma metastases, or heavily pigmented basal cell carcinoma. However, in contrast with the stable history of blue nevi, malignant tumors are generally associated with recent onset, rapid growth, and other clinical signs, such as erosions or ulceration. In the absence of a reliable history, blue lesions should be biopsied and sent for histopathologic examination. The so-called "blue-black rule" has been proposed as an additional dermoscopic clue to differentiate blue nevus from nodular melanoma [14]. This rule states that the combined presence of blue and black colors (either structureless or in the form of blotches or dots) should always raise the suspicion of nodular melanoma. Lesions with structureless blue and black color on dermoscopy should be biopsied.

Spitz nevus — Spitz nevus is a benign, indolent melanocyte proliferation that most commonly develops in children, adolescents, and young adults. There are two main clinical variants of Spitz nevus, the nonpigmented (classic Spitz nevus) and the pigmented, Reed-like Spitz nevus. Nonpigmented Spitz nevus typically presents as a rapidly growing pink nodule on the cheek of a child (picture 8). On dermoscopic examination, it often exhibits coiled vessels and a white network (also called reticular depigmentation or negative network) over a pink to reddish background (picture 9). (See "Spitz nevus and atypical Spitz tumors".)

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Reed nevus typically appears as a heavily pigmented, growing papule (picture 10). On dermoscopy, it reveals a structureless black to gray center intermingled with hypopigmented follicular openings and peripheral streaks, pseudopods, or globules (picture 11).

Solar lentigo — Solar lentigines are associated with UV exposure and skin aging and appear as multiple brownish spots, a few mm to >5 mm in diameter, that range in color from light brown to dark brown (picture 12). Histologically, they show increased deposition of melanin in keratinocytes and an increased number of melanocytes arranged in a linear fashion at the dermoepidermal junction. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Solar lentigo'.) Dermoscopy may show faint pigmented fingerprint structures or a structureless pattern. Frequently, a delicate, light brown pseudonetwork with well-defined borders and a "moth-eaten" edge is recognizable (picture 13) [15].

LENTIGO MALIGNA AND LENTIGO MALIGNA MELANOMA

The termslentigo maligna (LM) and

lentigo maligna melanoma (LMM) refer to in situ and invasive melanoma, respectively, arising on chronically sun-damaged skin. (See "Lentigo maligna: Clinical manifestations, diagnosis, and management" and "Melanoma: Clinical features and diagnosis", section on 'Lentigo maligna melanoma'.)

Dermoscopic features — LM and LMM exhibit a range of dermoscopic features that differ from those of melanoma arising on the trunk or extremities. These features are either related to the follicular openings or to the interfollicular skin. One or more of the following dermoscopic structures are commonly seen in LM and LMM [8,9,15-21]. ●Follicular structures: •Asymmetric pigmented follicular openings – They appear as gray circles within the follicular opening (picture 14). •"Circle-within-a-circle"– This feature consists ofan inner small gray circle within the follicular opening, surrounded by a larger, outer gray to gray-brown circle or lines (picture 15). •Target-like pattern, also called "dot-within-a-circle"– This feature refers to a gray dot or clod in the center of a hair follicle that is surrounded by a gray circle (picture 16). •Obliterated hair follicles – This feature refers to large gray to bluish blotches within follicular openings. They are a sign of invasive LMM (picture 17).

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•Irregularly distributed brown dots/globules – Light to dark brown dots/globules irregularly distributed throughout the lesion. ●Interfollicular structures: •Annular-granular pattern – This feature refers to densely aggregated, partially confluentgrey dots or clods that are located in the interfollicular space (picture 18). •Pigmented rhomboidal structures – This pattern consists of brown to grayish, angulated lines located in the interfollicular space that form rhomboids (picture 19). •Red rhomboidal structures – This pattern consists of linear vessels that are seen in the interfollicular space around the follicular openings (picture 20). •Increased density of the vascular network – The vascular network appears of higher density within the lesion than in the surrounding peripheral skin (picture 21). ●Colors: •White scar-like areas –White to gray structureless areas in-between the follicular openings. •Gray color – Presence of shades of gray color within the lesion. •Darkening at dermoscopic examination – Presence of a color that is invisible to the naked eye and appears on dermoscopy darker than all clinically observable shades of brown or gray in the lesion.

Progression model for lentigo maligna — Based upon dermoscopic criteria, a four-stepprogression model of LM has been proposed [22]. According to this model, asymmetric pigmented follicular openings, also called gray circles, gray dots within the follicular opening, and/or circles within circles represent the earliest features of LM (picture 14). These structures subsequently evolve to a so-called annular-granular pattern (picture 18), which consists of aggregated fine gray dots, gray globules, and streaks around the follicle. With further progression of the lesion, these streaks become longer and intersect with neighboring streaks, finally forming angulated lines between hair follicles called rhomboidal structures (picture 19). Further progression and invasion is represented by the development of obliterated hair follicles filled with black or blue-gray blotches (picture 17) and structureless blue areas, white scar-like, and milkyred areas [9].

BENIGN NONMELANOCYTIC LESIONS 2767

Sebaceous hyperplasia — A benign hyperplasia of the sebaceous glands or sebaceous hyperplasia (SH) is commonly seen on the forehead, nose, and cheeks of middle-aged or older patients (picture 22) [23]. Lesions are usually multiple and do not exceed the size of a few millimeters. (See "Cutaneous adnexal tumors", section on 'Sebaceous hyperplasia'.) Dermoscopically, the lesions are characterized by a structureless yellow to whitish center surrounded by short linear vessels (picture 23). These vessels are also called "crown vessels" because they embrace but do not cross the central parts of the lesion. In contrast, the arborizing vessels of nodular basal cell carcinoma are typically bright red in color, sharply focused, and branch all over the tumor's surface (picture 24).

Lichen planus-like keratosis — Lichen planus-like keratosis (LPLK) or lichenoid keratosis is considered a regressing solar lentigo or seborrheic keratosis. Clinically, it appears as a solitary, gray to brown papule or plaque;on dermoscopy, LPLK shows a coarse or fine, gray to blue, granular pigmentation covering most of the lesion (picture 25). Fully or nearly fully regressed LPLK is characterized by diffuse brownish gray granules, which may coalescence to form globules, streaks, or even structures similar to rhomboids [24-26]. Because LM may exhibit the same features as LPLK, a lesion dermoscopically characterized by signs of evident regression should always be biopsied and sent for histopathologic examination.

Seborrheic keratosis — Seborrheic keratoses are common benign tumors that are dermoscopically characterized by one or more of the following patterns[27-29]: ●Moth-eaten borders – The borders of the lesion show invaginations that result in a moth-eaten appearance (picture 26). ●Milia-like cysts –These areround, whitish or yellowish clods that correspond to small intraepidermal, keratin-filled cysts (picture 27A-B). They may also be seen in some congenital nevi and in papillomatous melanocytic nevi. ●Comedo-like openings (pseudofollicular openings) –Comedo-like openings arekeratin-filled invaginations of the epidermis that correspond histopathologically to comedo-like structures (picture 28); they are mainly seen in seborrheic keratosis or papillomatous melanocytic nevi. ●Sharp demarcation – Abrupt cutoff of pigmentation at the border (picture 29). ●Ring-like structures and fat fingers– These are brown ring-like structures that are densely aligned to one another. Sometimes they might be oval and elongated, resulting in a feature described as "fat fingers," which are typically seen in flat, reticulated seborrheic keratoses (picture 30)[27]. ●Fissures and ridges – These are irregular, linear, keratin-filled depressions that might result in a brain-like appearance to the lesion (picture 31).

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●Fingerprinting – Describes a network-like structure that is light brown and delicate, with the pattern of a fingerprint (picture 32). ●Hairpin blood vessels – Vascular loops resembling a hairpin. This typical vascular architecture is predominantly seen in irritated seborrheic keratosis (picture 33).

KERATINOCYTE SKIN CANCER

The term

keratinocyte skin cancer includes actinic keratosis (AK), intraepidermal carcinoma (IEC), including Bowen's disease, and invasive squamous cell carcinoma (SCC).

Actinic keratosis — Actinic keratosis (AK), also known as solar keratosis or keratinocytic intraepidermal neoplasia, is a common lesion which represents the earliest stage on a continuum with squamous cell carcinoma (SCC). (See "Epidemiology, natural history, and diagnosis of actinic keratosis".) AKs can be clinically subdivided into three grades, which correspond to distinctive dermoscopic patterns [30,31]: ●Grade 1, slightly palpable AK – Grade 1 AKs are dermoscopically characterized by a red pseudonetwork pattern and discrete white scales (picture 34). ●Grade 2, moderately thick AK – Grade 2 AKs show an erythematous background intermingled by white to yellow, keratotic, and enlarged follicular openings. These features are similar to the surface of a strawberry, hence the name "strawberry pattern" (picture 35A). ●Grade 3, very thick, hyperkeratotic AK – Grade 3 AKs exhibit either enlarged follicular openings filled with keratotic plugs over a scaly and white-yellow appearing background, or marked hyperkeratosis seen as white-yellow structureless areas (picture 35B)[31,32].

Pigmented actinic keratosis — Pigmented AK clinically resembles a darkly pigmented solar lentigo. Pigmented AK may be misdiagnosed as LM and vice versa because, with the exception of gray circles, it may exhibit all the criteria of LM (picture 3A-B) [21,33]. (See 'Lentigo maligna and lentigo maligna melanoma' above.)

Squamous cell carcinoma in situ (intraepidermal carcinoma) — Squamous cell carcinoma (SCC) in situ, also called intraepidermal carcinoma (IEC) or Bowen's disease (BD) is characterized by the presence of dotted and/or glomerular vessels, white to yellowish surface scales, and a red-yellowish background color (picture 36). Glomerular vessels represent a variation of dotted vessels but are larger in size and characterized by tortuous capillaries. Both dotted and glomerular vessels often appear within the same lesion and are distributed in small, densely-packed clusters or groups.

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Pigmented squamous cell carcinoma in situ — The most common appearance of pigmented SCC in situ is a structureless brown pattern, brown circles, as well as an asymmetric combination of structureless areas and brown dots. The structureless zone is usually hypopigmented (skin-colored, white, or pink) and often eccentrically located. An important clue for the diagnosis of pigmented SCC in situ is the presence of brown dots, which are arranged as radial lines in the periphery (picture 37) [34,35].

Invasive squamous cell carcinoma — The most important dermoscopic features of invasive forms of SCC are white circles, white structureless areas, masses of keratin (picture 38), as well as hairpin and linear-irregular vessels.

Pigmented invasive squamous cell carcinoma — Pigmented SCCs are rare. Dermoscopy features include blue structureless areas and polymorphic vessels [36].

Progression model for squamous cell carcinoma — A dermoscopic progression model of facial AK developing into SCC in situ and invasive SCC has been proposed [31]. AKs with increasing atypia tend to display dotted vessels around follicles. As the lesion evolves to SCC in situ, the dotted vessels become larger, more convoluted (glomerular vessels), and clustered (picture 36). Hair follicles in this area become smaller and then disappear. Keratotic follicles eventually form the discrete whitish, opaque, scaly areas typically seen in SCC in situ. With progression of SCC in situ to invasive SCC, the lesion becomes thicker and shows on dermoscopy hairpin and/or linear-irregular vessels. Along with these vascular changes, a central mass of keratin is formed and ulceration may occur. The so-called "red starburst pattern" (ie, peripheral red lines surrounding a central strawberry pattern) may be seen in evolving lesions (picture 39). Specifically, the red starburst pattern may be a sign of rapid growth of AK, IEC, or invasive SCC [31].

BASAL CELL CARCINOMA

The clinical and

dermoscopic aspects of basal cell carcinoma (BCC) are influenced by several factors, including histopathologic subtype, location, sex, and skin type. Nodular BCC is the most common type and typically presents on the face as a pink or flesh-colored papule (picture 40). Superficial BCCs most commonly occur on the trunk, and typically present as slightly scaly, nonfirm macules, patches, or thin plaques light red to pink in color (picture 41). (See "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma".)

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Nodular basal cell carcinoma — On dermoscopy, the hallmark of nonpigmented nodular-cystic BCC are focused, bright red, and branching arborizing vessels (picture 24). In addition to arborizing vessels, pigmented nodular BCCs typically exhibit loosely arranged blue-gray globules or dots that differ in size and number (picture 42).

Superficial basal cell carcinoma — The most classic features of nonpigmented superficial BCC are shiny white to red, translucent or opaque structureless areas and multiple small erosions (picture 43). This subtype lacks the classic arborizing vessels, but may reveal short, focused fine telangiectasias with relatively few ramifications. The pigmented variant of superficial BCC may display translucent light brown to grayish concentric structures, spoke-wheel areas, and peripheral finger-like projections (leaf-like structures) (picture 44A-B) [37].

MERKEL CELL CARCINOMA

Merkel cell carcinoma

(MCC) is a rare, aggressive cutaneous malignancy that predominantly affects older adults with light skin types. MCC is most often located in the head and neck region. Clinically, MCC presents as a rapidly growing, firm, shiny, flesh-colored or bluish-red, intracutaneous nodule (picture 45A-B). Dermoscopy shows a nonspecific polymorphous vascular pattern composed by linear vessels over a pink background (picture 46) [38].

DIFFERENTIAL DIAGNOSIS OF FACIAL LESIONS Flat lesions Pigmented — The differential diagnosis of flat pigmented facial lesions includes lentigo maligna (LM), solar lentigo, pigmented actinic keratosis (AK), and lichen planus-like keratosis (LPLK). The clinical recognition of these lesions is challenging, even if coupled with dermoscopy, and requires the consideration of additional clinical criteria, such as number and location of lesions and lesion surface, topography, and color. ●The lesion color is the single most important dermoscopic criterion to differentiate solar lentigo from LM. The latter often shows a combination of brown and gray color (ie, gray circles, gray dots, gray lines), whereas solar lentigo usually exhibits only brown color [6,10,15,17,22]. ●Surface scales; background erythema; white circles; and enlarged, white, follicular openings are an important clue for the diagnosis of grade 2 nonpigmented AK. However, the same pattern can also be seen in pigmented AK and represents an important clue for the diagnosis. Although gray color is

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the strongest clue for LM, it can also be seen in LPLK and pigmented AK. In the latter, evident follicular openings and erythema might represent important additional diagnostic clues. ●In flat, pigmented facial lesions lacking specific melanocytic dermoscopic features, the presence of irregularly distributed, brown dots/globules is more often associated with LM than with flat, nonmelanocytic skin neoplasms, such as pigmented AK, solar lentigo, flat seborrheic keratosis, or LPLK [39]. ●In flat lesions, patterns of gray circles are highly suspicious for facial melanoma, but other patterns do not exclude it. Regardless of pattern, the presence of gray color is a clue to malignancy. Lesions with gray colors should be biopsied and sent for histopathologic examination [40]. However, the histopathologic diagnosis of early LM may also be difficult, since early lesions may lack significant cytologic atypia or architectural disarrangement [41]. (See "Lentigo maligna: Clinical manifestations, diagnosis, and management".)

Nonpigmented — The differential diagnosis between grade 1 and 2 AKs and fully developed squamous cell carcinoma (SCC) is mainly based upon the presence of vascular patterns [31]. Dotted or glomerular vessels, hairpin vessels, and linear irregular vessels are most frequently seen in SCC. Additional criteria that are significantly associated with SCC include targetoid hair follicles, white structureless areas, a central mass of keratin, and ulceration.

Raised lesions — The differential diagnosis of raised or nodular lesions on the face, which includes dermal nevus and nodular basal cell carcinoma (BCC), is mainly based upon the presence of vascular patterns [42,43]. Vessels in intradermal nevi are usually blurred, curved, and show few ramifications. In contrast, nodular BCC displays dull-red, sharply focused, arborizing vessels that reveal multiple ramifications into finest capillaries.

BENEFITS AND LIMITATIONS OF DERMOSCOPY

Dermoscopy may improve the diagnostic accuracy of

formally trained clinicians for most nodular skin lesions occurring on the face. However, the dermoscopic diagnosis of flat, pigmented lesions remains challenging even for the experienced clinician [40]. Since the dermoscopic criteria to differentiate benign from malignant lesions have not been adequately evaluated in large studies, it is important to maintain a low threshold of clinical suspicion to perform a biopsy for histopathologic examination. For large lesions located on cosmetically sensitive areas that require a partial biopsy, dermoscopy may be especially useful to determine the most suspicious areas to be biopsied [44].

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SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dermoscopy".)

SUMMARY AND RECOMMENDATIONS ●The dermoscopic diagnosis of lesions located on the face may be challenging, due to the unique anatomic and histologic features of facial skin (figure 1) and their continuous changes caused by chronologic aging and photoaging. (See 'Introduction' above and 'Histologic features of facial skin' above.) ●While the pigment network is the dermoscopic hallmark of melanocytic pigmented lesions located on the trunk and extremities, a true pigment network is rarely seen on adult facial skin. Distinctive dermoscopic patterns found in facial pigmented lesions include the pseudonetwork (picture 2), gray circles, and yellow clods (picture 3A). (See 'Dermoscopic-pathologic correlation' above.) ●Facial melanocytic lesions are characterized by a variety of dermoscopic patterns: intradermal nevi typically show comma-shaped or curved vessels and a structureless skin colored to light brown background pigmentation (picture 5); blue nevi show a structureless blue/brown pigmentation (picture 7); Spitz nevi reveal coiled vessels and a white network background (picture 9). (See 'Benign melanocytic lesions' above.) ●Lentigo maligna and lentigo maligna melanoma exhibit a range of dermoscopic features that differ from those of melanoma arising on the trunk or extremities, including follicular and interfollicular structures: asymmetric pigmented follicular openings (picture 14); "circle-within-a-circle" structures (picture 15); target-like pattern (picture 16); obliterated hair follicles (picture 17); and pigmented rhomboidal structures (picture 19). (See 'Lentigo maligna and lentigo maligna melanoma' above.) ●The so-called "strawberry pattern" and white-yellow structureless areas are characteristic of actinic keratosis (picture 35A-B). However, pigmented actinic keratoses may be difficult to differentiate from lentigo maligna because, with the exception of gray circles, they may exhibit all the criteria of LM (picture 3A-B). White circles, white structureless areas, masses of keratin, as well as hairpin and linear-irregular vessels, are main features of squamous cell carcinoma (picture 38). (See 'Keratinocyte skin cancer' above.) ●Bright red arborizing vessels are the dermoscopic hallmark of nodular basal cell carcinoma (picture 24). Blue gray globules or dots can be seen in pigmented tumors (picture 42). Superficial basal cell carcinomas show white to red structureless areas, small erosions, and fine telangiectasias (picture 43). Pigmented variants may show brown to grayish concentric structures, spoke-wheel areas, or peripheral finger-like projections (picture 44A). (See 'Basal cell carcinoma' above.)

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Use of UpToDate is subject to the Subscription and License Agreement. Topic 93602 Version 12.0

GRAPHICS Comparison of photodamaged and normal skin on histologic examination

(A) Sun-protected skin. (B) Photoaged skin. Photoaged skin shows atypical keratinocytes, flattening of dermal papillae, and deposition of amorphous basophilic material in the dermis (solar elastosis). Graphic 83455 Version 3.0

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Anatomic differences between the truncal and facial skin

(A) Pigmentation along an undulated dermo-epidermal junction characterized by elongated rete ridges. (B) Pigmentation along a flattened dermo-epidermal junction characterized by a high density of hair follicles. Graphic 96220 Version 1.0 Dermoscopic images of pigment network and pseudonetwork

(A) True pigment network due to melanin along elongated rete ridges: pigmented lines that form a network pattern. (B) Facial pseudonetwork due to melanin along a flat dermo-epidermal junction: structureless pigmentation intermingled by hypopigmented follicular openings. Graphic 96221 Version 1.0

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Difference in pigment distribution in lentigo maligna and pigmented actinic keratosis of the face

(A) Pigmented melanocytes that invade the hair follicles and melanophages in the upper dermis. (B) Keratotic plugs within the follicular openings, pigmented keratinocytes, and melanophages in the upper dermis. Graphic 96222 Version 1.0 Dermoscopic patterns seen in lentigo maligna and pigmented actinic keratosis

(A) Lentigo maligna: Melanocytes extending down the follicular units appear as gray circles. (B) Pigmented actinic keratosis: Keratotic plugs appear as enlarged, white to yellow clods or rosettes. Graphic 96223 Version 5.0

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Intradermal nevus

A typical skin-colored intradermal nevus is present on the nose. Graphic 96671 Version 1.0

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Dermoscopic image of a facial intradermal nevus (Miescher nevus)

Structureless light brown pigmentation and comma-shaped vessels are characteristic dermoscopic features of facial intradermal nevi of the Miescher type. Residual brown globules and circles are also visible in this lesion. Graphic 96283 Version 1.0

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Blue nevus

Blue nevus on the face presenting as a small, bluish papule. Graphic 96672 Version 2.0

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Blue nevus

A blue nevus of the face presenting as a small, bluish macule. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 96233 Version 3.0

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Dermoscopic image of a facial blue nevus

The dermoscopic hallmark of blue nevi is a structureless, blue pigmentation. Graphic 96284 Version 2.0

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Spitz nevus

Spitz nevus presenting as a pink, symmetric, dome-shaped papule on the face of a child. Graphic 85817 Version 6.0

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Dermoscopic image of nonpigmented facial Spitz nevus

Coiled vessels and a white network (also called reticular depigmentation or negative network) over a pink to reddish background are characteristic dermoscopic features of nonpigmented Spitz nevus. Graphic 96285 Version 2.0

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Pigmented Spitz nevus (Reed nevus)

Pigmented Spitz nevus on the face of a four-year-old child. Graphic 96673 Version 1.0

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Dermoscopic image of a facial pigmented Spitz nevus (Reed nevus)

On dermoscopy, the Reed nevus is characterized by a structureless dark brown to black center with hypopigmented follicular openings and peripheral streaks, pseudopods, or globules. Graphic 96286 Version 1.0 Solar lentigines

Clinical image of multiple solar lentigines on the forehead. Graphic 96674 Version 1.0

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Dermoscopic image of a facial solar lentigo

Facial solar lentigines may show on dermoscopy a faint, light brown pseudonetwork with welldefined borders and a so-called "moth-eaten" edge. Graphic 96289 Version 4.0

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Dermoscopic image of lentigo maligna

Asymmetric, pigmented follicular openings appearing as small, gray circles in an early lentigo maligna. Graphic 96312 Version 2.0

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Dermoscopic image of lentigo maligna

Dermoscopic pattern of "circles within a circle" in an early lentigo maligna melanoma (Breslow thickness 0.3 mm); an inner, small, gray circle is surrounded by a larger, gray to brown circle. Graphic 96313 Version 2.0

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Dermoscopic image of lentigo maligna

Target-like pattern, also called "dot-within-a-circle" pattern, in a lentigo maligna. A gray dot surrounded by a gray circle is visible within the hair follicle. Graphic 96314 Version 3.0

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Dermoscopic image of lentigo maligna melanoma

Obliterated hair follicles in an invasive lentigo maligna melanoma (depth of invasion = 0.5 mm) appearing as structureless, gray-black blotches. Graphic 96315 Version 2.0

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Dermoscopic image of lentigo maligna

Annular-granular pattern in a lentigo maligna. Multiple gray dots are seen. Graphic 96316 Version 2.0

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Dermoscopic image of lentigo maligna melanoma

Pigmented, rhomboidal structures in a lentigo maligna melanoma (Breslow thickness 0.2 mm) appearing as angulated, gray to brown lines in the interfollicular space. Graphic 96317 Version 2.0

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Dermoscopic image of lentigo maligna

Red, rhomboidal structures in a lentigo maligna. Red lines are seen in the interfollicular spaces. Graphic 96318 Version 3.0

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Dermoscopic image of lentigo maligna

Increased density of the vascular network is visible in the right and lower part of the lesion. This feature, however, is not specific or diagnostic of lentigo maligna, as it can also be found in sundamaged skin or rosacea. Graphic 96319 Version 3.0

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Sebaceous hyperplasia A

yellowish papule is present on the forehead of this patient. Graphic 96675 Version 1.0

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Dermoscopic image of sebaceous hyperplasia

On dermoscopic examination, sebaceous hyperplasia shows a structureless yellow to whitish center surrounded by short linear vessels ("crown vessels") that do not cross the center. Graphic 96288 Version 1.0

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Dermoscopic image of nonpigmented nodular basal cell carcinoma

Bright red and branching arborizing vessels are the main dermoscopic feature of nodular nonpigmented basal cell carcinoma. Graphic 96302 Version 1.0

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Clinical and dermoscopic image of lichen planus-like keratosis

(A) Lichen planus-like keratosis, also called lichenoid keratosis, presenting as a solitary, gray to brown papule or plaque on the face. (B) On dermoscopy, coarse, large, and partially confluent gray dots are seen. Graphic 96329 Version 2.0

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Dermoscopic image of seborrheic keratosis: Moth-eaten borders

The presence of invaginations in the lesion edges gives it a moth-eaten appearance. Graphic 96676 Version 2.0

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Dermoscopic image of seborrheic keratosis: Milia-like cysts

Graphic 96677 Version 2.0

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Dermoscopic image of a facial seborrheic keratosis

Seborrheic keratosis arising on a solar lentigo. Parallel, curvy lines (fingerprint structures) are visible at the periphery of the lesion; multiple milia-like cysts and comedo-like openings are present in the center. Graphic 96291 Version 2.0

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Dermoscopic image of seborrheic keratosis: Comedo-like openings

Graphic 96678 Version 2.0

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Dermoscopic image of seborrheic keratosis: Sharp demarcation

Graphic 96681 Version 1.0

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Dermoscopic image of seborrheic keratosis: Fat fingers

The elongated, brown circles closely aligned to one another are called "fat fingers." Graphic 96683 Version 2.0

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Dermoscopic image of seborrheic keratosis: Fissures and ridges

Graphic 96682 Version 2.0

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Dermoscopic image of seborrheic keratosis

A delicate, network-like structure resembling a fingerprint is visible in this dermoscopic image of a seborrheic keratosis. Graphic 96685 Version 2.0

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Dermoscopic image of seborrheic keratosis: Hairpin blood vessels

In seborrheic keratoses, hairpin vessels appear as red, U-shaped structures on a whitish or light-pink background. Graphic 96686 Version 1.0

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Dermoscopic image of grade 1 actinic keratosis

Grade 1 actinic keratoses are characterized by a red pseudonetwork pattern and discrete, white scales. Graphic 96294 Version 2.0

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Dermoscopic image of grade 2 actinic keratosis

Grade 2 actinic keratosis shows on dermoscopy the so-called strawberry pattern, characterized by an erythematous background intermingled by white-to-yellow, keratotic, and enlarged follicular openings similar to the surface of a strawberry. Graphic 96295 Version 2.0

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Dermoscopic image of grade 3 actinic keratosis

On dermoscopy, grade 3 actinic keratoses show enlarged follicular openings filled with keratotic plugs over a scaly and white-yellow appearing background. Graphic 96296 Version 1.0

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Dermoscopic image of a facial pigmented actinic keratosis

This pigmented actinic keratosis shows an annular-granular pattern that closely resembles the pattern typically seen in lentigo maligna. Graphic 96297 Version 2.0

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Dermoscopic image of nonpigmented squamous cell carcinoma in situ (Bowen disease)

Large, coiled (glomerular) vessels in a grouped arrangement and yellow surface scales are the dermoscopic hallmarks of nonpigmented Bowen disease. Graphic 96298 Version 2.0

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Dermoscopic features of facial pigmented squamous cell carcinoma in situ (Bowen disease)

Pigmented Bowen disease is sometimes characterized by small, brown dots arranged in radial lines at the periphery of the lesion. Graphic 96376 Version 2.0

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Dermoscopic image of facial invasive squamous cell carcinoma

On dermoscopy, white circles surrounding a yellow clod over a white background are a clue for invasive squamous cell carcinoma. Graphic 96300 Version 2.0

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Progression model of keratinocyte skin cancer

Graphic 96668 Version 1.0

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Nodular basal cell carcinoma

Two nodular basal cell carcinomas are present on the nose and nasolabial fold of this patient. Graphic 96669 Version 1.0

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Superficial basal cell carcinoma

This erythematous, slightly scaly patch on the neck is representative of a superficial basal cell carcinoma. Graphic 96670 Version 1.0

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Dermoscopic image of pigmented nodular basal cell carcinoma of the face

Arborizing vessels and blue-gray globules or dots are visible in this pigmented nodular basal cell carcinoma. Graphic 96303 Version 1.0

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Dermoscopic features of superficial nonpigmented basal cell carcinoma

Superficial nonpigmented basal cell carcinoma is characterized by structureless white to red areas and multiple small erosions. Fine telangiectasias are also present. Graphic 96396 Version 1.0

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Dermoscopic image of pigmented superficial basal cell carcinoma of the face

Light brown to grayish globules are visible in this pigmented superficial basal cell carcinoma. Graphic 96305 Version 1.0

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Dermoscopic features of superficial pigmented basal cell carcinoma

Short, light brown finger-like projections (leaf-like structures) can be seen at the periphery of this superficial pigmented basal cell carcinoma. Graphic 96398 Version 1.0

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Merkel cell carcinoma

This blue-red, dome-shaped nodule is a Merkel cell carcinoma. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 70535 Version 5.0

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Merkel cell carcinoma

This blue-red, dome-shaped papule on the forehead is a Merkel cell carcinoma. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 50573 Version 5.0

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Clinical and dermoscopic images of Merkel cell carcinoma

(A) Merkel cell carcinoma presenting as a red nodule with scaling on the cheek of this patient. Note the background sun-damaged skin. (B) Dermoscopy shows a polymorphous, vascular pattern composed of linear vessels over a pink background. White scales are also present. Graphic 102595 Version 2.0

Contributor Disclosures Iris Zalaudek, MDGrant/Research/Clinical Trial Support: F. Hoffmann-La Roche [Melanoma, basal cell carcinoma]; Celgene Corporation; Novartis [Psoriasis]. Consultant/Advisory Boards: Novartis [Melanoma]; Sanofi Genzyme [Cutaneous squamous cell carcinoma]; Sun Pharmaceutical Industries [Basal cell carcinoma]; HEINE Optotechnik; FotoFinder [Dermoscopy]. Speaker's Bureau: Cieffe [Cutaneous oncology]; Almirall; Mylan; Meda Pharmaceuticals; Cantabria Labs Difa Cooper [Actinic keratosis]; La Roche-Posay Laboratoire Pharmaceutique [Skin cancer screening]; Novartis [Psoriasis]. Other Financial Interest: Laboratoires Pierre Fabre [Melanoma]; ISDIN; Beiersdorf; BioNike; Rilastil; Istituto Ganassini [Skin cancer screening].Danica Tiodorovic, PhD, MDNothing to discloseHensin Tsao, MD, PhDGrant/Research/Clinical Trial Support: Relay Therapeutics; Asana BioSciences [Melanoma (Dual BRAF/PI3K inhibitor, ERK 1/2 inhibitor)]. Consultant/Advisory Boards: Epiphany Dermatology [Basal cell carcinoma, melanoma, nevi, skin cancer screening]; World Care Clinical; Ortho Dermatologics [Melanoma (Imaging services)]. Consultant/Advisory Boards (Spouse): Ortho Dermatologics [Melanoma].Rosamaria Corona, MD, DScNothing to disclose Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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Conflict of interest policy

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Dermoscopy of pigmented lesions of the palms and soles uptodate.com/contents/dermoscopy-of-pigmented-lesions-of-the-palms-and-soles/print

Dermoscopy of pigmented lesions of the palms and soles Authors: Toshiaki Saida, MD, PhD Hiroshi Koga, MD Section Editor: Hensin Tsao, MD, PhD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 31, 2018.

INTRODUCTION

In populations with darker skin, melanoma occurs most

frequently in acral areas, with a particular predilection for the soles of the feet. In Japanese, almost one-half of cutaneous melanomas occur in acral areas and approximately 30 percent affect the sole [1]. The prognosis of acral melanoma is generally poor, mainly as a consequence of a delay in diagnosis [2,3]. Dermoscopy, a noninvasive technique performed by a handheld instrument called a dermatoscope, increases the clinician's diagnostic accuracy for pigmented lesions of the palms and soles and may help in the recognition of acral melanoma at an early, curable stage [4,5]. This topic will review the dermoscopic features of melanocytic and nonmelanocytic pigmented lesions of the palms and soles and the dermoscopic criteria for differentiating benign melanocytic nevi from early melanoma. The principles of dermoscopy and the use of dermoscopy for the evaluation of lesions located on the nonglabrous skin, face, mucosal surfaces, and nails are discussed separately. Dermoscopic algorithms for skin cancer triage are also discussed separately. ●(See "Overview of dermoscopy".) ●(See "Dermoscopic evaluation of skin lesions".) ●(See "Dermoscopy of facial lesions".) ●(See "Dermoscopy of mucosal lesions".) ●(See "Dermoscopy of nail pigmentations".) ●(See "Dermoscopy of nonpigmented nail lesions".) ●(See "Dermoscopic algorithms for skin cancer triage".)

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HISTOLOGIC FEATURES OF PALMOPLANTAR SKIN

The palmoplantar skin is

anatomically and histologically unique. It is characterized by a thick, compact, cornified layer and by the presence of dermatoglyphics, consisting of ridges and furrows (sulci) that run on the surface in a parallel fashion and form loops, whorls, and arches in highly individualized patterns. Hair follicles are absent, but eccrine sweat glands, whose ducts open in the center of surface ridges, are well developed. The pattern of the epidermal rete ridge is characteristic. In a tissue section cut perpendicularly to the surface skin markings, two types of rete ridges can be identified: the crista profunda limitans, situated under the surface furrow, and the crista profunda intermedia, situated under the surface ridge (picture 1) [4]. On scanning electron microscopy, these rete ridges appear as longitudinal parallel rows protruding into the dermis (picture 2) [6]. Transverse ridges bridging the longitudinal ridges also may be seen; they are generally short and thin but are more prominent in the peripheral areas of the palms and soles and in the foot arch. The assessment of the distribution of melanin granules and melanocytes in relation to the rete ridges is critical to differentiate acral nevi from early acral melanoma [7-9]. In acral nevi, melanocytes arranged in nests are predominantly located in the crista profunda limitans, although some melanocytes may be detected also in the crista profunda intermedia [9]. Melanin granules appear as regular columns situated in the cornified layer underneath the surface furrows, but they are usually absent under the surface ridges (picture 3). In contrast, in early acral melanoma, melanocytes arranged as solitary units are present mainly in the crista profunda intermedia underlying the surface ridges, although a few melanocytes can be seen also in the crista profunda limitans (picture 4).

DERMOSCOPIC FEATURES OF ACRAL MELANOCYTIC LESIONS Overview — Melanocytic lesions of the palms and soles exhibit unique dermoscopic patterns that are significantly different from those seen in nonglabrous skin, due to the distinctive histologic characteristics of the acral skin (picture 1). (See 'Histologic features of palmoplantar skin' above.) The main pigmentation patterns of acral melanocytic lesions are as follows (figure 1) [4,10,11]: ●Parallel furrow pattern – Linear pigmentation along the furrows of the skin markings ●Lattice-like pattern – Pigmented lines along and across the furrows

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●Fibrillar pattern – Fine fibrillar or filamentous pigmentation usually arranged in the direction crossing the parallel skin markings ●Parallel ridge pattern – Band-like pigmentation located on the ridges of the skin markings The first three patterns are typically seen in benign acquired nevi, whereas the parallel ridge pattern is the hallmark of acral melanoma. Since early melanoma and benign melanocytic nevi on the palms and soles may have a similar appearance on naked eye examination, the recognition of these specific pigmentation patterns by dermoscopy is of great help for the clinician in determining whether a lesion should be biopsied or not.

Acquired melanocytic nevi — Most melanocytic nevi detected on the palms and soles are acquired [12,13]. Approximately two-thirds of acquired acral nevi show one or combinations of the three major benign dermoscopic patterns: the parallel furrow pattern, the latticelike pattern, and the fibrillar pattern (figure 1) [4,10,11,13-18].

Parallel furrow pattern and its variants — The parallel furrow pattern results from a linear distribution of the pigment along the furrows of the skin markings, which run on the skin surface in a parallel fashion (figure 1). The basic type of parallel furrow pattern shows a single solid line of pigmentation in the furrows. Variants include the double solid line, single dotted line, and double dotted line (picture 5) [18]. The parallel furrow pattern is seen in approximately 50 percent of acral nevi in any ethnic group [5,19] and is occasionally associated with a light brown background pigmentation [18]. Orderly combinations of the parallel furrow pattern with the two other major dermoscopic patterns (latticelike and fibrillar) are also common in acral nevi (picture 6A-B) [5,18,20]. Rarely, the parallel furrow pattern may be detected in acral melanoma. However, in melanoma, this pattern is present focally or unevenly within the lesion, whereas in melanocytic nevi it is regularly distributed across the lesion. (See 'Melanoma' below.)

Lattice-like pattern — The lattice-like pattern is formed by pigmented lines along and across the furrows of the skin markings (figure 1 and picture 7). A light brown background pigmentation may be present. This pattern is detected in approximately 15 percent of acral nevi, most often in those located on the arch of the foot or in peripheral areas of the palms and soles, where the skin markings lose the typical parallel pattern [5,6,20]. The lattice-like pattern can be regarded as an anatomical modification of the parallel furrow pattern [18].

Fibrillar pattern — The fibrillar pattern consists of a densely packed, fine, fibrillar or filamentous pigmentation arranged perpendicularly or obliquely to the parallel skin markings (picture 8 and figure 1). It is detected in 10 to 20 percent of plantar nevi and rarely in palmar nevi. The

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pigment fibrils typically cover at least the whole width of one surface ridge (picture 8); if the fibrils starting on a furrow do not reach the neighboring furrow, the pattern is classified as parallel furrow pattern (picture 9). The fibrillar pattern results from the oblique arrangement of the thick, cornified layer of the plantar skin, due to the mechanical pressure exerted by the body weight, and may be considered an artifactual modification of the parallel furrow pattern [5,18,20]. In some cases, particularly in young individuals, a regular fibrillar pattern can be visualized as a parallel furrow pattern by advancing the cornified layer horizontally with the probe of a contact dermatoscope or by oblique view dermoscopy performed with a noncontact dermatoscope (picture 10) [21].

Regular versus irregular fibrillar pattern — The regular fibrillar pattern typically seen in melanocytic nevi should be differentiated from the irregular fibrillar pattern occasionally detected in acral melanomas. Criteria for regular fibrillar pattern are [5]: ●Regular and symmetrical overall arrangement of the fibrillar pigmentation ●Even thickness and length of each fibril ●Alignment of the starting points of the fibrils on a surface furrow In contrast, in the irregular fibrillar pattern, the overall arrangement of the pigmentation is asymmetrical and patchy, the fibrils vary in thickness and color, and their starting points do not lineup on a straight line in most cases (picture 11).

Minor (nontypical) patterns — In addition to the three major dermoscopic patterns (ie, parallel furrow pattern, lattice-like pattern, fibrillar pattern), minor patterns, formerly collectively called nontypical patterns, can be detected in approximately one-third of acquired melanocytic nevi of the palms and soles [16-18,22]. Minor patterns include: ●Globular pattern – Dots and globules arranged in a nonparallel fashion, often accompanied by diffuse light brown background (picture 12A) ●Acral reticular pattern – Reticulated pigmentation similar to the pigment network of the nonglabrous skin (picture 12A) ●Homogeneous pattern – Light brown, mostly structureless pigmentation with no other distinctive feature ●Globulo-streak-like pattern – Brown globules attached to linear or curvilinear streaks without relation to the skin markings (picture 12B) ●Transition pattern – Pigment network on the nonglabrous side and parallel furrow pattern or lattice-like pattern on the glabrous side of the lesion (picture 13)

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Congenital melanocytic nevi — Small congenital melanocytic nevi (≤1.5 cm) may occur on the palms and soles, but their prevalence is not known. Dermoscopic features typically detected in congenital melanocytic nevus of the palms and soles include the parallel furrow pattern, crista dotted pattern, and peas-in-a-pod pattern, as described below [23].

Parallel furrow pattern — The parallel furrow pattern, a major dermoscopic pattern most frequently detected in acquired acral nevi, is frequently also seen in acral congenital melanocytic nevi. In a dermoscopic study of 24 congenital nevi, 6 showed the parallel furrow pattern [23]. (See 'Parallel furrow pattern and its variants' above.)

Crista dotted pattern — The crista dotted pattern consists of dots/globules of pigment regularly distributed on the ridges of the skin markings (picture 14). In a series of congenital acral nevi described by the author, this pattern was observed in 3 of 24 lesions [23]. The crista dotted pattern results from the adnexocentric distribution of nevus cells, which is one of the histopathologic characteristics of congenital nevi. The dots/globules on the ridges correspond to nests of nevus cells surrounding the upper portion of eccrine ducts opening in the center of the surface ridges.

Peas-in-a-pod pattern — The peas-in-a-pod pattern is a combination of the parallel furrow and the crista dotted patterns (picture 15). This pattern, seen in 8 of 24 nevi in the author's series, is the most prevalent dermoscopic pattern of acral congenital melanocytic nevi [23].

Other findings — Congenital nevi of the palms and soles may also show [5,23-25]: ●Combinations of the three major dermoscopic patterns seen in acquired melanocytic nevi (ie, parallel furrow pattern, lattice-like pattern, and fibrillar pattern) ●Features similar to the parallel ridge pattern found in melanoma (picture 16) or other minor (nontypical) patterns, such as the globular and globulo-streak-like pattern (picture 12A-B) ●A blue-gray background pigmentation mostly seen in the central areas of the lesions, reflecting the presence of pigmented nevus cells in the dermis (picture 17) ●Enlarged pink ridges, seen in central areas of the lesions [26] The symmetric distribution of dermoscopic features and an even pigmentation support the diagnosis of congenital nevus. Elements of the clinical history (eg, presence since infancy, stable course over time) may be additional clues to the diagnosis. However, lesions with equivocal or suspicious dermoscopic features should be biopsied for histopathologic evaluation.

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Influence of age on dermoscopic patterns — Several studies indicate that the prevalence of specific dermoscopic patterns of melanocytic nevi on the palms and soles varies with age [27-29]. The crista dotted pattern and the peas-in-a-pod pattern are commonly detected in acquired acral nevi of children and adolescents. In one study, evaluating the dermoscopic images of 75 acral nevi in 69 patients younger than 18 years, the parallel furrow pattern and the crista dotted pattern were the most common patterns, detected in 71 and 21 percent of nevi, respectively [27]. Digital follow-up dermoscopic images obtained after a median follow-up time of 32 months showed a change in global pattern (from parallel furrow to lattice-like or fibrillar) in 5 of 31 nevi and a decrease or increase in local criteria (eg, pigmentation, size, and number of globules/dots) in 20. In another study, the peas-in-a pod pattern was observed in 20 percent of acral nevi seen in persons younger than 20 years but only in less than 1 percent of individuals older than 59 years [28]. An opposite trend was seen for nontypical patterns, detected in 36 percent of older individuals and in less than 10 percent of those younger than 20 years.

Nevi of the glabrous/nonglabrous skin transition zone — Melanocytic nevi located on the transitional zones between glabrous and nonglabrous skin (ie, peripheral areas of the palms and soles, lateral aspects of fingers and toes) (picture 18) may show unusual dermoscopic features. One of these is the so-called transition pattern, consisting of a typical pigment network in the nonglabrous portion of the lesion and a parallel furrow pattern or lattice-like pattern in the glabrous portion (picture 13) [17]. Nevi situated in the interdigital web spaces or on the lateral aspects of fingers or toes may show another unusual dermoscopic pattern composed of a densely arranged reticular or branched pigmentation (picture 19). On histology, melanocytic nevi located on transition zones often show a prominent proliferation of melanocytes arranged as solitary units within the epidermis that mimics melanoma in situ (picture 20) [30]. However, the symmetric, orderly intraepidermal distribution of melanocytes and the absence of nuclear atypias differentiate a benign nevus from melanoma.

Melanoma — The parallel ridge pattern and an irregular, diffuse pigmentation are highly sensitive and specific features of early and advanced acral melanoma, respectively. Advanced melanoma of the palms and soles may also show dermoscopic features characteristic of melanoma of nonglabrous skin, including irregular dots/globules, irregular streaks, blue-white veil, regression structures, and polymorphous vessels (picture 21) [4,11]. (See "Dermoscopic evaluation of skin lesions", section on 'Melanoma: Global and local features'.)

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Parallel ridge pattern — The parallel ridge pattern consists of a band-like pigmentation, tan to black in color, located on the ridges of the skin markings (figure 1 and picture 22A). It is highly characteristic of melanoma of the palms and soles and reflects the preferential proliferation of melanocytes in the crista profunda intermedia during the early horizontal growth phase (picture 4) [4,10,11,14,15]. In early melanoma, the parallel ridge pattern is evenly detected within the lesion, whereas in advanced melanoma it is focally distributed (picture 22A-B). Sensitivity and specificity of the parallel ridge pattern for the diagnosis of melanoma, including melanoma in situ, are 86 and 99 percent, respectively [14]. Occasionally, the parallel ridge pattern is detected in a variety of benign pigmented lesions of palms and soles, such as drug-induced pigmentations, Peutz-Jeghers syndrome, or pigmented warts. However, in most cases, these lesions can be correctly diagnosed based upon clinical findings and additional dermoscopic characteristics. (See 'Dermoscopic features of acral nonmelanocytic pigmented lesions' below.)

Irregular diffuse pigmentation — Irregular diffuse pigmentation is defined as a structureless pigmented area, tan to black in color, which is highly characteristic of acral melanoma (picture 22C) [11,14,31]. Sensitivity and specificity of irregular diffuse pigmentation are 85 and 97 percent, respectively. As expected, sensitivity is lower for melanoma in situ (69 percent), since the diffuse pigmentation reflects the florid proliferation of melanocytes in more advanced lesions [14].

Other features — Advanced melanoma of the palms and soles may show the same dermoscopic features of advanced melanoma of nonglabrous skin, including irregular dots/globules, irregular streaks, blue-white veil, regression structures, and polymorphous vessels (picture 21) [4,11]. However, the atypical pigment network, which is a major feature of melanoma of nonglabrous skin, is extremely rare in melanomas of the palms and soles [32]. Brown globules irregularly distributed on the ridges, reflecting transepidermal elimination of melanoma cell nests, can be a characteristic dermoscopic pattern of acral melanoma [33]. Of note, brown globules are regularly distributed on the ridges in congenital nevus [23] and Spitz nevus on the palms and soles [34]. (See "Dermoscopic evaluation of skin lesions", section on 'Melanoma: Global and local features'.) Occasionally, dermoscopic patterns typically seen in acral melanocytic nevi (eg, parallel furrow, lattice-like, and fibrillar patterns) can also be seen in advanced acral melanoma [35]. However, in melanoma these patterns usually have a focal or irregular distribution within the lesion (picture 22B). Acral melanoma may be amelanotic or hypomelanotic. In a series of 126 acral lentiginous melanomas, 34 (28 percent) were unpigmented [36]. In amelanotic or hypomelanotic melanomas, the presence of microscopic remnants of pigmentation and atypical vascular structures are

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important clues to the diagnosis [37]. Lesions with these dermoscopic findings should always be biopsied and sent for histopathologic examination. (See "Dermoscopic evaluation of skin lesions", section on 'Vascular structures in skin lesions'.)

Atypical melanosis of the foot — Atypical melanosis of the foot is an unusual plantar pigmented lesion that has clinical and dermoscopic, but not histologic, features of early acral lentiginous melanoma [38-41]. These lesions present as large macules with irregular borders and variegated colors (picture 23). On dermoscopy, they usually show the parallel ridge pattern typical of melanoma (picture 24) [40,41]. Although the clinical and dermoscopic features suggest melanoma, on histologic examination only a slightly increased number of melanocytes without cytologic atypias is detected in the crista profunda intermedia (picture 25). It has been hypothesized that these lesions may represent early or slowly evolving acral melanoma in situ [8,42,43].

THE THREE-STEP DERMOSCOPIC ALGORITHM

The three-step algorithm for the diagnosis and management of

melanocytic lesions on the palms and soles was originally proposed in 2007. Step 1 of this algorithm is based upon the high sensitivity, specificity, and positive predictive value (86, 99, and 94 percent, respectively) of the parallel ridge pattern for early acral melanoma [14,18]. Sensitivity, specificity, and positive predictive value of the parallel furrow pattern/lattice-like pattern for melanocytic nevi are 67, 93, and 98 percent, respectively [14]. A revised version of the three-step algorithm was published in 2011 and is presented here (algorithm 1) [44]: ●Step 1 – The lesion is examined for the presence of the parallel ridge pattern. If the parallel ridge pattern is found in any part of the lesion, the lesion should be biopsied regardless of the size. If the lesion does not show the parallel ridge pattern, proceed to Step 2. ●Step 2 – The lesion is examined for the presence of one or an orderly combination of the typical benign dermoscopic patterns (ie, typical parallel furrow pattern, typical lattice-like pattern, regular fibrillar pattern). If the whole area of the lesion shows one or a combination of two or three typical benign patterns, further dermoscopic follow-up is not needed. If the lesion shows equivocal dermoscopic features (ie, part or total absence of any typical/regular patterns) (picture 26), proceed to Step 3. ●Step 3 – The maximum diameter of lesions that do not show typical benign patterns is measured. Lesions >7 mm should be excised or biopsied for histopathologic evaluation [45]. Lesions ≤7 mm should be monitored clinically and dermoscopically at three- to six-month intervals. For the correct use of the three-step algorithm, it is important to keep in mind the following:

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●The algorithm has been developed for the differentiation of acquired melanocytic nevi from acral melanoma of the palms and soles and may not be appropriate for the evaluation of congenital nevi in those locations. In most cases, congenital nevi can be identified on the basis of their characteristic dermoscopic features (see 'Congenital melanocytic nevi' above). However, the threestep algorithm can be used to evaluate acral nevi whose type (acquired or congenital) cannot be determined. ●In the first step, it is crucial to correctly identify the furrows and ridges of the skin markings. Their recognition can be greatly facilitated by performing the "furrow ink test" before examining the lesion under the dermatoscope [46,47]. The periphery of the lesion is marked with liquid ink (eg, from a fountain pen) or with a whiteboard marker pen, preferably blue or green in color; the skin surface is then gently wiped with a dry paper towel. The surface furrows retain the blue or green ink and become clearly visible on dermoscopic examination as thin inked lines. The test will allow the clinician to assess whether the melanin pigmentation follows the ink lines as in the parallel furrow pattern (picture 27) or is located between the ink lines, thus representing a parallel ridge pattern (picture 28). Once the examination is completed, the marker pen ink in the furrows can be easily removed by wiping the skin with a wet paper towel. ●In the second step, the clinician must assess whether the benign patterns are typical or regular. Typical parallel furrow or lattice-like patterns are symmetrically and evenly distributed across the lesion. The criteria for classifying a fibrillar pattern as regular are described above (see 'Regular versus irregular fibrillar pattern' above). Orderly combinations of benign patterns are also considered as benign. If there is any uncertainty in classifying a pattern as benign, the lesion should be biopsied or monitored as described in Step 3. The decision not to follow-up lesions that are judged unequivocally benign in Step 2 is based upon the observation that the risk of acral melanoma developing in a preexisting nevus is extremely low [48,49]. In digital follow-up studies of acral melanocytic nevi, a change from a benign to a malignant pattern has not been reported [18,22,50]. However, changes within benign patterns have been observed in 20 to 70 percent of cases [22,50]. Lesions that cannot be unequivocally classified as benign should be biopsied for histopathologic evaluation if they are larger than 7 mm.

THE BRAAFF CHECKLIST

Based upon the dermoscopic

examination of 603 acral lesions (472 nevi and 131 acral melanomas, including 42 in situ lesions), a new six-variable scoring system has been developed for the diagnosis of acral melanoma [51]. This system, called the BRAAFF checklist, consists of six variables, each with a positive or negative value: ●Irregular blotch (+1) ●Parallel ridge pattern (+3) ●Asymmetry of structures (+1) ●Asymmetry of colors (+1)

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●Parallel furrow pattern (-1) ●Fibrillar pattern (-1) A total score of ≥1 is needed for a diagnosis of melanoma. The threshold of one point provided a sensitivity of 93 percent and a specificity of 87 percent [51].

DERMOSCOPIC FEATURES OF ACRAL NONMELANOCYTIC PIGMENTED LESIONS

Dermoscopy is helpful in the diagnosis

of a variety of benign pigmented lesions of the palms and soles, some of which may mimic acral melanoma [52]. In most cases, the correct diagnosis can be made based upon clinical history and/or associated signs and symptoms. A biopsy for histopathologic evaluation may be warranted when the diagnosis is uncertain.

Hemorrhage, hematoma, and hemangioma — Dermoscopic features of hemorrhage/hematoma and hemangioma of the palms and soles are similar to those seen in nonglabrous skin. However, due to the unique anatomical structure of the acral volar skin, some hemorrhagic lesions show characteristic dermoscopic patterns, as described below. (See "Dermoscopic evaluation of skin lesions", section on 'Criteria for hemangioma/angioma and angiokeratoma'.)

Black heel (calcaneal petechiae) — Black heel, also called calcaneal petechiae or talon noir, is an asymptomatic pigmentation of the heel secondary to intraepidermal extravasation of red blood cells, caused by shear-force injuries (eg, during vigorous sports) [53]. On naked-eye examination, black heel appears as a black macule or plaque that mimics melanoma (picture 29A-B). On dermoscopic examination, black heel shows a unique dermoscopic pattern called the "pebbles on the ridges," in which a reddish-black, pebble-like pigmentation is distributed on the ridge of the skin markings (picture 30) [4,10]. The pebble-like pigmentation corresponds to aggregation of hemosiderin in the superficial skin layers, mostly in the stratum corneum. With more abundant blood extravasations, the pebble-like pigmentation becomes confluent and forms a band-like pigmentation (picture 31) that mimics the parallel ridge pattern seen in melanoma [54]. However, the reddish tone, sharp demarcation, and subtle segmentation of the pigmented bands differentiate black heel from melanoma.

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PlayStation purpura/PlayStation fingertip — The so-called PlayStation purpura or PlayStation fingertip presents as brownish macules on the index or middle fingers, which result from subcorneal hemorrhages caused by a prolonged use of the handheld game controller device. On dermoscopy, these macules show a parallel ridge pattern [55,56]. However, the symmetric location on the index or middle fingers, the rusty/reddish hue of the color, and a history of prolonged video gaming are clues to the correct diagnosis.

Drug-induced acral pigmentation — Several anticancer drugs (eg, topical fluorouracil, doxorubicin, cyclophosphamide) may induce focal acral hyperpigmentation, such as pigmented macules and melanonychia [57-59]. Multiple small, brownish macules may develop on the hands or feet and are often accompanied by a linear pigmentation of the palmar and plantar creases. On dermoscopy, the hyperpigmented macules show a parallel ridge pattern similar to that seen in early acral melanoma (picture 32). Histology shows increased melanin in the basal layer of the epidermis and melanophages in the papillary dermis [57].

Peutz-Jeghers syndrome and LaugierHunziker syndrome — Peutz-Jeghers syndrome is a rare autosomal dominant disorder characterized by gastrointestinal polyposis in association with multiple small, hyperpigmented, mucocutaneous macules most often located on the lips and buccal mucosa (picture 33) and on the dorsal and volar aspect of hands and feet (picture 34A-B). On dermoscopy, the pigmented macules located on the volar skin show the parallel ridge pattern [60]. The diagnosis is based upon the characteristic distribution of the macules, family history, and demonstration of colonic hamartomas. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".) Laugier-Hunziker syndrome is a rare, acquired, macular hyperpigmentation of the lips, oral mucosa, and acral skin frequently associated with longitudinal melanonychia. In contrast with Peutz-Jeghers syndrome, Laugier-Hunziker syndrome is not associated with systemic disorders. On dermoscopy, the pigmented macules typically show the parallel ridge pattern, but cases with a parallel furrow pattern have been reported [61,62]. Histology shows increased melanin in basal keratinocytes, particularly in those located in the crista profunda intermedia, corresponding to the epidermal rete ridges underlying the surface ridges [62].

Volar melanotic macules — Volar melanotic macules are solitary or multiple brownish macules found on the palms and soles of individuals with darker skin types [6365]. On dermoscopy, they may show a parallel ridge pattern (picture 35). Histologically, volar melanotic macules are characterized by increased deposition of melanin in all epidermal layers, hyperpigmented solitary dendritic melanocytes scattered along the basal layer, and melanophages in the dermis [64].

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Pigmented ridged wart — The pigmented ridged wart is an uncommon type of plantar wart associated with a cystic component, caused by the human papillomavirus type 60 [66]. On dermoscopy, it shows a parallel ridge pattern and may mimic a verrucous type of acral melanoma [67-69]. When the clinical diagnosis is unclear, a biopsy is necessary to exclude melanoma. Histology reveals hyperkeratosis, acanthosis, large vacuolated cells in the malpighian and granular layers, and absence of abnormal melanocyte proliferation.

Tinea nigra — Tinea nigra is a superficial fungal infection of the palms and soles that presents as a large, brownish macule (picture 36). Dermoscopy reveals light brown, fine strands arranged in a reticular pattern [70]. The pigmentation does not follow the furrow or ridges of the skin markings. The diagnosis is confirmed by potassium hydroxide (KOH) examination of scrapings from the lesion.

Pigmentation due to chemicals — Accidental staining of the plantar skin with paraphenylenediamine, a derivative of aniline used in hair dyes and rubber products, can display the parallel ridge pattern on dermoscopy [52,71,72]. Palmar or plantar pigmentation caused by self-tanning products can also show the parallel ridge pattern. A detailed history, including the patient's occupation and hobbies, is important for a correct diagnosis. The pigment can be removed by shaving the superficial cornified layer with a scalpel.

SUMMARY AND RECOMMENDATIONS ●Dermoscopy, a noninvasive diagnostic technique performed by a handheld instrument called a dermatoscope, is of great value in the diagnosis and management of pigmented lesions of the palms and soles. (See 'Introduction' above.) ●Most acral acquired melanocytic nevi show one of three major dermoscopic patterns (figure 1): the parallel furrow pattern (picture 5), the lattice-like pattern (picture 7), and the fibrillar pattern (picture 8). (See 'Acquired melanocytic nevi' above.) ●Major dermoscopic patterns seen in acral congenital melanocytic nevi are the parallel furrow pattern (picture 17), the crista dotted pattern (picture 14), and the peas-in-a-pod pattern (picture 15). In addition, congenital nevus may exhibit variegated dermoscopic features mimicking those seen in melanoma. (See 'Congenital melanocytic nevi' above.) ●The parallel ridge pattern (figure 1 and picture 22A) is highly characteristic of early melanoma of the palms and soles. Advanced melanoma typically shows irregular diffuse pigmentation (picture 22B-C) but may also show dermoscopic features seen in melanoma of nonglabrous skin (eg,

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irregular dots/globules, irregular streaks, blue-white veil, regression structures, and polymorphous vessels). (See 'Melanoma' above.) ●A three-step algorithm (algorithm 1) has been proposed for the diagnosis and management of acquired melanocytic lesions on the palms and soles. (See 'The three-step dermoscopic algorithm' above.) ●Pigmented lesions other than melanoma and melanocytic nevus that can be found on the palms and soles include the so-called black heel and other hemorrhagic conditions, drug-induced pigmentations, Peutz-Jeghers and Laugier-Hunziker syndrome, pigmented ridged wart, and tinea nigra. Dermoscopy is useful in the diagnosis of these conditions. (See 'Hemorrhage, hematoma, and hemangioma' above and 'Dermoscopic features of acral nonmelanocytic pigmented lesions' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 16551 Version 11.0

GRAPHICS

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Histopathology of the volar skin

This tissue section was cut perpendicularly to the parallel skin markings. The ridges (orange bars) and furrows (arrows) are recognized on the surface. Under the epidermis, two kinds of epidermal rete ridges are recognized: the crista profunda intermedia (dashed arrows) underlying the surface ridges and the crista profunda limitans (arrowheads) underlying the surface furrows. The crista profunda intermedia is passed through by an intraepidermal eccrine duct. Graphic 89394 Version 2.0

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Surface electron microscopy of plantar skin

On the undersurface of the epidermis, two kinds of main longitudinal ridges, the crista profunda limitans and the crista profunda intermedia, are observed as parallel rows. Eccrine ducts are recognized as tube-like projections from the crista profunda intermedia. The short transverse ridges are also detected, bridging the main longitudinal ridges. Courtesy of Tetsuya Tsuchida, MD, PhD. Graphic 89395 Version 1.0

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Histopathologic features of acral nevi

Histopathologic features of acral nevus of the junctional type. The cornified layer slants slightly. (A) Nevus cells arranged in nests are predominantly located in the crista profunda limitans (arrows), and only a few melanocytes are detected in the crista profunda intermedia (asterisks) (hematoxylineosin stain). (B) Melanin granules in the cornified layer are detected as parallel columns regularly situated under the surface furrows (arrows), whereas they are mostly absent in the cornified layer under the surface ridges (asterisks) (Fontana-Masson stain). Reproduced with permissiomn from: Saida T, Koga H, Goto Y, Uhara H. Characteristic distribution of melanin columns in the cornified layer of acquired acral nevus: An important clue for histopathologic differentiation from early acral melanoma. Am J Dermatopathol 2011; 33:468. DOI: 10.1097/DAD.0b013e318201ac8f. Copyright © 2011 International Society of Dermatopathology. Unauthorized reproduction of this material is prohibited. Graphic 89622 Version 8.0

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Histopathologic features of early acral melanoma

Histopathologic features of the macular portion of an acral melanoma showing the parallel ridge pattern on dermoscopy. (A) Melanocytes arranged as solitary units are mainly observed in the crista profunda intermedia (asterisks), although a few melanocytes are also detected in the crista profunda limitans (arrows) (hematoxylin-eosin stain). (B) Melanin granules in the cornified layer are mostly derived from melanocytes in the crista profunda intermedia (Fontana-Masson stain). They are detected as broad columns under the surface ridges (blue bars). Melanin granules are mostly absent in the cornified layer under the surface furrow, corresponding to the underlying crista profunda limitans (arrows). This distribution corresponds well to the dermoscopic parallel ridge pattern. Reproduced with permissiomn from: Saida T, Koga H, Goto Y, Uhara H. Characteristic distribution of melanin columns in the cornified layer of acquired acral nevus: An important clue for histopathologic differentiation from early acral melanoma. Am J Dermatopathol 2011; 33:468. DOI: 10.1097/DAD.0b013e318201ac8f. Copyright © 2011 International Society of Dermatopathology. Unauthorized reproduction of this material is prohibited. Graphic 89623 Version 8.0

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Schematic representation of the dermoscopic patterns of melanocytic lesions located on the palms and soles

The parallel furrow, lattice-like, and fibrillar patterns are major dermoscopic patterns seen in acquired melanocytic nevus of the palms and soles, whereas the parallel ridge pattern is the most sensitive and specific dermoscopic pattern detected in acral melanoma. Reproduced with permission from: Saida T. Textbook of Dermoscopy, Nankodo Co. Ltd, Tokyo, 2011. Copyright © 2011 Toshiaki Saida, MD, PhD. Graphic 89396 Version 2.0

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Dermoscopic images of variants of the parallel furrow pattern in acquired melanocytic nevi of palms and soles

In the parallel furrow pattern, parallel pigmented lines are detected along the furrows of the skin markings. Variants of this pattern include: (A) single solid line variant, (B) double solid line variant, (C) single dotted line variant, and (D) double dotted line variant. Graphic 89403 Version 1.0

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Combination of the parallel furrow pattern and other benign dermoscopic patterns in acquired melanocytic nevi of the palms and soles

(A) In this lesion, the parallel furrow pattern is associated with the lattice-like pattern in the center of the lesion. (B) The parallel furrow pattern shows transition to the fibrillar pattern on the right side of this lesion. Reproduced with permission from: John Wiley & Sons, Inc. Saida T, Koga H, Uhara H. Key points in dermoscopic differentiation between early acral melanoma and acral nevus. J Dermatol 2011; 38:25. Copyright © 2011 Japanese Dermatological Association. All rights reserved. Graphic 89405 Version 5.0

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Combination of the three major dermoscopic patterns in melanocytic nevi of the palms and soles

In this nevus, the three major benign dermoscopic patterns, the parallel furrow (blue circle), fibrillar (dashed red circle), and lattice-like pattern (dotted green circle), are detected. Note that they are arranged in an orderly fashion. Inset: clinical photograph. Reproduced with permission from: Saida T, Koga H. Dermoscopic patterns of acral melanocytic nevi: Their variations, changes, and significance. Arch Dermatol 2007; 143:1423. Copyright © 2007 American Medical Association. All rights reserved. Graphic 89404 Version 9.0

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Dermoscopic image of an acquired melanocytic nevus on the palm: The lattice-like pattern

On dermoscopic examination, this acquired melanocytic nevus on the palm shows a pigment distribution that forms linear lines along and across the surface furrows in a lattice-like fashion. Graphic 89450 Version 1.0

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Dermoscopic image of an acquired melanocytic nevus on the sole: The fibrillar pattern

In this regular fibrillar pattern, the starting points of the fibrils align on the lines corresponding to the surface furrows (arrows). Graphic 89451 Version 1.0

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Dermoscopic parallel furrow pattern and fibrillar pattern

Because of the oblique arrangement of the cornified layer, the parallel furrow pattern sometimes shows features of fibrillar pattern. If the fibrils do not reach the neighboring furrow (A), the pattern is classified as parallel furrow pattern. If the fibrils reach or cross the neighboring furrow (B) or cover at least the whole width of one surface ridge, the pattern is classified as fibrillar. Graphic 89452 Version 1.0

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Oblique-view dermoscopy of the fibrillar pattern in an acral melanocytic nevus

This melanocytic nevus of the sole shows the regular fibrillar pattern on the ordinary dermoscopy (A). The green lines correspond to the furrows of the skin marking visualized by the furrow ink test. Oblique view dermoscopy using a noncontact dermatoscope changes the fibrillar pattern to the parallel furrow pattern, dotted line variant (B). Graphic 90127 Version 2.0

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Dermoscopic features of regular and irregular fibrillar pattern

In the regular fibrillar pattern of benign nevi (A), the overall arrangement of the fibrils is mostly symmetric and the starting points of the fibrils align on straight lines corresponding to the surface furrows. In contrast, in the irregular fibrillar pattern seen in melanoma (B), the fibrils are variable in color and thickness and are arranged in a disorderly, haphazard fashion. Their starting points do not align on a straight line. Graphic 89455 Version 1.0

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Minor dermoscopic patterns seen in acquired melanocytic nevi of palms and soles

(A) Globular pattern. (B) Acral reticular pattern. Graphic 89457 Version 1.0

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Minor dermoscopic patterns seen in acquired melanocytic nevi of palms and soles: Globulo-streaklike pattern

Globulo-streak-like pattern seen in two small acquired melanocytic nevi (arrows) affecting the arch areas. Graphic 90125 Version 2.0

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Dermoscopy of acral melanocytic lesions: Transition pattern

On dermoscopy, this nevus located on the inner aspect of the right heel shows the parallel furrow pattern in the lower portion and the reticular pattern in the upper portion. This pattern is characteristic of melanocytic nevi of the glabrous/nonglabrous skin transition zone. Inset: clinical photograph. Graphic 90126 Version 2.0

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Dermoscopic features of congenital nevi of the palms and soles: The crista dotted pattern

In the crista dotted pattern, brown globules are regularly distributed on the surface ridges. The globules correspond to nevus cell nests surrounding the distal portion of the eccrine ducts, which open in the center of the ridges. Graphic 89466 Version 1.0

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Dermoscopic features of congenital nevi of palms and soles: The peas-in-a-pod pattern

The peas-in-a-pod, commonly detected in congenital nevus on the palms and soles, is regarded as a combination of the parallel furrow pattern and crista dotted pattern. Graphic 89467 Version 1.0

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Dermoscopic features of a congenital plantar nevus

In this plantar congenital nevus, the dermoscopic pattern is similar to the parallel ridge pattern. However, the color is grayish and the pigmented bands are segmented, resembling the crista dotted pattern. These findings help in differentiating this pattern from the classic parallel ridge pattern seen in melanoma. Subtle features of the parallel furrow pattern, which is typical of acquired acral melanocytic nevi, are detected on the left side of this lesion. Graphic 89468 Version 2.0

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Dermoscopic features of congenital melanocytic nevus on the palms and soles: The parallel furrow pattern

In this plantar congenital nevus, the typical parallel furrow pattern is associated with a grayishbrown background pigmentation. The gray tone reflects the melanin granules in the dermis derived from the prominent intradermal component of congenital nevi. Graphic 89464 Version 1.0

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Clinical and histopathologic features of a melanocytic nevus located on the foot

Melanocytic nevus located in the fourth interdigital space of the right foot of a 23-year-old woman. This brownish-black macule, 5 mm in diameter, shows virtually no irregularity in shape or color. Reproduced with permission from: Saida T, Kawachi S, Koga H. Anatomic transitions and the histopathologic features of melanocytic nevi. Arch Dermatol 2008; 144:1232. Copyright © 2008 American Medical Association. All rights reserved. Graphic 90128 Version 12.0

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Dermoscopic features of an acral melanocytic nevus located in the transition zone between glabrous and nonglabrous skin

In this nevus located on the side of a toe, a densely arranged reticular or branched pigmentation is observed. Inset: clinical photo. Note that the histopathological features of melanocytic nevi located on the transition zone between glabrous and nonglabrous skin often mimic those of melanoma, showing prominent proliferation of solitary melanocytes within the epidermis. Courtesy of Akemi Ishida-Yamamoto, MD, PhD Graphic 89469 Version 2.0 Histologic features of melanocytic nevi of the glabrous/nonglabrous skin transition zone

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Clinical and histopathologic features of a melanocytic nevus located on a transition area (the fourth interdigital area of the right foot) of a 23-year-old woman. (A-C) In all of the histopathologic photographs (hematoxylin-eosin), we see that melanocytes proliferate mainly as solitary units within the epidermis, and many of them are situated above the dermoepidermal junction, mimicking histopathologic features of melanoma in situ. However, overall distribution of melanocytes within the lesion is mostly symmetrical and orderly. The nuclei of melanocytes are relatively large but not hyperchromatic; instead, they are vesicular. In addition, there is virtually no inflammatory cell infiltrate in the dermis. The original magnifications are x12, x38, and x84 for panels A, B, and C, respectively. Reproduced with permission from: Saida T, Kawachi S, Koga H. Anatomic transitions and the histopathologic features of melanocytic nevi. Arch Dermatol 2008; 144:1232. Copyright © 2008 American Medical Association. All rights reserved. Graphic 91380 Version 11.0

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Dermoscopic features of advanced melanoma of the sole

There is an ulcerated nodule on the right, surrounded by a blue white veil (star). The parallel ridge pattern (square) as well as the irregular fibrillar pattern (circle) are also detected. Reproduced with permission from: John Wiley & Sons, Inc. Saida T, Koga H, Uhara H. Key points in dermoscopic differentiation between early acral melanoma and acral nevus. J Dermatol 2011; 38:25. Copyright © 2011 Japanese Dermatological Association. All rights reserved. Graphic 89402 Version 5.0

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Parallel ridge pattern seen on dermoscopic examination of melanoma of palms and soles

The parallel ridge pattern represents band-like pigmentation on the ridges of the skin markings. In this melanoma in situ (A), the pattern covers almost all the lesion. In an early invasive melanoma of the sole (B), the parallel ridge pattern is detected only in the lower portion of the lesion (circle) and irregular diffuse pigmentation is observed in the upper portion. Graphic 89397 Version 1.0

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Dermoscopic features of macular areas of melanoma on the sole

In the macular areas of this advanced melanoma, the parallel ridge pattern is detected focally (red rectangle). An irregular fibrillar pattern (blue circle) and the parallel furrow pattern (green rounded rectangle) are also focally detected. Graphic 89398 Version 1.0

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Dermoscopic image of irregular diffuse pigmentation in a melanoma on the sole

In this advanced melanoma, irregular diffuse, structureless pigmentation of variable shades from tan to brownish black, predominates. Hints of the parallel ridge pattern also can be recognized. Graphic 89400 Version 1.0

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Clinical image of atypical melanosis of the foot

A 45 x 25 mm brownish macule with irregular shape and color on the volar aspect of the great toe. Graphic 90136 Version 2.0

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Dermoscopic image of atypical melanosis of the foot

On dermoscopic examination, atypical melanosis of the foot shows a typical parallel ridge pattern. Graphic 90137 Version 2.0

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Histopathologic characteristic of atypical melanosis of the foot

The melanocytes in the crista profunda intermedia are slightly increased in number. Eccrine ducts run through the epidermal rete ridges. Graphic 90138 Version 2.0

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The 3-step dermoscopic algorithm for the diagnosis and management of acquired melanocytic lesions of the palms and soles

Reproduced with permission from: John Wiley & Sons, Inc. Saida T, Koga H, Uhara H. Key points in dermoscopic differentiation between early acral melanoma and acral nevus. J Dermatol 2011; 38:25. Copyright © 2011 Japanese Dermatological Association. All rights reserved. Graphic 89477 Version 6.0

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Acral melanocytic lesion with equivocal dermoscopic features

A brown macule 6.5 mm in maximum diameter is present on the right fifth toe of a 63-year-old woman. On dermoscopic examination, the lesion does not show any typical/regular patterns. Graphic 90139 Version 2.0

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The furrow ink test: Parallel furrow pattern

In this acral lesion, the pigmented lines correspond to the furrows of the skin markings. The parallel furrow pattern is typical of acquired acral nevi. Graphic 90140 Version 2.0

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The furrow ink test: Parallel ridge pattern

In this acral melanocytic lesion, the band-like pigmentation is detected between the furrows, on the ridges of the skin markings. The parallel ridge pattern is typical of acral melanoma. Graphic 90141 Version 2.0

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Black heel (calcaneal petechiae)

The black specks on the heel result from intradermal hemorrhage due to trauma (eg, friction against shoes during vigorous sports). Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 89487 Version 3.0

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Black heel (calcaneal petechiae)

Aggregated black specks on the heel resulting from intraepidermal hemorrhage caused by shearforce injuries (eg, during vigorous sports). Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 89488 Version 3.0

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Dermoscopic features of the "black heel"

The "black heel" results from the formation of tiny petechiae in the superficial skin tissue of the heel caused in most cases by friction with tight, ill-fitted sport shoes. Reddish to black, globular pigmentation on the ridges (the pebbles on the ridges) is characteristic. Inset: clinical photograph. Graphic 89473 Version 2.0

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Dermoscopic features of superficial hematoma in the plantar skin

On dermoscopy, a superficial hematoma in the plantar skin shows a pigment distribution reminiscent of the parallel ridge pattern. However, the reddish tone and demarcation of the lesion and the presence of reddish black globules are helpful in differentiating hematomas from melanocytic lesions. Graphic 89474 Version 1.0

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Dermoscopic features of pigmentation induced by 5-fluorouracil

The drug-induced light brown pigmentation is accentuated on the surface ridges, resembling the parallel ridge pattern. This pigmentation can be differentiated from melanoma based upon the presence of multiple brown macules bilaterally on the palms and soles and history of drug intake. Graphic 89475 Version 1.0

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Peutz-Jeghers syndrome

Multiple pigmented macules are present on the lips. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 55335 Version 4.0

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Peutz-Jeghers syndrome

Multiple hyperpigmented macules on the dorsum of the hand of a patient with Peutz-Jeghers syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 89493 Version 2.0 Cutaneous hyperpigmentation in Peutz-Jeghers syndrome Multiple hyperpigmented macules on the volar aspect of the thumb in a patient with Peutz-Jeghers syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 89492 Version 3.0

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Volar melanotic macule

The picture shows one of several light-brown macules noted on the soles of a middle-aged Japanese man. The macule has regular borders and even pigmentation. On dermoscopy, it shows a typical parallel ridge pattern. Graphic 90143 Version 2.0 Tinea nigra A well-dermarcated brown patch on the palm of a three-year-old boy with tinea nigra. The patch had been slowly expanding for six months. A potassium hydroxide preparation revealed grayish brown branching hyphae typical of tinea nigra which is caused by a dermatiaceous fungus Phaeoannellomyces werneckii. Copyright © Samuel Freire da Silva, MD, Dermatlas; http://www.dermatlas.org. Graphic 89558 Version 3.0

Contributor Disclosures Toshiaki Saida, MD, PhDNothing to discloseHiroshi Koga, MDNothing to discloseHensin Tsao, MD, PhDGrant/Research/Clinical Trial Support: Relay Therapeutics; Asana BioSciences [Melanoma (Dual

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BRAF/PI3K inhibitor, ERK 1/2 inhibitor)]. Consultant/Advisory Boards: Epiphany Dermatology [Basal cell carcinoma, melanoma, nevi, skin cancer screening]; World Care Clinical; Ortho Dermatologics [Melanoma (Imaging services)]. Consultant/Advisory Boards (Spouse): Ortho Dermatologics [Melanoma].Rosamaria Corona, MD, DScNothing to disclose Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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Dermoscopy of nail pigmentations - UpToDate uptodate.com/contents/dermoscopy-of-nail-pigmentations/print

Dermoscopy of nail pigmentations Author: Antonella Tosti, MD Section Editor: Hensin Tsao, MD, PhD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Sep 18, 2019.

INTRODUCTION

Nail pigmentation is most commonly caused by

deposits of melanin or hemosiderin within the nail plate. It is rarely due to deposits of other pigments of endogenous or exogenous origin. Melanin deposits result from activation or proliferation of nail matrix melanocytes and in most cases present as a longitudinal pigmented band called longitudinal melanonychia or melanonychia striata [1]. Nail dermoscopy (onychoscopy) can greatly improve the differential diagnosis of nail pigmentation and helps clinicians with at least minimal training in dermoscopy to distinguish benign lesions, which do not require additional examinations, from lesions that require excision for pathologic evaluation or regular follow-up [2,3]. However, dermoscopy should not be considered a substitute for pathology in the differential diagnosis of doubtful cases of longitudinal melanonychia [4]. This topic will discuss the causes of nail pigmentation and the dermoscopic evaluation of benign and malignant pigmented nail lesions. Nail disorders are discussed separately. The dermoscopic evaluation of cutaneous and mucosal lesions is also discussed separately. Dermoscopic algorithms for skin cancer triage are also discussed separately. ●(See "Overview of nail disorders".) ●(See "Overview of dermoscopy".) ●(See "Dermoscopic evaluation of skin lesions".) ●(See "Dermoscopy of facial lesions".) ●(See "Dermoscopy of mucosal lesions".)

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●(See "Dermoscopy of pigmented lesions of the palms and soles".) ●(See "Dermoscopic algorithms for skin cancer triage".)

ANATOMY OF THE NAIL AND DISTRIBUTION OF NAIL MELANOCYTES

The nail apparatus includes the nail matrix, the nail bed,

the nail folds, and the hyponychium (figure 1). The nail matrix is localized very close to the bone, under the proximal nail fold and in the lunula area. It consists of a proximal part that produces the dorsal nail plate and a distal part that produces the ventral nail plate. The nail plate strictly adheres to the nail bed, whose rete ridges are longitudinally oriented. Nail matrix melanocytes are quiescent, not confined to the basal layer, and frequently clustered. They are more numerous in the distal than in the proximal matrix [5]. Melanocytes of the proximal matrix are DOPA-negative and cannot be activated, whereas melanocytes of the distal matrix are DOPA-positive and can be activated [6]. This explains why most pigmented nail lesions originate in the distal matrix and are localized in the ventral nail plate. The nail bed only contains DOPA-negative dormant melanocytes, which cannot be activated.

CAUSES OF NAIL PIGMENTATION Nail pigmentation due to melanin deposition — Melanonychia can be caused by activation or proliferation of nail matrix melanocytes. Some fungi can produce melanin and also cause melanonychia. Melanonychia due to melanocyte activation often involves several nails and is more common in dark phototypes. Common causes of melanocyte activation include traumas, inflammatory nail disorders, drugs, and nonmelanocytic tumors [1,3]. Melanonychia due to melanocyte proliferation includes nail matrix nevi, lentigo, and melanoma. (See "Overview of nail disorders", section on 'Longitudinal melanonychia'.)

Nail pigmentation due to blood deposition — Blood extravasation is common in toenails as a consequence of acute or chronic repetitive trauma. It can cause a dark nail pigmentation that may be clinically difficult to distinguish from melanic pigmentation.

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EXAMINATION OF NAIL AND PERIUNGUAL TISSUES Types of dermatoscopes — Dermoscopy of the nail plate and periungual tissues can be performed using both polarized and nonpolarized dermatoscopes. Areas to be examined include the nail plate, the nail plate free edge, the hyponychium, and the nail folds (figure 1). Dermoscopy can also be utilized intraoperatively to assess the morphology and margins of the lesion and to optimize excision. Nonpolarized contact dermoscopy of the nail plate requires the use of ultrasound gel as interface medium, as it allows better contact with the convex nail surface. For nonpolarized contact dermoscopy of the free edge, gel or alcohol can be used as interface medium; alcohol is used for evaluation of the proximal and lateral nail folds and hyponychium. Intraoperative dermoscopic examination of the nail matrix is usually performed with polarized, noncontact instruments.

Limitations of nail dermoscopy ●The main limitation of dermoscopy in the evaluation of nail pigmentation due to melanin deposition is that the lesions that are examined with dermoscopy correspond to the melanin deposition in the nail plate, and not to the site of melanin production. ●The diagnostic accuracy of nail dermoscopy may be poorer than naked-eye examination when performed by clinicians with limited experience in the interpretation of nail dermoscopy. Dermoscopy requires at least a minimal amount of training to provide advantage over the clinical examination. ●Dermoscopy alone cannot establish the diagnosis of malignancy; histopathologic examination remains the gold standard for the diagnosis of malignant lesions of the nail apparatus.

DERMOSCOPIC PATTERNS OF NAIL PLATE PIGMENTATION Background color — When examining longitudinal melanonychia of the nail plate with a dermatoscope, the most important feature to evaluate first is the color of the band background.

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●Bands with gray background are in most cases due to melanocyte activation and usually do not require further studies. The gray background may be homogeneous or appear as thin, regular, longitudinal lines (picture 1). In case of melanocyte activation caused by trauma, blood spots or splinter hemorrhages can also be seen (picture 2). ●Bands with brown/black background are associated with melanocyte proliferation [7-10]. Although dermoscopy can help distinguish between benign and malignant lesions, excision for pathologic evaluation is necessary for the definitive diagnosis of suspicious lesions [11].

Arrangement of lines within brown/black bands — In lesions with a brown/black background that suggests melanocyte proliferation, it is important to look at the shape and distribution of the lines within the band. ●Longitudinal lines with regular thickness, spacing, coloration, and parallelism suggest a benign lesion (nevus or lentigo) (picture 3). Margins of benign lesions are also sharp. ●Longitudinal lines of irregular thickness, spacing, parallelism, and color have been associated with nail melanoma (picture 4) [7-10,12]. However, establishing if lines are regular or irregular is often difficult and somewhat subjective [13]. In addition, this criterion is not suitable in children, as nevi in children almost always present as lines of different color and thickness [14].

Homogeneous black pigmentation — In the author's experience, it is not uncommon to see nail melanoma presenting with a brown or black homogeneous band with no visible lines but areas of pigment variation (picture 5).

Dots and globules — Dots and globules corresponding to clumps of atypical melanocytes within the nail plate have been associated with melanoma in adults [15]. However, dots and globules are not uncommon in benign nevi in childhood (picture 6), where they may represent a dermoscopic sign of regression of melanonychia [16]. It is in fact not uncommon for nevi in children to fade with time [17].

Blood spots — Blood spots from subungual hemorrhage appear as well-circumscribed dots or blotches with a red to red-black pigmentation. Blood spots are not uncommon in advanced melanoma, due to tumor bleeding [12].

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DERMOSCOPY OF NAIL PLATE FREE EDGE

Examination of the distal edge of the nail plate is important to

establish the localization of the pigment within the nail plate. In most cases of melanonychia, the pigment is in the lower (ventral) part of the nail plate because most bands originate from the distal matrix (picture 7) [18]. Distal edge dermoscopy is not useful when the nails are very thin, as in small children, or when the pigment is very light or dark (picture 8) [14].

DERMOSCOPY OF PROXIMAL NAIL FOLD

The periungual spread of pigment is called the Hutchinson sign (picture 9) [19]. It can

involve the proximal and lateral nail folds and also the hyponychial skin, and is considered a clue to the diagnosis of subungual melanoma. However, a pseudo-Hutchinson sign has been reported in a variety of benign lesions, including nevi, ethnic-type melanonychia and drug-induced nail pigmentation. (See "Overview of nail disorders", section on 'Longitudinal melanonychia'.) The micro-Hutchinson sign is a pigmentation of the cuticle that is not visible to the naked eye but can be seen on dermoscopy [19]. It has been reported as a quite specific but uncommon dermoscopic feature of early melanoma of the nail apparatus [7,12,15]. However, the microHutchinson sign has also been described in congenital nevi in children (picture 10) and, in the author's experience, is also commonly seen in benign lesions in dark-skinned individuals (picture 11) [20]. Moreover, very dark lesions may be visible through the cuticle that is transparent (pseudoHutchinson sign) (picture 12) [19].

DERMOSCOPY OF THE HYPONYCHIUM

The presence of pigmentation in the hyponychial skin is

a true Hutchinson sign and is highly characteristic of nail melanoma [21]. On dermoscopy, the distribution of the pigmentation shows the same parallel ridge pattern described for acral melanoma (picture 13). (See "Dermoscopy of pigmented lesions of the palms and soles", section on 'Parallel ridge pattern'.) In contrast, pigmentation of the hyponychium occasionally observed in benign lesions, particularly in nevi, has a different pattern consisting of a brushy linear structure across the skin marks (picture 14).

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INTRAOPERATIVE DERMOSCOPY OF THE NAIL MATRIX

Intraoperative dermoscopy allows the

direct visualization of the nail matrix.Four nail matrix dermatoscopic patterns have been described in longitudinal melanonychia [22]: ●Fine, regular, grayish lines are characteristic of melanocyte activation (95 percent sensitive, 100 percent specific) ●Regular, longitudinal, brown lines are characteristic of benign melanocyte hyperplasia (100 percent sensitive, 95 percent specific) (picture 15) ●Regular longitudinal brown lines with globules or blotches of regular size are characteristic of nevi (100 percent sensitive, 100 percent specific) ●Longitudinal lines with irregular color and thickness (with or without globules or blotches) are characteristic of melanoma (87 percent sensitive, 100 percent specific) (picture 16) Intraoperative dermoscopy may increase accuracy in the diagnosis of early melanoma [23].

DIFFERENTIAL DIAGNOSIS OF NAIL PIGMENTATIONS Approach — The clinical differential diagnosis of melanonychia is challenging. Dermoscopy can differentiate nonmelanic (eg, subungual hematomas, infections) from melanic pigmentations due to melanocyte activation or proliferation. The color of the band indicates whether it results from melanocytic activation (gray band) or proliferation (brown/black band) [2]. An algorithmic approach to the differential diagnosis and management of melanonychia is provided in the figure (algorithm 1). Although dermoscopy can help distinguish between benign and malignant nail lesions, excision for pathologic evaluation is necessary for the definitive diagnosis of suspicious lesions [11,24]. Excision is preferred to biopsy, as it is important for the pathologist to evaluate the whole lesion. There are reports in the literature of misdiagnosis of nail melanoma due to false negative incisional biopsies [1]. For lesions measuring 3 mm or less, a punch excision is indicated. Otherwise, a tangential matrix excision (shave biopsy of the matrix) is recommended [1,14]. (See "Nail biopsy: Indications and techniques", section on 'Nail matrix biopsy'.)

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Ethnic-type melanonychia — Longitudinal melanonychia is common in individuals with dark phototypes and typically affects multiple nails (picture 17) [25]. In individuals of African descent, melanonychia occurs in up to 77 percent of young adults and almost 100 percent over 50 years [25]. In Japanese populations, it affects 10 to 20 percent of adults. On dermoscopy, this type of physiologic melanonychia presents as a gray homogeneous band with or without thin regular lines (picture 1) [1].

Traumatic melanonychia — Traumatic or frictional melanonychia may occur in the fingernails of individuals who bite or traumatize the proximal nail fold and cuticle [26]. It is also common in the fourth and fifth toenails, which are exposed to chronic friction from shoes. Dermoscopy shows a gray homogeneous pale brown or gray band; dots due to blood extravasation and splinter hemorrhages are common (picture 2).

Drug-induced melanonychia — Drugs causing melanonychia include chemotherapy agents, antimalarials, and psoralens [27]. Drug-induced nail pigmentation typically affects several nails and may present as longitudinal or transverse melanonychia. Dermoscopy shows gray homogeneous bands with or without thin regular lines (picture 18).

Postinflammatory melanonychia — Melanonychia can develop in nails affected by inflammatory skin conditions such as psoriasis, lichen planus, or Hallopeau acrodermatitis. A single nail can be affected. On dermoscopy, the band has a gray background.

Fungal melanonychia — Some nondermatophytic molds (particularly Neoscytalidium dimidiatum) and Trichophyton rubrum (var nigricans) produce pigmented hyphae that cause nail pigmentation [28]. In most cases, dermoscopy shows multicolored pigmentation with presence of yellow dots and spikes (picture 19). The presence of black pigment aggregates (coarse granules and/or pigment clumps), which histologically correspond to fungal colonies, may also be present [29].

Nevi — Nail matrix melanocytic nevi are most commonly seen in children and may be congenital or acquired. Nevi represent approximately 12 percent of longitudinal melanonychia in adults and 48 percent in children. Bands of longitudinal melanonychia due to nail matrix nevi can vary in size, from a few millimeters to the whole nail width, as well as in color, from light brown to black. Periungual pigmentation is common in congenital nevi. In children, lesions may enlarge very rapidly and may become more intensely pigmented or show a fading of the pigmentation [17,30-32]. Dermoscopic features of nevi are different in adults and in children [33]. In adults, it is typical to observe a brown background color with longitudinal brown to black regular parallel lines (picture 3). In children, the lines are usually very irregular, present variations in color and thickness, and often

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show loss of parallelism (picture 20). Black dots, corresponding to melanin granules 6 mm, irregular borders, asymmetry, variable pigmentation, and change in appearance of a longstanding pigmented lesion. (See 'Atypical nevi' below and "Screening and early detection of melanoma in adults and adolescents" and 'Biopsy considerations' below.)

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COMMON ACQUIRED MELANOCYTIC NEVI Clinical features General features — Common (banal) nevi have a wide variety of clinical appearances. However, they tend to be ≤6 mm in diameter and symmetric with a homogeneous surface, even pigmentation, round or oval shape, regular outline, and sharply demarcated border (picture 1). Close inspection sometimes reveals pigmentary stippling or perifollicular hypopigmentation. Nevi are often concentrated in sun-exposed areas of the trunk or, particularly in girls, on the lower extremities [16]. Less commonly, they occur in acral sites such as the palms, soles, and nail matrix. As many as onethird of children and adolescents have acquired nevi on the scalp, and nevi in this location may be a marker for the development of a greater total number of nevi [17].

Nevi on palms/soles — Nevi on the palms and soles (acral melanocytic nevi) occur in individuals of all ethnic backgrounds, but are more common in those with dark skin pigmentation or numerous melanocytic nevi [18-21]. Nevi located on the palms and soles are usually of the junctional or compound type, and are typically brown to dark brown in color. They often have linear streaks of darker pigmentation that reflect the prominent skin markings in these sites. (See "Dermoscopy of pigmented lesions of the palms and soles".) Referral to a dermatologist is generally warranted when acquired acral nevi have marked asymmetry, mottled pigmentation, or a large size (≥6 mm). (See "Pathologic characteristics of melanoma", section on 'Acral lentiginous melanoma'.)

Nevi originating from the nail matrix — Acral nevi or lentigines that involve the nail matrix can present as longitudinal melanonychia, a tan, brown, or black streak caused by increased melanin deposition in the nail plate (picture 2). In darkly pigmented individuals, longitudinal melanonychia is commonly seen on multiple nails due to increased melanin production by normal nail matrix melanocytes (picture 3). Streaks that develop in childhood are usually benign [22]. However, single bands that are dark/irregular in color or wide (≥4 mm), become darker or wider with time, are associated with nail dystrophy, or have extension of pigmentation beyond the nail fold may warrant biopsy of the nail matrix to exclude melanoma [23]. (See "Overview of nail disorders", section on 'Longitudinal melanonychia' and 'Biopsy considerations' below.)

Natural history — Common acquired melanocytic nevi begin to appear after the first six months of life, increase in number during childhood and adolescence, reach a peak count in the third decade, and then slowly regress with age [11,24]. Substantial nevus turnover also occurs during the first two decades of life. For example, over a three- to four-year period in early

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adolescence, the net number of nevi increases by a mean of 40 to 60 percent and approximately 15 percent of nevi disappear [24,25]. Although a changing nevus may raise concern for melanoma in an adult, enlargement and increased elevation occur as part of the normal natural history of nevi in children and adolescents [26]. The clinical and histologic evolution of individual lesions from junctional to compound to dermal nevi (figure 1) can correspond to this cycle. ●Junctional nevi – Junctional nevi are macular or minimally raised, have preserved skin markings, and range from brown to black in color, sometimes with darker pigmentation in the center than at the edge (picture 4). They can be similar in appearance to simple lentigines. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Simple lentigo'.) ●Compound nevi – Compound nevi are classically pigmented papules, but in some lesions the degree of elevation is subtle. Their surface can be smooth and dome-shaped or papillomatous, and they vary in color from tan to dark brown (picture 5). The more symmetric and uniform in color a compound nevus is, especially when tan to medium brown in color, the less one needs to worry about the lesion ●Intradermal nevi – Nevus cells residing in the dermis often lose their capacity to produce melanin. As a result, intradermal nevi are usually skin-colored to tan papules that are dome-shaped, papillomatous, or pedunculated with a soft, rubbery texture (picture 6). Occasionally, they have speckles of brown pigmentation, terminal hairs, or pseudo-horn cysts (ie, accumulations of keratin within invaginations of hyperplastic epidermis). Pseudo-horn cysts occur more frequently in seborrheic keratoses, which typically develop in adults, than in intradermal nevi. (See "Overview of benign lesions of the skin", section on 'Seborrheic keratosis'.) Dermoscopic evaluation of acquired melanocytic nevi in children most often reveals a globular pattern, especially in lesions located on the head, neck, or upper trunk. In contrast, a reticular pattern is more common in acquired nevi located on the extremities and in children with darker pigmentation, as well as in nevi that develop during adulthood [27]. Histologically, the globular pattern is associated with a prominent dermal component with or without large junctional nests, while the reticular pattern corresponds to a prominent junctional component with lentiginous melanocytic hyperplasia with or without small junctional nests. Acquired nevi with a globular pattern are threefold more likely to have an underlying somatic BRAF V600Eactivating mutation than those with a reticular pattern (approximately 90 versus approximately 30 percent, respectively) [28].

Management — Most acquired nevi remain benign throughout the lifetime of a person and require no treatment other than longitudinal observation. However, having a large number of acquired nevi increases the risk of melanoma, and patients with multiple acquired nevi should be followed with periodic total body skin examinations and counseled regarding sun protection [29]. (See "Risk factors for the development of melanoma", section on 'Typical nevi' and "Primary prevention of melanoma" and "Melanoma: Clinical features and diagnosis", section on 'Introduction'.)

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Because more than half of cutaneous melanomas arise de novo (ie, not in association with a nevus), there is no benefit to "prophylactic" removal of nevi. Nevertheless, when melanocytic nevi are removed, no matter what the reason, the specimens should always be sent for histologic examination. (See 'Biopsy considerations' below and "Pathologic characteristics of melanoma".)

ATYPICAL NEVI

Atypical nevi are benign acquired melanocytic nevi that

share, usually to a lesser degree, some of the clinical features of melanoma such as asymmetry, border irregularities, color variability, and diameter >6 mm (picture 7A-C). Considerable controversy has surrounded terms such as dysplastic nevus, and the 1992 NIH Consensus Conference recommended the use of the more clinically descriptive term "atypical nevus". They also recommended that the lesions be described histologically as "nevi with architectural disorder," with specification of the degree of melanocytic atypia present (ie, none, mild, moderate, or severe) [30]. Atypical nevi are associated with a total increased number of acquired nevi (eg, greater than 50). In white populations, the prevalence of atypical nevi is approximately 2 to 10 percent [31]. Atypical nevi often do not appear until puberty and are believed to develop throughout life [32]. Their density is generally greater on areas of the body that receive intermittent sun exposure (eg, the trunk and lower extremities) (picture 8) than sites that are not exposed to sun (eg, breast and buttocks). Many patients with multiple nevi exhibit a predominant morphologic type of nevus, or a "signature nevus" [33]. A nevus that has different characteristics from other nevi in a given patient (the "ugly duckling") should be regarded with particular suspicion [34]. The "eclipse" nevus is a type of compound nevus that often develops on the scalp of children and is characterized by a tan center and brown, oftentimes stellate rim (picture 9A-B). Despite their two colors and irregular borders, eclipse nevi have benign behavior and (in the absence of a superimposed concerning feature) do not need to be biopsied or excised [35]. The clinical and dermoscopic features, diagnosis, differential diagnosis, and management of atypical nevi are discussed in detail separately. (See "Atypical (dysplastic) nevi".)

HALO NEVI Clinical features — The halo nevus (Sutton's nevus) is a melanocytic nevus surrounded by a round or oval, usually symmetric, halo of depigmentation. This pigment loss often heralds the spontaneous regression of the central nevus via a process thought to involve a T-cell mediated immune response to nevus antigens [36]. The halo phenomenon typically involves common acquired melanocytic nevi, but may also be seen with congenital nevi, blue nevi, Spitz nevi, and melanoma. Halo nevi occur in up to 5 percent of white children 6 to 15 years of age [37,38], and have a higher incidence in patients with an increased number of nevi and a personal or family history of vitiligo. The back is the most common location for halo nevi, and multiple lesions are present in

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approximately half of cases [37,39]. Any one of four clinical stages can be seen, with the duration of the process ranging from months to several years [40]; the interval between Stages I/II and Stage IV can be up to a decade [41]: ●Stage I – Pigmented nevus surrounded by a halo of depigmentation (picture 10). ●Stage II – Pink nevus surrounded by a halo of depigmentation (picture 11). ●Stage III – Circular area of depigmentation, with disappearance of the nevus. ●Stage IV – Normal-appearing skin after repigmentation of the halo. In some cases, the central nevus may darken rather than lighten, developing hyperpigmentation in a reticular pattern [42]. Hyperkeratotic surface change of the benign central nevus has been reported to occur in some children prior to halo development and also concomitantly with the halo phenomenon [43,44].

Management — It is important to assess the clinical features of the central nevus. A biopsy is not indicated if the central nevus is banal in appearance [45]. Because children with halo nevi often have an increased number of nevi in general, a total body skin examination should be performed. Referral to a dermatologist may be warranted. (See 'Common acquired melanocytic nevi' above.) If there are atypical or worrisome features, then a biopsy of the central nevus can be performed. However, there is no reason to excise the halo. Although development of multiple halo nevi is not unusual in adolescents and young adults, it is rare in middle-aged and older adults; in the latter population, the possibility of the halo nevi representing an immune reaction to a cutaneous or ocular melanoma must be considered. (See 'Atypical nevi' above and 'Biopsy considerations' below.)

BLUE NEVI Clinical features — Blue nevi are benign proliferations of dendritic dermal melanocytes that actively produce melanin. The blue color (ceruloderma) is due to the preferential scattering of shorter wavelengths of light by the dermal melanin, a phenomenon known as the Tyndall effect. The sites of predilection of blue nevi (eg, the head and neck, dorsal aspect of the distal extremities, and sacral area) represent locations where active dermal melanocytes are normally still present at the time of birth. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Dermal melanocytoses'.) Several variants of blue nevi have been described [46]:

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●The common blue nevus typically presents as a solitary, uniformly blue to blue-black, dome-shaped papule with preserved skin markings that measures 5 mm in diameter. (See "Pathologic characteristics of melanoma", section on 'Acral lentiginous melanoma'.) ●Nevi originating in the nail matrix that present as single bands of dark color or are ≥4 mm wide; the threshold for biopsy is considerably lower in adults than in children. (See "Overview of nail disorders", section on 'Longitudinal melanonychia'.) ●Nevi with marked asymmetry (based on irregular outline and/or color variation), areas of regression (oftentimes gray-blue or white in color), development of areas of pink or red color, or a history of rapid change or symptoms. (See "Melanoma: Clinical features and diagnosis", section on 'Introduction' and "Melanoma: Clinical features and diagnosis", section on 'Management of suspicious lesions'.)

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●An atypical nevus that has different clinical characteristics as compared to the remainder of the nevi in a given patient (ie, the "ugly duckling"). ●A halo nevus in which the central nevus has atypical or worrisome features. (See 'Halo nevi' above.) ●A cellular blue nevus that has developed a superimposed change (eg, a papulonodule). (See 'Blue nevi' above.) ●A Spitz nevus with atypical clinical features (eg, diameter >1 cm, asymmetry, or ulceration). (See 'Spitz nevi' above and "Spitz nevus and atypical Spitz tumors".) An occasional misconception is that the presence of hairs within a melanocytic nevus is a sign of benignity. However, melanoma can develop within congenital nevi (which often contain terminal hairs) and "de novo" cutaneous melanomas can have the same density of terminal hairs as the surrounding skin [59]. Pigmented lesions with features suspicious for melanoma should be biopsied regardless of the presence or absence of hair.

Procedure — The preferred biopsy technique for lesions suspicious for melanoma is one that allows histologic examination of the entire lesion.

Other considerations — It is important to give the dermatopathologist information (eg, foci of eccentric hyperpigmentation) about any pigmented lesion that has been biopsied.

SUMMARY AND RECOMMENDATIONS ●Common (banal) acquired melanocytic nevi tend to be ≤6 mm in diameter and symmetric with a homogeneous surface, even pigmentation, round or oval shape, regular outline, and sharply demarcated border (picture 1). (See 'Common acquired melanocytic nevi' above.) ●Atypical nevi are benign acquired melanocytic nevi that share some of the clinical features of melanoma (ie, asymmetry, border irregularities (picture 7C and picture 7A)), color variability, and diameter >6 mm (picture 7B). (See "Atypical (dysplastic) nevi".) ●Multiple atypical nevi are a phenotypic marker of increased risk of melanoma. The risk of melanoma depends also upon the total number of nevi, family and/or personal history of melanoma, and sun exposure history. (See "Inherited susceptibility to melanoma".) ●The halo nevus is a melanocytic nevus surrounded by a round or oval halo of depigmentation (picture 10). The halo phenomenon usually involves common acquired melanocytic nevi, but may also be seen with congenital nevi, blue nevi, Spitz nevi, and melanoma. (See 'Halo nevi' above.)

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●Blue nevi are benign proliferations of dendritic dermal melanocytes that actively produce melanin; they typically occur on the head and neck, dorsal aspect of the distal extremities, and sacral area. Multiple blue nevi may indicate a syndrome such as the Carney complex (table 1). (See 'Blue nevi' above.) ●Spitz nevi are uniformly pink, tan, red or red-brown, dome-shaped, hairless papules or nodules; they are usually symmetric, well-circumscribed, and 9 cm on the head or >6 cm on the body. ●Giant – G1>40 to 60 cm; G2>60 cm.

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For large and giant nevi, the number of "satellite nevi" surrounding the nevus helps inform evaluation and monitoring for these patients. Large and giant CMN are further categorized by the number of satellite lesions present, as follows: ●S – 0 ●S1 – 50 Additionally, color heterogeneity, surface rugosity, the presence of dermal or subcutaneous nodules, and hypertrichosis can each be graded from 0 (none) to 2 (marked). Because of their distribution, giant CMN are sometimes referred to as "garment" or "bathing trunk" nevi; in addition, they are frequently accompanied by multiple smaller, widely disseminated "satellite" nevi (picture 3). Most giant CMN can be categorized into one of six anatomical distributions, termed the "six Bs": bolero (upper back and neck), back (central back, spares buttocks and shoulders), bathing trunk (mainly genital area and buttocks, does not extend to shoulders or neck), breast/belly (isolated to breast and/or abdomen), body extremity (only on extremity, spares genitals or shoulders), and body (involves most of body, overlap of bolero and bathing trunk) [16].

DERMOSCOPIC FEATURES

The main dermoscopic

features seen in CMN as well as in acquired melanocytic nevi are pigment network, aggregated globules, and/or diffuse homogeneous brown pigmentation (figure 1) [17]. Common dermoscopic patterns seen in CMN are reticular, globular/cobblestoning, homogenous, and a mixture of these (ie, multicomponent) [18]. (See "Overview of dermoscopy" and "Dermoscopic evaluation of skin lesions".) However, CMN may exhibit exaggerated dermoscopic features compared with acquired melanocytic nevi, such as perifollicular hypopigmentation (picture 4), skin furrow hyperpigmentation, and prominent follicular structures [19,20]. Additional features include hypertrichosis (picture 5), perifollicular pigment changes (picture 6), target globules (picture 7), focal areas of hypopigmentation, and network thickening (picture 8). Some authors have noted that a target network with dots, globules, or blood vessels (picture 9) is a more distinctive feature of CMN [20]. Dermoscopic features detected in CMN of the palms and soles include [21] the parallel furrow pattern which is also common in acquired acral nevi (picture 10). A more prominent crista dotted (picture 11) or peas-in-a-pod (picture 12) pattern may also be seen, reflecting an increased number of nevus cell nests around distal eccrine ducts. (See "Dermoscopy of pigmented lesions of the palms and soles".)

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DIAGNOSIS

The diagnosis of a medium-sized, large, or giant CMN is usually

straightforward, based upon clinical appearance and history of presence since birth or early childhood. Small congenital nevi may be difficult to distinguish from acquired nevi if history is uncertain. However, dermoscopic examination may be helpful in differentiating small CMN from atypical CMN. The differential diagnosis of medium-sized or large CMN may include a plexiform neurofibroma. A plexiform neurofibroma is favored if the lesion has a "bag of worms" texture on palpation or if there are other findings suggestive of neurofibromatosis-1. The major entities in the differential diagnosis of a small or medium-sized CMN are a smooth muscle hamartoma and mastocytoma. Dermoscopy, presence of a Darier sign, and/or biopsy may be helpful in the latter situation. (See "Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations".)

NATURAL HISTORY

CMN enlarge in proportion to the child's

growth, with estimated size increase factors from infancy to adulthood as follows [22]: ●Head – 1.7-fold ●Trunk and upper extremities – 2.8-fold ●Lower extremities – 3.3-fold CMN tend to grow more rapidly during early infancy [23]. In addition to increasing in size, CMN undergo other age-related changes in appearance. They often begin as flat, evenly pigmented patches that later become elevated with a pebbly (picture 2), verrucous, or cerebriform surface and darker, lighter, mottled, or speckled pigmentation [24]. Dermal melanocytes within CMN may undergo peripheral nerve sheath differentiation, or neurotization, which results in the development of soft nodules and large plexiform neurofibroma-like plaques [4]. CMN located on the scalp may have a particular tendency to gradually lighten and regress over time [25]. The halo phenomenon (ie, the development of a depigmented halo around the nevus), which is more commonly observed with acquired melanocytic nevi, represents another means by which CMN in any site can regress [26]. In some cases, the development of halo nevus depigmentation is preceded by the development of dermatitis on and/or around the nevus [27]. During the neonatal period, transient erosions or ulcerations may arise at sites of obvious friction within medium-sized and large CMN as a reflection of increased skin fragility. (See 'Management' below.)

Proliferative nodules — Proliferative nodules are benign melanocytic proliferations that occasionally develop within large or giant CMN [28]. They may be congenital or appear during infancy or childhood. Because of their rapid growth and clinical characteristics such

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as firmness or ulceration, biopsy is usually performed to exclude melanoma. However, distinction from melanoma on histologic examination may prove difficult because of the presence of large, atypical melanocytes and mitoses. This is a situation where evaluation by experienced dermatopathologists is essential, and techniques such as comparative genomic hybridization or mass spectroscopy imaging proteomic analysis may be helpful (picture 13) [28,29]. (See "Spitz nevus and atypical Spitz tumors", section on 'Comparative genomic hybridization'.)

COMPLICATIONS Melanoma — The risk for the development of melanoma within small- and mediumsized CMN is controversial but is thought to be less than 1 percent over a lifetime [3]. Melanomas most often occur after puberty and tend to arise at the dermal-epidermal junction, in contrast to the earlier onset and deeper origin of many melanomas arising within large CMN. For patients with large or giant CMN, the risk of developing melanoma (cutaneous or extracutaneous) is estimated to be approximately 2 to 5 percent over a lifetime, with approximately one-half of this risk during the first five years of life (ie, one-half of the melanomas that develop occur by three to five years of age) (table 1) [30,31]. In a cohort study including 349 children with CMN (145 with large CMN), five (3.4 percent) developed a fatal melanoma at one to seven years of age [32]. In all cases, the projected adult size of the nevus was >60 cm and satellite nevi were present at birth. Particularly in large or giant CMN, cutaneous melanomas can arise subepidermally, making early recognition difficult. Palpation of the entire nevus surface is an important part of the physical exam to try to detect deep nodules. In some patients, the site of the primary melanoma is the central nervous system (CNS) or retroperitoneum, whereas others have no identifiable primary site. Patients with a "giant" (>40 cm) CMN in a posterior axial location that is associated with numerous satellite nevi have the greatest risk of developing melanoma. Melanomas less often arise within nevi restricted to the head or an extremity; to date, no well-documented, primary cutaneous melanomas have been reported to develop within satellite nevi themselves. (See "Risk factors for the development of melanoma".)

Neurocutaneous melanosis — Patients with CMN may rarely develop neurocutaneous melanosis (NCM), a proliferation of melanocytes in the CNS, as well as the skin. NCM encompasses both leptomeningeal melanosis and CNS melanosis [33]. NCM may be asymptomatic (noted on screening magnetic resonance imaging [MRI]) or symptomatic. The latter is associated with a poor prognosis, with a high mortality rate in the first few years of life [34,35]. Risk factors for NCM include [36-38]: ●A large CMN, especially if >40 cm predicted final size and in a posterior axial location ●Multiple satellite nevi

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●More than two medium-sized CMN (especially if numerous) In a study of patients with large CMN, 26 of 379 (7 percent) of whom had been diagnosed with NCM, those with >20 satellites had a fivefold increased risk for NCM compared with those with ≤20 satellites [39]. NCM can also develop in patients with nevus of Ota. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Nevus of Ota'.) Structural abnormalities of the CNS (eg, Dandy-Walker malformation/posterior fossa cysts), defects of the vertebrae or skull, and intraspinal lipomas occasionally occur in association with NCM [40]. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Dandy-Walker malformation'.) NCM is best detected by MRI with gadolinium contrast. Symptomatic NCM develops in approximately 3 to 10 percent of infants and children with high-risk CMN [37]. Neurologic manifestations (eg, hydrocephalus, seizures) may result from intracranial hemorrhage, impaired cerebrospinal fluid circulation, spinal cord compression, or malignant transformation of the melanocytes [3,41]. Clinical presentation occurs at a median age of two years, and prognosis is often poor even in the absence of malignancy [42]. Developmental delay and/or seizures have been reported in up to 15 to 25 percent of children with large or multiple CMN (some of whom did not have MRI evidence of NCM), with more favorable overall outcomes [32,37,40]. Asymptomatic NCM, diagnosed on the basis of MRI evidence of CNS melanosis, is found in 5 to 25 percent of infants and children with high-risk CMN [4,43]. In one five-year follow-up study, only 1 of 10 patients with MRI findings suggestive of CNS melanosis went on to develop neurologic symptoms [33]. For patients with abnormal clinical or MRI findings, referral to a pediatric neurologist for further monitoring is appropriate. If NCM is detected, repeat MRIs should be performed, with the frequency guided by the degree of involvement and clinical findings [14].

Other malignancies — Other malignancies, such as rhabdomyosarcoma, liposarcoma, and malignant peripheral nerve sheath tumors, have been reported in the setting of large CMN [44].

MANAGEMENT Small/medium CMN — Small and medium-sized CMN are managed on an individual basis depending on factors that affect ease of monitoring (eg, color, thickness/topography, and location), clinical history, parents' anxiety, and cosmetic concerns [4]. As an example, a multinodular black CMN on the scalp that is partially obscured by dense hair growth would be difficult to follow clinically, whereas a thin light brown lesion on the face would be relatively simple to observe. However, the latter might be removed for cosmetic reasons, and the former may spontaneously lighten during childhood.

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Periodic evaluation of small- and medium-sized CMN is most important after puberty, since the risk of melanoma arising within these lesions during childhood is extremely low. Baseline photographs can be helpful, and dermoscopy represents a useful tool for assessing changes. (See "Dermoscopic evaluation of skin lesions".) Patients and parents should be instructed to perform skin self-examinations and to bring focalchanges in color, border, or topography (eg, a red or black papule, nodule, or crust) to the clinician's attention. (See "Screening and early detection of melanoma in adults and adolescents", section on 'Patient self-examination'.)

Large CMN — Early surgical removal is often desired for large CMN because of their cosmetic and psychosocial sequelae and concern for possible malignant transformation. Complete excision is difficult to achieve; however, resection of bulky and cumbersome portions of large CMN can be beneficial for some patients. Elimination of every nevus cell may be impossible because of the large area of skin affected, the anatomic site (eg, distal extremity, periocular area, genitalia), and involvement of deeper structures (eg, fat, fascia, muscle). Even theoretically complete surgical excision cannot completely eliminate future risk of melanoma, as some melanomas in these patients may develop in the CNS or retroperitoneum. In many cases, close clinical observation with no surgical removal of the lesion is a reasonable choice. Factors that affect the decision to perform surgery as well as to determine the timing of surgery include the size and location of the large CMN, the technical difficulty of the procedure(s) required, and anesthesia options. When possible, complete removal of large CMN usually necessitates staged excision with the use of tissue expanders and, occasionally, skin grafting [45]. When surgical excision is not feasible, cosmetic benefit may potentially be obtained from procedures such as curettage, dermabrasion, and ablative laser therapy (eg, carbon dioxide or erbium:yttrium aluminum garnet lasers, sometimes combined with pigment-directed lasers). During the neonatal period, there is a lower risk of excessive scarring following such interventions, and nevus cells are more accessible because they are concentrated in the upper dermis [46,47]. Curettage can be performed during the first two weeks of life, taking advantage of a cleavage plane between the upper and mid-dermis exclusive to neonatal skin. However, nevus cells remain in the dermis after all of these procedures, as evidenced by frequent repigmentation as well as several reports of the subsequent development of melanoma in treated areas [48-52]. This underscores the need for lifelong clinical observation. Regardless of the treatments employed, patients with large CMN (or scars after their excision) should be followed with periodic skin and general physical examinations. Palpation of the nevus and/or scars is essential for detection of focal induration. Histologic evaluation is indicated for firm nodules or indurated areas. Even theoretically complete removal of a large CMN does not eliminate the risk of melanoma, since melanoma of the CNS and other visceral primary sites (eg, the retroperitoneum) may still occur [53].

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Proliferative nodules that develop within large CMN during infancy can have histologic features of melanoma yet behave in a benign manner. Techniques such as comparative genomic hybridization can help to distinguish proliferative nodules (usually having no chromosomal aberrations or only numeric changes) from melanoma (typically demonstrating gains/losses of chromosomal fragments) [40]. Mass spectroscopy imaging proteomic analysis may also help differentiate proliferative nodules from melanoma [29]. (See 'Proliferative nodules' above.)

Surveillance for neurocutaneous melanosis — Patients with a large CMN plus multiple (especially >20) satellite nevi or with multiple medium-sized CMN are at risk for NCM and should be followed with serial head circumference measurements, neurologic examinations, and developmental assessments [3,37,39]. This monitoring includes evaluation for signs and symptoms of increased intracranial pressure, mass lesions, and spinal cord compression [3,39]. Gadolinium-enhanced magnetic resonance imaging (MRI) of brain and spine should be performed in any high-risk patient exhibiting neurologic symptoms, and we suggest that asymptomatic high-risk patients also be screened for NCM with gadolinium-enhanced MRI of the brain and spine, ideally during the first six months of life before myelination, which may obscure evidence of melanosis [42]. For very young infants, it may be possible to obtain initial high-quality MRI images without general anesthesia using "feed and wrap" techniques that allow a swaddled infant to sleep during the imaging procedure [54]. Given the poor prognosis, aggressive surgical procedures for CMN removal should be postponed in patients with symptomatic NCM. NCM in an asymptomatic patient does not necessarily preclude skin surgery.

SPECKLED LENTIGINOUS NEVUS

Speckled lentiginous nevus (SLN) or nevus spilus is a hyperpigmented, macular,

patch-type, tan or light brown patch with superimposed darker brown macules and papules (picture 14A-B). The "background" tan patch (café-au-lait macule-like) of an SLN is usually noted at birth or soon after, with brown "spots" appearing within the lesion over time. The superimposed, pigmented macules and papules can range from lentigines to junctional, compound, and intradermal nevi to Spitz nevi and blue nevi. There are two distinct subtypes of SLN: those with only macular speckles and those with papular as well as macular speckles [55]. Several lines of evidence suggest that SLN, which have a prevalence of approximately 2 percent, represent a subtype of CMN [56]. Some SLN have patterns of distribution reflecting embryonic development (eg, block-like with a sharp demarcation at the midline or following the lines of Blaschko).

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The risk of developing melanoma in SLN is thought to be similar to classic CMN of the same size range. SLN should therefore be followed clinically with periodic examinations and biopsy of suspicious areas. (See 'Management' above and "Risk factors for the development of melanoma", section on 'Congenital nevi'.)

SUMMARY AND RECOMMENDATIONS ●Congenital melanocytic nevi (CMN) occur in 1 to 3 percent of newborn infants; large or giant CMN occur in approximately 1 of 20,000 births. (See 'Epidemiology' above.) ●The color of CMN ranges from tan to black, and the borders often are geographic and irregular. Many CMN have an increased density of dark, coarse hairs (picture 3). (See 'Clinical features' above.) ●Giant CMN are sometimes referred to as "garment" or "bathing trunk" nevi and are frequently accompanied by multiple smaller, widely disseminated "satellite" nevi (picture 3). (See 'Clinical features' above.) ●CMN enlarge in proportion to the child's growth and undergo other age-related changes in pigmentation or surface characteristics. Superimposed papules and nodules can develop, which occasionally require histologic examination to exclude the development of a cutaneous melanoma. (See 'Natural history' above.) ●The risk of melanoma developing within a CMN is correlated with the size of the nevus (table 1). (See 'Melanoma' above and "Risk factors for the development of melanoma", section on 'Congenital nevi'.) ●Patients with CMN may have proliferation of melanocytes in the central nervous system as well as the skin (neurocutaneous melanosis, NCM). Patients with either a large CMN accompanied by satellite nevi or numerous medium-sized CMN are at risk of NCM. NCM can be asymptomatic or may present with neurologic symptoms such as hydrocephalus and seizures. (See 'Neurocutaneous melanosis' above.) ●Small- and medium-sized CMN are managed on an individual basis depending upon ease of monitoring (eg, color and location), clinical history, parents' anxiety, and cosmetic concerns. (See 'Small/medium CMN' above.) ●Large CMN are associated with the risks of cosmetic and psychosocial sequelae as well as the potential for malignant transformation. Clinical observation is a reasonable choice in many cases. When possible, surgical excision of large areas of nevus may require tissue expanders and skin grafts. The timing of surgery and the surgical techniques are based upon size, location, and anesthesia options. (See 'Large CMN' above.)

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●We suggest that patients at risk of NCM be screened with gadolinium-enhanced magnetic resonance imaging of the brain and (especially if the nevus overlies the posterior axis) spine during the first six months of life (Grade 2C). (See 'Surveillance for neurocutaneous melanosis' above.)

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Congenital and inherited hyperpigmentation disorders uptodate.com/contents/congenital-and-inherited-hyperpigmentation-disorders/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Nov 12, 2019.

INTRODUCTION

Hyperpigmentation is the darkening or increase in the

natural color of the skin, usually due to an increased deposition of melanin (hypermelanosis) in the epidermis and/or dermis. Less frequently, it may be caused by the deposition in the dermis of endogenous or exogenous pigments, such as hemosiderin, iron, or heavy metals. Hyperpigmentation is a feature of a multitude of clinical conditions, ranging from normal variations of skin color to acquired and inherited syndromes, and is one of the most common reasons for dermatologic consultation, particularly in patients with darker skin types [1-3]. Although hyperpigmentation is not harmful, it can cause significant cosmetic disfigurement and become a persistent psychosocial burden for the patient, due to the limited efficacy of the available treatments. This topic will review the approach to the patient with congenital and inherited hyperpigmentation disorders. Incontinentia pigmenti and pigmentary mosaicism are discussed separately. Acquired disorders of pigmentation are also discussed separately. ●(See "Incontinentia pigmenti".)

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●(See "Pigmentary mosaicism (hypomelanosis of Ito)".) ●(See "Acquired hyperpigmentation disorders".) ●(See "Melasma: Management".)

PATHOPHYSIOLOGY OF SKIN PIGMENTATION Determinants of skin color — The color of human skin is mainly determined by the two types of melanin, the black-brown eumelanin and the yellow-red pheomelanin, which are present in individuals of all skin colors, though their ratio is highly variable and determines the hue of the skin [4-6]. Melanin is produced by melanocytes, specialized cells of neural crest origin that reside in the basal layer of the epidermis. The biosynthesis of melanin occurs in lysosome-like organelles called melanosomes, which are transported to the cell periphery and transferred from the dendritic tips of the melanocytes to the surrounding keratinocytes [7]. Each melanocyte is associated with up to 40 basal keratinocytes to form the so-called epidermal melanin unit [8]. Differences in the number, size, and aggregation of melanosomes within the melanocytes and keratinocytes, but not in the overall number of melanocytes, contribute to ethnic differences in skin color [9,10]. Darker skin types have a higher content of melanin, higher eumelanin-to-pheomelanin ratio, nonaggregated and larger melanosomes,and slower melanosome degradation within the keratinocytes [11].

Genetic basis of pigmentary disorders — The biochemical pathway of melanogenesis is under complex genetic control, with hundreds of genes and genetic polymorphisms involved in the modulation of type and distribution of pigmentation [7,12,13]. However, only a few of them have been identified as the cause of specific monogenic hyperpigmentation disorders [13]. Mutations affecting genes involved in the differentiation and migration of melanocyte precursors in the neural crest or in the proliferation and activity of mature melanocytes may be involved in the pathogenesis of hyperpigmentation associated with inherited syndromes [7]. The genetic defects associated with a number of inherited and syndromic hyperpigmentation disorders are summarized in the table (table 1).

PATIENT EVALUATION AND DIAGNOSIS

The diagnosis of hyperpigmentation disorders may be challenging.

An algorithmic approach to the diagnosis based upon history and clinical parameters is shown in

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the figure (algorithm 1). In most cases, the initial patient evaluation involves a detailed personal and family medical history and a complete physical examination, which should include a careful search for additional cutaneous and extracutaneous signs and symptoms. Questions that may be useful for the evaluation of patients with hyperpigmentation disorders include [14]: ●Is the disorder congenital or acquired? ●Is the disorder isolated or part of a syndrome? ●Is the pigmentation localized or diffuse? ●Is the pigmentation well circumscribed or ill defined? ●Does the pigmentation have a pattern (eg, linear, reticular)? ●Is the pigmentation associated with inflammation and/or prior cutaneous injury? ●Is the pigmentation stable, progressing, or regressing?

History — A detailed family history may be helpful to determine whether the disorder is congenital and isolated or inherited and, in the latter case, what is the probable inheritance pattern [15]. However, although congenital or inherited hyperpigmentation disorders are often present at birth, history may be misleading, since parents may not have noted it for months or longer. The course of the disorder is also a useful parameter in the clinical diagnosis of hyperpigmentation disorders. Inherited disorders of hyperpigmentation are often stable, whereas most acquired forms show progression or regression.

Skin examination — In all patients with hyperpigmentation disorders, a complete skin examination should be performed under visible light and Wood's light. Important clinical parameters include: ●Extent of the pigmentary abnormality (localized versus diffuse) ●Color hue (shades of brown/black, slate-gray/blue) ●Morphology of individual lesions ●Distribution (eg, dermatomal, following Blaschko lines) ●Pattern (eg, linear, reticular, nonfigurate)

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A careful search for associated cutaneous and extracutaneous signs and symptoms may provide important clues to the diagnosis in patients with hyperpigmentation disorders associated with genetic syndromes.

Wood's light examination — Wood's light, also known as "black light," is ultraviolet A light with a peak emission at 365 nm [16]. The patient is examined in a darkened room with the light source held at 10 to 15 cm from the skin. Wood's light can be helpful in determining disease extent (eg, sun-exposed areas, areas previously involved by inflammatory processes, dermatomal distribution, following Blaschko lines) and whether the pigment deposition is predominantly epidermal, dermal, or mixed; however, its effectiveness is limited in patients with darker skin tones [17,18]. ●Epidermal hypermelanosis – Under natural light, epidermal hypermelanosis appears light brown to dark brown in color. The pigmentation, as well as the contrast between involved and uninvolved skin, is enhanced when viewed under a Wood's lamp. ●Dermal hypermelanosis – Under natural light, dermal hypermelanosis has a bluish or ashen gray hue with margins less defined than epidermal hypermelanosis. The pigmentation is not accentuated by the Wood's light. ●Mixed hypermelanosis – Mixed hypermelanosis appears light to dark brown under natural light, whereas Wood's light examination will show enhancement in some areas and none in others.

Skin biopsy — A skin biopsy for histopathologic evaluation is not routinely performed for the diagnosis of hyperpigmentation disorders. However, it may be necessary when the clinical diagnosis is uncertain. Standard stains (eg, hematoxylin and eosin, Fontana-Masson silver stain) and histochemical techniques (eg, Mart-1, Melan-A) are used to evaluate the number and localization of melanocytes and melanin granules in the epidermis and dermis. The main histopathologic findings in selected acquired and congenital or inherited hyperpigmentation disorders are summarized in the table (table 2).

CIRCUMSCRIBED HYPERPIGMENTATION Congenital dermal melanocytosis — Congenital dermal melanocytosis is a group of hyperpigmentation disorders characterized by the presence of melaninproducing melanocytes in the dermis. They are most commonly seen in Asian populations and include the nevus of Ito (picture 1), nevus of Ota (picture 2), and the so-called Mongolian spots (picture 3).

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The congenital dermal melanocytoses are discussed separately. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Dermal melanocytoses' and "Skin lesions in the newborn and infant", section on 'Dermal melanocytosis'.)

Café-au-lait macules — Café-au-lait macules are sharply demarcated, hyperpigmented macules or patches that are typically two to three shades darker than the normal, uninvolved skin (picture 4). They vary in size from a few millimeters to more than 10 cm and can occur anywhere on the body. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Café-au-lait macule'.) Café-au-lait macules are often present at birth or appear in the first months of life. Isolated lesions are common and usually have no clinical significance. In contrast, multiple café-au-lait macules may represent the cutaneous marker of underlying genetic disorders such as neurofibromatosis type 1 and McCune-Albright syndrome. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.) Café-au-lait macules are difficult to treat. Partial clearance may be achieved with laser treatment, but recurrence is common [19]. (See "Laser and light therapy for cutaneous hyperpigmentation".)

Nevus spilus — Nevus spilus, also called speckled lentiginous nevus, is a hyperpigmented macule or patch with superimposed darker brown macules and papules (picture 5). The darker macules and papules may consist of junctional, compound, Spitz, atypical, or blue nevi. (See "Congenital melanocytic nevi", section on 'Speckled lentiginous nevus'.)

Segmental pigmentation disorder — Segmental pigmentation disorder is a form of pigmentary mosaicism characterized by hypo- or hyperpigmented patches with a segmental pattern that has been referred to as block-like, flag-like, or resembling a checkerboard [20]. Any site can be affected, but the trunk is favored. The shape is frequently quadrangular, and the margins may be serrated [21]. (See "Pigmentary mosaicism (hypomelanosis of Ito)", section on 'Segmental pigmentation disorder'.)

DIFFUSE LINEAR HYPERPIGMENTATION Pigmentary demarcation lines — The color of skin normally exhibits variation in hue and intensity at various sites of the body [22]. In all skin types, the dorsal skin surfaces are relatively more pigmented than the ventral surfaces. Pigmentary demarcation lines

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(also known as Futcher or Voigt lines) are a frequent finding, particularly in dark-skinned individuals. They are symmetric, bilateral, and are present from infancy to adulthood. Eight types of pigmentary demarcation lines (A to H) have been described [23]: ●Type A – Lateral aspect of upper anterior portion of arms, across the pectoral area (picture 6A-B) ●Type B – Posterior medial portion of lower limb (picture 7) ●Type C – Vertical hypopigmentation line in pre- and parasternal areas ●Type D – Posterior medial area of spine ●Type E – Bilateral aspect of chest, from the mid-third of clavicle to periareolar skin ●Type F – A straight or curved convex line sharply demarcating a relatively darker zone from a light area over the face; a V-shaped hyperpigmented line between the malar prominence and the temple (picture 8) ●Type G – W-shaped hyperpigmented lines between the malar prominence and the temple (picture 9) ●Type H – Linear bands of hyperpigmentation from the angle of the mouth to the lateral aspects of the chin (picture 10) Type A or Futcher lines are the most common type. They appear as sharp, easily recognizable lines located on the lateral aspect of the anterior portion of the upper arm, delineating the contrast in depth of color between the lateral and medial side of the arm (picture 6A).

Incontinentia pigmenti — Incontinentia pigmenti, also known as BlochSulzberger syndrome (MIM #308300), is an X-linked dominant multisystem disease that is usually lethal in males. It presents in newborns with linear papules and vesicles (picture 11A-B). Within weeks or months, these lesions progress to verrucous streaks, which typically resolve leaving streaks of hyperpigmentation (picture 12A-B). At three to six months of age, hyperpigmented whorls and swirls appear along Blaschko lines (picture 13). By the second or third decade of life or sooner, the hyperpigmented whorls may gradually become hypopigmented and may leave subtle atrophy. Incontinentia pigmenti is discussed in greater detail elsewhere. (See "Incontinentia pigmenti".)

Linear and whorled nevoid hypermelanosis — Linear and whorled nevoid hypermelanosis (LWNH), also called linear nevoid hypo-/hyperpigmentation, is a clinical manifestation of pigmentary mosaicism (previously known as hypomelanosis of Ito) characterized by hyperpigmented macules in a streaky

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configuration along the lines of Blaschko, mainly located on the trunk and limbs (picture 14A-B) [24,25]. The pigmentation is present at birth or appears in the first few weeks of life, progresses for one to two years, and then stabilizes. In some patients, hypo- and hyperpigmented macules coexist. (See "Pigmentary mosaicism (hypomelanosis of Ito)".) There are isolated reports of associated extracutaneous abnormalities, involving mostly the central nervous system, musculoskeletal system, and heart. The presence of genetic mosaicism has been documented in a few patients (mosaic trisomy 7, 14, 18, 20, and X-chromosomal mosaicism) [26-28]. The diagnosis is clinical. Histology is nonspecific and shows increased pigmentation of the basal layer with prominent melanocytes and variable presence of pigmentary incontinence. The differential diagnosis includes the pigmented stage of incontinentia pigmenti and epidermal nevus. (See "Incontinentia pigmenti" and "Epidermal nevus and epidermal nevus syndrome".)

DIFFUSE RETICULAR HYPERPIGMENTATION Dowling-Degos disease — Dowling-Degos disease (DDD), also known as reticulate pigmented anomaly of flexures, is a rare autosomal dominant genodermatosis associated in approximately one-half of cases with loss-of-function mutations in the gene that encodes keratin 5, KRT5[29]. Mutations in POFUT1 and POGLUT1 (which encode the protein O-fucosyltransferase 1 and O-glucosyltransferase 1, respectively) involved in the Notch signaling pathway, have been found in affected individuals who do not have mutations in KRT5 [30-33]. The disease has been reported worldwide and affects both genders equally. Onset is typically during the third to fourth decade of life. DDD is characterized by an acquired reticular hyperpigmentation that begins in the axillae and groin and later involves other body folds, including intergluteal and inframammary folds, neck, and inner aspects of the arms and thighs (picture 15A-B). Generalized forms with more extensive distribution have also been described [34]. Associated features include comedo-like lesions on the back or neck, pitted perioral or facial scars, and epidermoid cysts[35]. Pruritus is a common accompanying symptom. The diagnosis is based upon the clinical features and the examination of a skin biopsy. Histology shows increased pigmentation of the basal layer and finger-like rete ridges with thinning of the suprapapillary epithelium. The differential diagnosis includes a group of related genodermatoses with reticular pigmentation, including:  

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●Haber's syndrome – Haber's syndrome is characterized by a photosensitive rosacea-like facial eruption, keratotic papules, prominent comedones, pitted scars, and reticulate hyperpigmentation on the trunk, proximal extremities, and axillae [36]. ●Galli-Galli disease – Galli-Galli disease is a rare autosomal dominant disorder considered to be an allelic variant of DDD [37-39]. It has the same clinical and histologic features of DDD, with the exception of the presence of suprabasal nondyskeratotic acantholysis on histopathology. ●Reticulate acropigmentation of Kitamura – (see 'Reticulate acropigmentation of Kitamura' below). There are no effective treatments for DDD. Topical retinoids, skin-lightening agents, and laser therapy have been used in a limited number of patients with varying success[40,41].

Reticulate acropigmentation of Kitamura — Reticulate acropigmentation of Kitamura (RAK) is a rare genodermatosis characterized by atrophic, hyperpigmented macules with an initial acral distribution. A mutation in the ADAM10 gene encoding a zinc metalloproteinase has been identified in a RAK family[42]. RAK has been reported worldwide, but the majority of cases are from Japan. The disease presents in childhood or adolescence with hyperpigmented, slightly depressed macules, often in a reticulate pattern, on the dorsum of the hands and feet. The distinguishing element of this disorder is the atrophic appearance of the lesions. During adulthood, the macules may darken and spread to other sites. Associated findings are pits on the palms, soles, and dorsal aspect of phalanges as well as breaks in palm and sole dermatoglyphics. Histologically, the hyperpigmented macules show epidermal atrophy and elongated rete ridges that contain increased melanin. The differential diagnosis of RAK includes other diseases presenting with reticular or punctate hyperpigmentation, such as dyskeratosis congenita, dyschromatosis universalis hereditaria, Franceschetti-Jadassohn's syndrome, and DDD. Overlapping cases of RAK and DDD have been reported [43]. There are no effective therapies for RAK. Topical azelaic acid has been successfully used in a single case report [44].

X-linked reticulate pigmentary disorder — X-linked reticulate pigmentary disorder with systemic manifestations (XLPDR, MIM #301220) is a very rare genodermatosis caused by mutations in the POLA1 gene, encoding the catalytic subunit of DNA polymerase-alpha, an essential component of the DNA replication machinery and a critical regulator of the type I interferon response [45,46]. Cells derived from patients with the mutation show increased expression of genes involved in type I interferon signaling pathways and other proinflammatory genes [45]. The disorder was first described in a Canadian family in 1981 and initially called familial cutaneous amyloidosis. Only a few families and one sporadic case have been reported.

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The affected males have a distinctive facies with upswept frontal hairline and flared eyebrow and present in the first few months of life with recurrent pneumonias, bronchiectasis, chronic diarrhea, and failure to thrive. By early childhood, male patients develop a generalized reticulate hyperpigmentation and hypohidrosis. Additional systemic manifestations include corneal inflammation and scarring, enterocolitis resembling inflammatory bowel disease, and recurrent urethral strictures. These inflammatory manifestations are believed to be autoinflammatory phenomena due to increased production of interferon-alpha and other cytokines [45]. In females, XLPDR is characterized by patchy, linear hyperpigmentation following the lines of Blaschko that resemble stage III incontinentia pigmenti, in the absence of systemic manifestations. (See "Incontinentia pigmenti".)

Naegeli-Franceschetti-Jadassohn syndrome — Naegeli-Franceschetti-Jadassohn syndrome (MIM #161000) is a rare, autosomal dominant form of ectodermal dysplasia caused by heterozygous mutations in the KRT14 gene at 17q21,2 [47,48]. Clinical features include reticular hyperpigmentation of the skin (picture 16), palmoplantar keratoderma, absence of dermatoglyphs (picture 17), hypohidrosis, and heat intolerance. The hyperpigmentation appears in early childhood, increases during the first 10 years of life, and begins to fade around puberty. Dental abnormalities and early tooth loss are common. Nail dystrophy and malalignment can also be seen in these patients.  

Dermatopathia pigmentosa reticularis — Dermatopathia pigmentosa reticularis (MIM #125595) is an autosomal dominant disorder closely related to NaegeliFranceschetti-Jadassohn syndrome [49]. It is caused by mutations in the KRT14 gene and characterized by the triad of reticulate hyperpigmentation, noncicatricial alopecia, and onychodystrophy. In contrast with Naegeli-Franceschetti-Jadassohn syndrome, there are no dental abnormalities. Variable features include adermatoglyphia, hypohidrosis or hyperhidrosis, and palmoplantar hyperkeratosis [50]. 

Dyskeratosis congenita — Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome associated with characteristic mucocutaneous features and an increased risk of developing several malignancies, in particular, squamous cell carcinoma (especially mucosal), acute myelogenous leukemia, and Hodgkin disease[51]. DC is inherited in an X-linked recessive fashion, but autosomal recessive and dominant forms also have been reported. It is caused by mutations in the DKC1 gene encoding the protein dyskerin, which is involved in telomerase stabilization and maintenance [52]. Telomerase dysfunction leads to chromosome instability and likely plays a role in tumorigenesis. The mucocutaneous manifestations of DC include (picture 18):

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●A lacy, reticulated pattern of hyperpigmentation involving primarily the neck, upper chest, and upper arms, which develops during the first decade of life. ●Nail dystrophy manifesting as longitudinal ridging, splitting, and early pterygium. ●Teeth anomalies, including malformed, missing, or aberrant spacing (picture 19). ●Leukoplakia of the oral mucosa, most often involving the tongue (picture 20). DC is discussed in detail separately. (See "Dyskeratosis congenita and other short telomere syndromes".)

Dyschromatosis symmetrica hereditaria — Dyschromatosis symmetrica hereditaria is characterized by small, irregular, hyper- and hypopigmented macules on the dorsal aspects of hands and feet (picture 21AB) [53]. It is caused by over 200 described mutations in the ADAR1 gene encoding an adenosine deaminase and shows an autosomal dominant inheritance pattern [54,55]. Most cases are reported from East Asia (Japan, Korea, China), but the disorder has also been observed in European, AfroCaribbean, and Indian individuals[56]. The majority of patients develop hyper- and hypopigmented macules by the age of six. Lesions typically increase in size and number until adolescence and then stabilize and persist indefinitely. The diagnosis is clinical. (See "The dyschromatoses", section on 'Dyschromatosis symmetrica hereditaria'.)

Dyschromatosis universalis hereditaria — Dyschromatosis universalis hereditaria (DUH) is a rare disorder characterized by hypo- and hyperpigmented macules in a generalized distribution (picture 22) [57]. It is most frequently seen in Asian countries, particularly in Japan and India [58]. DUH is caused by mutations in the ABCB6 (ATP-binding cassette subfamily B, member 6) gene and is inherited in an autosomal dominant fashion with variable penetrance [59,60]. Hypo- and hyperpigmented macules usually appear in the first years of life on the hands and then extend to the face, trunk, and extremities. The diagnosis is clinical. (See "The dyschromatoses", section on 'Dyschromatosis universalis hereditaria'.)

DIFFUSE HYPERPIGMENTATION, NONFIGURATE 3109

Familial progressive hyperpigmentation — Familial progressive hyperpigmentation (FPH1) is a rare autosomal dominant disorder characterized by irregular patches of cutaneous and mucosal hyperpigmentation that are present either at birth or in early infancy and increase in size and number with age [61]. FPH1 has been mapped to chromosome 19p13.1-pter, although mutations in a specific gene have not been identified [62]. Familial progressive hyperpigmentation-2, also called familial progressive hyperpigmentation with or without hypopigmentation (FPH2, FPHH, MIM #145250) or melanosis universalis hereditaria, is rare autosomal dominant disorder with variable penetrance caused by mutations in the KITLG gene on chromosome 12q21.32, encoding the C-Kit ligand [63]. FPH2 is characterized by patches of cutaneous hyperpigmentation, café-au-lait macules, and larger, hypopigmented, ash-leaf macules that are present either at birth or in early infancy and increase in size and number with age.

Carbon baby — Universal acquired melanosis or "carbon baby" syndrome is an exceedingly rare type of progressive hyperpigmentation of unknown etiology occurring in children [64,65]. The darkening of the skin starts in the first few months of life on the face and limbs and gradually progresses to involve the entire body surface. On histopathology, there is heavy melanin deposition in the basal and suprabasal layers of the epidermis and presence of melanophages in the dermis [64].

H syndrome — H syndrome (MIM #602782) is a rare, multisystem, autoinflammatory disorder mainly affecting patients of Arab and, less commonly, Indian descent [66]. First described in 2008, H syndrome is characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, and short stature [67,68]. H syndrome is part of the histiocytosis-lymphadenopathy plus syndrome, which includes three other histiocytic disorders once thought to be separate entities: Faisalabad histiocytosis, sinus histiocytosis with massive lymphadenopathy (familial Rosai-Dorfman disease), and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome. This group of diseases is caused by homozygous or compound heterozygous mutation in the SLC29A3 gene on chromosome 10q22, encoding the solute carrier family 29 member 3, also called the equilibrative nucleoside transporter 3, which mediates the uptake of precursors for nucleotide synthesis by salvage pathways. (See "Peripheral lymphadenopathy in children: Etiology", section on 'Rosai-Dorfman disease'.)  The clinical manifestations of H syndrome are widely variable; its hallmark is cutaneous hyperpigmentation, which becomes apparent during childhood and is associated with sclerodermatous skin induration and hypertrichosis (picture 23) [69]. The hyperpigmented and hypertrichotic plaques are mainly located on the middle and lower part of the body. Extracutaneous manifestations may include sensorineural hearing loss, hepatosplenomegaly, short stature, cardiac anomalies (atrial septal defect, ventricular septal defect, mitral valve prolapse, and cardiomegaly), varicose veins, dilated lateral scleral vessels, facial telangiectasias, hallux valgus and fixed flexion

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contractures of fingers and toes, scrotal masses, and gynecomastia. Lymphadenopathy, which may be generalized or localized, has been reported in 24 percent of patients and insulin-dependent diabetes mellitus in 23 percent [69]. Laboratory abnormalities include mild microcytic anemia, elevated erythrocyte sedimentation rate, elevated liver enzymes, growth hormone deficiency, high gonadotropin levels, and low to normal testosterone levels. A biopsy of the involved skin shows hyperkeratosis, acanthosis, and increased melanin deposition in basal keratinocytes; widespread fibrosis of the dermis and subcutis; and an interstitial inflammatory infiltrate composed of small to medium-sized histiocytes, dendrocytes, plasma cells, lymphocytes, and mast cells (picture 24) [70].   The diagnosis of H syndrome is suspected based upon the clinical findings. Mutational analysis will confirm the diagnosis when there is uncertainty or in patients with mild or incomplete phenotypes. There is no established treatment for H syndrome. Therapies that have been attempted include systemic corticosteroids, immunosuppressive agents, interferon-alpha, adalimumab, and radiotherapy [69].

GENETIC SYNDROMES ASSOCIATED WITH LENTIGINOSIS

Genetic syndromes associated with lentiginosis are

summarized in the table (table 3).

Carney complex — Carney complex (MIM #160980), previously called LAMB (lentigines, atrial myxoma, mucocutaneous myxoma, blue nevi) or NAME (nevi, atrial myxoma, myxoid neurofibroma, ephelides) (table 4), is a clinically heterogeneous autosomal dominant disorder characterized by the presence of atrial myxomas, lentigines, skin tumors, and endocrine overactivity. They are caused by mutations in the PRKAR1A gene, encoding the protein kinase regulatory subunit 1A, located at 17q22-24. Lentigines occur most commonly on the face, especially on the lips, eyelids, conjunctiva, and oral mucosa (picture 25), but may be widespread and involve the trunk, extremities, and genitalia[71]. Other skin lesions include junctional and compound nevi, blue nevi, and cutaneous myxomas. The diagnostic criteria of Carney complex are summarized in the table (table 5). Given the rarity of this disorder, patients with suspected Carney complex (and their family members) should be referred to specialized centers with expertise in this area for diagnosis and genetic testing [72]. Carney complex is discussed in detail elsewhere. (See "Carney complex".)

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LEOPARD syndrome — LEOPARD syndrome (MIM #151100), also called Noonan syndrome with multiple lentigines, is a rare, autosomal dominant disorder caused by mutations in the protein tyrosine phosphatase, PTPN11 gene [73]. LEOPARD is an acronym for the major features of this disorder, including multiple lentigines, electrocardiogram (ECG) conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. LEOPARD syndrome belongs to a group of developmental disorders called RAS/MAPK pathway syndromes, which include Noonan syndrome, neurofibromatosis type 1, neurofibromatosis type 1like syndrome (Legius syndrome), cardiofaciocutaneous syndrome, Costello syndrome, and capillary malformation-arteriovenous malformation syndrome [74,75]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Capillary malformations (port wine stains) and associated syndromes", section on 'Capillary malformation-arteriovenous malformation syndrome'.) Multiple lentigines are the most prominent manifestation of LEOPARD syndrome and are present in more than 90 percent of the patients. They appear during infancy and early childhood and increase in number over time to involve a large portion of the skin, including the face (picture 26), neck, and upper trunk (picture 26). Lentigines may also occur on the palms, soles, and sclerae. Café-au-lait macules similar to those found in neurofibromatosis type 1 occur in approximately one-half of the patients. The diagnosis of LEOPARD is difficult, given the highly variable expressivity of the syndrome. In the first year of life, before the appearance of lentigines, the diagnosis can be clinically suspected in infants presenting with three main features: characteristic facial features, hypertrophic cardiomyopathy, and café-au-lait macules [76]. The diagnosis can be confirmed by molecular screening for PTPN11 mutations. The management of patients with LEOPARD syndrome requires a multidisciplinary approach involving dermatology, cardiology, endocrinology, and other appropriate specialists. Genetic counseling is indicated and involves clinical and cardiologic examination of parents and molecular analysis if appropriate.

Peutz-Jeghers syndrome — Peutz-Jeghers syndrome is an autosomal dominant disorder characterized by mucocutaneous lentigines with intestinal polyposis. It is caused by mutations in the STK11 gene, encoding serine/threonine kinase 11. The lentigines are typically present at birth or appear during childhood. They predominantly affect the perioral and periorbital areas but may involve the volar and dorsal aspects of the hands and feet (picture 27A-D). Mucosal lesions may affect the palate, tongue, buccal mucosa, and conjunctivae. This syndrome is associated with pancreatic carcinoma and ovarian and testicular tumors. The main entity in the differential diagnosis is Laugier-Hunziker syndrome. The diagnosis and management of Peutz-

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Jeghers syndrome is discussed in detail separately. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management" and "Juvenile polyposis syndrome".)

Bannayan-Riley-Ruvalcaba syndrome — Bannayan-RileyRuvalcaba syndrome (BRRS) is a rare, autosomal dominant, gastrointestinal hamartomatous polyposis syndrome caused by germline mutations in the PTEN tumor suppressor gene [77]. It is part of Cowden syndrome-1, also called PTEN hamartoma tumor syndrome or multiple hamartoma syndrome (MIM #158350). The clinical manifestations of BRRS arise early in childhood and include hypotonia, delayed psychomotor development, seizures, diarrhea, intussusception, and anemia. Cutaneous manifestations include genital lentigines, facial verrucae, vascular malformations, lipomas, acanthosis nigricans, and multiple acrochordons. Hyperpigmented macules involving the glans penis (picture 28) or vulva are the most specific finding related to the syndrome. The diagnosis and management of BRRS are discussed in more detail elsewhere. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Bannayan-Riley-Ruvalcaba syndrome'.)

GENETIC SYNDROMES ASSOCIATED WITH CAFÉ-AU-LAIT MACULES Genetic syndromes associated with café-au-lait macules are

summarized in the table (table 3).

Neurofibromatosis type 1 — Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by a mutation in the NF1 gene, encoding the protein neurofibromin, a tumor suppressor expressed in many human cells, primarily in neurons, glial, and Schwann cells [78]. Neurofibromin belongs to a family of GTPase-activating proteins (GAPs) that downregulate the cellular proto-oncogenes p21-ras, an important determinant of cell growth and regulation. The presence of six or more café-au-lait macules (picture 29) (>5 mm in prepubertal individuals and >15 mm in postpubertal individuals), cutaneous neurofibromas (picture 30A-B), and axillary or inguinal freckling (picture 31) are the hallmark of NF1. Other manifestations of NF1 include plexiform neurofibromas, optic pathway gliomas, and other central and peripheral nervous system tumors. The clinical manifestations, diagnosis, and management of NF1 are discussed separately. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Neurofibromatosis type 1 (NF1): Management and prognosis".)

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Neurofibromatosis type 1-like syndrome (Legius syndrome) — Neurofibromatosis type 1-like syndrome or Legius syndrome is an autosomal dominant disorder caused by germline loss-of-function mutations in SPRED1, encoding a protein that downregulates the RAS/mitogen activated protein kinase (RAS/MAPK) pathway [79,80]. Clinical features include multiple café-au-lait macules, with or without flexural freckling. Importantly, Legius syndrome lacks neurofibromas and central nervous system tumors. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Legius syndrome'.)

McCune-Albright syndrome — McCune-Albright syndrome is a rare mosaic disorder caused by postzygotic activating mutations of the GNAS1 gene, encoding the alpha subunit of the stimulatory G protein [81]. The syndrome is characterized by the triad of polyostotic fibrous dysplasia, café-au-lait macules, and endocrine hyperactivity, classically causing precocious puberty [82]. (See "Definition, etiology, and evaluation of precocious puberty".) The café-au-lait macules appear at birth or shortly after and are the first manifestation of the disease. They have an irregular border described as a "coast of Maine" border and are often unilateral, with midline demarcation and a tendency to follow the Blaschko lines (picture 32 and picture 33). Later in life, some patients may develop oral mucosal lentigines [83]. There are no effective treatments for hyperpigmented patches associated with McCune-Albright syndrome. The Q-switched ruby laser has been successfully used in a single patient with facial hyperpigmentation [84].

SUMMARY AND RECOMMENDATIONS ●Hyperpigmentation is the darkening or increase in the natural color of the skin, usually due to an increased deposition of melanin (hypermelanosis) in the epidermis and/or dermis. It is a feature of a multitude of clinical conditions, ranging from normal variations of skin color to acquired and inherited syndromes. (See 'Introduction' above and 'Pathophysiology of skin pigmentation' above.) ●Diagnosis of most hyperpigmentation disorders is made on clinical grounds. The initial patient evaluation involves a detailed medical and family history and a complete skin examination. Important clinical parameters include the extent of the pigmentary abnormality, color hue and morphology of individual lesions, distribution, and pattern. An algorithmic approach to the diagnosis based upon history and clinical parameters is shown in the figure (algorithm 1).

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●Congenital and inherited hyperpigmentation disorders may be localized (eg, congenital dermal melanocytosis, café-au-lait macule) or diffuse. The latter often show a linear configuration that follows the lines of Blaschko (eg, incontinentia pigmenti, linear and whorled nevoid hypermelanosis) or a reticular pattern (eg, Dowling-Degos disease, reticulate acropigmentation of Kitamura, dyskeratosis congenita). (See 'Circumscribed hyperpigmentation' above and 'Diffuse linear hyperpigmentation' above and 'Diffuse reticular hyperpigmentation' above.) ●Multiple lentigines and café-au-lait macules are the hallmark of several genetic syndromes. Carney complex, LEOPARD (multiple lentigines, electrocardiogram [ECG] conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome, and Peutz-Jeghers syndrome are predominantly associated with lentiginosis. Genetic syndromes associated with café-au-lait macules include neurofibromatosis type 1, Legius syndrome, and McCune-Albright syndrome. (See 'Genetic syndromes associated with lentiginosis' above.)

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Vitiligo: Pathogenesis, clinical features, and diagnosis uptodate.com/contents/vitiligo-pathogenesis-clinical-features-and-diagnosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Feb 03, 2017.

INTRODUCTION

Vitiligo is a relatively common acquired disorder of

pigmentation characterized by the development of well-defined white macules on the skin. Biopsies of lesional skin reveal a loss of epidermal melanocytes [1-4]. Lesions may occur in a localized or generalized distribution and may coalesce into large, depigmented areas. Given the contrast between the white areas and normal skin, the disease is most disfiguring in darker skin types and has a profound impact on the quality of life of both children and adults [5,6]. Patients with vitiligo often experience stigmatization, social isolation, and low self-esteem [7-10]. This topic will review the pathogenesis, classification, clinical manifestations, and diagnosis of vitiligo. The management and prognosis of vitiligo are discussed separately. Other pigmentation disorders are also discussed separately.

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●(See "Vitiligo: Management and prognosis".) ●(See "Acquired hypopigmentation disorders other than vitiligo".) ●(See "Acquired hyperpigmentation disorders".) ●(See "Melasma: Management".) ●(See "Postinflammatory hyperpigmentation".)

EPIDEMIOLOGY

Vitiligo is the most frequent cause of depigmentation [2-

4,11]. Estimated prevalence rates range from 0.1 to 2 percent in both adults and children [12-16]. Vitiligo affects equally males and females, without racial, ethnic, or socio-economic predilections [13]. It may appear at any age from early childhood to late adulthood, with peak incidences in the second and third decade of life [17]. Approximately one-third of patients with vitiligo are children, and 70 to 80 percent of adult patients develop vitiligo prior to age 30 years [2].

ETIOLOGY

The etiology of vitiligo is unknown. Patients commonly attribute the

onset of their disease to specific triggering events such as physical injury or illness, sunburn, emotional stress, or pregnancy, but there are no data supporting a causative role for these factors. The frequency of comorbid autoimmune diseases is significantly elevated in patients with vitiligo and in their first-degree relatives, suggesting an autoimmune etiology for this disorder [13]. Recipients of hematopoietic stem cell transplantation (HSCT) appear to have an increased risk of developing vitiligo [18,19]. In a Korean nationwide population study including 2747 HSCT recipients and 8241 controls, HSCT recipients had a three-fold increased risk of having vitiligo compared with controls (odds ratio 3.13, 95% CI 1.86-5.27) [20]. Allogeneic HSCT and bone marrow-sourced stem cells were independently associated with the development of vitiligo after HSCT. The pathogenetic mechanisms underlying the development of vitiligo in HSCT recipients are unclear. They may include adoptive transfer of vitiligo from donor [21], immunosuppression associated with preparative regimens, or chronic graft-versus-host disease [22].

PATHOGENESIS

Multiple theories have been proposed for melanocyte

destruction in vitiligo. These include genetic, autoimmune, neural, biochemical, oxidative stress, viral infection, and melanocyte detachment mechanisms. Although the autoimmune and oxidative stress theories are best supported by research data, none of the proposed theories are in themselves sufficient to explain the diverse vitiligo phenotypes [3,23,24]. The so-called "convergence theory" suggests that multiple mechanisms may contribute to the disappearance of melanocytes in vitiliginous skin and that vitiligo may indeed represent a disease spectrum [25].

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Genetics — Family clustering of vitiligo suggests a genetic basis for the disease [13,26]. Genetic studies indicate a non-Mendelian, multifactorial, polygenic inheritance pattern [27-29]. Twenty-five to 50 percent of persons with vitiligo have affected relatives, and approximately 6 percent have siblings with the disorder [13,26]. A survey conducted among 2624 vitiligo patients from North America and the United Kingdom found a 6 percent prevalence of vitiligo in siblings of patients with vitiligo [13]. In this cohort, the concordance in monozygotic twins was only 23 percent, suggesting that nongenetic factors and/or environmental triggers play a role in the pathogenesis of the disease. Genetic studies have identified approximately 36 susceptibility loci for nonsegmental vitiligo [30]. The majority of the susceptibility genes encode immunoregulatory proteins, whereas several encode melanocyte proteins. Multiple studies have also implicated human leukocyte antigen loci in vitiligo, including A2, DR4, DR7, DQ7, DR1, B13, DQW3, CW6, and A30 [24,27,28,31,32]. In genome-wide association studies, several genes with known associations with other autoimmune disorders were identified as potential susceptibility loci for generalized vitiligo, including PTPN22, LPP, IL2RA, UBASH3A, C1QTNF6, and genes encoding major histocompatibility complex (MHC) I and MHC II molecules [16,17,23,24,33-36]. However, there is significant genetic heterogeneity in different ethnic groups. A genome-wide linkage study performed in 71 white multiplex families with vitiligo found highly significant linkage to the autoimmune disease susceptibility locus AIS1 on chromosome 1p31, suggesting that AIS1 is a major susceptibility locus in Caucasians [29]. In contrast, genetic studies in Chinese families have shown linkage evidence to chromosome 4q13-q21 [37]. Other candidate genes for vitiligo susceptibility include the catalase gene, vitiligo-associated protein 1 on chromosome 2p16, and the guanosine triphosphate cyclohydrolase I gene [23,27,28]. The NALP1 gene on chromosome 17p13, encoding the NACHT leucine-rich repeat protein 1, a regulator of the innate immune system, has been linked to vitiligo-associated multiple autoimmune disease, a group of diseases including various combinations of vitiligo, autoimmune thyroid disease, and other autoimmune and autoinflammatory syndromes [38].

Autoimmunity — Historically, vitiligo has been associated with several autoimmune diseases, including Hashimoto's thyroiditis, Graves' disease, type 1 diabetes mellitus, alopecia areata, pernicious anemia, rheumatoid arthritis, autoimmune polyglandular syndrome, and psoriasis [17,24,39,40]. A survey in North America and the United Kingdom found that approximately 20 percent of 2624 vitiligo probands had a history of autoimmune thyroid disease compared with 2 percent of the general population [13]. Many humoral and cell-mediated immune aberrations have been reported in vitiligo patients, including an increased frequency of organ-specific autoantibodies, such as antithyroglobulin, antithyroid peroxidase, antiparietal cells, and antinuclear antibodies [41,42]. The presence of antibodies to surface and cytoplasmic melanocyte antigens in the sera of vitiligo patients lends additional support to the autoimmune pathogenesis of this disease [43-45]. These antibodies can

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induce the destruction of melanocytes grown in culture by complement-mediated lysis and antibodydependent cellular cytotoxicity [43,44]. In addition, melanocyte antibodies, when passively administered to nude mice grafted with human skin, have a destructive effect on melanocytes within the skin graft [46]. Studies also suggest that cytotoxic T lymphocytes may play a significant role in melanocyte destruction in vitiligo [47]. Numerous activated cytotoxic T lymphocytes have been reported in the perilesional area of the vitiliginous skin, often in apposition to disappearing melanocytes [48]. These infiltrating lymphocytes are predominantly cytotoxic CD8+ lymphocytes that express the skin homing receptor cutaneous leucocyte-associated antigen receptor. Moreover, purified CD8+ T cells isolated from lesional skin of vitiligo patients can induce melanocyte apoptosis in autologous nonlesional skin explants [49,50]. Multiple cytokines have also been implicated in the destruction of melanocytes in vitiligo. Several studies have documented increased expression of tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-10, and IL-17 in lesional skin of patients [3]. Investigations suggest that the interferon gamma-induced chemokine CXCL-10 is a key mediator of melanocyte destruction [51].

Melanocyte self-destruction hypothesis — The selfdestruction hypothesis proposes that melanocytes may be destroyed from an intrinsic increased sensitivity to oxidative stress arising from toxic phenolic compounds formed during the synthesis of melanin [52]. This hypothesis is supported by the observation that a number of ubiquitous compounds containing catechols, phenols, and sulfhydryls (eg, industrial chemicals, cleaning agents, some hair dyes) can induce hypopigmentation, depigmentation, or both. Possible mechanisms for altered pigment production by these compounds include melanocyte destruction via free-radical formation, inhibition of tyrosinase activity, and interference with the production or transfer of melanosomes [53]. Additional data suggest that phenols can activate the unfolded protein response in melanocytes, causing induction of factor X-box binding protein 1, which leads to the production of IL-6 and IL-8 and recruitment of immune cells to the affected areas [49].

Oxidative stress hypothesis — Several studies suggest that oxidative stress may be the initial event in the destruction of melanocytes [54,55]. An imbalance of intracellular redox status and a significant depletion of enzymatic and nonenzymatic antioxidants have been demonstrated in the epidermis of patients with active vitiligo [56]. Low catalase and glutathione levels (but increased superoxide dismutase and xanthine oxidase levels) have also been found in the peripheral blood of patients with vitiligo [53]. Defective recycling of 6-tetrahydrobiopterin (6BH4), increased production of hydrogen peroxide, and decreased catalase levels have also been found in lesional skin of patients with vitiligo [54,55,57]. The altered tetrahydrobiopterin homeostasis may result in increased levels of toxic metabolites (eg, 6BH4 and 7-tetrahydrobiopterin) and hydrogen peroxide and reduced levels of catalase, a key enzyme involved in hydrogen peroxide removal, which may further contribute to cell death [58].

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Oxidative stress may also contribute to melanocyte destruction in susceptible individuals via activation of the innate immune response [2,3]. Reactive oxygen species can act as danger signals and activate pattern recognition receptors to initiate inflammation, with local recruitment of innate immune cell populations, such as macrophages, natural killer cells, and inflammatory dendritic cells [49].

Neural hypothesis — The neural hypothesis posits that nerve endings situated near pigment cells may secrete a neurochemical mediator that is cytotoxic to the melanocytes [24]. This hypothesis is supported by the observation that the distribution of the depigmented areas in segmental vitiligo is related to dermatomes, even though the segments are almost never strictly dermatomal [24,59]. Moreover, vitiligo has been reported following neurologic disorders such as viral encephalitis, multiple sclerosis with Horner syndrome, and peripheral nerve injury [24,60]. Laboratory findings also support the neural hypothesis. Axon degeneration has been seen in dermal nerves of vitiliginous skin but not in dermal nerves of normal skin [61]. Immunohistochemistry studies of nerve endings in skin surrounding vitiligo lesions have shown abnormalities in the expression of nerve growth factors and neuropeptides [62]. Blood levels of certain neuropeptides are increased among patients with active vitiligo [63,64].

Melanocytorrhagy hypothesis — This theory proposes that melanocyte loss in vitiligo is secondary to chronic melanocyte detachment from the basement membrane. Causes include trauma, reactive oxygen species, autoimmune defects, and abnormal synthesis of extracellular matrix proteins leading to impaired cell adhesion [52,65].

CLINICAL FEATURES General features — Vitiligo typically presents with asymptomatic depigmented macules and patches, milk or chalk white in color, that lack clinical signs of inflammation (picture 1). Severe sunburn, pregnancy, skin trauma, and/or emotional stress may precede the disease onset. Lesions can appear at any age and anywhere on the body, with a predilection for the face and areas around the orifices, genitals, and hands. They vary in size from a few millimeters to many centimeters and usually have convex borders well-demarcated from the surrounding normal skin. Vitiligo may show more than one color shade. Trichrome lesions are characterized by zones of white, light-brown, and normal skin color and are most often observed in darker-complexioned individuals. Quadrichrome lesions may have a perifollicular or marginal hyperpigmentation, whereas pentachrome lesions present also a blue hue [12,66]. Another clinical variant is the so-called vitiligo ponctué, which exhibits tiny, confetti-like depigmented macules. Depigmented hairs are often present in lesional skin. While such hairs indicate a reduction or loss of the follicular reservoir for repigmentation, their presence does not invariably preclude the repigmentation of a lesion (picture 2). Poliosis, a decrease or absence of melanin or color in head

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hair, eyebrows, and/or eyelashes, may also be a manifestation of vitiligo (picture 3) [60]. Premature graying of scalp hair may occur in patients with vitiligo and in their families. Halo nevi (picture 4A) have been identified in 6 to 26 percent of children with nonsegmental vitiligo (NSV) and may portend the development of generalized vitiligo [67-70]. (See "Acquired melanocytic nevi (moles)", section on 'Halo nevi'.) Based upon the analysis of a large series of patients with vitiligo, two age-related clinical phenotypes have been identified [71]. Patients with childhood onset (before age 12 years) often have a family history of vitiligo and/or premature hair graying, associated halo nevi, and Koebner phenomenon, and report previous episodes of depigmentation and repigmentation. In contrast, patients with vitiligo onset during adolescence or early adulthood frequently report a personal or family history of autoimmune diseases and have disease localized to the face and/or acral sites [71].

Clinical classification — A detailed classification scheme for vitiligo has been proposed in 2012 by the Vitiligo Global Issues Consensus Conference [11]. Vitiligo is classified in two broad categories: NSV (the most common) and segmental vitiligo (SV) (table 1). NSV is further divided into subtypes based upon the distribution of skin lesions (ie, generalized, acral or acrofacial, mucosal, localized, universal, and mixed pattern). Rare subtypes are included in the undetermined/unclassified group.

Nonsegmental vitiligo — NSV includes the generalized, acrofacial or acral, mucosal, and universal subtypes (table 1). Generalized and acral or acrofacial vitiligo are most common. ●Generalized vitiligo is characterized by bilateral, often symmetrical, depigmented macules or patches occurring in a random distribution over multiple areas of the body surface. Generalized vitiligo may begin in childhood or early adulthood and often occurs at sites subjected to pressure, friction, and/or trauma. Depigmented patches are common on the face, trunk, and extremities. ●Acrofacial or acral vitiligo consists of depigmented macules confined to the distal extremities and/or the face (picture 5). It may later include other body sites, resulting in typical generalized vitiligo [2,11]. A subcategory of the acrofacial type is the lip-tip variety, in which lesions are confined to the cutaneous lips (picture 6) and distal tips of the digits. ●Mucosal vitiligo typically involves the oral and/or genital mucosa. It may occur in the context of generalized vitiligo or as an isolated manifestation. Isolated mucosal vitiligo that has not changed its characteristics after at least two years is defined as undetermined or unclassified type. ●Universal vitiligo refers to complete or nearly complete depigmentation of the skin. Some skin areas and hairs may be partially spared. Universal vitiligo usually results from progression of generalized vitiligo.

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●Vitiligo minor or hypochromic vitiligo is characterized by an incomplete loss of pigmentation resulting in areas of the skin that are paler than the surrounding skin. Vitiligo minor is more frequently seen in dark-skinned individuals [72].

Segmental vitiligo — SV typically occurs in a dermatomal or quasi-dermatomal pattern, most frequently along the distribution of the trigeminal nerve (picture 7). While being the least common type of vitiligo, SV begins in most cases during childhood [8,73]. The areas of depigmentation usually stabilize within a year and rarely spread beyond the affected dermatome. There is early involvement of hair follicles (leukotrichia), with histologic evidence of destruction of the follicular melanocyte reservoir. Plurisegmental vitiligo may have multiple segments involved, either unilaterally or bilaterally. The onset of different segmental lesions may or may not be simultaneous. Plurisegmental vitiligo can be differentiated from bilateral NSV by the restriction of the lesions to identifiable segments, presence of leukotrichia, and protracted course.

Koebner phenomenon — Repeated mechanical trauma (friction) and other types of physical trauma such as scratching, chronic pressure, or cuts along with allergic or irritant contact reactions may trigger vitiligo on areas such as the neck, elbows, and ankles [74]. This is known as the Koebner phenomenon, also called "isomorphic response," which describes the development of skin disease in sites of skin trauma. The Koebner phenomenon has been reported in 20 to 60 percent of vitiligo patients [74].

Ocular involvement — Melanocytes of the eye, ear, and leptomeninges also may be affected in vitiligo [75,76]. Depigmented areas of the retinal pigment epithelium and choroid have been reported in 30 to 40 percent of patients [77-79]. These asymptomatic lesions do not interfere with visual acuity.

Associated disorders Autoimmune diseases — Vitiligo is frequently associated with autoimmune thyroid disease and other autoimmune or immune-mediated diseases, including alopecia areata, psoriasis, type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease, pernicious anemia, linear morphea, myasthenia gravis, discoid and systemic lupus erythematosus, and Sjögren syndrome [13,80-84]. Patients with comorbid autoimmune diseases are more likely to have generalized vitiligo compared with patients without associated diseases [83]. ●In a review of 2441 adult patients (mean age 51 years) with vitiligo, 12 percent had an autoimmune thyroid disorder, 8 percent psoriasis, 3 percent rheumatoid arthritis, and 2 percent inflammatory bowel disease [81]. Approximately 40 percent of patients had elevated antinuclear antibodies and 50 percent elevated antibodies to thyroid peroxidase.

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●In another retrospective study of 1098 patients with vitiligo, approximately 20 percent had one or more comorbid autoimmune diseases, most commonly thyroid disease (12 percent) [83]. Alopecia areata was the second most common comorbid disease (2.8 percent), followed by psoriasis, inflammatory bowel disease, and type 1 diabetes mellitus. Vitiligo may also be a clinical feature of polyglandular autoimmune syndromes, in particular autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy, and Addison's disease with autoimmune thyroid disease (Schmidt's syndrome) [85,86].

Genetic syndromes — Vitiligo is associated with several genetic disorders, which include: ●Vogt-Koyanagi-Harada syndrome – Vogt-Koyanagi-Harada syndrome is a rare multisystem disease characterized by chronic uveitis, poliosis (decrease or absence of melanin or color in head hair), alopecia, dysacousia, vitiligo, and signs of meningeal irritation. Vogt-Koyanagi-Harada syndrome usually manifests in the third decade of life and, although reported in all ethnic groups, tends to be more severe in darker-skinned populations, especially Asians. (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Systemic inflammatory diseases'.) ●Alezzandrini syndrome – Alezzandrini syndrome is a rare condition characterized by unilateral facial vitiligo, unilateral retinal degeneration, poliosis (decrease or absence of melanin or color in head hair), and hearing loss [87,88]. ●Kabuki syndrome – Kabuki syndrome is a rare multisystem disorder caused by mutations in the KMT2D and KDMA6 genes and characterized by developmental delay, mild to moderate intellectual disability, skeletal and visceral anomalies, dermatoglyphic anomalies, and a characteristic facial dysmorphism [89]. Some of these patients also have immunologic defects and/or autoimmune diseases, including vitiligo [90-92].

Melanoma — Rarely, hypopigmented patches resembling vitiligo may precede a diagnosis of cutaneous melanoma [93-95]. The presence of vitiligo-like depigmentation in patients with melanoma is thought to be a marker of an immune response against the tumor and may be an indicator of favorable prognosis in advanced disease [42,96].

Psychosocial issues — Vitiligo may be a psychologically devastating disorder, with a major impact on the patient’s self-image and self-esteem [9,97]. The mental health and emotional burden of vitiligo is more severe in women and in dark-skinned individuals in whom the lesions of vitiligo are more prominent [2,98-100]. In some countries, the confusion with leprosy is an important cause of social stigma and isolation. Children with vitiligo may suffer from severe psychologic trauma, resulting in impaired social and emotional development and compromised quality of life later in adulthood [101,102].

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CLINICAL COURSE

The clinical course of vitiligo is unpredictable.

Lesions can remain stable or progress slowly for years [2]. In most cases, the extent and distribution of lesions change during the course of a person's lifetime by centrifugal expansion of current lesions and/or the appearance of new lesions. Progression is more common in patients who have a family history of nonsegmental vitiligo, a longer duration of disease, Koebner phenomenon, and mucosal involvement, but the rate of progression in the individual patient is unpredictable [2,12,14]. Flare-ups are common and may be separated by stable periods. Stable vitiligo is most common in children and adolescents, regardless of ethnicity and skin type [73]. Lesions can be considered stable if no change is detected by serial photography in a 12-month period [11].

DIAGNOSIS Clinical — The diagnosis of vitiligo is in most cases straightforward, based upon the clinical finding of acquired, discrete, well-demarcated, uniformly white macules with convex borders surrounded by normal skin in the absence of inflammation or textural changes [12,14,103]. Elements of history that are helpful for the diagnosis include: ●Age at onset of lesions ●Factors or events that may have preceded onset ●Symptoms associated with the lesions ●Progression or spread of lesions ●Changes observed in lesions over time ●Presence of concomitant diseases ●Current medications ●Occupational history/exposure to chemicals ●Family history of vitiligo and autoimmune diseases

Diagnostic aids — The diagnosis of vitiligo may be facilitated by the use of a Wood's lamp (a handheld device emitting ultraviolet A light at approximately a 365 nm wavelength), especially in individuals with pale skin [14]. Under the Wood’s light, the depigmented areas emit a bright blue-white fluorescence and appear sharply demarcated [12]. (See "Office-based dermatologic diagnostic procedures", section on 'Wood's lamp examination (black light)'.)

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Dermoscopy may be helpful in differentiating evolving vitiligo patches from other diseases with similar patterns of hypopigmentation. On dermoscopy, vitiliginous macules typically show residual perifollicular pigmentation and telangiectasia, which are absent in other hypopigmentation disorders [104,105].

Pathology — A skin biopsy is not routinely required for the diagnosis of vitiligo. However, the examination of a skin biopsy that includes the lesion border and an adjacent, uninvolved area of skin, along with careful clinicopathologic correlation, may be helpful to establish the diagnosis in patients with hypopigmented or depigmented lesions of questionable etiology. On histology, vitiligo reveals complete loss of melanin pigment in the epidermis and absence of melanocytes, with occasional lymphocytes at the advancing border of the lesions (picture 8). Other findings include vacuolar degeneration of basal and parabasal keratinocytes, focal spongiosis, and a dermal lymphohistiocytic infiltrate at the dermoepidermal interface, especially in perilesional skin of actively spreading vitiligo [106,107]. Immunohistochemical staining shows a preponderance of CD8+ T lymphocytes in the inflammatory infiltrate [108].

Laboratory studies — Given the relatively high frequency of the association of vitiligo with autoimmune thyroid disease, it is reasonable to screen all patients with vitiligo, and especially those with generalized disease and extensive involvement of the body surface, for thyroid function [82,109,110]. (See 'Associated disorders' above.) European guidelines based upon expert consensus recommend the assessment of thyroid function (thyroid-stimulating hormone, antithyroperoxidase, and antithyroglobulin antibodies) in all patients with vitiligo [52]. They also recommend the measurement of additional autoantibodies only if the patient's history, family history, or physical examination suggests other autoimmune diseases. Antinuclear antibodies should be assessed prior to phototherapy. If present in high titers, rheumatologic referral before initiating treatment may be appropriate. (See "Clinical significance of antinuclear antibody staining patterns and associated autoantibodies".)

DIFFERENTIAL DIAGNOSIS

Many common and

uncommon disorders are characterized by areas of depigmentation that may mimic vitiligo [10,14,111-116].To differentiate vitiligo from mimickers, it is important to evaluate the skin texture and whether there is or is not complete depigmentation. Vitiligo is not associated with scaling or textural changes, although some patients may rarely develop inflammatory vitiligo characterized by raised erythematous borders. The increased skin firmness typical of morphea and lichen sclerosus helps differentiate these conditions from vitiligo [12]. Vitiligo affecting only the genital area can be difficult to differentiate from lichen sclerosus, which can also coexist with vitiligo [113]. A skin biopsy may be necessary to clarify the diagnosis in difficult cases. Conditions that are frequently confused with vitiligo include (see "Acquired hypopigmentation disorders other than vitiligo"):

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●Nevus depigmentosus – Nevus depigmentosus (picture 9) is a circumscribed, segmental area of depigmentation or hypopigmentation usually present at birth or detected in the first years of life [14]. The lesion shows little change over time, although it may enlarge as the patient grows. Nevus depigmentosus is a form of cutaneous mosaicism, caused by an altered clone of melanocytes with a decreased ability to produce melanin, abnormal melanosomes, and inability to transfer pigment to keratinocytes [117,118]. When seen under a Wood's lamp, the contrast between lesional and normal skin is less marked than in vitiligo [12,14]. ●Pityriasis alba – Pityriasis alba commonly affects children and is considered a component of the spectrum of atopic dermatitis. It is characterized by hypopigmented, mildly scaling patches common on sun-exposed areas (picture 10A-B). Such patches usually clear with or without treatment with low-potency corticosteroids. (See "Acquired hypopigmentation disorders other than vitiligo", section on 'Pityriasis alba'.) ●Idiopathic guttate hypomelanosis – Idiopathic guttate hypomelanosis is a common disorder characterized by multiple small, asymptomatic porcelain-white macules primarily on the sunexposed areas of the limbs [66,119]. Its incidence increases with age and is seen in up to 80 percent of patients over the age of 70 years. Once present, lesions do not change in size or coalesce. Melanocytes are present, although they may be reduced in number. (See "Acquired hypopigmentation disorders other than vitiligo", section on 'Idiopathic guttate hypomelanosis'.) ●Tinea (pityriasis) versicolor – Tinea versicolor is a superficial yeast infection that can cause loss of pigment. It is caused by saprophytic, lipid-dependent yeasts in the genus Malassezia (Pityrosporum). It presents as pale macules typically located on the upper trunk and chest, with a fine, dry surface scale [12,45]. Involved areas often fluoresce a golden yellow when examined under a Wood's lamp [12]. (See "Tinea versicolor (pityriasis versicolor)".) ●Halo nevus – Halo nevus, also called Sutton nevus, is a melanocytic nevus surrounded by a round or oval halo of depigmentation (picture 4A-B) [120]. This pigment loss often heralds the spontaneous regression of the central nevus. A single circular lesion on the trunk of a young person may represent a resolving halo nevus. (See "Acquired melanocytic nevi (moles)", section on 'Halo nevi'.) ●Piebaldism – Piebaldism (MIM #172800) is a rare autosomal-dominant disorder presenting at birth with anterior midline depigmentation and a white forelock (poliosis) (picture 11). Irregular depigmented areas may also be present on the trunk and extremities. Rarely, lesions show a hyperpigmented border [112]. Distribution on the forehead and chin supports the diagnosis. ●Progressive macular hypomelanosis – Progressive macular hypomelanosis is characterized by nonscaling hypopigmented patches of the trunk caused by Cutibacterium (formerly Propionibacterium) acnes (picture 12). The condition is most common in young patients. (See "Acquired hypopigmentation disorders other than vitiligo", section on 'Progressive macular hypomelanosis'.)

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●Chemical leukoderma – Chemical leukoderma initially presents with depigmentation at the contact area but may later spread to other areas. Occupational hazards for chemical leukoderma include phenolic-catecholic derivatives including monobenzyl ether of hydroquinone (monobenzone), para tertiary butyl catechol, para tertiary butyl phenol, paraphenylenediamine and amino phenol, para tertiary amyl phenol, hydroquinone, and monomethyl ether [14]. Leukoderma secondary to chemicals can also be induced by dyes, perfumes, detergents, cleansers, insecticides, rubber condoms, rubber slippers, black socks and shoes, eyeliner, lip liner, lipstick, toothpaste, antiseptics with phenolic derivatives, mercuric iodide-containing "germicidal" soap, and arsenic-containing compounds [121,122]. In 2013, thousands of patients in Japan developed depigmentation after using a brightening cream containing rhododendrol (4-[4hydroxyphenyl]-2butanol), a competitive inhibitor of tyrosinase [123,124]. Hydroquinone, a depigmenting agent widely used for the treatment of melasma, induces a reversible hypopigmentation of the skin at the site of application. In contrast, monobenzone, which is used as a depigmenting agent in the treatment of widespread vitiligo, can induce a permanent and generalized depigmentation. ●Drug-induced leukoderma – Potent topical or intralesional corticosteroids may induce hypopigmentation at the site of application, particularly in darkly pigmented individuals. Depigmentation mimicking vitiligo may occur in patients treated with the epidermal growth factor receptor inhibitor gefitinib, the tyrosine kinase inhibitor imatinib mesylate [125,126], interferon pegylated [127,128], and transdermal methylphenidate patch [122]. ●Hypopigmented mycosis fungoides – Hypopigmented mycosis fungoides (MF) is an uncommon variant of early-stage MF seen more often in children and in patients with darker skin (picture 13A-B) [129,130]. It presents with widespread hypopigmented patches with mild scaling and atrophy. Telangiectasias may also be present in the lesions. Histopathology does not show a complete absence of melanocytes but rather a minimal number of melanocytes as well as the morphologic and immunophenotypic findings suggestive of cutaneous T cell lymphoma. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".) Additional conditions that should be differentiated from vitiligo include postinflammatory hypopigmentation, leukoderma associated with melanoma and scleroderma, and the late stages of treponematosis and onchocerciasis.

SUMMARY AND RECOMMENDATIONS ●Vitiligo is an acquired disorder of pigmentation affecting approximately 1 percent of the world population and is characterized by the development of well-defined white macules on the skin. (See 'Introduction' above and 'Epidemiology' above.)

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●Multiple theories have been proposed to explain melanocyte destruction in vitiligo. These include genetic susceptibility, autoimmunity, and oxidative stress. (See 'Pathogenesis' above.) ●Vitiligo typically presents with asymptomatic depigmented macules and patches that lack clinical signs of inflammation (picture 1). Lesions can appear at any age and anywhere on the body. Based upon the distribution pattern of depigmented lesions, vitiligo is classified into two broad categories, segmental (picture 7) and nonsegmental (most common), and in several subtypes, such as generalized, acral or acrofacial, and universal (table 1). (See 'General features' above and 'Clinical classification' above.) ●Vitiligo is frequently associated with autoimmune thyroid disease. Alopecia areata, psoriasis, inflammatory bowel disease, and several other autoimmune and genetic disorders have also been linked to vitiligo. (See 'Associated disorders' above.) ●The diagnosis of vitiligo is in most cases made clinically. A skin biopsy can be performed in patients with hypopigmented or depigmented lesions of uncertain etiology. Given the relatively high frequency with which autoimmune thyroid disease occurs in patients with vitiligo, it is reasonable to screen all patients with vitiligo for thyroid function. (See 'Diagnosis' above and 'Laboratory studies' above.)

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Vitiligo: Management and prognosis - UpToDate uptodate.com/contents/vitiligo-management-and-prognosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 05, 2017.

INTRODUCTION

Vitiligo is a relatively common acquired chronic disorder

of pigmentation characterized by the development of white macules on the skin due to loss of epidermal melanocytes [1,2]. The depigmented areas are often symmetrical and usually increase in size with time. Given the contrast between the white patches and areas of normal skin, the disease is most disfiguring in darker skin types and has a profound impact on the quality of life of children and adults [3,4]. Patients with vitiligo often experience stigmatization, isolation, and low self-esteem [5-8]. Although there is no cure for the disease, the available treatments may halt the progression of the disease and induce varying degrees of repigmentation with acceptable cosmetic results in many cases. This topic review will discuss the management of vitiligo. The pathogenesis, clinical features, and diagnosis of vitiligo are discussed separately. Other pigmentation disorders are also discussed separately. ●(See "Vitiligo: Pathogenesis, clinical features, and diagnosis".)

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●(See "Acquired hypopigmentation disorders other than vitiligo".) ●(See "Acquired hyperpigmentation disorders".) ●(See "Melasma: Management".) ●(See "Postinflammatory hyperpigmentation".)

PATIENT EVALUATION Assessment of severity — The evaluation of the patient with vitiligo involves a detailed history and a complete skin examination to assess disease severity and individual prognostic factors. Factors that may influence the approach to treatment include: ●Age at onset of lesions ●Type of vitiligo (segmental, nonsegmental) ●Mucosal involvement, Koebner phenomenon ●Rate of progression or spread of lesions ●Previous episodes of repigmentation ●Type and response to previous treatments ●Family history of vitiligo and/or autoimmune diseases ●Presence of concomitant diseases ●Current medications and supplements ●Occupation, exposure to chemicals ●Effects of disease on the quality of life A full-body skin examination should be performed to assess the extent of the disease, with particular attention to sites of vitiligo predilection, such as the lips and perioral area, periocular areas, dorsal surface of the hands, fingers, flexor surface of the wrists, elbows, axillae, nipples, umbilicus, sacrum, groin, inguinal/anogenital regions, and knees [9]. The percentage of the body area involved can be estimated by the so-called 1 percent rule or "palm method." In both children and adults, the palm of the hand, including the fingers, is approximately 1 percent of the total body surface area (TBSA), while the palm excluding the fingers is approximately 0.5 percent of the TBSA. An alternative method is the "rule of nines": ●Each leg represents 18 percent of the TBSA.

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●Each arm represents 9 percent of the TBSA. ●The anterior and posterior trunk each represent 18 percent of the TBSA. ●The head represents 9 percent of the TBSA.

Goals of treatment — The goals of treatment for vitiligo should be set with the individual patient or parents in the case of children, based upon the patient's age and skin type, the extent, location, and degree of disease activity, and the impact of the disease on the patient's quality of life. An open discussion with the patient about the limitations of treatment may be helpful to create realistic expectations. Nonsegmental vitiligo has an unpredictable course, and treatment is often challenging. However, multiple therapies, including topical agents, light therapies, and autologous grafting procedures, have demonstrated efficacy for repigmentation of vitiligo [10]. The response to treatments is generally slow and may be highly variable among patients and among different body areas in the same patient. The best outcomes are often achieved in darker skin types (Fitzpatrick IV to VI), although satisfactory results are often seen also in lighter skin types (Fitzpatrick II, III). Facial and truncal lesions respond well to treatment, while acral areas are extremely difficult to treat.

Psychosocial aspects — The patient's psychologic profile and ability to cope with a lifelong disease should be carefully evaluated at the time of treatment planning. Psychologic support should be offered to patients if needed. (See 'Psychologic interventions' below.)

APPROACH

Our approach to the management of patients with vitiligo is

generally consistent with published guidelines [11,12]. Topical, systemic, and light-based therapies are available for the stabilization and repigmentation of vitiligo (table 1) [13-17]. Treatment modalities are chosen in the individual patient on the basis of the disease severity, patient preference (including cost and accessibility), and response evaluation. Combination therapies, such as phototherapy plus topical or oral corticosteroids, are usually more effective than single therapies [18]. Despite treatment, however, vitiligo has a highly unpredictable course, and the long-term persistence of repigmentation cannot be predicted [18].

Stabilization of rapidly progressive disease — For patients who experience rapid progression of vitiligo, with depigmented macules spreading over a few weeks or months, we suggest low-dose oral corticosteroids as first-line therapy for the stabilization (cessation of spread) of the disease (table 1). Oral prednisone is given at the dose of 5 to 10 mg per day in children and 10 to 20 mg per day in adults for a maximum of two weeks. If needed, treatment can be repeated in four to six weeks.

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In adult patients, alternatives to oral prednisone include oral mini-pulse therapy with dexamethasone 2.5 mg on two consecutive days weekly for an average of three months or intramuscular triamcinolone 40 mg in a single administration. Treatment with triamcinolone can be repeated in four to six weeks for a maximum of three injections. (See 'Systemic corticosteroids' below.) Stabilization therapy can be given with or without concomitant narrowband ultraviolet B (NB-UVB) phototherapy. However, for patients with active disseminated disease affecting multiple anatomic sites, we suggest that systemic corticosteroids and NB-UVB phototherapy be initiated concomitantly. The disease is expected to stabilize in one to three months. In both adults and children in whom systemic corticosteroids are contraindicated, NB-UVB phototherapy alone may be used to stabilize active vitiligo. NB-UVB is administered two to three times weekly. (See 'Narrowband ultraviolet B phototherapy' below.)

Vitiligo involving 2 cm) lesions on the trunk or extremities with illdefined margins, occurring in areas of marked sun damage with mottled pigmentation, may also benefit from staged excision. While reconstruction can often be done by the dermatologist in an outpatient setting, some wounds or patients may require reconstructive surgery performed under general anesthesia in the operating room.

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Staged excision is considered by some experts to be the optimal surgical technique for LM, as it permits the evaluation of the surgical margins in a comprehensive manner similar to Mohs surgery but relies on permanent sections rather than frozen sections. Permanent sections require a longer processing time than frozen sections; however, rush readings can usually be obtained in less than 24 hours. After delineating the LM clinical margins, a surgical margin of 5 mm is drawn around the lesion (figure 2). The gross clinical lesion ("tumor debulk") is excised down to the deep dermis, oriented, and sent to the laboratory as a fresh specimen or placed in a formalin bottle. The margins are then excised to the deep dermis, divided, marked to preserve orientation, and placed in individually labeled formalin bottles. The tumor debulk tissue is serially sectioned in various ways (multiple vertical "bread loaf" sections or radial sections) and examined for invasive melanoma [68-72]. The peripheral margins are inked with the same color consistently applied to the outer surface (true outer surgical margin). Each segment of the peripheral margin is sectioned vertically "en face" to allow the examination of the entire true margin. The permanent sections are evaluated by a dermatopathologist experienced in pigmented lesions. Some consulting pathologists prefer to receive an inked intact specimen, which they evaluate by the radial technique. It is important to have excellent communication between the surgeon and the pathologist on these cases. After the pathologist has examined the specimen histologically, the margin status and location of residual melanoma in situ is then communicated to the surgeon. The patient returns 24 to 48 hours later for reexcision of involved margins, and the process is repeated until negative peripheral margins are achieved. Reconstruction of the defect is then performed. The wound is managed during the intervening time period by standard dressings. Electrocautery is performed to stop bleeding, and then the wound is cleaned with sterile saline or soap and water. Petrolatum is applied to the wound, then it is covered with nonadherent dressing and secured by tape. We usually surmount this simple dressing with a pressure bandage constructed with rolled gauze, secured by tape. Large wounds do well with application of a sterile gauze impregnated with bismuth and petrolatum. The patient does not need to change the bandage since they will be returning for either further excision or repair of the defect. Deferring reconstruction is not harmful to the end result and has in fact been shown to be associated with fewer postoperative complications when repair is done with a full-thickness skin graft [73]. There are several variations of the staged excision, including the "square procedure," perimeter, contoured, spaghetti, and serial disk techniques [74-79]. In some of these techniques, the margin specimens are cut en face in vertical sections that contain 100 percent of the peripheral margins. These techniques generally deal with the margins first, leaving the center part of the lesion in situ until the margins are clear. While the patient may be somewhat more comfortable in the intervening period without a large wound, there is a 10 to 20 percent risk of identifying invasive lentigo maligna melanoma (LMM) requiring deeper excision only at the end of the process [14-17]. Recurrence rates of 0 to 6 percent have been reported after staged excision at a mean follow-up time of 23 to 138 months [15,67-71,77,79-81].

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Mohs micrographic surgery — Mohs micrographic surgery (MMS) is a technique that involves a beveled excision of the tumor with a margin of normal-appearing tissue using a scalpel angled at 45 degrees to the skin surface. MMS uses frozen horizontal sections that allow for examination of the entire peripheral and deep margins of the tumor with maximal preservation of uninvolved tissue and is especially useful for the treatment of nonmelanoma skin cancers in cosmetically sensitive areas. (See "Mohs surgery".) We do not perform Mohs surgery with frozen section for the treatment of LM. Differentiating atypical melanocytic hyperplasia from benign melanocytic hyperplasia or actinic keratinocytic damage is difficult on frozen section and requires considerable experience in MMS and high-quality frozen sections [82]. Rapid immunostaining with MART-1 or Mel-5 may help in identifying the melanocytes on frozen sections and appears to provide information similar to that obtained from permanent sections [83-85]. Some Mohs surgeons, after a final negative frozen layer, excise an additional margin of 1 to 3 mm and send it for permanent sections. Some also send the central debulking specimen for permanent vertical sections for a more accurate staging of the tumor. In one study including 116 patients with LM, 5 percent of margins that were negative on frozen sections were positive on permanent sections [86]. In a review of 173 cases with an initial diagnosis of LM or melanoma in situ and treated with MMS, the examination of permanent sections of the central debulking specimens led to an upstaging of the tumor in 14 (8 percent) of cases [87]. In another review of LM and LMM cases treated with a staged excision technique with rush paraffinembedded sections, 15 of 91 cases (16 percent) that were initially diagnosed as LM were found to be invasive melanomas [16]. Recurrence rates of 0 to 2 percent have been reported for LM excised by MMS after a follow-up time of 29 to 44 months [64,83,88-91].

Nonsurgical therapies Overview — Nonsurgical therapy for LM should only be considered under select clinical circumstances: in older, frail patients in whom surgical excision is not feasible; when problematic reconstruction is anticipated; and in patients who decline surgery [54]. Alternatives to surgery include radiotherapy, topical imiquimod, cryosurgery, and laser therapy. As the risk of evolution into invasive melanoma is low and generally takes many years, it may be appropriate to closely monitor patients of advanced age with significant comorbidities rather than pursue immediate treatment. Nonsurgical techniques have not been evaluated in randomized trials. One study reviewed 1086 cases of melanoma in situ treated with surgery or nonsurgical interventions. Overall, 721 cases involved the head or neck. The five-year recurrence rate was 6.8 percent for surgical excision and 31 percent for radiotherapy, laser therapy, and cryosurgery combined as a single category [92]. An international randomized trial comparing RT with imiquimod is being conducted by the Australia and New Zealand Trials Group in patients with LM in whom surgery is not suitable. The primary endpoint of the trial is the treatment failure rate at six months after completion of treatment.

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Drawbacks of nonsurgical therapies include: ●Lack of histologic examination of the entire tumor for foci of dermal invasion not evident at the initial biopsy. In a series of 117 LM and LMM treated with staged excision, unsuspected invasive melanoma was found in 16 percent of specimens initially diagnosed as LM [16]. ●Lack of histologic margin control. ●Post-treatment monitoring based upon clinical examination or random biopsies that may not show tumor persistence or recurrence.

Radiation therapy — Radiation therapy (RT) is not commonly used as a primary therapy for LM. However, RT may be a treatment option for older patients who have large LM lesions and for whom surgical removal would not be feasible (picture 19); RT can also be used as adjuvant treatment in patients with positive margins following surgical excision when further surgical resection is not feasible [42,93]. Data on the use of RT in LM are mainly derived from retrospective series using various definitions of local control with variable follow-up periods [94,95]. In an Australian review of eight retrospective, single-institution studies including 349 patients with LM treated primarily with RT, the overall recurrence rate was 5 percent after a median follow-up of three years [93]. Progression to LMM occurred in 1.4 percent of patients. In another series of 593 patients with LMs and early LMM treated with Grenz rays as primary therapy, partial surgical removal followed by RT alone, and wide excision followed by postoperative RT, the clearance rates were 83, 90, and 97 percent, respectively, after a median follow-up time of approximately five years [94]. In a systematic review of 10 studies on radiotherapy, the reported complete response rates varied between 80 to 100 percent. Combining the data of 454 patients from the 10 studies, there were 52 local recurrences and, therefore, a recurrence rate of 11.5 percent after RT [95]. The NCCN guidelines suggest potential regimens of 64 to 70 Gy in 32 to 35 fractions over six to seven weeks, 50 to 57 Gy in 20 to 23 fractions in four to five weeks, or 35 Gy in 5 fractions over four to five weeks [42]. A typical dose is 50 to 54 Gy in 2 Gy fractions with superficial energy radiation treating to a depth of 5 mm. (See "Radiation therapy in the management of melanoma", section on 'Cutaneous primary lesions'.) In Europe, low energy Grenz rays (12 kV) or soft x-rays (20 to 50 kV) delivered at a depth of approximately 1 mm have been used for the treatment of LM and LMM. In one study, low energy (12 kV) Grenz rays (total dose 100 to 120 Gy in 10 to 12 fractions given at three- to four-day intervals) delivered at a depth of approximately 1 mm were used in 93 patients with LM with a recurrence rate of 5.4 percent after a mean time of 46 months [5].

Topical imiquimod — Imiquimod 5% cream is approved by the US Food and Drug Administration for the treatment of actinic keratoses, superficial basal cell carcinomas, and warts. It has been used off label as primary treatment for LM in patients in whom surgery is not feasible or as

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adjuvant therapy after narrow-margin surgical resection or incomplete histologic resection [96]. The mechanism of action proposed is that imiquimod induces a local inflammatory response of T helper lymphocytes mixed with cytotoxic cells, monocytes, and macrophages, leading to a cytotoxic T cellmediated immune response against the tumor [97]. Several systematic reviews of retrospective case series and a few randomized and nonrandomized studies support the use of imiquimod in patients with LM who are poor surgical candidates based on reported clinical and histopathologic response rates of over 70 percent [95,96,98,99]. However, the optimal frequency of application and duration of treatment with imiquimod have not been determined [100].   A 2017 systematic review of 40 observational studies and one randomized trial including 509 patients with LM treated with topical imiquimod one to seven times per week for 4 to 36 weeks found a complete clinical clearance rate of 78.3 percent [99]. Post-treatment histopathologic examination performed in 370 patients demonstrated histopathologic clearance in 77 percent. The recurrence rate was 2.2 percent after a mean follow-up period of 18.6 months. In nine patients (1.8 percent), LM progressed to LMM an average of 3.9 months (range 0 to 11 months) after completion of treatment. However, a subsequent small, single-arm trial found a much lower pathologic clearance rate [101]. In this study, 28 patients older than 45 years with primary untreated and histologically confirmed LM were treated with imiquimod five times per week for 12 weeks and then underwent complete surgical excision of the lesion. Following imiquimod treatment, only 10 patients (37 percent, 95% CI 19-58 percent) achieved the primary outcome (complete histologic clearance); partial regression and definite residual LM were observed in nine and seven patients, respectively [101].

PROGNOSIS

Lentigo maligna (LM) has a tendency for subclinical spread.

Atypical melanocytes often extend for a considerable distance from the clinical margin of LM, sometimes involving "skip" areas. This phenomenon is described as the "field effect" and is responsible for recurrence of LM at the edge after an initial, apparently successful treatment. However, in the absence of progression to lentigo maligna melanoma (LMM), LM does not shorten life expectancy. In a review of 270 patients with LM (n = 124) or LMM who underwent one or multiple surgeries until complete excision was achieved, there were no disease-related deaths among patients with LMM [102]. Recurrence may occur after a prolonged disease-free interval, making assessment of the efficacy of therapy difficult in studies with follow-up time ≤5 years. A few retrospective studies have reported recurrence rates for conventional wide surgical excision of 6 to 9 percent after a mean follow-up time of 5 to 10 years [64-67]. In a single institution review of 649 cases of LM and thin LMM treated surgically, a local recurrence was reported in 41 cases (6.3 percent) [103]. Among 29 cases with histologically documented recurrence, the median time to recurrence was 49 months (range 7 to 194).

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Recurrence rates of 0 to 2 percent have been reported for LM excised by Mohs micrographic surgery (MMS) after a follow-up time of 29 to 38 months [64,83,88-90].

FOLLOW-UP

There is no evidence base to determine the optimal follow-up for

patients with lentigo maligna (LM). We typically see patients twice yearly lifelong, as recurrence of LM can occur after many years, and these patients have an increased risk of melanoma and nonmelanoma skin cancers. We perform a full-body skin examination at each follow-up visit. Examination for recurrent lesions or new primary lesions is enhanced by the use of a Wood's light in a darkened room, dermoscopy, or, where available, reflectance confocal microscopy (RCM) [104].

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management" and "Society guideline links: Mohs surgery".)

SUMMARY AND RECOMMENDATIONS ●Lentigo maligna (LM) is a slowly evolving type of melanoma in situ that typically occurs in the sundamaged skin of the face and neck of older individuals (picture 1A-E). The risk of progression to invasive lentigo maligna melanoma (LMM) ranges from 5 to 20 percent. The development of darker pigmentation, sharper borders, or elevated or nodular areas are clinical signs of progression. (See 'Epidemiology and natural history' above.) ●Clinically, LM presents as an atypical macular lesion characterized by irregular shape, variegated color, and variable size (picture 1A-E). Dermoscopic features of LM include asymmetrical, pigmented follicular openings (atypical pseudonetwork); angulated lines/rhomboidal structures; and gray dots and globules (picture 5A). The surrounding skin typically shows evidence of chronic solar damage (solar elastosis, solar lentigines, or actinic keratoses). (See 'Clinical features' above and 'Dermoscopic features' above.) ●The diagnosis of LM is made by histologic examination. Excisional biopsy with narrow margins is ideal for diagnosis. For large lesions or lesions located in cosmetically sensitive areas, it is acceptable to perform one or more incisional biopsies of the most irregular or heavily pigmented areas. Dermoscopy may be helpful in the selection of the biopsy site. Histologically, LM is characterized by an increased number of atypical melanocytes, often spindle shaped, arranged in single cells or in small nests along the dermoepidermal junction. (See 'Diagnosis' above and 'Histopathologic features' above.)

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●For patients with LM, we suggest surgical excision, rather than radiation therapy (RT) or topical imiquimod, as first-line treatment (Grade 2C). Surgical margins of 0.5 to 1 cm are an accepted standard for wide local excision. If available, surgical techniques that allow complete margin control, such as staged excision with permanent sections ("slow Mohs"), are a preferred option for LMs located in facial areas, where sparing normal tissue is essential to preserve cosmetic appearance and function (figure 1). (See 'Surgery' above.) ●Nonsurgical therapies, such as RT and topical imiquimod, are treatment options for older patients who are not surgical candidates and for patients in whom surgical excision is not feasible or reconstruction is anticipated as difficult. Main drawbacks of nonsurgical approaches are the lack of histologic examination of the entire tumor for foci of invasive melanoma not evident at the initial biopsy and lack of histologic margin control. RT or imiquimod may also be used as adjuvant treatment in patients with positive margins following surgical excision, when further surgical resection is not feasible. (See 'Nonsurgical therapies' above.)

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Melanoma: Clinical features and diagnosis uptodate.com/contents/melanoma-clinical-features-and-diagnosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Dec 04, 2019.

INTRODUCTION

Melanoma is the most serious form of skin cancer. In

the United States, it is the fifth most common cancer in men and women [1]; its incidence increases with age. Five-year survival rates for people with melanoma depend on the stage of the disease at the time of diagnosis. There are five stages: stage 0 is in situ (intraepithelial) melanoma, stages I and II are localized invasive cutaneous disease, stage III is regional nodal disease, and stage IV is distant metastatic disease (table 1). Most people with thin stage I melanoma can expect prolonged diseasefree survival and likely cure following treatment, whereas those with more advanced stage II to IV disease are more likely to develop metastatic disease [2,3]. This topic will discuss the clinical features and diagnosis of cutaneous melanoma. The principles and rationale of screening and early detection of melanoma are discussed separately, as are histopathologic features, initial management, and staging of melanoma. The clinical features, diagnosis, and management of mucosal melanoma, ocular melanoma, and melanoma in children are also discussed separately.

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●(See "Screening and early detection of melanoma in adults and adolescents".) ●(See "Pathologic characteristics of melanoma".) ●(See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".) ●(See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".) ●(See "Mucosal melanoma".) ●(See "Initial management of uveal and conjunctival melanomas".) ●(See "Melanoma in children".)

MELANOMA SUBTYPES

There are four major subtypes of

invasive cutaneous melanoma: superficial spreading (picture 2D), nodular melanoma (picture 1), lentigo maligna (picture 3D), and acral lentiginous (picture 4C). Most melanomas arise as superficial tumors that are confined to the epidermis, where they may remain for several to many years. During this stage, known as the horizontal or "radial" growth phase, the melanoma is almost always curable by surgical excision alone. Melanomas that infiltrate into the dermis are considered to be in a "vertical" growth phase and have metastatic or "tumorigenic" potential. Nodular melanomas have no identifiable radial growth or in situ phase and appear to enter the vertical growth phase from their inception, resulting in thicker tumors at diagnosis. (See "Pathologic characteristics of melanoma", section on 'Growth phases of melanoma'.) The probability of metastases with invasive, vertical growth-phase melanoma is most strongly predicted by measuring the thickness of the tumor (ie, Breslow depth), in millimeters, from the granular cell layer of the epidermis (or overlying area of ulceration) to the deepest malignant cell in the dermis or subcutaneous fat [4]. Other histologic factors, including ulceration of the tumor, mitotic rate, presence of lymphovascular invasion, microsatellites, perineural invasion, and the presence of lymphocytes infiltrating the tumor, can also affect risk of local recurrence and/or metastatic potential of the tumor. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma", section on 'Eighth edition AJCC TNM staging'.)

Superficial spreading melanoma — Superficial spreading melanoma is the most common histologic subtype, accounting for approximately 70 percent of all melanomas [5]. Over 60 percent of superficial spreading melanomas are diagnosed as thin, highly curable tumors that are less than or equal to 1 mm thickness [6]. Approximately two-thirds of all melanomas arise de novo without an associated nevus [7], though superficial spreading melanoma is the subtype most likely to be associated with a preexisting nevus. Superficial spreading melanoma can occur in any anatomic location but has a predilection for the back in men and women and lower extremities in women.

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Superficial spreading melanoma typically presents as a variably pigmented macule or thin plaque with an irregular border, ranging from a few millimeters to several centimeters in diameter (picture 2A-E). Lesions may have multiple shades of red, blue, black, gray, and white. The pathologic features of superficial spreading melanoma are described separately. (See "Pathologic characteristics of melanoma", section on 'Superficial spreading melanoma'.)

Nodular melanoma — Nodular melanomas are the second most common type, accounting for 15 to 30 percent of all melanomas [5]. They may appear as darkly pigmented, pedunculated, or polypoid papules or nodules (picture 1) but frequently present with uniform color or amelanotic/pink hue, symmetric borders, and relatively small diameter, making early detection difficult [8-11]. While the majority of superficial spreading melanomas and lentigo maligna melanomas are diagnosed at less than 1 mm thickness, most nodular melanomas are thicker than 2 mm at the time of the diagnosis. Likewise, over 50 percent of melanomas greater than 2 mm in thickness are the nodular subtype [11]. The pathologic features of nodular melanoma are discussed separately. (See "Pathologic characteristics of melanoma", section on 'Nodular melanoma'.)

Lentigo maligna melanoma — Lentigo maligna melanoma most commonly arises in chronically sun-damaged areas of the skin in older individuals and begins as a tan or brown macule [12]. The lesion gradually enlarges over years and may develop darker, asymmetric foci of pigmentation, color variegation, and raised areas that signify vertical growth within the precursor in situ melanoma, which is termed "lentigo maligna" (picture 3A-D). Lentigo maligna melanoma accounts for 10 to 15 percent of all melanomas, although the incidence is rising in the United States [5,13], particularly in older individuals. The pathologic features of lentigo maligna melanoma are discussed separately. (See "Lentigo maligna: Clinical manifestations, diagnosis, and management" and "Pathologic characteristics of melanoma", section on 'Lentigo maligna melanoma'.)

Acral lentiginous melanoma — The acral lentiginous subtype accounts for less than 5 percent of all melanomas [5]. However, it is the most common type of melanoma among dark-skinned individuals, who are at lower risk for more sun-related melanoma subtypes. Acral lentiginous melanomas arise most commonly on palmar, plantar, and subungual surfaces (beneath the nail plate). Acral lentiginous melanomas first appear as dark brown to black, irregularly pigmented macules or patches (picture 4A-C) [14], with raised areas, ulceration, bleeding, and/or larger diameter generally signifying deeper invasion in the dermis. Occasionally, acral melanoma can present as amelanotic or hypomelanotic lesions mimicking benign diseases, such as warts, calluses, tinea pedis, nonhealing ulcers, or ingrown toenails [15-17]. Subungual melanoma arises from the nail matrix and usually presents as a longitudinal brown or black band in the fingernail or toenail, with or without nail dystrophy (picture 5A-D). Subungual melanoma may present as a mass below the nail plate (with or without pigmentation) with ulceration

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and nail plate destruction. It can also mimic conditions such as onychomycosis or paronychia, which leads to delay in diagnosis [18]. Since pigmented longitudinal bands within the nail plate can be observed in a number of benign nail conditions, dermatology specialist consultation is often necessary for diagnosis [19]. (See "Overview of nail disorders", section on 'Longitudinal melanonychia' and "Dermoscopy of nail pigmentations" and "Dermoscopy of nail pigmentations", section on 'Melanoma'.) The pathologic features of acral lentiginous melanoma are discussed separately. (See "Pathologic characteristics of melanoma", section on 'Acral lentiginous melanoma'.)

Other variants Amelanotic melanoma — All melanoma subtypes may present as amelanotic or hypomelanotic lesions clinically, though this is most commonly observed with nodular and desmoplastic subtypes. Although amelanotic melanoma is less common than clinically pigmented melanoma, representing approximately 2 to 10 percent of cases, it poses serious diagnostic challenges for patients and clinicians alike. Lesions may present as pink or red macules, plaques, or nodules, often with well-defined borders (picture 6A-B) [20-23]. Some tumors may present a subtle light-brown pigmentation. Amelanotic melanomas are often clinically confused with benign lesions (eg, melanocytic nevus, inflamed seborrheic keratosis, ruptured hair follicle or cyst, hemangioma, pyogenic granuloma), often leading to considerable delay in the diagnosis and potential worse prognosis.

Spitzoid melanoma — The term "spitzoid melanoma" has been used to indicate a subset of melanomas that have a morphologic resemblance to Spitz tumors, both clinically and histologically. These lesions usually present as faintly erythematous growing papules or nodules. They can be amelanotic or have a brown, black, or blue color. Although spitzoid melanomas generally have more severe histologic atypia than atypical Spitz tumors, histologic differentiation of these lesions may be challenging, often requiring additional molecular tests (table 2). (See "Spitz nevus and atypical Spitz tumors".)

Desmoplastic melanoma — Desmoplastic melanoma is a rare but histologically and clinically distinct variant of melanoma [24]. It presents as a slowly growing plaque, nodule, or scar-like growth, and it is usually amelanotic and located in chronically sun-exposed areas of older patients. Desmoplastic melanoma may clinically simulate a scar, other benign process, or nonmelanoma skin cancer (eg, basal cell or squamous cell carcinoma) and so tends to be diagnosed when the tumor is thicker [25].

Pigment synthesizing (animal-type) melanoma — Pigment synthesizing (animal-type) melanoma (also termed "melanocytoma") is a rare subtype of melanoma comprised of heavily pigmented dermal epithelioid and spindled melanocytes [26,27]. It presents as a blue-black or blue, slow-growing nodule most frequently located on the extremities and, less

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commonly, on the head/neck and trunk. Animal-type melanoma is considered an indolent type of melanoma, with low incidence of metastasis and low mortality rate, despite a high frequency of positive sentinel lymph nodes. The histopathologic diagnosis may be difficult due to overlapping features with other dermal melanocytic proliferations, such as common blue nevus, cellular blue nevus, malignant blue nevus, and Spitz nevus. (See "Acquired melanocytic nevi (moles)" and "Spitz nevus and atypical Spitz tumors".)  

PROGNOSTIC FACTORS

Tumor thickness is the single

most important determinant of prognosis, followed by histologic ulceration (incorporated into American Joint Committee on Cancer [AJCC] staging across all tumor [T] and nodal [N] classifications) and mitotic rate (previously incorporated in the seventh edition AJCC staging for T1 melanoma but not in the 2017 eighth edition AJCC staging (table 1)). However, mitotic index remains of prognostic significance for all tumor thicknesses. Survival rates decline as tumor thickness increases. The data supporting the classification of tumor thickness and nodal status are discussed separately. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma", section on 'Primary tumor (T)'.) Early detection of melanoma is therefore crucial to improve patient outcome and save lives. Although most melanomas are detected by patients themselves [28,29], clinician detection is associated with thinner, more curable tumors [30-33].

CLINICAL DIAGNOSIS

The clinical recognition of melanoma,

and in particular of early melanoma, may be challenging, even for the most experienced dermatologist. It has been estimated that the sensitivity of the clinical diagnosis of experienced dermatologists is approximately 70 percent [34]. However, the use of diagnostic aids such as dermoscopy, which requires some training, may greatly improve the sensitivity and specificity of the clinical diagnosis [35]. (See 'Dermoscopic examination' below.)

History and risk factors — Key questions that should be asked to patients presenting with a lesion that is of concern or for a general examination of their nevi include: ●When was the lesion (or a change in a preexisting lesion) first noticed? ●Does the patient have a personal or family history of melanoma or other skin cancers? ●Does the patient have a history of excessive sun exposure and/or tanning bed use? ●Did the patient suffer severe sunburns during childhood or teenage years? ●Does the patient have a cancer-prone syndrome (eg, familial atypical mole-melanoma syndrome or xeroderma pigmentosum)? ●Is the patient immunosuppressed?

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●Did the patient receive prolonged psoralen plus ultraviolet A (PUVA) therapy? The patient's phenotypic features associated with an increased risk of melanoma should also be assessed (see "Risk factors for the development of melanoma", section on 'Phenotypic traits'). They include: ●Fair-complexioned phototype ●Red or blond hair ●Light eye color ●Presence of a large number (>50) of melanocytic nevi (common nevi) ●Presence of atypical melanocytic nevi (benign nevi that clinically share some of the clinical features of melanoma, such as large diameter, irregular borders, and multiple colors) (see "Atypical (dysplastic) nevi") Although presence of a large number of common nevi is a strong risk factor for cutaneous melanoma, the majority of melanomas arise de novo. A 2017 meta-analysis of 38 studies including over 20,000 melanomas found that only 29 percent were nevus-associated, with the rest arising de novo [7]. Risk factors associated with amelanotic melanoma include intense freckling, absence of nevi on the back, sun-sensitive phototype, and history of a previous amelanotic melanoma [36].

Visual examination — Clinicians assess the probability that a pigmented lesion is a melanoma using a complex cognitive process that includes a combination of the following steps: visual analysis and pattern recognition, comparative analysis of nevus patterns in an individual patient, and dynamic analysis [37]: ●Visual analysis and pattern recognition typically assesses whether a given pigmented lesion has one or more features that may suggest melanoma, including asymmetry, irregular borders, variegated color, and diameter >6 mm. These features have been included in the widely adopted ABCDE checklist, a clinical prediction rule that was devised to help clinicians and laypeople identify suspicious lesions [38]. (See 'ABCDE criteria' below.) ●The intrapatient comparative analysis uses the so-called "ugly duckling" sign, which refers to the presence of a single lesion that does not match the patient's nevus phenotype (the so-called "signature nevus") [39]. (See 'The "ugly duckling" sign' below.) ●A history of change in size, color, or shape of a preexisting melanocytic lesion (the "E" for "evolution" in the ABCDE checklist) is the most important clinical criterion for the diagnosis of melanoma. A change can be noted by the patient or documented by comparison of serial clinical or dermoscopic images.

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The diagnostic accuracy of visual inspection was examined in a systematic review and metaanalysis of 49 studies that reported accuracy data for the diagnosis of melanoma based on over 34,000 lesions, including 2500 melanomas [40]. In a subset of six studies of in-person evaluation by visual inspection of participants presenting for the first time with a suspicious pigmented lesion, the summary sensitivity and specificity were 92.4 percent (95% CI 26.2-99.8 percent) and 79.7 percent (95% CI 73.7-84.7 percent), respectively. However, the included studies were highly heterogeneous, as shown by the wide confidence interval, in particular, for sensitivity. No difference in diagnostic accuracy was noted in studies reporting the use of popular algorithms (eg, ABCDE, seven-point checklist) or in studies including participants with prior testing referred for specialist evaluation.

Clinical prediction rules — The "ugly duckling" sign, the ABCDE rule of melanoma, and the Glasgow revised seven-point checklist can help identify melanoma. However, melanomas in children and adolescents often lack the conventional ABCDE criteria and may be amelanotic. (See "Melanoma in children", section on 'Physical examination'.)

The "ugly duckling" sign — The "ugly duckling" sign is based upon the observation that, in an individual with multiple nevi, the nevi tend to exhibit one or more predominant morphologic types (the "signature nevi"), defining a relatively specific "profile." A pigmented lesion that is obviously different from the others in a given individual must be considered suspicious, even if it does not fulfill the ABCD criteria. The "ugly duckling" sign was proposed as an additional criterion for the clinician to identify those lesions in patients with multiple nevi that deserve special attention [39] and is a central component of the so-called intrapatient comparative analysis [41]. The predictive value of the "ugly duckling" sign has not been systematically studied. However, the "ugly duckling" sign has been shown to play an important role in the overall pattern recognition process that expert clinicians use to diagnose a pigmented lesion in their daily practice [34]. Although individual clinicians may have a different threshold in the perception of an "ugly duckling," there is a good agreement beyond chance among experts in the recognition of lesions that are different from the signature nevi in a given patient [41,42].

ABCDE criteria — In 1985, dermatologists from New York University first devised the acronym ABCD (asymmetry, border irregularity, color variegation, diameter >6 mm) to educate primary care clinicians and laypeople on the identification of early melanoma [43]. These criteria apply most commonly to the superficial spreading subtype and are less applicable to nodular and desmoplastic melanoma subtypes. In 2004, the criteria were enhanced with the addition of "E" (evolution) to incorporate the fundamental concept of change, including a modification over time of a preexisting nevus or the development of a new lesion, especially in individuals older than 40 years [38]: ●Asymmetry (if a lesion is bisected, one half is not identical to the other half (picture 2B)) ●Border irregularities (picture 2B-C)

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●Color variegation (presence of multiple shades of red, blue, black, gray, or white (picture 2E)) ●Diameter ≥6 mm ●Evolution: a lesion that is changing in size, shape, or color, or a new lesion The diagnostic accuracy of the ABCD mnemonic has been assessed in a few studies, all having methodologic limitations [44,45]. The sensitivity and specificity of the ABCDE criteria vary when they are used individually or in combination, and the risks of over- and under-referral must be balanced accordingly. The use of a single criterion is sensitive but not specific, meaning that many benign lesions would be biopsied or referred, whereas using more than one criterion for referral is more specific but increases the chance of missing malignant lesions. In a retrospective study of 1140 lesions, including 460 melanomas, the sensitivity in identifying a lesion as a melanoma was 97 percent when using a single criterion and 43 percent when using all five criteria jointly. By contrast, specificity was 36 percent for a single criterion and 100 percent for all five criteria [46]. The use of the ABCDE criteria as a training tool for primary care clinicians may improve their ability to detect melanoma at an early stage [47,48]. In primary care settings, patients with a pigmented lesion that is changing and has one of the ABCD criteria noted above should be strongly considered for referral to an expert in skin cancer.

The revised seven-point checklist — Another set of criteria for referral or biopsy, the Glasgow seven-point checklist, were developed in the United Kingdom from a retrospective review of patients with melanoma and subsequently revised. Its use is promoted in primary care settings to guide referral by the United Kingdom National Institute for Clinical Excellence and by the Scottish Intercollegiate Guidelines Network [49,50]. The seven-point checklist includes three major and four minor features [51]: Major: ●Change in size/new lesion ●Change in shape ●Change in color Minor: ●Diameter ≥7 mm ●Inflammation ●Crusting or bleeding

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●Sensory change The presence of any major feature or at least three minor features is an indication for referral [50,51]. One study to evaluate the sensitivity and specificity of the revised seven-point checklist found a sensitivity of 100 percent and specificity of 37 percent in the diagnosis of 65 melanomas and 100 benign pigmented lesions [52]. The only validation study using prospective data from a randomized trial evaluating the addition of a diagnostic aid to the management of suspicious skin lesions in primary care found a sensitivity of 92 percent and a specificity of 33 percent for melanoma when using at least one major and one minor feature [53].

Difficult melanomas — Less common subtypes of melanoma, such as nodular melanomas, desmoplastic melanomas, amelanotic and hypomelanotic melanomas, melanomas of the nail unit, and melanomas occurring in children, may be difficult to diagnose clinically and dermoscopically, as they lack the clinical features usually associated with melanoma and frequently mimic benign skin lesions. Several alternative clinical criteria have been proposed to help clinicians maintain a high index of suspicion when evaluating persistent pink or red lesions. ●Nodular melanomas, and in particular those with little or no pigmentation ("pink lesions"), are characterized by delay in diagnosis, emphasizing the importance of recognizing change in a lesion (E for evolving) or the "ugly duckling" sign. Because the ABCDE criteria are likely to miss early nodular melanomas, the EFG rule was proposed to facilitate the clinical diagnosis of melanomas that can appear as innocent lesions [54]: •Elevation •Firm on palpation •Continuous growth for one month ●The ABCDE rule is not applicable for melanomas of the nail unit, which usually present as a longitudinal brown or black nail plate band, with or without nail dystrophy. Approximately one-third of these lesions lack a clinically apparent pigmentation [55]. An alternative ABCDEF mnemonic has been proposed for subungual melanomas [56]: •Age, African-Americans, Asians, and Native Americans •Brown to black band •Change in the nail band •Digit most commonly involved (great toe and thumb) •Extension of the pigment onto the proximal and/or lateral nailfold •Family or personal history of melanoma

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A biopsy of the nail matrix may be warranted for a pigmented nail band with any of the following characteristics: patient age >50 years, dark color, solitary, width >3 mm, dyshomogeneous pigmentation, change in shape or pigmentation, or irregular margins (algorithm 1). The presence of periungual pigmentation (Hutchinson sign) is an additional diagnostic clue. ●The clinical presentation of melanoma in children often defies the conventional ABCDE criteria. In particular, the "evolution" criterion may not be helpful at an age in which the new onset/evolution of common nevi is normal. Alternative criteria, such as ABCD and CUP, have been proposed for clinical detection of suspicious lesions in children [57] (see "Melanoma in children", section on 'Diagnosis'): •Amelanotic •Bleeding, bump •Color uniformity •De novo, any diameter •Color pink/red, changing •Ulceration, upward thickening •Pyogenic granuloma-like lesions, pop-up of new lesions

Dermoscopic examination — Dermoscopic examination should be performed on all suspicious pigmented lesions. This technique is widely used in dermatologic settings (but not in primary care settings) for the clinical diagnosis of pigmented and nonpigmented skin lesions and requires training to provide an advantage over the naked-eye clinical examination [35]. In experienced practitioners, dermoscopy improves both the sensitivity and specificity of the clinical diagnosis of melanoma. Most importantly, dermoscopy improves the confidence in the diagnosis of benign pigmented lesions, reducing the number of unnecessary biopsies. A meta-analysis of nine studies of dermoscopy compared with naked-eye examination in the diagnosis of melanoma concluded that for clinicians with at least some training in dermoscopy, the addition of dermoscopy to the unaided clinical examination increases the sensitivity in detecting melanoma (90 versus 71 percent) but has similar specificity (80 to 90 percent) [35]. Similar findings were found in a subsequent meta-analysis of 26 studies. At a fixed specificity of 80 percent, sensitivity for dermoscopy plus visual inspection was 92 percent versus 76 percent for visual inspection alone [58]. Surveys indicate that it is routinely used by approximately 90 percent of dermatologists in Europe, 50 to 80 percent in the United States, and 100 percent in Australia [59-61].

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The principles of dermoscopy and the dermoscopic evaluation of skin and special site lesions are discussed in detail separately. Online tutorials on dermoscopy can be found at www.dermoscopy.org or www.genomel.org/dermoscopy. ●(See "Overview of dermoscopy".) ●(See "Dermoscopic evaluation of skin lesions".) ●(See "Dermoscopic algorithms for skin cancer triage".) ●(See "Dermoscopy of facial lesions".) ●(See "Dermoscopy of pigmented lesions of the palms and soles".) ●(See "Dermoscopy of mucosal lesions".) ●(See "Dermoscopy of nail pigmentations".)

Other noninvasive diagnostic aids — Imaging technologies, including dermoscopy, confocal microscopy, and multispectral imaging, may improve the early recognition of melanoma [62,63]. Among them, dermoscopy is the most widely used and studied diagnostic tool.

Reflectance confocal microscopy — Reflectance confocal microscopy (RCM) is an imaging technology that allows the in vivo identification of cells and tissues of the epidermis and papillary dermis with nearly histologic resolution [64]. RCM uses a low-power laser that emits near-infrared light (830 nm) that reflects off structures in the epidermis and creates a three-dimensional image, with resolution of approximately 1 millimicron, comparable with standard histology at approximately 30x magnification. Melanin granules have a high refractive index, resulting in more light to be reflected back to the confocal microscope [63]. Thus, areas of higher melanin concentration will appear as bright areas on a confocal image. In clinical practice, RCM may be an addition to clinical and dermoscopic examination for lesions with equivocal clinical and/or dermoscopic features. In particular, RCM may help in the recognition of amelanotic or hypomelanotic melanomas [65-67] and in mapping lentigo maligna margins before surgical excision [68]. RCM allows a relatively rapid imaging of multiple lesions and can be used for digital monitoring of equivocal lesions over time. Disadvantages of RCM include the high costs of the instrumentation, limited availability, and a longer time to examine a single lesion (approximately seven minutes) compared with clinical and dermoscopic examination [69]. Moreover, RCM is highly operator dependent and requires formal training.

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RCM has high sensitivity and specificity in the diagnosis of skin cancers, using histopathology as the gold standard. In one study, the RCM sensitivity among experienced users ranged from 86 to 100 percent and specificity from 72 to 91 percent [70].

Multispectral imaging — Multispectral imaging devices that have been approved as diagnostic aids in the evaluation of skin lesions include MelaFind, SIAscope, and MoleMate [62]. ●MelaFind is a handheld device that evaluates lesions with multispectral images in 10 different spectral bands, from blue (430 nm) to near-infrared (950 nm) [63]. It uses an automated software for image generation and analysis and provides a recommendation on whether to biopsy a given lesion or not. In a multicenter study, 1612 pigmented lesions (including 127 melanomas) scheduled for biopsy after clinical and, if available, dermoscopic examination by experienced clinicians were evaluated in a blind manner with MelaFind [71]. MelaFind was found to have a sensitivity of 98.4 percent and specificity of 9.5 percent in the diagnosis of melanoma. Similar results have been found in a real-life clinical setting [72]. Initially approved by the United States Food and Drug Administration (FDA) in 2011, MelaFind was recalled in 2015 because some of its software was not included in its premarket approval from the FDA. ●SIAscope is a multispectral device that emits radiation ranging from 400 to 1000 nm and generates eight narrowband spectrally filtered images that demonstrate the vascular composition, pigment network, and collagen content of a lesion. However, SIAscope does not seem to have a higher sensitivity or specificity in detecting suspicious lesions than dermoscopy, and its use in clinical practice cannot be recommended [73]. ●The MoleMate tool is a computerized device using the SIAscope technology combined with a scoring algorithm thought to improve the detection and referral of suspicious lesions in primary care settings. In a randomized trial involving 15 general practices, the proportion of lesions appropriately managed was similar among the primary care clinicians using clinical criteria (history, naked-eye examination, and seven-point checklist) alone and those also using the MoleMate tool [74].

Smartphone applications — Numerous smartphone applications (apps) have been developed for the detection of melanoma by nonspecialist users, including patients and primary care clinicians [75]. They generally provide information about melanoma and sun protection; some are intended for the monitoring of skin lesions by storing images and comparing serial images over time to detect changes, and others use a teledermatology system to send images for expert review. Other applications capture and classify lesion images by comparing them with a set of exemplar images and provide an estimate of the probability that a lesion is benign or malignant. A main concern is that these applications are not subject to any type of validation or regulation. Despite disclaimers that they are intended for educational purposes only, they may be viewed by some users as a substitute for medical advice. One study evaluating the performance of four applications for the diagnosis of 188 lesions found that sensitivity ranged from 7 to 98 percent and specificity from 30 to 94 percent [76]. The application with the highest sensitivity (98 percent) was a tool for store-and-forward

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teledermatology. Although limited to a small number of applications, the results of this study show that the performance of these applications is variable and unreliable.

Computer-assisted diagnosis — Several studies have evaluated the performance of computer-assisted diagnosis of melanoma based upon algorithms built using large sets of dermoscopic images of benign and malignant pigmented lesions [77-82]. The performance of a novel system using deep convolutional neural networks (CNN) trained on a very large set of clinical images was tested against 21 expert dermatologists for the diagnosis of melanoma versus benign nevus [83]. Using a set of 130 clinical images and 11 dermoscopic images of pigmented lesions, the deep CNN outperformed the average of the dermatologists in the classification of melanoma versus benign nevus. Similar results were obtained in another study using 100 dermoscopic images of melanoma and atypical nevi to compare the performance of a CNN trained with a set of over 12,000 dermoscopic images with that of 157 dermatologists with various levels of experience [84]. The CNN outperformed nearly 90 percent of dermatologists. Although promising, additional prospective studies in real-life settings are necessary to validate these results before artificial intelligence-based systems can be incorporated into clinical practice.

HISTOPATHOLOGIC DIAGNOSIS Biopsy — A complete full-thickness excisional biopsy of suspicious lesions with 1 to 3 mm margin of normal skin and part of the subcutaneous fat should be performed whenever possible. Narrow-margin excision allows the assessment of the entire lesion without compromising subsequent wider surgery or potential staging with the sentinel lymph node biopsy technique [85,86]. Partial incisional biopsy may be acceptable if the excision of the entire lesion is not feasible (eg, large lesions, lesions on face, palm or sole, ear, distal digit, subungual lesions); for large lesions, multiple biopsies may be needed to minimize sampling errors. (See "Skin biopsy techniques".) In the United States, according to the National Comprehensive Cancer Network and the American Academy of Dermatology guidelines, excisional biopsy techniques may include an elliptical or punch excision, saucerization, or deep shave/saucerization biopsy, also referred to as a "scoop" biopsy or "disk excision" [87,88]. However, in contrast with saucerization, which is performed using a shave biopsy blade and extends into the reticular dermis, a disk excision is a full-thickness circular incision performed with a scalpel and extending vertically into the subcutaneous fat. Both guidelines recommend that superficial shave biopsy should be limited to lesions for which the suspicion of melanoma is low and performed to a depth below the anticipated plane of the lesion. A broad shave biopsy is often most helpful for diagnosis of melanoma in situ, lentigo maligna type. By contrast, the revised United Kingdom guidelines recommend that shave biopsies should be avoided as they may lead to incorrect diagnosis due to sampling error [85]. There is general consensus that partial or incisional biopsy may be occasionally acceptable for very large lesions or for certain sites, including the face, palm or sole, ear, distal digit, or subungual lesions [85,86,89].

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Detailed clinical information on excised lesions, including anatomic location, type of biopsy performed and intent (excisional or incisional), size of the lesion, and marking of suspicious foci, should be provided to the pathologist; additional information on ABCDE criteria, dermoscopic features, or clinical or dermoscopic images, if available, would also be useful, especially for incisional or punch biopsies [90,91]. Biopsy of the nail matrix may be warranted for a pigmented nail band with any of the following characteristics: dark color, solitary, dyshomogeneous pigmentation, change in shape or pigmentation, width >3 mm, or irregular margins. The presence of periungual pigmentation (Hutchinson sign) is an additional indication for biopsy (algorithm 1). (See "Nail biopsy: Indications and techniques".)

Histopathology — The definitive diagnosis of melanoma is histopathologic. Since no single pathologic feature of melanoma is diagnostic, the histopathologic diagnosis is based upon a combination of architectural, cytologic, and host response features. The presence of atypical melanocytes (ie, melanocytes that are larger than normal and have large hyperchromatic nuclei, irregular nuclear shape and nuclear polymorphism, abnormal chromatin pattern, and prominent nucleoli) and architectural disorder (ie, asymmetry, poor circumscription, nests of melanocytes of various sizes and shapes in the lower epidermis and dermis) are required for the diagnosis (picture 7). The histopathologic features of the major subtypes of melanoma are reviewed in detail separately. (See "Pathologic characteristics of melanoma".) Although the histopathologic diagnosis of melanoma is often straightforward, in some cases, it can be difficult even for the experienced pathologist. In addition, the interpretation of a melanocytic lesion is largely subjective and may vary among pathologists and even experienced dermatopathologists [92,93]. In a study of accuracy and reproducibility of the histopathologic diagnosis of melanocytic skin lesions, 187 pathologists experienced in pigmented lesion interpretation independently evaluated 240 melanocytic lesions ranging from benign nevi to dysplastic nevi to invasive melanoma [93]. The diagnostic accuracy using a consensus diagnosis of experienced pathologists as reference was relatively high for benign nevi (including mildly dysplastic nevi) and T1b invasive melanoma (92 and 72 percent, respectively) but poor for lesions with moderate atypia, lesions with severe atypia, melanoma in situ, and T1a invasive melanoma (25, 40, and 43 percent, respectively) [93]. A subsequent analysis evaluating whether second opinions improved the overall reliability of diagnosis found that the rates of misclassification of difficult melanocytic lesions were lower when the second or third reviewer was a pathologist with specific training in dermatopathology compared with a general pathologist [94]. However, the differences were modest (5 to 10 percent), and the overall rate of misclassification, using consensus diagnosis of experienced pathologists as reference, remained high even when the second and third reviewers were dermatopathologists (40.7 percent, 95% CI 38.4-43.1).    

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Ancillary techniques — Immunohistochemistry can be helpful in the evaluation of difficult melanocytic lesions. The most widely used markers are S-100, MART-1, and HMB-45 (table 3). Newer molecular techniques may aid in melanoma diagnosis [95]. These include comparative genomic hybridization, fluorescence in situ hybridization (FISH), gene expression profiling of tumors [96], and adhesive patch genomic analysis [97]. FISH allows the evaluation of specific chromosomal abnormalities associated with melanoma and is emerging as a tool to diagnose equivocal melanocytic lesions [98-100].

DIFFERENTIAL DIAGNOSIS

Multiple melanocytic and

nonmelanocytic lesions may simulate melanoma clinically and sometimes histologically. They include: ●Common melanocytic nevus (picture 8) (see "Acquired melanocytic nevi (moles)") ●Atypical melanocytic nevus (picture 9A-B) (see "Atypical (dysplastic) nevi") ●Traumatized nevus ●Blue nevus (picture 10) (see "Acquired melanocytic nevi (moles)", section on 'Blue nevi') ●Lentigo (ink spot) (picture 11) ●Spitz nevus (picture 12) (see "Spitz nevus and atypical Spitz tumors") ●Pigmented basal cell carcinoma (picture 13) (see "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma") ●Pigmented actinic keratosis (picture 14) (see "Epidemiology, natural history, and diagnosis of actinic keratosis") ●Seborrheic keratosis (picture 15A-F) (see "Overview of benign lesions of the skin", section on 'Seborrheic keratosis') ●Pyogenic granuloma (picture 16A-B) (see "Pyogenic granuloma (lobular capillary hemangioma)") ●Cherry hemangioma (picture 17A-B) (see "Overview of benign lesions of the skin", section on 'Cherry angioma') ●Dermatofibroma (picture 18A-C) (see "Overview of benign lesions of the skin", section on 'Dermatofibroma') ●Keratoacanthoma (picture 19A-B) (see "Keratoacanthoma: Epidemiology, risk factors, and diagnosis")

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For acral melanoma and melanoma of the nail unit, the differential diagnosis includes (see "Dermoscopy of pigmented lesions of the palms and soles"): ●Verrucous squamous cell carcinoma of the sole (see "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis", section on 'Verrucous carcinoma') ●Melanonychia striata (picture 20) (see "Overview of nail disorders", section on 'Longitudinal melanonychia') ●Acral melanocytic nevi (picture 21) (see "Dermoscopy of pigmented lesions of the palms and soles", section on 'Acquired melanocytic nevi') ●Subungual hematoma (picture 22) (see "Subungual hematoma") ●Pyogenic granuloma (picture 23) (see "Pyogenic granuloma (lobular capillary hemangioma)") ●Periungual warts (see "Cutaneous warts (common, plantar, and flat warts)")

MANAGEMENT OF SUSPICIOUS LESIONS Referral — Primary care clinicians who identify a skin lesion that is not clearly benign should have a relatively low threshold for referral to a dermatologist for dermoscopic examination and evaluation of whether biopsy is indicated. Guidelines published in 2010 by the British Association of Dermatologists suggest the following indications for referral [85]: ●A new mole appearing after the onset of puberty that is changing in shape, color, or size ●A longstanding mole that is changing in shape, color, or size ●Any mole that has three or more colors or has lost its symmetry ●A mole that is itching or bleeding ●Any new persistent skin lesion, especially if growing, pigmented, or vascular in appearance, and if the diagnosis is not clear ●A new pigmented line in a nail, especially where there is associated damage to the nail ●A lesion growing under a nail

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Follow-up — Baseline clinical documentation of lesion size and appearance and, if possible, baseline clinical and dermoscopic images of suspicious lesions that are not excised should be taken at the time of first examination and stored for comparison. These lesions should be examined three months after the initial examination (ie, short interval follow-up) and compared with the baseline images to detect possible changes and early signs of melanoma.  

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

SUMMARY AND RECOMMENDATIONS ●There are four main types of cutaneous melanoma: superficial spreading melanoma (picture 2D), lentigo maligna melanoma (picture 3D), acral lentiginous melanoma (picture 4C), and nodular melanoma (picture 1). Less common variants include amelanotic melanoma, spitzoid melanoma, and desmoplastic melanoma. (See 'Melanoma subtypes' above and 'Other variants' above.) ●Tumor thickness is the single most important prognostic factor for patients with localized melanoma; the 10-year survival is 92 percent for patients with melanomas ≤1 mm thick and declines to 50 percent for patients with tumors >4 mm thick. Histologic findings of ulceration and mitotic rate are also significant prognostic features. (See 'Prognostic factors' above.) ●The patient's history (including personal and family history of melanoma, sun exposure habits, and history of sunburns), presence of fair skin, >50 common nevi, and/or clinically atypical nevi are important aspects of the clinical evaluation. (See "Risk factors for the development of melanoma", section on 'Geographic and ethnic variation'.) ●Early signs of melanoma include asymmetry, irregular borders, variegated color, diameter ≥6 mm, and a recent change in or development of a new lesion, particularly in adults. A skin lesion that looks different from other surrounding lesions ("ugly duckling" sign) is an important finding in patients with multiple nevi. (See 'Clinical prediction rules' above.) ●Imaging technologies, including dermoscopy, confocal microscopy, and multispectral imaging, have been introduced to improve the early recognition of melanoma. The use of dermoscopy, after adequate training, can substantially improve the recognition of suspicious lesions. (See 'Dermoscopic examination' above and 'Other noninvasive diagnostic aids' above.)

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●A complete full-thickness excisional biopsy of suspicious lesions with 1 to 3 mm margin of normal skin and part of the subcutaneous fat should be performed whenever possible. Partial incisional biopsy may be acceptable for very large lesions or for certain sites, including the face, palm or sole, ear, distal digit, or subungual lesions. (See 'Biopsy' above.) ●The definitive diagnosis of melanoma is histopathologic, based upon a combination of architectural, cytologic, and host response features. Immunohistochemical stainings may be helpful in difficult cases (table 3). (See "Pathologic characteristics of melanoma".) ●Primary care clinicians who identify a skin lesion that is not clearly benign should have a relatively low threshold for referral to a dermatologist for dermoscopic examination and evaluation of whether biopsy is indicated. A change in a long-standing mole or a new persistent skin lesion, especially if growing and pigmented, are the most important criteria for referral. Additional indications include any mole with three or more colors or loss of symmetry; moles that are itching or bleeding; a new pigmented band in a nail, particularly if associated with nail plate damage; and any lesion growing under the nail. (See 'Management of suspicious lesions' above.)

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Risk factors for the development of melanoma uptodate.com/contents/risk-factors-for-the-development-of-melanoma/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Feb 27, 2020.

INTRODUCTION

Melanoma is the most serious form of skin cancer. The

rapid increase in the incidence of melanoma and its associated mortality require a detailed understanding of the risk factors associated with melanoma. Here we will review epidemiologic changes in the incidence and mortality, specific risk factors, and the management of patients at high risk for the development of melanoma. Primary prevention, screening, and techniques of skin examination are discussed separately. ●(See "Primary prevention of melanoma".) ●(See "Screening and early detection of melanoma in adults and adolescents".) ●(See "Melanoma: Clinical features and diagnosis".)

EPIDEMIOLOGY

The incidence of melanoma is rising dramatically

worldwide, and mortality rates are beginning to decrease, likely due to increasing early detection efforts and significant breakthroughs in advanced melanoma treatment. Understanding the epidemiology provides information about important causative factors and prevention.

Incidence — In the United States, melanoma is the fifth leading cancer in men and women [1]. An estimated 96,480 new cases of melanoma will be diagnosed in the United States in 2019, with an annual incidence rate of 27 per 100,000 among non-Hispanic whites, 5 per 100,000 among Hispanics, and 1 per 100,000 in blacks and Asians/Pacific Islanders [2].

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Based on data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results (SEER) combined database, the number of reported cases of invasive melanoma increased steadily between 2001 and 2015 [3]. Between 2006 and 2015, the increased incidence was largely accounted for by cases in adults older than 40 years.     In contrast, trends in melanoma incidence were different for children, adolescents, and young adults. The incidence rates remained low and stable among children (age 0 to 9 years), while for both adolescents (age 10 to 19 years) and young adults (age 20 to 29 years), the incidence peaked at approximately 2004 to 2005 and then began to decrease [3]. Between 2006 and 2015, the incidence rate decreased among adolescent boys and girls by 4.4 percent (95% CI -1.7 to -7.0) and 5.4 percent (95% CI -3.3 to -7.4), respectively, and by 3.7 percent (95% CI -2.5 to -4.8) and 3.6 percent (95% CI -2.8 to -4.5) among young adult men and women, respectively. Overall, the number of reported cases of melanoma in adolescents and young adults decreased by 23.4 percent from 2006 to 2015 [3]. One hypothesis to explain this decreasing trend in melanoma incidence among persons younger than 30 years is that it may be related to a change in sun-protection behavior. However, as the national registry data do not include information on melanoma risk factors, such as skin pigmentation, ultraviolet (UV) light exposure, sunburn history, and sun-protective behavior, this hypothesis remains to be proven. The incidence of melanoma is also rising worldwide. The estimated age-standardized incidence rates of melanoma in men and women worldwide increased from 2.3 and 2.2/100,000 people, respectively, in 1990 to 3.1 and 2.8/100,000 people in 2008 [4,5]. In 2015, the global number of melanoma cases was 351,880, with an age-standardized incidence rate of 5 per 100,000 persons per year [6]. Between the early 1970s and 2000, the estimated incidence of melanoma in Central Europe increased from 3 to 4 cases/100,000 inhabitants per year to 10 to 15 cases/100,000 inhabitants per year [7]. An analysis of data from 18 European cancer registries showed that between 1995 and 2012 the incidence of both invasive and in situ melanoma increased annually by 4 and 7.7 percent, respectively, in men and by 3 and 6.3 percent, respectively, in women [8]. The overall increase in the incidence of invasive melanoma was predominantly due to an increase in the incidence of thin tumors. Data from the Queensland Cancer Registry for the period 1995 to 2014 confirmed that the incidence of melanoma in Queensland, Australia, is the highest in the world (72 per 100,000 per year) [9]. While the incidence of in situ melanoma increased over the 20-year period across all age groups, the incidence of invasive melanoma decreased among individuals under the age of 40 years, was stable in the age group 40 to 60 years, and increased among individuals older than 60 years. Some investigators have suggested that the reported increase in melanoma incidence results at least in part from of an increasing number of skin biopsies and significant variability in the histologic interpretation of early evolving lesions [10]. However, this explanation does not account for the increase in melanoma mortality rates, particularly in older men.

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Others have speculated that the increasing incidence of melanoma is related to a rise in screening for melanoma, leading to the detection of thinner, more indolent lesions [11]. However, a study of SEER data (1992-2004) from non-Hispanic whites found increasing incidence of melanoma of all thicknesses and among all socioeconomic levels [12]. Individuals of low socioeconomic status, who were believed to be less likely to have access to screening services, exhibited the highest increase in melanoma incidence when compared with subjects with higher socioeconomic status. In a study of a population-based screening program, the incidence of in situ and invasive melanomas in the screened population increased throughout the one-year screening period, but returned to baseline levels in the three years after the screening program was discontinued [13]. In the control region, by contrast, a small increase in incidence was observed throughout the study period. These results suggest that screening accounts for some, but not all, of the increase in melanoma incidence. Melanoma is rare in children and adolescents, and approximately 90 percent of these cases are in those ≥10 years of age [14-17]. (See "Melanoma in children", section on 'Epidemiology'.)

Geographic and ethnic variation — The interplay of genetic and environmental risk factors likely accounts for the wide variation in melanoma incidence in different ethnic groups and geographic areas, as evidenced by the following: ●In an analysis from the SEER database from 2000 to 2004, the male incidence rates in whites, Hispanics, Asians/Pacific islanders, blacks, and Native Americans were 27.2, 4.5, 1.7, 1.1, and 4.1 per 100,000 individuals, respectively [18]. ●Lower extremity lesions were more common among non-white groups, as were acral lentiginous lesions [18]. ●An increased incidence of melanoma is associated with an increased UV index and lower latitude only in non-Hispanic whites. No evidence to support the association of UV exposure and melanoma incidence in black or Hispanic populations was observed [19].

Mortality — In Australia, a trend towards a decrease in melanoma mortality rates between the late 1980s and 2002 was demonstrated for both men and women aged 35 to 54 years (-2.4 and -2.9 percent per year, respectively), whereas the rates remained stable for those aged 55 to 79 years [20]. An analysis of data from the Queensland Cancer Registry for the period 1995 to 2014 showed decreased or stable mortality rates in all age groups except in men aged 60 years or older [9]. In the United States, the overall mortality from melanoma has remained stable from 1982 to 2011, with over 9000 individuals dying from it every year [21]. From 2002 through 2006, the mortality rates decreased in men and women younger than 65 years, but increased for older individuals (+6.6 percent for men and +0.6 percent for women) [22,23]. From 2007 to 2016, the death rate for melanoma declined by approximately 2 percent per year in adults 50 years of age and older and by approximately 4 percent per year in those younger than 50 [2]. The decline in mortality noted in younger patients may represent the effects of public education on early detection and treatment.

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There are no clinical trials demonstrating that screening decreases the mortality from melanoma. However, five years after the completion of a screening program involving about 400,000 participants in Germany, the mortality rates from melanoma in the screened area were 50 percent lower than those observed in the nonscreened regions [24]. (See "Screening and early detection of melanoma in adults and adolescents".)

ULTRAVIOLET RADIATION Epidemiologic evidence — Although a direct causal relationship between solar ultraviolet (UV) radiation and melanoma cannot be demonstrated experimentally, the evidence from indirect studies is overwhelming and leaves little doubt that UV exposure is a major risk factor for melanoma: ●Clinical and epidemiologic evidence demonstrates higher rates of melanoma in people with extensive or repeated intense exposure to sunlight. The majority of melanomas develop on sunexposed skin, particularly in areas that are more susceptible to sunburn. Individuals with naturally dark skin or whose skin darkens easily upon sun exposure have lower rates of melanoma, supporting the concept that greater penetration of UV light into the skin results in a higher risk [25]. (See 'Timing and pattern of sun exposure' below.) ●The major case-control studies assessing sun exposure, sunburn, and melanoma incidence were analyzed in a systematic review [26]. Intermittent exposure and sunburn in adolescence or childhood were strongly associated with an increased risk of melanoma, while occupational exposure did not confer an increased risk. These findings support the hypothesis that melanoma risk is affected primarily by intermittent intense sun exposure. (See 'Timing and pattern of sun exposure' below.) ●Adjusted for skin type, the geographic incidence of melanoma is highest in equatorial areas and decreases proportionately with distance from the equator, with its correspondingly lower level of UV exposure [27]. Geographic variation in melanoma and nonmelanoma skin cancer rates is also documented in African Americans [28]. ●Studies strongly indicate that a decrease in recreational sun exposure following the diagnosis of primary melanoma, and thus a change in future individual behavior, can significantly diminish the chance of a second primary melanoma [29,30].

UVA versus UVB irradiation — Ultraviolet B radiation (UVB, wavelengths 290 to 320 nm) appears more closely associated with the development of melanoma than ultraviolet A (UVA, wavelengths 320 to 400 nm). This is supported by the higher incidence of melanoma in equatorial regions than in latitudes farther from the equator, as UVB radiation is most intense at the equator while UVA intensity varies less across latitudes.

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Although UVB appears to be more important than UVA as a risk factor, a causal link to UVA exposure is also supported by data from patients using tanning beds and/or treated with psoralen plus ultraviolet A (PUVA) for psoriasis. (See 'Indoor tanning' below and 'PUVA therapy' below.)

Pathogenetic mechanisms — Two independent pathogenetic pathways for UV-induced melanomagenesis have been postulated: a melanin-independent pathway associated with direct UVB-induced DNA damage and a UVA-initiated, pigment-dependent pathway associated with indirect oxidative DNA damage in melanocytes [31]. UVB-induced mutations are typically cytosine-to-thymine transitions arising from cyclobutane pyrimidine dimers (CPDs) that are rapidly formed in the DNA as an effect of UVB irradiation. In contrast, UVA radiation generates CPDs in melanocytes for over three hours after exposure ("dark CPDs") by a mechanism that involves melanin, in particular pheomelanin, and reactive oxygen species as cofactors [32]. Furthermore, in experimental studies, both UVA and UVB radiation have been shown to accelerate BRAF-mediated melanomagenesis through TP53 mutation [33].

Timing and pattern of sun exposure — The pattern and timing of sun exposure appear to be important for skin cancer. Nonmelanoma cancers are associated with cumulative sun exposure and occur most frequently in areas maximally exposed to the sun (eg, face, dorsal hands, forearms). In contrast, melanomas tend to be associated with intense, intermittent sun exposure and sunburns and they frequently occur in areas exposed to the sun only sporadically (eg, the back in men, the legs in women) [34-36]. This association with intermittent sun exposure may not be true for all body sites; for example, melanomas of the head and neck are more frequent in patients with high occupational sun exposure [37,38]. Exposure early in life seems particularly important. Individuals who have had five or more severe sunburns in childhood or adolescence have an estimated twofold greater risk of developing melanoma [34,39]. Moreover, the incidence of melanoma is higher among people who migrate from northern to more equatorial latitudes; this effect is seen predominantly among those who were children at the time of migration [40,41]. It is not clear why intermittent extreme sun exposure appears to increase the risk of melanoma, whereas chronic suberythemogenic exposure is associated more with nonmelanoma skin cancer. After severe UV radiation-induced DNA damage, keratinocytes (from which squamous and basal cell carcinomas arise) undergo apoptosis, or programmed cell death. In contrast, melanocytes are resistant to this level of radiation, and their survival results in the propagation of mutated genes, especially if damaged DNA is not fully repaired [25,42]. This may be an evolutionarily selected advantage for the organism, as the melanocytes survive a sunburn and can protect regenerating keratinocytes. However, on a cellular level, melanocytes that have suffered mutation of growth-regulating genes may have an unwanted growth advantage,

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resulting in disordered control of cell cycling and replication. Despite the high mortality associated with melanoma, the mechanisms that diminish melanocyte apoptosis may paradoxically be evolutionarily selected, as melanomas most often arise after the age of childbearing.

Indoor tanning — In the 1920s, "sun therapy" gained popularity as a cure for multiple maladies. The French fashion designer Gabrielle "Coco" Chanel further glamorized the deep tan as a status symbol. Fifty years later, commercial tanning beds, which emit UVA light, became widespread. Results from the United States 2010 National Health Interview Survey and 2011 Youth Risk Behavior Survey (YRBS) reveal that nearly a third of white women aged 18 to 25 years reported indoor tanning in the past year, with approximately 15 percent engaging in frequent indoor tanning (≥10 sessions in the previous year) [43,44]. A subsequent analysis of data from the 2009, 2011, 2013, and 2015 YRBS, however, showed a substantial decrease in the rate of high school students engaging in indoor tanning, from 15.6 percent (95% CI 13.7-17.6) in 2009 to 7.3 percent (95% CI 6.0-8.9) in 2015 [45]. The decrease was significant among both female (from 25.4 to 10.6 percent) and male students (from 6.7 to 4 percent). Indoor tanning was also positively associated with sunburn, with 82 percent of indoor tanners reporting in 2015 at least one sunburn during the preceding year versus 54 percent of those who did not engage in indoor tanning. The reasons for the decline in the use of indoor tanning among high school students in the United States is incompletely understood. It is possible that multiple factors, including the acknowledgment of the role of UV-emitting tanning devices as a carcinogen to human skin by the World Health Organization [46], increased taxation on indoor tanning implemented in 2010, and restriction of minors from accessing indoor tanning in most states, may have increased the awareness of the health risks associated with indoor tanning in the general population. A systematic review of 88 observational studies with nearly 500,000 participants from 16 Western countries found a summary prevalence of ever exposure to indoor tanning of 36 percent among adults, 55 percent among university students, and 19 percent among adolescents [47]. Regulations restricting the access to indoor tanning facilities to young individuals have been implemented worldwide; they are reviewed in detail elsewhere. (See "Primary prevention of melanoma", section on 'Tanning bed use'.) Based upon evidence from multiple studies suggesting that tanning beds increase the risk of melanoma, in 2009 the World Health Organization International Agency for Research on Cancer (IARC) classified ultraviolet light emitted from tanning beds as a human carcinogen [46,48]. Subsequent observational studies and meta-analyses have confirmed the association between indoor tanning and melanoma [49-52]. Case-control studies have also found an association between tanning devices and ocular melanoma [53-55]. ●A 2014 meta-analysis of 31 observational studies including nearly 250,000 participants found an overall 16 percent increase of melanoma risk for "ever" versus "never" use of tanning beds (summary odds ratio [OR] 1.16, 95% CI 1.05-1.28) [49]. However, the risk was increased by 61 percent for

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individuals reporting more than one year of use and 34 percent for a lifetime exposure to more than 10 sessions. The risk was also increased by 35 percent for first use before age 25 years. ●A population-based case-control study including 681 patients with melanoma and 654 matched controls younger than 50 years found that women who had ever tanned indoors had a two- to sixfold increased risk of melanoma compared with women who had never tanned indoors [56]. Of note, among women aged 30 to 39 years and 40 to 49 years, indoor tanning was strongly associated with the risk of melanoma after controlling for known phenotypic and lifestyle risk factors for melanoma (OR 3.5, 95% CI 1.2-9.7 and OR 2.3, 95% CI 1.4-3.6, respectively). In all age groups, the risk was consistently increased for women who started tanning indoors before age 25 years and for those who reported >10 lifetime tanning sessions. The possibility that the association between tanning bed use and melanoma in fair-skinned individuals is overestimated due to residual confounding cannot be excluded. Tanning bed use may be a marker of populations more exposed to the sun. Studies have shown that tanning bed users are more likely to be regular sunbathers and to have poorer sun protection behavior than nonusers [57,58]. A common misconception about indoor tanning is that it may be helpful to prevent sunburn, a recognized risk factor for melanoma [59] (see "Sunburn", section on 'Prevention'). A reanalysis of data from a population-based, case-control study including more than 1800 participants examined the risk of melanoma associated with indoor tanning among individuals with and without history of sunburn [60]. In this analysis, among individuals who reported no lifetime sunburns, melanoma patients were almost four times more likely to have used tanning beds than controls, after adjusting for potential confounders (OR 3.87, 95% CI 1.68-8.91).

PUVA therapy — Exposure to oral methoxsalen (psoralen) and ultraviolet A radiation (PUVA) used in the treatment of psoriasis and other skin conditions is associated with a late increase in the risk of melanoma. In a multicenter series of 1380 patients with severe psoriasis who were first treated with PUVA in 1975 and 1976, the incidence of invasive or in situ cutaneous melanomas was not elevated above that expected in the general population in the first 15 years following treatment. However, the incidence rate for all melanomas was increased fivefold between 16 and 20 years, and more than 12 times than expected beyond 20 years of follow-up [61]. The amount of PUVA treatment was also a factor; patients who received high doses of PUVA had a greater risk for melanoma. (See "Treatment of psoriasis in adults", section on 'Ultraviolet light'.)

PHENOTYPIC TRAITS Skin pigmentation and tanning ability — Light skin pigmentation, red or blond hair, blue or green eyes, freckling tendency, and poor tanning ability (table 1), which reflect the skin sensitivity to sunlight, are well-known risk factors for melanoma. In a meta-

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analysis of observational studies, light skin phototype, blue eye color, red hair, and high freckle density were associated with a two- to fourfold increase in melanoma risk (table 2) [62].

Typical nevi — Although some nevi are precursors to cutaneous melanoma, they are more often markers of increased risk [63], as only approximately one-third of melanomas arise from preexisting nevi [64]. Common nevi are usually ≤5 mm in diameter and can be raised or flat with a round shape and uniform color (picture 1). Most of these nevi occur in photo-exposed areas.

Number of nevi — Studies have supported a strong association of high total body nevus counts with melanoma (table 2) [65-68]. The relative risk (RR) of melanoma that is associated with high total nevus counts ranges from 1.6 to 64 with a dose-response effect based upon the number of nevi present (including routine junctional, compound, and dermal nevi) [69-72]. The number most often cited as the cut-off for increased melanoma risk is 50 to 100 nevi, which is associated with a RR of 5 to 17 [73,74]. However, a meta-analysis of observational studies found that increased risk may be present in individuals with more than 25 nevi [75]. In this study, 42 percent of melanoma cases were attributable to having ≥25 typical nevi (population attributable fraction [PAF] = 0.15). Lower nevus counts were less strongly associated with melanoma (PAF for 0 to 10 nevi = 0.04, PAF for 11 to 24 nevi = 0.07). The number of nevi on one arm appears to be predictive of the total body nevus. In a United Kingdom study involving 3694 female twins with a median age of 47 years, women with >11 nevi on the right arm were approximately nine times more likely to have a total body count of >100 nevi (odds ratio [OR] 9.4, 95% CI 6.7-13.1) [76].

"Divergent pathway" model — The "divergent pathway" model describes the theory that individuals with the propensity to develop fewer melanocytic nevi require greater sun exposure to promote the development of melanoma, and tend to develop melanoma on chronically sun-exposed sites (eg, head or neck) [65,66,77,78]. Conversely, individuals with large numbers of nevi may require less solar stimulation to drive the development of melanoma and are prone to develop melanoma in sites where large numbers of nevi are found, such as the back. This "divergent pathway" model suggests that melanomas on different sites of the body may occur via different mechanisms. A meta-analysis of 24 observational studies found that high nevus counts were more strongly associated with the development of melanoma on the legs or trunk (RR 1.79, 95% CI 1.56-2.06 and 1.67, 1.45-1.92, respectively) when compared with anatomical sites associated with chronic sun exposure, such as the head or arms (RR 1.42, 1.23-1.64 and 1.60, 1.39-1.83, respectively) [68]. In addition, a pooled analysis of ten case-control studies (2406 female melanoma patients and 3119 female controls) identified a statistically significant trend indicating an association of increasing numbers of nevi with melanoma on the trunk and limbs, but not with melanoma of the head and neck [66]. The relative risks for melanoma in women with high numbers of nevi compared with women with no nevi were reported as highest for melanoma on the trunk (OR 4.6, 95% CI 2.7-7.6) and limbs (OR 3.4, 1.5-7.9), followed by the head and neck (OR 2.0, 0.9-4.5).

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Congenital nevi — Congenital melanocytic nevi (CMN) are classically defined as melanocytic nevi present at birth or within the first few months of life. These occur in 1 to 2 percent of newborn infants, and large or giant CMN occur in approximately 1 of 20,000 births. For patients with large CMN, the risk of developing melanoma (cutaneous or extracutaneous) is estimated to be approximately 2 to 5 percent over a lifetime, with most melanomas occurring in the first five years of life [79]. The clinical features, complications, and management of CMN are discussed separately. (See "Congenital melanocytic nevi".)

Atypical nevi — Atypical nevi are benign, acquired melanocytic neoplasms that share some of the clinical features of melanoma, such as asymmetry, irregular borders, multiple colors, and diameter >5 mm. The terms "atypical nevi" and "dysplastic nevi" are clinically used interchangeably, although in theory a dysplastic nevus refers to a histologic diagnosis. Although atypical nevi are benign lesions, they are strong phenotypic markers of an increased risk of melanoma, especially in individuals with numerous nevi and/or a family history of melanoma (table 2). In a meta-analysis of observational studies, the relative risk of melanoma associated with atypical nevi was 1.5 (95% CI 1.3-1.6) for the presence of a single atypical nevus and 6.36 (95% CI 3.80-10.33) for five atypical nevi versus none [80]. The clinical features, diagnosis, and management of atypical nevi are discussed in detail elsewhere. (See "Atypical (dysplastic) nevi".)

FAMMM syndrome and atypical mole syndrome — Some familial cases of melanoma occur in the setting of the familial atypical multiple mole and melanoma (FAMMM) syndrome and the atypical mole syndrome (AMS). The FAMMM syndrome was originally described in families showing concordance for malignant melanoma and a cutaneous phenotype characterized by multiple large moles of variable size and color (reddish-brown to bright red) with pigmentary leakage [81,82]. Their lifetime cumulative incidence of melanoma approached 100 percent. The atypical mole syndrome (AMS), sometimes also called the dysplastic nevus syndrome (DNS), refers to patients who have 50 to 100 or more nevi, at least one of which is ≥8 mm in diameter, and at least one with atypical features, without personal or family history of melanoma [83]. (See "Atypical (dysplastic) nevi".)

PERSONAL HISTORY OF MELANOMA

A personal history of melanoma is associated with a higher risk of

developing a second primary cutaneous and noncutaneous melanoma (table 2) [84-88]. A population-based study using data from the Swedish Cancer Registry from 1958 to 2010 found that

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patients with either familial or sporadic melanoma have a two- to threefold increased risk of a subsequent melanoma and that the risk remains stable for patients with two or more previous melanomas [89]. An additional population-based study in the United States has shown that individuals with prior cutaneous melanoma were more likely to develop a second cutaneous melanoma (standardized incidence ratio [SIR] 8.17, 95% CI 8.01-8.33), ocular melanoma (SIR 1.99, 95% CI 1.54-2.53), oral melanoma (SIR 6.87, 95% CI 2.23-16.04), and vaginal/exocervical melanoma (SIR 10.17, 95% CI 4.65-19.30) [88]. Although the risk is highest in the first year after the initial diagnosis, it persists over time, and estimates of the risk of developing a second melanoma have ranged from 2 to 11 percent at five years [85,90]. In a study of 2253 patients with primary melanoma from the German Central Malignant Melanoma Registry, 146 patients (6.5 percent) developed a second primary melanoma during a median follow-up time of 73 months; in 70 patients (3 percent), a second primary tumor was detected in the first year of follow-up, and in 39 patients (1.7 percent) in the first 30 days [91]. The risk is similar for patients whose first primary cancer was either in situ or invasive melanoma [90]. Patient characteristics may influence the probability of developing additional lesions. For individuals with a history of both dysplastic nevi and cutaneous melanoma, the risk of a second primary lesion is greater than for those with a sporadic cutaneous melanoma [92]. Age and lesion site also may be markers for increased risk. In one population-based study, patients who were less than 30 years of age at the time of the initial diagnosis or who had a history of melanoma on the head or neck had a greater risk for developing a second primary lesion than other melanoma survivors [84]. An analysis of data from the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2006 on 551 adolescents and young adults with an invasive first primary melanoma and subsequent primary melanoma and 38,110 adolescents and young adults with only a first primary melanoma found that non-Hispanic white ethnicity, younger age at first diagnosis of melanoma, and female gender were associated with an increased risk of developing a subsequent melanoma [93]. High nevus counts, strong family history of melanoma (melanoma in more than one first-degree relative), and melanoma type also affect the risk of developing additional primary melanoma [94]. In a cohort of 1083 melanoma patients who were followed for more than 16 years, the hazard ratios (HR) for developing a second primary melanoma were highest for patients with high nevus counts (HR 2.91, 95% CI 1.94-4.35), strong family history of melanoma (HR 2.12, 95% CI 1.34-3.36), and for patients having lentigo maligna melanoma (HR 1.80, 95% CI 1.05-3.07) or nodular melanoma (HR 2.13, 95% CI 1.21-3.74) as the first primary melanoma [94]. Data obtained from the SEER registry from 1973 to 2006 indicate that compared with first melanomas, second melanomas tend to be thinner at the time of diagnosis (78 versus 70 percent 60 years old [56]. Strong evidence in a population-based case-control study in Queensland, Australia showed that, when compared with unscreened patients, primary care clinician screening was associated with thinner melanoma lesions [51]. Melanoma lesion thickness was thinner among patients who reported having a full skin examination by a clinician during the three years preceding a diagnosis of melanoma, compared with those who had not had a skin examination. Screened patients had a 14 percent lower risk for a lesion >0.75 mm thick. The decrease in risk was greatest for the thickest melanomas (risk reduction 40 percent for lesions ≥3 mm). Similarly, in the Western Pennsylvania primary care physician-based screening intervention, clinician screening was associated with a higher rate of melanoma diagnoses, including increased diagnoses of stage T1 (≤1 mm) melanoma and melanomas in situ, but not thicker melanomas [58].

Effect of clinician specialty — Study results vary as to whether there are differences between the results of skin examination by dermatologists and primary care clinicians [59]. Some studies showed that detection by a dermatologist rather than a non-dermatologist resulted in thinner and earlier-stage lesion detection [60,61]. In a multivariate analysis of 816 melanoma patients, detection by a dermatologist was the strongest predictor of melanoma less than 1 mm in thickness (odds ratio [OR] 0.45; 95% CI 0.28-0.73) [52]. Although few data are available to evaluate the visual examination in the screening setting, one study found that dermatologists were better at detecting melanoma from photographs of pigmented lesions than were primary care physician [62]. Other studies found no difference between dermatologist and primary care clinician examination. Medicare beneficiaries who had seen both dermatologists and primary care providers in the ambulatory setting within the 24-month period prior to diagnosis had the best outcomes, and there was no difference in stage at diagnosis for individuals who saw only dermatologists or only primary care providers [63]. Further, a systematic review of 32 studies concluded that the available data were inadequate to demonstrate differences between dermatologists and primary care physicians in diagnostic accuracy of lesions suggestive of melanoma [64]. Whether or not melanoma detection rates vary by clinician specialty, the value of clinician training to detect melanoma has been demonstrated in several studies. Few medical professionals have specific education in early detection of melanoma [65-69]. In a population-based screening program in the United States, the rate of melanoma diagnosis rose almost 80 percent among patients screened at practices with the highest proportion of providers trained using INFORMED (INternet

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curriculum FOR Melanoma Early Detection), an online educational system for primary care clinicians [67,70-72]. Outcomes among patients could not be directly compared due to the absence of individual patient-level data.

Patient self-examination efficacy — The importance of skin self-examination to detect suspicious lesions is intuitive. A few studies have associated patient self-examination of the skin with the detection of thinner tumors, a reduced risk of advanced melanoma, and reduction in mortality [45,52,73-75]. A major United States case-control study showed that, at a median of 5.4 years, individuals who reported skin awareness were at lower risk of death from melanoma than those who did not report skin awareness [45]. The study also suggested that the 15 percent of melanoma patients who practiced self-examination experienced a reduced risk of advanced melanoma (OR 0.58; 95% CI 0.31-1.11) [45,75]. A workplace time series conducted in northern California from 1965 to 1996, involving a preawareness, education, and skin screening program, resulted in a reduction in the incidence of thicker melanoma and a lower-than-expected death rate compared with the statewide cancer registry statistics over the time period assessed [76]. In a survey study of 566 newly diagnosed melanoma patients, routine skin self-examination of some/all of the body (compared with none) was associated with nearly twice the likelihood of a thin (≤1 mm) melanoma at diagnosis (OR 1.98; 95% CI 1.24-3.18), with the greatest benefits observed in individuals older than 60 years and in men who used a melanoma picture to aid in self-examination [56]. Lesion-directed screening, in which clinicians evaluate lesions identified by patients using predetermined criteria, required less time and resulted in similar melanoma detection rates as total skin examination in a study that compared total body examination by experienced dermatologists in two sociodemographically similar regions in Belgium [77]. Lesion-directed screening showed a similar detection rate (2.3 versus 3.2 percent) but was 5.6 times less time-consuming. Further investigation of public education leading to lesion-directed screening may show a cost-benefit for patients and practitioners. However, even many individuals at a high risk of melanoma do not do skin self-examination [78,79]. Rates of self-examination may be increased by programs that involve computer-assisted patient education, telecommunication reminders, partner hands-on tutorials, partner involvement in skin self-examination, cues and aids, brief counseling and follow-up telephone call, and tailored feedback letters [80-82]. In a two-year randomized trial including 494 melanoma patients and their partners, the effect of a structured educational intervention on the performance of skin self-examination and early detection of new melanomas was examined [81]. During the two years of follow-up, a total of 66 patients (13.4 percent) developed a new melanoma. In the group receiving the intervention, 43

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melanomas (33 in situ) were identified by patients or their partners and 10 by clinicians; by contrast, all 16 melanomas in the control group were identified by clinicians and none by the patient-partner pairs. A survey tool for patients to assess their awareness of freckling, moles, and atypical nevi may help high-risk patients become aware of their risk status by identifying their own skin findings that place them at increased risk [25]. With this tool, concordance between the patient's report and the clinician’s skin examination, measured on a scale where 1 = perfect agreement, was good for freckles (0.67), moderate to good for moles (0.60) and moderate for atypical nevi (0.43).

Other considerations Feasibility of community screening — A randomized trial of population screening in Australia, where the rate of melanoma is higher than in most other countries, showed that community-based melanoma screening programs are feasible [83]. The trial included three components: (1) community education to provide information about melanoma and screening; (2) education and support for medical practitioners to improve clinician skills; and (3) free skinscreening services. The study design called for randomizing 44 Queensland communities, but this was not completed due to lack of funding. Rates of performance of the whole-body skin cancer examination were measured by surveys of residents [83,84]. Baseline screening rates were similar in intervention and control towns (11.2 and 11.3 percent, respectively). At two years, screening rates rose to 35 percent in intervention towns compared with 14 percent in control communities [85]. More than 16,000 whole-body examinations were performed by general practitioners and special screening services, with skin cancer detected in 2.4 percent (33 melanomas, 259 basal cell carcinomas, and 97 squamous cell carcinomas) [86]. The specificity of the skin examination for melanoma was 86 percent.

Cost-effectiveness — Models have been developed based upon the prevalence of melanoma and the predicted impact of detecting early-stage disease. One cost-effectiveness model suggested that, when screening for melanoma is performed by a dermatologist, it is reasonably costeffective compared with other cancer screening strategies [87]. Another analysis, based on computer simulation, suggested that one-time melanoma screening for the general United States population over 50 years of age and screening every two years for first-degree relatives of melanoma patients would be cost-effective [88]. However, the applicability of a model to a particular clinical environment depends on the similarity between the assumptions used in the model and the specifics of the environment.

HARMS OF SCREENING

The harms of screening for

melanoma include the potential that false-positive findings on skin examination will lead to an increased number of dermatology referrals and unnecessary biopsies, with resulting anxiety, scarring, and expense and the possibility of overdiagnosis (ie, the diagnosis of melanoma that is either non-growing or so slow-growing that it would never become clinically meaningful during the

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patient’s lifetime). Screening also has "opportunity costs,” ie, the recognition that a clinician's time is a finite resource that is best spent on care that provides the greatest opportunities for benefits to the patient and is of known effectiveness. Data quantifying the potential harms of melanoma screening are scant [82]; however the United States Surveillance Epidemiology and End Result (SEER) results indicate an increase in detection of early-stage melanoma without benefit on mortality [89]. This discrepancy suggests overdiagnosis, in which lesions detected only as a result of screening would not have led to clinical significant symptoms. Overdiagnosis can lead to treatment of biologically indolent lesions with increased patient morbidity and health-related costs. (See "Evidence-based approach to prevention", section on 'Risk of overdiagnosis (pseudodisease) in cancer screening'.) Specifically, analysis of SEER data suggests that, despite efforts to improve screening and detection, melanoma detection practices have not lowered rates of prognostically unfavorable tumors [89-93]. Based on SEER data from 1986 to 2001, there was a 2.5-fold increase in skin biopsy rates among patients aged 65 and older [89]. This was associated with increased detection of in situ and earlystage invasive melanoma but not increased detection of advanced melanoma, and melanoma mortality rates remained stable during the reporting period [89]. Analysis of SEER data from the subsequent eight years similarly found increases in the rates of skin biopsy and an associated increase in melanoma in situ detection[90]. The incidence of invasive melanoma initially increased but then decreased, and the associations between skin biopsy and invasive melanoma incidence were complex and varied in state-level analyses. A few small studies suggested that screening by primary care clinicians trained in skin cancer screening was not associated with an increase in utilization of dermatology services. In a United States population-based melanoma screening program, 1572 patients were screened by primary care clinicians trained using an online educational system. Screening was associated with increased rates of melanoma diagnosis but was not associated with increased rates of dermatology visits, biopsies, or surgeries [67,70-72]. Similarly, in a small Veterans Affairs (VA) health care system pilot study, trained primary care clinicians offered screening to 258 patients; 189 accepted screening, and there were no differences between the number of dermatology referrals or skin biopsies in the preand post-training periods [94]. In the VA study, the psychosocial impact of screening for melanoma was evaluated; a sample of screened patients reported positive reactions to clinician screening (though some patients preferred dermatologist examination), lack of psychosocial harms (eg, discomfort undressing, distress over referrals), and appreciation of screening as a valuable addition to their health care [95]. The population-based screening program surveyed a small sample of patients who were biopsied as a result of screening; biopsied patients reported no difference in anxiety or depression compared with patients screened but not biopsied [96]. Larger studies are needed to more clearly define the harms of melanoma screening.

APPROACH TO SCREENING 3217

High-risk patient screening — After determining the patient’s risk (see 'Assessing risk for melanoma' above), for those at high risk for developing melanoma or for mortality due to melanoma, we suggest screening for melanoma with routine full-body skin examination by a clinician with skin expertise. We feel this is particularly important for patients at especially high risk due to a history suggesting a familial melanoma syndrome or a personal history of multiple atypical nevi. We also pay special attention to individuals who have never been screened for skin cancer. The appropriate frequency for clinician examinations is uncertain. We suggest screening at least once each year for patients with increased risk due to family history or multiple atypical nevi. (See 'Clinician total body skin examination' below and "Melanoma: Clinical features and diagnosis", section on 'Clinical diagnosis'.) Additionally, we suggest educating high-risk and very high-risk patients about melanoma risk factors and appearance and advising them to look at their skin monthly and alert their clinicians if they note changing moles or other suspicious skin lesions. (See 'Patient self-examination' below.) Surveillance of patients in melanoma-prone kindreds is described separately. (See "Inherited susceptibility to melanoma", section on 'Surveillance in melanoma-prone kindreds'.) Genetic testing may be useful to detect increased risk for melanoma only in very limited situations, generally for patients with multiple family members with melanoma. This is described separately. (See "Inherited susceptibility to melanoma".) Several expert groups endorse recommendations that patients at high risk of developing melanoma should be educated regarding the need for regular clinician examinations, patient skin selfexamination, and sun protection [97,98]. (See 'Recommendations of expert groups' below and "Primary prevention of melanoma", section on 'Sun protection'.) Although there have been no randomized trials of screening in high-risk populations, other studies have shown benefit to screening high-risk patients at risk for advanced disease and death from melanoma. In observational studies, monitoring and educating persons with multiple nevi or atypical moles within the familial melanoma setting by surveillance and education of family members of melanoma patients in United States, the Netherlands, and Sweden led to the detection of thinner melanomas [99]. Data from a large skin cancer screening program in the United States demonstrated the highest yield of screening for melanoma in men 50 years or older [100]. (See 'Effectiveness of screening' above.)

Approach to non-high-risk population — We suggest not routinely screening the non-high-risk population by clinician skin examination, aside from those people with risk factors that warrant screening due to age and sex (white men age 50 and above) or due to personal or family histories of risk factors. However, evaluation of any suspicious lesions identified by a clinician or patient is warranted. (See 'Assessing risk for melanoma' above.)

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We do suggest the clinician carefully observe the skin when the patient is undergoing physical examination in the course of a routine or sick visit (opportunistic case finding), particularly in those areas of the skin that are hard for patients themselves to see. Clinicians should remain vigilant for any suspicious lesions [101] for any patient and make appropriate referrals (to dermatology where possible) for further evaluation of all lesions with prominent features of the ABCDE rule, the “ugly duckling” sign, the Glasgow seven-point checklist, or other concerning signs or symptoms (eg, itching, bleeding, a lesion growing under a nail or as a pigmented line in a nail) [101]. (See 'Recognizing melanoma' below and "Melanoma: Clinical features and diagnosis", section on 'Referral'.) We suggest patients who are not at high risk of melanoma be aware of melanoma clinical warning signs and look at their skin for any concerning lesions. If a partner, family member, or friend is assisting the patient in examining the skin, it is helpful to have that individual know the patient’s moles as well so they can identify the ones that change, particularly in hard-to-see areas. A photograph can be helpful for this. Patients who report a “changing mole” to the clinician should have further evaluation of the lesion. If possible, the evaluation should be done by a dermatologist. (See "Melanoma: Clinical features and diagnosis", section on 'Dermoscopic examination' and "Melanoma: Clinical features and diagnosis", section on 'Other noninvasive diagnostic aids'.) All patients should be educated about the importance of sun protection. (See "Primary prevention of melanoma", section on 'Sun protection'.)

Performing skin examination — Methods to screen for melanoma involve visual examination of the skin. Both clinicians and patients should have a systematic approach and need to know what to look for in order to perform an effective total body skin examination.

Clinician total body skin examination — The clinician performing a total body skin examination should standardize the order in which the examination is performed, both to ensure completeness and because the clinician examination serves as a model for patient skin self-examination. Thus, if a clinician ignores an area, it may convey the unintended message to the patient that this area is unimportant and that they can ignore it as well. Melanomas can occur anywhere on the skin surface. Screening the total skin surface, including the scalp and soles of the feet, all of which are harder to view with self-examination, could aid early detection. Men have more lesions of the back whereas women have more lesions on their lower legs, since these are common areas for sunburn and sun exposure [102]. (See 'Effectiveness of screening' above.) Clinician examination for skin cancer can be carried out in a few minutes, with the following tools and technique:

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●Tools •Source of bright light •Magnifying lens •For health providers trained in its use, a dermatoscope (see "Overview of dermoscopy") ●Perform the skin examination in a systematic order •Seated examination of: -Face, head and neck -Scalp (part the hair or use a blow dryer) -All surfaces of arms and hands •Seated or standing examination of: -Posterior aspect of the upper body •Supine examination of: -Chest, abdomen, anterior thighs and legs, dorsal feet, soles, and toe webs •Prone examination of: -Calves, posterior thighs, buttocks, and back

Patient self-examination — In self-examination, particular attention must be devoted to screening of the back, particularly for men, because approximately one-half of melanomas occur on the trunk on men [103-105] and approximately one-third on the back [47]. It is difficult to perform self-examination of the back, so partners, friends, or family may need to participate in the examination. Having a partner involved in skin self-examination may increase the rates of self-examination performance and melanoma detection. It is helpful to have that individual know the patient’s moles as well so they can identify the ones that change, particularly in hard-to-see areas. Patients and/or partners can also take photographs of suspect moles [20]. Patients who detect a suspect skin lesion should contact their clinicians promptly for further evaluation. ●Tools •Full-length mirror •Hand mirror (for closer inspection of the back of the neck, scalp, back, and buttocks)

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●Perform the skin examination in systematic order •Entire front and back of the body •Sides of the body with arms raised •Palms, forearms, upper arms, and axillae •Back of the legs and feet, toe web spaces, and soles of feet

Recognizing melanoma — Certain tools can help clinicians and patients identify lesions to evaluate further for melanoma. The "ugly duckling" sign, the ABCDE rule of melanoma, and the Glasgow revised seven-point checklist can help identify melanoma. However, melanomas in prepubertal and pubertal children often lack the conventional ABCDE criteria and may be clinically amelanotic (nonpigmented). Detecting melanoma in children is discussed separately. (See "Melanoma in children", section on 'Physical examination'.) ●Ugly duckling sign – The "ugly duckling" sign refers to an “ugly duckling” pigmented lesion that looks different than surrounding nevi [106]. Whereas most nevi (or “families” of nevi) tend to resemble one another, an “outlier” nevus (brown or pink in coloration) that looks different from the rest is cause for evaluation for melanoma.   ●ABCDE criteria – The ABCDE criteria are valuable for educating patients and clinicians about what to look for in a skin lesion [107,108]. Criteria A, B, C, and D describe characteristics of a lesion that may be indicative melanoma, whereas criterion E describes evolution of the lesion’s characteristics. •Asymmetry (picture 1B) •Border irregularities (picture 1C) •Color variegation (ie, different colors within the same region) (picture 1A) •Diameter ≥6 mm •Enlargement or Evolution of color change, shape, or symptoms For a patient with a lesion that meets at least one of criteria A, B, C, or D and that meets criterion E, referral to a dermatologist for evaluation that may include biopsy is a reasonable approach. This selection process balances risks of over- and under-referral. Using a single criterion for referral improves sensitivity but risks over-referral, while requiring three or more criteria improves specificity but risks under-referral. Studies that evaluate the diagnostic accuracy, sensitivity, and specificity of these criteria in identifying a lesion as melanoma are discussed separately. (See "Melanoma: Clinical features and diagnosis", section on 'ABCDE criteria'.)

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●Glasgow seven-point checklist – The revised seven-point checklist is used as a tool for early detection of melanoma by patients and clinicians [109]. If a patient notes at least one major feature or at least three minor features, the patient should seek professional advice. If a clinician notes these during examination, further evaluation of the lesion is warranted. (See "Melanoma: Clinical features and diagnosis", section on 'The revised seven-point checklist'.) The Glasgow checklist includes: •Major features (evaluate further if at least one is present): -Change in size/new lesion -Change in color -Change in shape •Minor features (evaluate further if at least three are present): -Inflammation -Bleeding or crusting -Sensory change -Lesion diameter ≥7 mm Examples of typical melanomas are shown in photographs (picture 1A-I).

Investigational approaches — In addition to visual screening, research is ongoing to find tests to detect melanoma at an early stage when cure is feasible. Studies of patients known to have melanoma have led to identification of a set of autoantibody biomarkers. In a study of 124 melanoma patients and 121 healthy controls, the panel of 10 autoantibodies to tumor-associated antigens had a sensitivity of 79 percent and a specificity of 84 percent for primary melanoma detection [110]. This small, early report of a blood test method has not been validated or studied in a screening population. Additional studies are therefore needed to determine if use of such a biomarker panel would be beneficial or harmful if used in routine population-based screening.

RECOMMENDATIONS OF EXPERT GROUPS Screening recommendations from expert groups are diverse.

Most expert groups do not explicitly recommend skin cancer screening in the general, non-high-risk population.

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●The American Cancer Society notes that some clinicians include skin examination in a routine checkup and that it is important to do skin self-examination, preferably monthly, and report any concerns to a clinician. They note that examination can help find cancers early and is especially important for people at higher risk [111]. ●The US Preventive Services Task Force (USPSTF) provided recommendations on skin cancer screening in 2016 and on behavioral counseling related to skin cancer prevention in 2018. The 2016 evaluation of skin cancer screening found insufficient evidence to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in asymptomatic adults [37]. The USPSTF noted that potential harms of screening for skin cancer (eg, physical and psychologic effects related to misdiagnosis, overdiagnosis, and resultant cosmetic or functional harms from biopsy and overtreatment) have not been adequately addressed. The USPSTF in 2016 found insufficient evidence that regular visual skin examination by a clinician can reduce skin cancer–related morbidity and mortality in any population, including persons with increased risk of skin cancer (such as those with a family history of melanoma). The USPSTF 2018 recommendation statement on skin cancer prevention and behavioral counseling found inadequate evidence on the benefits and harms of counseling asymptomatic adults without a history of skin cancer about skin self-examination [112]. As a means of primary prevention for asymptomatic people without a history of skin cancer, the USPSTF recommends counseling people ages 6 months to 24 years with fair skin types about minimizing exposure to ultraviolet radiation. USPSTF further recommends selectively offering this counseling to people over age 24 years with fair skin types, taking into account their risk factors [112]. ●The American Academy of Dermatology does not have specific recommendations regarding skin cancer screening. They provide guidance for dermatologists to hold public skin cancer screening and education events [113]. However, the American Academy of Dermatology encourages everyone to perform skin selfexamination to check for signs of skin cancer and get a skin examination from a clinician [114]. Dermatologists can make individual recommendations as to how often a person needs to perform these exams based on risk factors, including skin type, history of sun exposure, and family history. ●The Cancer Council of Australia states that “in the absence of substantive evidence as to its effectiveness in reducing mortality from melanoma, population-based skin screening cannot be recommended” [115]. However, the Council recommends that people become familiar with their skin and consult a clinician if they notice any changes. ●The Australian Cancer Network recommends monthly skin self-examination and biannual full-body skin examination by a clinician for high-risk individuals [98].

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●The Canadian Cancer Society recommends that all people have their skin checked as part of a yearly checkup [116]. For the high-risk population, expert groups do recommend skin examinations. Genetic testing is a consideration in limited circumstances (eg, multiple diagnoses of melanoma in the patient or the patient's family, or a history of pancreatic cancer). ●The Melanoma Genetics Consortium recommends that members of high-risk families have a baseline skin examination by a trained health care provider beginning at the age of 10, with follow-up every six months until the nevus pattern is stable and the patient is judged competent at selfsurveillance, and then annual follow-up [97]. The Consortium recommends that DNA testing for mutations in melanoma susceptibility genes be performed only rarely outside of defined research programs [97,117]. This recommendation is based upon a lack of knowledge regarding the penetrance of CDKN2A mutations, the failure to identify mutations in more than 60 percent of hereditary melanoma kindreds, and limited data on the efficacy of prevention and surveillance strategies. Similar recommendations have been made by the American Society of Clinical Oncology [118].

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

INFORMATION FOR PATIENTS

Several websites

describing self-examination are available for patient access [119,120]: ●The American Academy of Dermatology ●The Skin Cancer Foundation In addition, UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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●The Basics topics (see "Patient education: Melanoma skin cancer (The Basics)") ●Beyond the Basics topics (see "Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)" and "Patient education: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS ●No randomized trials have been conducted to establish the efficacy of screening for melanoma on mortality reduction, and observational studies evaluating the impact on mortality are mixed. Although the majority of melanomas are initially detected by patients themselves, melanomas detected by clinicians have consistently been shown to be thinner than those found by patients or their significant others. (See 'Effectiveness of screening' above.) ●Patients with certain risk factors are at high risk of developing or dying from melanoma. (See 'Assessing risk for melanoma' above.) ●For high-risk patients, as above, we suggest screening for melanoma (Grade 2C). We feel particularly strongly about screening patients who are at very high risk due to a very strong family history or a personal history of multiple atypical nevi. We pay special attention to individuals in the high-risk and very high-risk groups who have never been screened for skin cancer. Screening involves a full-body skin examination performed yearly by a clinician who has had appropriate training in the identification of melanoma (clinician examination) as well as education for patients about melanoma risk factors and appearance and advice to look carefully at their skin (patient self-examination) monthly. Patient education also includes advice to alert their clinician if self-examination detects changing moles or other suspicious skin lesions. (See 'High-risk patient screening' above.) ●For the general population outside of these high-risk groups, we do not routinely screen with clinician skin examination. However, for patients without identified increased risk, clinicians should remain vigilant for any suspicious lesions identified in the course of a routine or sick visit (opportunistic case finding). All patients should be aware of melanoma clinical warning signs and bring any concerning lesions to the clinician’s attention. (See 'Approach to non-high-risk population' above.) ●The ABCDEs of melanoma, Glasgow revised seven-point checklist, and the "ugly duckling" sign can help identify melanoma. (See "Melanoma: Clinical features and diagnosis", section on 'Clinical prediction rules' and 'Recognizing melanoma' above.)

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●When suspicious lesions are detected, appropriate referrals are warranted (to a dermatologist where possible) for further evaluation of all such lesions. (See "Melanoma: Clinical features and diagnosis", section on 'Clinical diagnosis'.) ●All patients should be educated about the importance of sun protection. (See "Primary prevention of melanoma", section on 'Sun protection'.)

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Melanoma in children - UpToDate uptodate.com/contents/melanoma-in-children/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 31, 2019.

INTRODUCTION

Pediatric melanoma, usually defined as melanoma

occurring in patients younger than 20 years, is rare, representing approximately only 1 to 4 percent of all melanomas [1,2]. Because of its rarity, the biology and clinical behavior, as well as the histopathologic features of pediatric melanoma, are not well characterized. The diagnosis is often extremely difficult to establish, especially in prepubertal children, in whom melanoma may present as a nonspecific, nonpigmented lesion or benign lesion, resulting in frequent misdiagnosis, thicker lesions, and delayed treatment [3]. This topic will discuss the clinical presentation, diagnosis, and management of melanoma in children. Melanoma in adults is discussed separately. Spitz nevi and atypical Spitz tumors are also discussed separately. ●(See "Melanoma: Clinical features and diagnosis".)

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●(See "Pathologic characteristics of melanoma".) ●(See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".) ●(See "Spitz nevus and atypical Spitz tumors".)

TERMINOLOGY

The term "juvenile melanoma" is only of historical

relevance. Introduced by Sophie Spitz in 1948, it describes childhood melanocytic lesions with histologic features of melanomas but less aggressive clinical behavior compared with adult melanomas [4]. These lesions remain distinct from banal nevi and conventional melanoma and are now collectively regarded as Spitz tumors, a disease spectrum including benign Spitz nevi, Spitz melanomas, and variants of uncertain malignant potential. These lesions are discussed in detail separately. (See "Spitz nevus and atypical Spitz tumors".)

EPIDEMIOLOGY Incidence — Melanoma is rare in individuals younger than 20 years, with an estimated annual incidence rate of nine per million in those aged 15 to 19 years, according to the Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review 1975-2014 [5]. Melanoma is even rarer in younger children, with estimated annual incidence rates of one, two, and three per million in the age groups 1 to 4, 5 to 9, and 10 to 14, respectively [5]. Lower incidence rates of pediatric melanoma have been reported among Hispanic and American Indian children 40 cm adult diameter, respectively) have a slightly increased risk of developing melanoma, estimated to be approximately 2 to 5 percent [17-20]. (See "Congenital melanocytic nevi".) In a 2013 meta-analysis of 14 studies including 2578 patients with large congenital melanocytic nevi, melanoma developed in 51 patients (2 percent) at a mean age of 13 years (range 0 to 58 years), with a mortality rate of 55 percent [17]. Most melanomas developed in giant congenital nevi or in large congenital nevi associated with multiple satellite nevi [17]. Of note, melanomas associated with congenital melanocytic nevi may arise in the central nervous system in a substantial proportion of cases or, less frequently, in other extracutaneous locations. In an analysis of a United Kingdom cohort of 448 children with congenital melanocytic nevi observed between 1988 and 2016, 12 children (2.7 percent) developed a melanoma [21]. Of these 12 primary melanomas, seven were primary melanomas of the central nervous system, two were primary cutaneous, one was primarily lymph nodal, and two were melanomas with unknown primary. The authors found that an abnormal screening magnetic resonance imaging (MRI) of the central nervous system in the first year of life in these patients was associated with a higher melanoma risk compared with a normal screening MRI (12 versus 2 percent, respectively). (See "Congenital melanocytic nevi", section on 'Neurocutaneous melanosis'.)

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Spitz melanoma — Spitz melanomas are predominantly seen in preadolescent children [22,23]. These lesions have histologic features and characteristic genetic alterations of Spitz tumors, such as activating HRAS mutations or kinase fusions. They have clinicopathologic features, biologic behavior, and a prognosis distinct from adult-type "spitzoid melanoma." The clinical features, diagnosis, and management of atypical Spitz tumors are discussed separately. (See "Spitz nevus and atypical Spitz tumors", section on 'Spitz melanoma'.)

Congenital and infantile melanoma — Congenital and infantile melanoma, defined as melanoma present at birth or developing in the first year of life, is exceedingly rare, with only a few cases reported in the literature. Reported cases and series suggest a male predominance and a predilection for the head and neck area [24]. In a retrospective review of 87 women with placental or fetal metastases, 27 cases were attributed to melanoma [25]. The fetus was affected in six cases, and five of six infants succumbed to disease. In one report of transplacental metastasis of terminal maternal melanoma, the infant experienced spontaneous regression of all lesions and was disease free at the time of the report publication [26]. There are no long-term follow-up data on unaffected children born to mothers with metastatic melanoma to exclude the possibility of a delayed presentation of the disease. However, neonates who do not present melanoma metastases at birth should be considered at high risk and undergo close clinical monitoring. Some experts recommend clinical evaluation several times during the first year of life and when necessary thereafter. Pathologic examination of the placenta for melanoma is also warranted in these cases.

PATHOGENESIS

Despite sharing similar risk factors with adult

melanoma, pediatric melanoma is considered to be biologically distinct from adult melanoma due to several distinctive features: greater thickness at presentation, higher frequency of amelanotic lesions, greater rate of sentinel node positivity, and overall less aggressive clinical course [3]. Whether the greater thickness at presentation is due to delayed diagnosis or more rapid growth in children has not been determined. Congenital melanoma can arise de novo, in association with a congenital nevus, or from transplacental metastases from metastatic maternal melanoma. The pathophysiology of transplacental spread of melanoma is unclear. Factors involved may include the high vascularity of the placenta, placental production of angiogenic and growth factors, and impaired fetal immune response. Molecular testing has provided insights in the molecular pathogenesis of pediatric melanoma. The results of a study of whole-genome or whole-exome sequencing and targeted sequencing of 23 pediatric melanoma samples, including 15 conventional (superficial spreading and nodular) melanomas, 3 melanomas associated with congenital nevi, and 5 Spitz melanomas, are summarized below [27]:

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●Conventional melanomas from 15 adolescent patients aged 10 to 20 years, 10 of whom died of disease, were histologically similar to adult melanoma and showed a high burden of somatic single nucleotide mutations, of which over 80 percent were consistent with ultraviolet radiation (UVR) damage. The activating BRAF V600 mutation was found in 13 of 15 patients (87 percent) and TERT promoter mutations in 12 of 13 patients. Alterations (deletion or inactivating mutation) were common in tumor suppressor genes CDKN2A (mutation in 15 percent and biallelic deletion in 21 percent) and PTEN (mutation in 23 percent and biallelic deletion in 14 percent). ●All three melanomas associated with congenital nevi (all children were 12 months in 62 percent of patients, and, in keeping with the diagnostic delay, more than 90 percent of childhood cases and 50 percent of adolescent cases were diagnosed with stage IIa disease or higher [11]. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

DERMOSCOPIC FEATURES

Dermoscopy has

emerged as a useful tool to differentiate the morphology of various pediatric skin lesions that resemble melanoma. Evaluation using a dermatoscope is painless and well tolerated by children in the clinic [36]. Ten melanoma-specific dermoscopic structures have been identified: atypical network, negative network, streaks, shiny white structures, atypical dots and globules, irregular blotch, blue-white veil, regression structures, peripheral brown structureless areas, and atypical vessels. The presence of at least 1 of these 10 structures should raise suspicion of melanoma. Since melanomas in children are often amelanotic, the examination of vascular structures is of primary importance (table 1). Any nodular pink lesion with dotted vessels, milky red globules, or serpentine vessels should be considered suspicious for melanoma. (See "Dermoscopic evaluation of skin lesions", section on 'Melanoma: Global and local features' and "Dermoscopic evaluation of skin lesions", section on 'Vascular structures in skin lesions'.)

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An analysis of 49 dermoscopic images from 52 pediatric melanoma cases (mean age, range 2 to 20) found that the dermoscopic patterns most frequently associated with non-Spitz melanomas were the multicomponent pattern and nevus-like pattern (58 and 25 percent, respectively) [34]. The multicomponent pattern is the "classic" dermoscopic melanoma patter    n encountered in superficial spreading-type melanoma, with most cases presenting irregular globules, atypical network, bluewhite veil, atypical vessels, and negative network. Spitz melanomas showed in most cases a "vascular, pink, Spitz-like pattern" with atypical vessels and shiny white structures or a "pigmented, Reed-like" pattern with black, blue-gray, and dark brown colors, peripheral streaks, and dark blotches. In this study, all cases of melanoma revealed at least one of the aforementioned melanoma-specific structures. However, even in the absence of melanoma-specific structures and atypical vascular morphology, all lesions that do not manifest an unequivocal benign pattern and lesions that appear atypical should be considered for histopathologic examination. A useful approach may also include measurement, photography, and close clinical follow-up for evaluation of lesion evolution.

DIAGNOSIS

The diagnosis of melanoma in children is challenging due to its

rarity and often atypical clinical presentation. It requires a high index of suspicion based upon history, clinical, and dermoscopic findings, as well as a low threshold for the decision to perform a biopsy. The definitive diagnosis is reliant upon histopathologic evaluation.

History — A prominent feature in pediatric melanoma is lesion evolution over time. However, melanoma evolution in children may be misinterpreted as the expected and natural evolution of benign, pigmented lesions during childhood and adolescence. Patients or parents may report a history of bleeding, particularly for ulcerated lesions. Additional complaints may include pain, itch, or discomfort, all of which can prompt evaluation in the clinic. Moreover, patients and parents should be queried for recent treatments (eg, wart removal preparations) or trauma, as melanoma may have been misdiagnosed and treated as a benign entity.

Physical examination — In older adolescents and young adults, most melanomas are of the non-Spitz variety, and most of these will manifest the conventional "ABCDE criteria" (asymmetry, border irregularity, color variegation, large diameter, evolving lesion). In contrast, melanomas in prepubertal and pubertal children are often Spitz melanoma type, and most of these will lack the conventional ABCD features. In addition, the "evolving lesion" criterion may not be helpful at an age in which the new onset/evolution of common nevi is normal. Additional sets of pediatric criteria (the pediatric ABCD and the CUP criteria) have therefore been proposed to be used in combination with the conventional ABCDE rule [11,37]: ●A = Amelanotic ●B = Bleeding, bump

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●C = Color uniformity ●D = De novo, any diameter ●C = Color is pink/red, changing ●U = Ulceration, upward thickening ●P = Pyogenic granuloma-like lesions, pop-up of new lesions While these additional criteria may increase sensitivity for melanoma detection, they are not specific for melanoma. In a study of 52 pediatric melanoma cases, of which 15 were Spitz and 37 non-Spitz melanomas, only 40 percent of Spitz melanomas and 13 percent of non-Spitz melanomas fulfilled the proposed pediatric ABCD criteria [34].   When assessing a new pink/red papule in a child, it is important to also consider associated features, such as bleeding, history of trauma, itch or pain, growth or change over time, or similar lesions elsewhere, in the decision of whether to clinically monitor or biopsy a particular lesion. If a lesion suspicious for melanoma is found on skin examination, palpation of the regional lymph nodes should be performed to evaluate for enlarged nodes. Additionally, evaluation of congenital nevi should include palpation for subcutaneous changes.

Biopsy — Biopsy is warranted when there is clinical suspicion of melanoma. The entire lesion should be removed, unless the lesion is large and/or in a cosmetically sensitive area. Excisional biopsy including the subcutaneous fat with a small (2 mm) rim of normal-appearing skin should be pursued. Superficial shave biopsies are not recommended because the full depth of the lesion is required to determine the maturation of melanocytes, evaluate the base of the lesion, and obtain an accurate measure of tumor thickness.

Pathology — Not only are pediatric melanomas difficult to diagnose clinically, but they may also be challenging histopathologically. It can be difficult to distinguish a Spitz melanoma from an atypical Spitz tumor because they have similar architectural and cytologic features, although the number and severity of atypical features are increased for melanomas (picture 1). For example, a large lesion diameter (especially >1 cm), increased mitotic rate (especially >6 per mm2), high cellular density, and ulceration raise concern for malignancy in Spitz tumors. Moreover, there are pigmented tumors of uncertain malignant potential, and there are challenging pigmented lesions for which expert dermatopathologists cannot reach consensus on a diagnosis [38]. (See "Spitz nevus and atypical Spitz tumors", section on 'Histopathology'.) Data on the frequency of each of the histologic subtypes of pediatric melanoma have not collected systematically, but it is estimated that approximately 40 to 50 percent of pediatric melanomas are of the conventional subtype (adult melanoma-like), which shares similar morphologic features with adult cutaneous melanoma (ie, superficial spreading and nodular) [39]. The same criteria for the

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histologic diagnosis, classification, and stage grouping for adult melanoma are applied to the pediatric conventional subtype. The affected individuals typically are adolescents or postpubertal children. Lentigo malignant melanoma (the histologic subtype that typically arises on chronically sun-damaged skin) almost never occurs in children/adolescents, and acral lentiginous melanoma (melanoma on glabrous skin) is exceedingly rare in this population [40]. (See "Pathologic characteristics of melanoma".) Among pediatric melanomas, childhood tumors may show more aggressive histopathologic features than adolescent tumors (picture 4A-B), despite a paradoxically better survival [11]. A retrospective review of published fatal pediatric melanomas reported that childhood melanomas (up to age 10 years) were thicker than adolescent melanomas, with a mean Breslow thickness of 8.5 mm compared with adolescent melanoma mean Breslow thickness of 3.7 mm [41]. In another cohort of 12 children and 20 adolescents with melanoma, the median Breslow thickness was 3.5 mm for lesions in children versus 1.5 mm in adolescents [22].

Molecular tests — Genomic criteria (eg, multiple chromosomal copy number variations observed by comparative genomic hybridization [CGH] or fluorescence in situ hybridization [FISH]) and alterations in the TERT promoter [23,29] may provide support for the diagnosis of melanoma in Spitz atypical tumors. Laboratory diagnostic approaches, including FISH, CGH, and genomic sequencing, promise to further our understanding and diagnosis of these lesions, but studies have provided inconsistent results. Thus, histopathology remains the gold standard for melanoma diagnosis. The commercial FISH tests and those used in research settings utilize a variety of probes to identify copy number gains and losses in melanoma and Spitz tumors. Some of the probes that identify copy number alterations include chromosomes 6p25, 6q23, 11q13, 9p21, and 8q24 [42]. It is often helpful to first examine for 9p21 deletions. Since this region contains the CDKN2A gene, which encodes P16, immunohistochemistry staining for p16 can be performed to confirm expression and therefore lack of homozygous deletion. Complete absence of p16 expression can be due to homozygous deletion or inactivating mutations, or a combination of both. FISH has been utilized to examine chromosomal deletions and copy number gains in a study of 64 patients with atypical Spitz tumors, with five years of uneventful follow-up and 11 patients with atypical Spitz tumors resulting in locally advanced or metastatic disease or death [42]. Although nonpediatric patients were included in this cohort, the analysis found that homozygous 9p21 deletions were strongly associated with clinically aggressive behavior of the tumor; 6p25 or 11q13 chromosomal gains were also associated with aggressive clinical behavior. However, the role of homozygous 9p21 deletion as a marker of aggressive behavior remains controversial. In another study including 85 patients younger than 18 years with atypical Spitz neoplasms, 17 were FISHpositive; of the nine FISH-positive patients with homozygous deletions in 9p21, only two experienced local recurrence or distant metastasis during a follow-up period of 3 to 89 months [43]. In another study including 56 patients (median age 9 years, range 2 to 61 years) with atypical Spitz tumors or Spitz melanomas, FISH analysis for ROS1, NTRK1, ALK, BRAF, and RET performed in 51 tumors

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demonstrated gene rearrangements in 23 of 51 tumors (45 percent) in mutually exclusive groups [29]. Moreover, the presence of TERT promoter mutations was the most significant predictor of metastatic dissemination.   Another study utilized four-probe FISH analysis on 50 atypical Spitz tumors in pediatric patients with a follow-up of 1 to 300 months and found that FISH was not able to distinguish atypical Spitz tumors from Spitz nevi [44]. Another study also using the four-probe FISH test on both adult and pediatric Spitz tumors found FISH to be more useful in the diagnosis of adult tumors than pediatric tumors [45]. Melanomas arising in congenital nevi have also been studied with genomic analysis using CGH or probing for specific gene abnormalities with FISH in a small number of cases. CGH analysis typically shows copy number alterations of whole chromosomes in proliferative nodules, whereas copy number variations in regions or segments of chromosomes are observed in melanomas arising in association with giant congenital nevi [46].

Imaging — Imaging is typically reserved for evaluation of regional and distant disease spread for cases with deep tumor involvement. In adults, ultrasound has been proposed as an alternative to sampling the sentinel lymph node (SLN), although studies have provided inconsistent results. One study including 716 melanoma patients participating in the Multicenter Selective Lymphadenectomy Trials-I and -II found that the sensitivity of routine preoperative high-resolution targeted ultrasonography to detect a positive node was low (24.3 percent, 95% CI 19.5-28.7 percent), suggesting that the routine use of this technique cannot be used reliably as an alternative to sentinel lymph node biopsy (SLNB) [47]. In contrast, some European centers have demonstrated value of routine high-resolution ultrasound examination of the regional node field in the detection of nodal recurrence among patients who did not have SLNB or had positive biopsy without completion lymph node dissection [48]. There are no standards for imaging pediatric melanoma, and in many cases, we follow adult recommendations. Utilization of ultrasound monitoring of regional lymph node basin in children can be performed for those unable to have a SLNB or those with positive node without a completion dissection. Brain metastases are best evaluated with magnetic resonance imaging (MRI). Lung and liver metastases are best evaluated by computerized tomography (CT). Positron emission tomography (PET) imaging is not routinely utilized, due to low rates of detection of metastatic disease and high false-positive rates associated with inflammation and presence of "brown fat" that is typical of younger patients.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis

of melanoma in children includes a variety of cutaneous lesions, including:

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●Common or dysplastic nevi – These nevi present as pigmented papules and macules that may be characteristically round and symmetric (common nevi (picture 5)) or include clinically atypical features of asymmetry, border irregularity, color variegation, or large diameter (atypical nevi (picture 6)). Nevi are present in nearly all pediatric patients, and their number increases over the first three decades of life, with a peak during childhood and adolescence. Histologically, these lesions lack criteria for melanoma. These lesions are expected to bleed only with trauma, and unexplained bleeding should be investigated further. (See "Acquired melanocytic nevi (moles)" and "Atypical (dysplastic) nevi".) ●Spitz nevi and atypical Spitz tumors – These pigmented (picture 7) or pink papules (picture 8) are more common among young pediatric patients. Classic Spitz nevi are typically monitored clinically without biopsy or intervention, while those with concerning features on clinical or dermoscopic examination should be biopsied for histopathologic evaluation [49]. (See "Spitz nevus and atypical Spitz tumors".) ●Blue nevi – Blue nevi are dark blue-gray papules (picture 9) and macules that may raise concern due to their characteristic dark color, corresponding to the presence of melanocytes deeper in the dermis. (See "Acquired melanocytic nevi (moles)", section on 'Blue nevi'.) ●Proliferative nodules – Proliferative nodules may appear as papules within a congenital nevus and have atypical histology (picture 10) but reassuring genomic studies [50]. In a comparison of proliferative nodules and lethal melanomas arising in congenital nevi of children, one study reported that proliferative nodules more frequently arise from dermis, occur in multiple sites instead of one single focus, and have infrequent ulceration (3 of 22 proliferative nodules versus 2 of 2 lethal melanomas) [51]. These authors also reported that histologically proliferative nodules had lower mitotic rates (50) are risk factors for the development of melanoma (see "Acquired melanocytic nevi (moles)" and "Atypical (dysplastic) nevi"). Sun protection has been shown to reduce the development of nevi in children. However, it remains unclear whether sun protection can reduce the risk of melanoma through this pathway. (See 'Sun protection and nevi' above.) ●Tanning bed use is associated with an increased risk for melanoma and should be avoided. Additional studies are necessary to explore whether some individuals develop a biochemical addiction to tanning. (See 'Tanning bed use' above.) ●There is limited and conflicting evidence that vitamin D, nonsteroidal anti-inflammatory agents, or lipid-lowering agents have a chemopreventive effect on melanoma. Other agents are under investigation for therapeutic prevention of melanoma and nonmelanoma skin cancer. (See 'Chemoprevention' above.) ●A variety of public health programs, most notably the Australian SunSmart campaign, have resulted in improved sun protection as well as stabilization of incidence rates that were increasing precipitously in earlier years. The US Preventive Services Task Force (USPSTF) recommends counseling young adults, adolescents, children, and parents of young children about minimizing exposure to UV radiation for persons aged 6 months to 24 years with fair skin types to reduce their risk of skin cancer and selectively offering this counseling to people over age 24 years with fair skin types, based on their risk factors. (See 'Public health measures' above.)

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Prevention and management of skin cancer in solid organ transplant recipients uptodate.com/contents/prevention-and-management-of-skin-cancer-in-solid-organ-transplant-recipients/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Mar 11, 2019.

INTRODUCTION

Solid organ transplant recipients are at increased risk

for cutaneous malignancies (most commonly squamous cell carcinoma), a finding related to longterm immunosuppression. Because some skin cancers demonstrate aggressive biologic behavior in the setting of immunosuppression, care must be taken to identify and treat early lesions appropriately. In addition to treatments that directly target cutaneous malignancies, modulation of immunosuppression and preventive measures play an important role in the management of these patients. Organ transplant recipients with a history of skin cancer should be followed closely for the development of new lesions, locally recurrent lesions, and metastatic disease. The prevention and management of skin cancers in organ transplant recipients will be reviewed here. The epidemiology and risk factors for skin cancers in organ transplant recipients, as well as a summary of other malignancies that develop with increased frequency after solid organ transplantation, are discussed separately. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients" and "Development of malignancy following solid organ transplantation".)

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PRETRANSPLANTATION SCREENING

A dermatologic consultation is recommended before

transplantation for the screening and treatment of skin cancer and precursor lesions. All suspicious lesions should be excised and sent for pathologic examination. Actinic keratoses, porokeratoses, and viral warts should be treated. A careful history of previous skin cancer should also be obtained to determine the appropriate follow-up frequency or the wait time before proceeding to transplantation [1,2].

Wait time — For patients with a history of prior cutaneous malignancy, the wait time before undergoing transplantation depends upon the tumor type and stage, presence or absence of high-risk features, and availability of a management approach alternative to transplantation. Consensus-based recommendations from the International Transplant Skin Cancer Collaborative are summarized here [2]: ●Transplant candidates with extensive field disease (ie, multiple actinic keratoses, disseminated porokeratosis) but without a history of skin cancer may proceed to transplantation, with the recommendations that all field disease be appropriately managed by the dermatologist. ●For patients with basal cell carcinoma or low-risk squamous cell carcinoma (SCC) that has been surgically excised with clear margins, no waiting time is required. ●For patients with a history of high-risk SCC (table 1) and for those with Merkel cell carcinoma stage IIa or less (local disease; any tumor size not invading bone, muscle, fascia, or cartilage; negative lymph nodes (table 2)), a two- to three-year waiting time is required. ●For patients with SCC and local nodal disease, a five-year wait time is considered prudent, following appropriate treatment with lymph node dissection and adjuvant radiation therapy. ●For transplant candidates with a history of melanoma in situ/lentigo maligna, no waiting period is required, but the patient should be followed up with regular skin exams. ●For renal transplant candidates with a history of stage Ia/Ib/IIa melanoma, a two- to five-year wait time is required before transplantation. A five-year delay is required for patients with stage IIb/IIc melanoma. ●Patients with distant metastatic diseases are not eligible for transplantation in most circumstances.

PREVENTION

Organ transplant recipients are approximately 65 to 250 times

more likely to develop squamous cell carcinoma (SCC), which may be aggressive and associated with a much higher mortality rate than in the general population [3-5]. The preventive management

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of these patients requires a close collaboration between the dermatologist and transplant team and may involve: ●Patient education concerning sun protection and skin self-examination ●Choice and modulation of immunosuppressive therapy ●Chemoprevention ●Post-transplantation surveillance

Sun protection — Prior to and following transplantation, patients should be educated about the importance of sun protection and the recognition of the early signs of cutaneous malignancies. Sun avoidance and the regular use of sunscreens and sun-protective clothing is recommended [6]. The daily use of sun-protective measures may decrease the incidence of actinic keratoses and SCC in organ transplant recipients. In a nonrandomized controlled study of 120 transplant recipients, patients using daily sunscreen developed fewer actinic keratoses and SCCs than subjects with intermittent sunscreen use [7]. Despite the lack of high-quality evidence supporting the value of sunprotection measures for the prevention of post-transplant skin cancer, organ transplant recipients should be strongly encouraged to comply with sun-protective measures, including the use of daily sunscreen [8]. (See "Selection of sunscreen and sun-protective measures".) Vitamin D deficiency is more likely to occur in patients who engage in strict sun protection. With approval of the patient's transplant team, vitamin D supplementation can be initiated in deficient patients [9].

Choice and modulation of immunosuppressive regimen — The choice of the immunosuppressive regimen may influence the risk of post-transplant skin cancer. Regimens including mammalian target of rapamycin (mTOR) inhibitors such as sirolimus and everolimus rather than calcineurin inhibitors may reduce the risk for skin cancer and prolong the time to onset [10].

mTOR inhibitors — Compared with calcineurin inhibitor-based regimens, immunosuppression with the mTOR inhibitors sirolimus or everolimus may reduce the risk for malignancies, including nonmelanoma skin cancer, in organ transplant recipients [10-19]. ●A 2014 meta-analysis of 21 randomized trials using individual data from 5876 kidney and kidneypancreas transplant recipients who received immunosuppressive regimens either with or without sirolimus found that sirolimus was associated with a 40 percent reduction in the risk of malignancy

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and nonmelanoma skin cancer, compared with controls (adjusted hazard ratio [HR] 0.60, 95% CI 0.39-0.93) [20]. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. However, sirolimus was associated with an increased risk of death (HR 1.43, 95% CI 1.21-1.71). The increased mortality was driven by increased cardiovascular and infection-related deaths in the sirolimus group. An increased risk of all-cause mortality and death from malignancy associated with mTOR inhibitors (either sirolimus or everolimus) was also found in an observational study of 9353 kidney transplant recipients (HR 1.47, 95% CI 1.23-1.76 and HR 1.37, 95% 1.09-1.71, respectively) [21]. ●In a 2015 meta-analysis including 39,039 kidney recipients, sirolimus was associated with a 51 percent reduction in the incidence of nonmelanoma skin cancer (incidence rate ratio [IRR] 0.49, 95% CI 0.32-0.76) [22]. This association was much stronger in trials comparing patients treated with sirolimus with those treated with cyclosporine (IRR 0.19, 95% CI 0.04-0.84), suggesting that the protective effect of sirolimus may be in part driven by the withholding of cyclosporine. ●In a five-year extension trial that compared sirolimus-based versus calcineurin inhibitor-based immunosuppression in kidney transplant recipients with one or multiple cutaneous SCCs, patients in the sirolimus group maintained a lower skin cancer rate over five years, with no difference in rejection or mortality between the two groups [23]. At five years, the rates of new skin cancers in the sirolimus group were significantly lower than those in the calcineurin inhibitor group (22 versus 59 percent for SCC, 20 versus 37.5 percent for basal cell carcinoma [BCC], and 34 versus 66 percent for other skin cancers). The benefit was most marked in patients who converted to a sirolimus-based regimen after the development of the first cutaneous SCC (HR 0.20, 95% CI 0.07-0.57).

Mycophenolate mofetil versus azathioprine — A few studies have shown that mycophenolate mofetil and mycophenolic acid are associated with a lower incidence of skin cancer in solid organ transplant recipients compared with azathioprine [24,25]. In a single-institution study including 544 patients who underwent lung transplantation, with a median survival of 11 years, the sequential use of azathioprine and mycophenolate mofetil, each for least one year, was associated with a lower risk of developing a cutaneous SCC compared with azathioprine use only (HR 0.24; 95% CI 0.10-0.56) [26].

Reduction of immunosuppressive therapy — Because increased intensity and duration of immunosuppression appear to promote the development of cutaneous malignancies in organ transplant recipients, reduction of immunosuppression may be considered in patients who develop numerous lesions, recurrent disease, or metastatic disease [2732]. However, no randomized trials have evaluated the effect of reduction in immunosuppression on the development of multiple, recurrent, or aggressive SCC. A few observational studies suggest that reduction of immunosuppression may be of benefit:

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●In a randomized trial of 231 renal transplant recipients, treatment with normal doses of cyclosporine and azathioprine versus low doses of these agents resulted in significantly fewer patients with squamous cell or basal cell cancers in the low-dose group (14.7 versus 22.6 percent) [29]. Low-dose therapy was associated with a higher rate of acute graft rejection (7.8 versus 0.9 percent), but graft survival rates were similar. ●In a series of six organ transplant recipients with a history of multiple post-transplantation SCCs, cessation of immunosuppressive therapy was associated with reductions in skin cancer development in four [30]. One patient who improved after cessation of immunosuppression had recurrence of new skin cancers after retransplantation and reinitiation of immunosuppressive therapy. ●In a retrospective study of nine renal transplant recipients with deeply invasive SCC and/or regional metastatic disease (involving adjacent soft tissues or lymph nodes), those patients in whom immunosuppression was reduced or discontinued had a significantly longer duration of survival free of distant metastatic disease compared with patients whose immunosuppression was unchanged [31]. Since reduction of immunosuppression can increase the risk for graft rejection, the risks and benefits of adjusting the level of immunosuppression must be carefully considered on an individual basis. Definitive guidelines have not been established. An expert consensus on the reduction of immunosuppression for specific skin cancer scenarios in organ transplant recipients has been published (table 3) [32]. (See "Development of malignancy following solid organ transplantation", section on 'Reduction of immunosuppressive therapy'.)

Chemoprevention for SCC — Chemopreventive measures are considered for patients who develop multiple (more than five) SCCs per year, aggressive SCCs, or accelerated development of SCCs [33]. Medications and strategies that have been studied for the prevention of SCC in organ transplant recipients include acitretin, nicotinamide, capecitabine, and photodynamic therapy.

Acitretin — Systemic retinoids such as acitretin, isotretinoin, and etretinate (no longer commercially available) have been used for the prevention or reduction of nonmelanoma skin cancers [34-38]. Data from two randomized trials support the benefit of acitretin: ●In an open-label, randomized, crossover trial of 23 organ transplant recipients treated for 12 months with 25 mg/day of acitretin or a dose titrated according to patient tolerance, significantly fewer SCCs developed during acitretin therapy than during the treatment-free period [39]. A nonsignificant trend towards a reduction in BCC was also noted. Nine patients withdrew from the study due to drug-related side effects. ●In a six-month, randomized trial of 44 renal transplant patients treated with 30 mg/day of acitretin or placebo, significantly fewer skin cancers developed in patients treated with acitretin [40]. The majority of skin cancers detected (17 out of 20) were SCCs; new SCCs developed in 11 versus 47

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percent of patients in the respective groups. In contrast, a randomized dose-comparison trial in renal transplant recipients found no benefit of acitretin 0.2 or 0.4 mg/kg/day for three months followed by 0.2 mg/kg/day for nine months in the prevention of skin cancer [41]. Although actinic keratoses decreased by 50 percent with treatment in both groups, the numbers of new SCCs, BCCs, and keratoacanthomas were similar in the pretreatment and post-treatment periods. The majority of patients did not tolerate the dose of 0.4 mg/kg/day and required early dose reductions. The major side effects of systemic retinoids include teratogenicity; dryness of the eyes, nose, lips, mouth, and skin (picture 1); abnormalities in liver function tests; and hyperlipidemia. Periodic laboratory monitoring is necessary. Since pregnancy must be avoided for three years after the discontinuation of acitretin, treatment usually is not given to women of childbearing potential. Contraception is required for only one month after the completion of isotretinoin; however, evidence for the efficacy of this agent for chemoprevention in organ transplant recipients is limited to a case report in which a patient improved with 0.5 mg/kg/day [42]. Acitretin should be started at low doses to facilitate tolerance of adverse effects [33]. We typically begin with 10 mg a day and gradually increase at one- to two-week intervals by increments dictated by patient tolerance of side effects. We treat most patients with a maintenance dose of 25 mg per day, but the final dose is individualized to balance clinical response with side effects. Acitretin is now available in multiple dose forms (10, 17.5, and 25 mg), which allows for a more individualized daily dose [33]. The effect of acitretin is limited to the duration of therapy; lesion development recurs rapidly after cessation of therapy [39,40]. Further studies are necessary to determine the long term safety, efficacy, and optimal treatment regimen for acitretin as a chemopreventive agent in organ transplant recipients.

Nicotinamide — A randomized trial of oral nicotinamide 500 mg twice daily for 12 months in 386 immunocompetent participants with a history of two or more nonmelanoma skin cancers found a 20 percent reduction in the number of new BCCs and a 30 percent reduction in the number of new SCCs in the nicotinamide group, compared with the placebo group [43]. However, data on solid organ transplant recipients are limited and inconsistent. ●A phase 2 trial including 22 renal transplant recipients randomized to nicotinamide 500 mg twice daily or placebo found a nonsignificant 35 percent reduction in the rate of new skin cancers at six months [44]. ●Another small study including 24 renal transplant recipients with actinic keratoses treated with nicotinamide 250 mg three times daily or placebo for six months found that nicotinamide was more effective than placebo in inducing partial or complete regression of actinic keratoses and lightdamaged skin [45].

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Larger randomized trials are needed to determine whether nicotinamide is effective as a chemopreventive agent in renal transplant recipients.

Capecitabine — Treatment with capecitabine, an oral chemotherapeutic agent, may reduce the development of new cutaneous SCCs in solid organ transplant recipients. Following a report in which treatment with capecitabine halted the development of new cutaneous carcinomas and improved existing lesions in three transplant patients with histories of multiple SCCs [46], additional reports have suggested benefit [47,48]. In a case series in which 10 solid organ transplant recipients who had developed at least two nonmelanoma skin cancers within six months were treated with 21-day cycles of capecitabine (0.5 to 1.5 g/m2 per day on days 1 to 14) for 5 to 24 months, 9 (90 percent) had reductions in the incidence of SCCs after beginning capecitabine [47]. Overall, the mean number of SCCs that developed per month decreased from 0.56±0.28 in the pretreatment period (generally 8 to 12 months) to 0.16±0.11 in the first year of the treatment period. Moderate to severe side effects led to dose alterations in seven patients, including two who eventually had to discontinue treatment. Additional studies are necessary to determine the efficacy and safety of capecitabine in this setting.

Photodynamic therapy — Studies assessing the efficacy and duration of effect of photodynamic therapy (PDT) for the prevention of SCC have yielded variable results [49-53]. In one split-site randomized trial involving 25 renal transplant recipients with clinically normal skin, patients received PDT at the start of the study and at six-month intervals for five years [53]. After three years of follow-up, actinic keratosis (AK) developed in 63 percent of untreated skin areas compared with 28 percent in PDT-treated skin, with a total number of 43 AKs in untreated skin versus 8 in treated skin. (See "Treatment of actinic keratosis", section on 'Photodynamic therapy'.)

Post-transplantation surveillance — After organ transplantation, patients should continue to have complete skin examinations on a regular basis. The frequency of visits depends upon the patient's risk factors and medical history. Definitive guidelines have not been established; we typically utilize the following follow-up schedule: ●No history of skin cancer or AK – once yearly ●History of AK or one low-risk nonmelanoma skin cancer– every six months ●Multiple nonmelanoma skin cancers or a history of a high-risk SCC – every three months ●History of pretransplant melanoma or melanoma in situ – every six months ●Post-transplant melanoma – every three months for two years, then at least every six months ●Rapidly developing tumors, aggressive tumors, or metastatic skin cancer – every four to six weeks In all patients with a history of skin cancer, examination should include the palpation of lymph nodes.

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In a Canadian population-based study including over 10,000 transplant recipients followed up for a median of 5.4 years, adherence to annual post-transplantation dermatologic examination for at least 75 percent of the follow-up time was associated with a 34 percent reduction in the rate of advanced nonmelanoma skin cancer compared with patients with less than 75 percent adherence, after adjusting for ethnicity and history of pretransplant actinic keratosis and skin cancers (HR 0.66, 95% CI 0.48-0.92) [54]. Of note, in this cohort only 45 percent of patients were ever seen by a dermatologist following transplantation and only 2 percent were fully adherent to annual skin examination during the entire post-transplant period.

Skin self-examination — Organ transplant recipients should be instructed to perform a skin self-examination on a monthly basis. The American Academy of Dermatology provides online information and tutorials on skin self-examination and early detection of skin cancer. Several randomized trials and a systematic review support the efficacy of educational interventions using written materials, videos, or mobile device applications in promoting sun-protection behaviors among kidney transplant recipients [55-58]. However, none of these studies directly demonstrated the efficacy of such interventions in reducing the incidence of skin cancer after transplantation.

MANAGEMENT Actinic keratosis — Actinic keratoses (AK) occasionally progress to squamous cell carcinoma (SCC), and the presence of multiple AK on photodamaged skin can make it more difficult to detect early SCCs (picture 2A-B). Thus, the treatment of these lesions is an important component of the management of organ transplant recipients. (See "Treatment of actinic keratosis".) Local destructive therapies such as cryotherapy, electrocautery, curettage, or carbon dioxide laser can be used for the management of individual lesions. Field therapy with topical fluorouracil or imiquimod is an option for patients with numerous lesions. Initially, concerns over the induction of immune activation and subsequent organ rejection with topical imiquimod limited the use of this agent in the transplant population. However, the initial results of small randomized trials suggesting that this agent can be used safely have been tempered by a single report of acute renal failure in a patient treated with imiquimod for viral warts to a surface area that may have exceeded that used to treat AK [59]. In treating AK, imiquimod is applied to limited areas (60 to 100 cm2) three times per week for up to 16 weeks [60,61]. The management of AK is discussed in greater detail separately. Photodynamic therapy (PDT) has also been used for the management of AK, though the response to treatment in organ transplant recipients may be less favorable than in immunocompetent populations [62]. Several studies have investigated the role of interventions to augment PDT efficacy and reduce the pain associated with conventional PDT in this population [63-65]. In a small randomized trial, treatment of the involved areas with ablative fractional laser in combination with daylight PDT was more effective than daylight PDT or conventional PDT alone and better tolerated than conventional PDT [65].

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Squamous cell carcinoma — SCC is the most common cutaneous malignancy in solid organ transplant recipients [3,27,66,67]. As in the immunocompetent population, cutaneous SCC is most likely to occur in patients with fair skin [67-69]. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients".) In comparison with SCC in immunocompetent patients, SCC in organ transplant recipients is more likely to manifest as aggressive disease [70]. In an observational study, clinical and histopathologic factors associated with aggressive behavior of SCC and basal cell carcinoma (BCC) were evaluated in 276 transplant recipients (153 with SCC and 123 with BCC) and 277 immunocompetent patients (154 with SCC and 123 with BCC) [71]. The SCC recurrence rate was substantially higher among organ transplant recipients than immunocompetent patients (13 versus 2 percent). Moreover, histopathologic features associated with aggressive behavior, including deep tissue involvement, perineural invasion, and lymphatic invasion, were observed with significantly higher frequency among transplant recipients than among immunocompetent patients. In contrast, no difference in the clinical behavior of BCC was noted between the two groups. The prognosis is poor for the 5 to 8 percent of patients who develop metastases (picture 3) [70,72]; in a retrospective study that included 58 organ transplant recipients with distant or systemic metastases of cutaneous SCC, the three-year disease-specific survival rate was 29 percent [70]. Thus, once detected, prompt, appropriate management of early SCC is essential [70,73].

Patient evaluation — All lesions that are suspicious for SCC should be pathologically examined to confirm the diagnosis and to evaluate for features associated with aggressive disease (see 'Lesion classification' below). Biopsies of papular or nodular lesions should extend at least into the deep reticular dermis [74]. Patients who are determined to have cutaneous SCC should undergo a complete skin examination and palpation of draining lymph nodes. The need for additional laboratory or radiologic evaluation is based upon the detection of findings that suggest locoregional or metastatic spread of disease. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".)

Lesion classification — In immunocompetent patients, a combination of clinical and histopathologic features is used to classify individual SCCs as low risk or high risk for aggressive clinical behavior. These classifications are used to guide the approach to treatment. In the 7th edition American Joint Committee on Cancer (AJCC) staging system for cutaneous squamous skin cancer (table 4), tumors were classified as T2 or at higher risk if they were >2 cm in greatest dimension or any size with two or more high-risk features (ie, >4 mm depth, Clark level IV, perineural invasion, lymphovascular invasion, primary site on the ear or nonglabrous lip, and poorly differentiated histology) [75]. Immunosuppression was not included as a high-risk feature because traditionally clinical risk factors are not included in staging.

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In September 2016, the AJCC and the Union for International Cancer Control (UICC) issued the 8th Edition of staging guidelines [76]. The new guidelines came into general use in January 2018 and contain an updated cutaneous SCC staging system encompassing tumors located on the head and neck only, since the system was developed within the AJCC's head and neck committee. The new cutaneous SCC staging system has expanded the criteria for upstaging to T3 (table 5). (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Staging'.) Although the prognostic value of the 7th edition AJCC staging system for cutaneous SCC has been substantiated in a retrospective study including heart and lung transplant patients [77], a subsequent study suggests that the Brigham and Women's Hospital (BWH) alternative staging criteria (table 6) may better identify tumors in immunosuppressed patients with high potential for poor outcomes. However, in this relatively small study, the majority of lesions that had poor outcomes were either AJCC 7th edition T1/T2 or BWH T1/T2a [78]. Studies evaluating the prognostic value of the 8th edition of the AJCC staging system are eagerly awaited. Further modifications to the AJCC staging system have been proposed with the aim of a more accurate stratification of prognostic groups [79,80]. Additional high-risk clinical and histologic features of SCC that may be considered when selecting treatment include [81]: ●Location in the "mask areas" of face (central face, eyelids, eyebrows, periorbital, nose, lips, chin, mandible, preauricular and postauricular skin/sulci, temple, ear), genitalia, hands, and feet ●Large size – ≥10 mm on scalp, forehead, cheeks, neck or pretibial area; ≥20 mm on trunk or extremities ●Indistinct borders ●Rapid growth ●Recurrent lesion ●Lesion in site of chronic inflammation or prior radiation therapy ●Presence of neurologic symptoms ●Histology •Poorly differentiated •Acantholytic (adenoid), adenosquamous, desmoplastic, or metaplastic (carcinosarcomatous) histopathologic subtypes •Perineural, lymphatic, or vascular involvement

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Treatment — Based upon multiple population-based studies indicating an increased likelihood for aggressive disease in organ transplant recipients, invasive SCCs in this group of patients are generally considered high-risk lesions [3,74,82-84]. Thus, procedures that provide pathologic confirmation of complete tumor removal, such as Mohs surgery or conventional surgical excision with margin control, are the preferred treatments for invasive SCCs in these patients to prevent local recurrence and disease spread. Lesions classified as high-risk SCC by AJCC criteria or alternative staging systems may require additional workup (eg, computed tomography or magnetic resonance imaging, sentinel lymph node biopsy) and/or adjunctive therapy.

SCC in situ (Bowen's disease) — Options for the treatment of SCC in situ are similar to those in immunocompetent patients. Frequently employed therapies include surgical excision, electrodesiccation and curettage (ED&C), and topical chemotherapy [85]. The results of small randomized trials suggest that imiquimod, a topical immunomodulating agent, can be used safely in organ transplant recipients when applied to limited areas (60 to 100 cm2) [60,61]. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma", section on 'Bowen's disease (squamous cell carcinoma in situ)'.)

Invasive lesions without additional high-risk features — Common treatments for SCCs in organ transplant recipients that lack other features of aggressive disease (eg, small, well-differentiated lesions in low-risk sites) include surgical excision and ED&C. Destructive treatments such as ED&C do not provide pathologic confirmation of lesion removal and are primarily reserved for SCC in situ or carefully selected invasive lesions that lack additional high-risk features.

Surgical excision — SCCs without additional high-risk features are frequently managed with conventional surgical excision. Lesions should be excised with a margin of tissue that extends 4 to 6 mm beyond the peripheral edge of erythema, and the specimen should be sent for postoperative pathologic margin assessment. Mohs surgery, a tissue-preserving, specialized surgical procedure that is used to evaluate 100 percent of the tissue margins, is generally not necessary. However, Mohs surgery may be appropriate in cases where tissue conservation is desired. (See "Mohs surgery".)

Electrodesiccation and curettage — ED&C, a procedure that involves three cycles of scraping of the tumor with a curette followed by electrodesiccation, is an alternative treatment for lower risk lesions. The efficacy of ED&C for SCC in organ transplant recipients is supported by the results of a retrospective study of 211 SCCs in 48 patients [86]. After a mean follow-up period of 50 months, residual or recurrent SCC occurred in only 6 percent. The procedure often results in a depressed, hypopigmented oval scar and is generally reserved for lesions in noncosmetically sensitive sites, such as the trunk and extremities (excluding hands and feet). (See "Minor dermatologic procedures", section on 'Curettage and electrodesiccation' and "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma", section on 'Curettage and electrodesiccation'.)

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Advantages of ED&C are that the procedure is quick, generally well tolerated, and less expensive than excisional surgery. The rapid nature of the procedure can facilitate the treatment of patients who repetitively develop new lesions. The main disadvantage of ED&C is the lack of histologic margin control, which underlies the importance of carefully selecting lesions for treatment. ED&C should generally not be performed in hair-bearing areas because the presence of terminal hair follicles may reduce the efficacy of the procedure. In addition, ED&C cannot reliably eradicate lesions that extend into the subcutaneous fat. If fat is reached early during the curettage stage, ED&C should be abandoned and the tumor should be removed surgically. Some clinicians choose to perform ED&C at the time of biopsy on lesions that are clinically consistent with small, well-differentiated SCCs. If pathology results demonstrate aggressive histopathologic features, subsequent surgical excision should be performed to ensure adequate tumor removal. All sites treated with ED&C should be followed closely for lesion recurrence. We typically follow such patients at three to six month intervals.

Cryosurgery — Cryosurgery is infrequently used for the management of low-risk SCC in immunocompetent patients because of the difficulty in obtaining the requisite temperatures for tumor destruction in a uniform manner and the significant tissue edema and drainage that follow the procedure. In addition, recurrent disease is sometimes difficult to detect in the resulting scar. Although we typically do not use cryosurgery for the treatment of SCC in organ transplant recipients, practitioners with extensive experience in its use for skin malignancies may find it useful. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma", section on 'Cryotherapy'.)

Invasive lesions with additional high-risk features — SCCs in immunosuppressed patients that demonstrate other high-risk features (eg, large size, poor differentiation, high-risk site) should be managed with techniques that provide pathologic confirmation of tumor removal. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".) Mohs surgery is our preferred treatment for SCCs in such patients. Mohs surgery is a tissue-sparing surgical technique that provides evaluation of 100 percent of the margins of excised tissue. (See "Mohs surgery".) Although reported cure rates for Mohs surgery for SCC exceed those for other treatment modalities (five-year cure rates of greater than 96 percent) [87,88], there have been no randomized trials comparing the efficacy of Mohs surgery with other therapies for SCC. One retrospective study that evaluated the efficacy of Mohs surgery for 260 high-risk SCCs in 215 patients (20 percent of whom were immunosuppressed) found local recurrences of only three lesions (1.2 percent) at a mean follow-up of 3.9 years [89]. Six tumors metastasized (2.3 percent), resulting in one fatality.

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Unfortunately, Mohs surgery is time consuming and not universally available. If Mohs surgery cannot be performed, surgical excision with intraoperative frozen sections may be used to remove aggressive lesions. If neither technique is available and tissue conservation is not a concern, conventional surgical excision with postoperative margin examination may be used. Lesions treated with conventional surgical excision should be excised with at least 6 to 10 mm margins beyond the edge of erythema [73]. Guidelines from the National Comprehensive Cancer Network state that lesions ≥20 mm on the trunk or extremities should be excised with 10 mm margins [74]. As in immunocompetent patients, the role of sentinel lymph node biopsy for SCC in organ transplant recipients remains uncertain. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma", section on 'Sentinel lymph node biopsy'.)

Indications for radiation therapy — Radiation can be used to treat SCCs in patients who are unable to tolerate surgery. Radiation also is used as an adjunctive therapy for lesions that cannot be completely excised or that demonstrate extensive perineural involvement, especially nerves of larger diameter [73]. A disadvantage of radiation therapy is a possible increased risk for the future development of skin cancer in treated sites [90] and possible increased difficulty in treating recurrences. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Radiation therapy' and "Epidemiology and risk factors for cutaneous squamous cell carcinoma", section on 'Ionizing radiation' and "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma", section on 'Ionizing radiation'.)

Severe or metastatic disease — The management of organ transplant patients with life-threatening, metastatic disease is challenging. Metastatic disease has responded to systemic therapies such as platinum-based chemotherapeutic agents, capecitabine [46], and cetuximab [91,92]. Fatal diffuse alveolar damage has been reported in two lung transplant patients treated with cetuximab for metastatic cutaneous SCC, which raises concern about its use in such patients [93]. Treatment with the checkpoint inhibitor pembrolizumab in one renal transplant recipient with metastatic SCC was associated with tumor regression and acute allograft rejection [94]. (See "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas".)

Basal cell carcinoma — Basal cell carcinoma (BCC) is not associated with the same level of morbidity and mortality as SCC in organ transplant recipients. The management of BCC in this population resembles management in the immunocompetent patients. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence" and "Treatment of basal cell carcinomas at high risk for recurrence".) Imiquimod is a topical immunostimulatory agent that is sometimes used for the treatment of superficial BCC. The use of imiquimod for limited periods on small areas (60 to 100 cm2) appears to be safe in organ transplant recipients [60,61]. (See 'Actinic keratosis' above and "Treatment and prognosis of basal cell carcinoma at low risk of recurrence", section on 'Imiquimod'.)

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Melanoma — The management of melanoma in organ transplant recipients usually parallels the care of melanoma in the general population [95]. Patients with early-stage melanoma frequently can be managed with surgical excision; sentinel lymph node biopsy is indicated for lesions >1 mm in depth. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".) The use of systemic immunomodulatory or molecularly targeted therapies for metastatic melanoma has not been specifically studied in the organ transplant population. Immunostimulatory therapies such as interferon are generally considered unfavorable due to the possibility of graft rejection [96]. (See "Interleukin 2 and experimental immunotherapy approaches for advanced melanoma" and "Molecularly targeted therapy for metastatic melanoma".) The use of immune checkpoint inhibitors for metastatic melanoma treatment in solid organ transplant recipients is controversial due to minimal data to guide care. Case reports suggest ipilimumab may be more tolerated than programmed cell death protein 1 (PD1) inhibition in these patients, but further study is needed. Graft rejection has been documented with both medications [97-99]. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition".)

Immunosuppression reduction — The appropriate management of immunosuppression in patients diagnosed with melanoma has not been definitively determined; however, in general, immunosuppression should be reduced to the minimal regimen necessary to maintain organ tolerance (table 3). Greater reduction in immunosuppression can be considered in advanced cases, if the benefits of doing so are perceived to exceed the risks associated with rejection of the transplanted organ. Immunosuppression with sirolimus has been associated with a reduced risk of malignancy in organ transplant recipients [11,100]. However, the specific impact of sirolimus in patients who develop melanoma after organ transplantation is unknown.

Kaposi sarcoma — Reducing the level of immunosuppression is the primary therapy for Kaposi sarcoma in organ transplant recipients (table 3) [28,101]. In addition, regression of Kaposi sarcoma has been reported in renal transplant patients after a change in immunosuppressive medication from cyclosporine to sirolimus [102-105]. Local and systemic therapies may also be used in the management of these patients. (See 'mTOR inhibitors' above and "Development of malignancy following solid organ transplantation", section on 'Kaposi sarcoma'.)

Merkel cell carcinoma — No specific guidelines exist for the management of Merkel cell carcinoma in organ transplant recipients [106,107]. Surgical excision is the usual treatment of choice with radiation as an adjuvant therapy in some cases [106]. (See "Staging and treatment of Merkel cell carcinoma".)

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Reductions in immunosuppressive regimens have been reported to lead to temporary and partial regression of Merkel cell carcinoma in a few patients (table 3) [108,109]; however, additional studies are necessary to determine the best approach to treatment in organ transplant recipients.

FOLLOW-UP

Solid organ transplant recipients who have been treated for skin

cancer should have complete skin examinations on a regular basis. The palpation of lymph nodes should be performed at each visit. The frequency of visits depends upon the patient's medical history and the type and clinical behavior of the tumor. (See 'Post-transplantation surveillance' above.)

PROGNOSIS

A cohort study including nearly 500,000 patients who received a

solid organ transplantation in the United States between 1987 and 2013 examined the all-cause and skin cancer-specific mortality [110]. After a median follow-up time of 4.5 years (range 1.8 to 8.3 years), the skin cancer (squamous cell carcinoma, melanoma, and Merkel cell carcinoma) specific mortality was approximately 35 per 100,000 person-years, a rate nearly nine times higher than that reported for the general population [111]. Of interest, skin cancer-specific mortality was higher than breast cancer- and colon cancer-specific mortality (11.52 and 23.53 per 100,000 person-years, respectively). White patients in the 5- to 10-year post-transplantation period had the highest risk (hazard ratio 6.29, 95% CI 4.63-8.53). Other factors significantly associated with the risk of death from skin cancer included male sex, age >50, and thoracic transplantation. Although limited prognostic data are available on patients who develop melanoma following organ transplantation, the results of a few studies suggest that while organ transplant recipients with thin melanomas may have survival rates that are comparable to patients in the general population, those with thicker lesions may have worse prognoses [95,112,113]. The largest study is a retrospective review of records from 638 patients with 724 post-transplantation melanomas that compared threeyear survival rates in this population with survival data on melanoma patients from the Surveillance, Epidemiology, and End Results (SEER) Program [112]. Melanoma-specific survival rates were lower than expected among organ transplant recipients with melanomas with 1.5 to 3.0 mm Breslow thickness but not significantly different from SEER data for lesions 2 mm thick) [113]. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".) Data on the prognosis of patients with melanoma prior to organ transplantation also are limited [95,112,114]. An analysis of the data from two retrospective studies [113,115] with a total of 17 patients who had invasive melanoma prior to organ transplantation (median depth 1 mm, range 0.35 mm to 18 mm) found no disease recurrences or disease-related deaths after organ transplantation within a median follow-up period of 5.5 years [116]. Of note, the majority of patients were

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transplanted more than two years after treatment of their melanomas. In contrast, recurrences of pretransplant melanoma were reported in 6 out of 31 patients in another retrospective study [114]. The six patients died 6 to 30 months after transplantation. Merkel cell carcinoma in transplant recipients tends to have a more aggressive course than in immunocompetent patients; approximately 70 percent of patients develop lymph node involvement, and the mortality rate at two years is estimated to be 56 percent [107]. Therefore, patients should be followed closely for the development of metastatic disease. (See "Staging and treatment of Merkel cell carcinoma", section on 'Prognostic factors'.)

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nonmelanoma skin cancer".)

SUMMARY AND RECOMMENDATIONS ●Chronic immunosuppression in organ transplant recipients is associated with a high risk for cutaneous malignancies. Squamous cell carcinoma (SCC) is the most common skin cancer in this population and is often associated with aggressive biologic behavior. Early detection and treatment of cutaneous malignancies, modulation of immunosuppression, and preventive measures play an important role in the management of these patients. (See 'Introduction' above.) ●A dermatologic consultation is recommended before transplantation for the screening and treatment of skin cancer and precursor lesions. A careful history of previous skin cancer should be obtained to determine whether a wait time is needed before proceeding to transplantation. (See 'Pretransplantation screening' above and 'Wait time' above.) ●The preventive management of skin cancer in organ transplant recipients requires a close collaboration between dermatologists and transplant teams and involves patient education, choice and modulation of the immunosuppressive regimen, and post-transplantation surveillance. (See 'Prevention' above.) ●Transplant recipients should be counseled on sun avoidance, the use of sunscreens and sunprotective clothing, and the warning signs of cutaneous malignancy. Patients should be instructed to perform a skin self-examination on a monthly basis. (See 'Sun protection' above.) ●Because type, intensity, and duration of immunosuppression appear to promote the development of cutaneous malignancies in organ transplant recipients, modification or reduction of immunosuppression may be beneficial for patients who develop numerous lesions, recurrent disease, or metastatic disease (table 3). (See 'Choice and modulation of immunosuppressive regimen' above.)

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●Chemoprevention with acitretin may be of benefit in patients who develop multiple or aggressive SCCs. (See 'Chemoprevention for SCC' above.) ●After transplantation, patients should continue to have total body skin examinations on a regular basis. We typically perform full skin examinations at least once yearly on fair-skinned individuals. More frequent examinations are indicated in patients with a history of actinic keratoses or skin cancer. Daily sun protection should be strongly encouraged. (See 'Post-transplantation surveillance' above.) ●All lesions suspicious for SCC in organ transplant patients should be biopsied and sent for pathologic evaluation. Patients should be staged based on the American Joint Committee on Cancer 8th edition criteria (table 5) and the alternative Brigham and Women's Hospital staging scheme (table 6). The treatment of SCCs is based upon the presence or absence of high-risk features. (See 'Squamous cell carcinoma' above.) ●Because SCCs in organ transplant recipients are generally considered high-risk lesions, excisional therapies that provide evaluation of histologic margins are generally preferred. Some clinicians perform electrodesiccation and curettage at the time of biopsy on lesions that are clinically consistent with small, well-differentiated SCCs. If pathology results demonstrate aggressive histopathologic features, subsequent surgical excision should be performed to ensure adequate tumor removal. (See 'Invasive lesions without additional high-risk features' above.) ●For SCCs in organ transplant recipients that exhibit additional high-risk features, we suggest treatment with Mohs surgery due to the high cure rates and tissue-sparing effect of this treatment (Grade 2B). If Mohs surgery is not available, excision with intraoperative frozen sections can be utilized. If neither of these options is feasible, patients can be managed with conventional surgical excision with postoperative margin assessment. (See 'Invasive lesions with additional high-risk features' above.) ●Basal cell carcinoma (BCC), melanoma, and Merkel cell carcinoma are managed similarly in organ transplant recipients and immunocompetent patients. Modulation of immunosuppression is the primary treatment for Kaposi sarcoma in organ transplant recipients. There are no definitive guidelines regarding alteration in immunosuppressive regimens in patients with BCC, melanoma, or Merkel cell carcinoma. The risks and benefits of reduction in immunosuppression should be considered carefully. (See 'Basal cell carcinoma' above and 'Melanoma' above and 'Kaposi sarcoma' above and 'Merkel cell carcinoma' above.) ●Population-based data on skin cancer mortality among organ transplant recipients are limited. A cohort study including nearly 500,000 patients who received a solid organ transplantation in the Unites States estimated a mortality from all skin cancers, including SCC, melanoma, and Merkel cell carcinoma, of approximately 35 per 100,000 person-years, a rate nearly nine times higher than that reported for the general population. (See 'Prognosis' above.)

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Cellulitis and skin abscess: Clinical manifestations and diagnosis uptodate.com/contents/cellulitis-and-skin-abscess-clinical-manifestations-and-diagnosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Mar 28, 2019.

INTRODUCTION

Cellulitis, abscess, or both are among the most common

skin and soft tissue infections [1-3]. Cellulitis (which includes erysipelas) manifests as an area of skin erythema, edema, and warmth; it develops as a result of bacterial entry via breaches in the skin barrier [4]. A skin abscess is a collection of pus within the dermis or subcutaneous space. Misdiagnosis of these entities is common [5], and possible alternative diagnoses should be considered carefully. (See 'Differential diagnosis' below.) The epidemiology, microbiology, clinical manifestations, and diagnosis of cellulitis and skin abscess are reviewed here. Issues related to treatment of cellulitis and abscess are discussed separately. (See "Cellulitis and skin abscess in adults: Treatment".) Issues related to skin and soft tissue infections associated with specific epidemiologic factors (such as diabetes, animal bites, and water exposure) are discussed separately. (See "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities" and "Animal bites (dogs, cats, and other animals): Evaluation and management" and "Soft tissue infections following water exposure".) Issues related to infection involving the gluteal area and perineum are discussed separately. (See "Pilonidal disease" and "Perianal and perirectal abscess".)

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EPIDEMIOLOGY

Cellulitis is observed most frequently among middle-

aged and older adults. Erysipelas occurs in young children and older adults [6,7]. The incidence of cellulitis is about 200 cases per 100,000 patient-years [8] and, in nontropical regions, has a seasonal predilection for warmer months [8-12]. Skin abscess may occur in healthy individuals with no predisposing conditions. Predisposing factors associated with risk of cellulitis and/or skin abscess include [13-22]: ●Skin barrier disruption due to trauma (such as abrasion, penetrating wound, pressure ulcer, venous leg ulcer, insect bite, injection drug use) ●Skin inflammation (such as eczema, radiation therapy, psoriasis) ●Edema due to impaired lymphatic drainage ●Edema due to venous insufficiency ●Obesity ●Immunosuppression (such as diabetes or HIV infection) ●Skin breaks between the toes ("toe web intertrigo"); these may be clinically inapparent ●Pre-existing skin infection (such as tinea pedis, impetigo, varicella) Lymphatic compromise may occur following surgical procedures (such as saphenous venectomy or lymph node dissection) or in the setting of congenital abnormalities. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Post-venectomy cellulitis' and "Cellulitis following pelvic lymph node dissection".) An additional risk factor for development of purulent skin and soft tissue infections is close contact with others with methicillin-resistant Staphylococcus aureus infection or carriage. (See "Methicillinresistant Staphylococcus aureus (MRSA) in adults: Epidemiology" and "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'Epidemiology and risk factors'.)

MICROBIOLOGY Cellulitis and erysipelas — The most common cause of cellulitis is betahemolytic streptococci (groups A, B, C, G, and F), most commonly group A Streptococcus or Streptococcus pyogenes; S. aureus (including methicillin-resistant strains) is a notable but less common cause [4,18,23-29]. Gram-negative aerobic bacilli are identified in a minority of cases.

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The vast majority of erysipelas cases are caused by beta-hemolytic streptococci [7,23,30,31]. One study of nonpurulent cellulitis including 179 patients found that beta-hemolytic streptococci accounted for 73 percent of cases (diagnosed by positive blood culture results or serologic testing for anti-streptolysin-O and anti-DNase-B antibodies) [28]. No etiology was identified in 27 percent of cases, but the overall clinical response rate to beta-lactam therapy was 96 percent. Less common causes of cellulitis include Haemophilus influenzae type b (buccal cellulitis), clostridia and non-spore-forming anaerobes (crepitant cellulitis), Streptococcus pneumoniae, and Neisseria meningitidis [32-38]. In immunocompromised patients, the spectrum of potential pathogens is much broader, and infectious disease consultation is warranted. Pathogens implicated in special clinical circumstances discussed in detail separately include: ●Pasteurella multocida and Capnocytophaga canimorsus (see "Animal bites (dogs, cats, and other animals): Evaluation and management") ●Aeromonas hydrophila and Vibrio vulnificus (see "Soft tissue infections following water exposure") ●Pseudomonas aeruginosa (see "Fever and rash in immunocompromised patients without HIV infection" and "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities" and "Pseudomonas aeruginosa skin and soft tissue infections") ●Group B Streptococcus (see "Group B streptococcal infection in neonates and young infants", section on 'Other focal infection' and "Cellulitis following pelvic lymph node dissection", section on 'Streptococcal sex syndrome') ●Clostridium species (see "Clostridial myonecrosis") ●Erysipelothrix rhusiopathiae (see "Erysipelothrix infection") ●S. pneumoniae (see "Orbital cellulitis") ●Cryptococcus neoformans (see "Fever and rash in immunocompromised patients without HIV infection") ●Streptococcus iniae (see "Fever and rash in the immunocompetent patient") ●Helicobacter cinaedi (see "Fever and rash in HIV-infected patients") ●Mycobacterium abscessus (see "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum")

Skin abscess — The most common cause of skin abscess is S. aureus (either methicillin-susceptible or methicillin-resistant S. aureus), which occurs in up to 75 percent of cases. Risk factors are summarized in the table (table 1); many patients with MRSA infection have no risk factors [3,39-44].

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A skin abscess can be caused by more than one pathogen [40,45-47]; isolation of multiple organisms (including S. aureus together with S. pyogenes and gram-negative bacilli with anaerobes) is more common in patients with skin abscess involving the perioral, perirectal, or vulvovaginal areas [40]. Organisms of oral origin, including anaerobes, are seen most frequently among intravenous drug users [40]. Unusual causes of skin abscess include nontuberculous mycobacteria, blastomycosis, nocardiosis, and cryptococcosis (see related topics). Most abscesses are due to infection. However, sterile abscesses can occur in the setting of injected irritants. Examples include injected drugs (particularly oil-based ones) that may not be fully absorbed and so remain at the site of injection, causing local irritation. Sterile abscesses can turn into hard, solid lesions as they scar.

CLINICAL MANIFESTATIONS

Patients with skin

and soft tissue infection may present with cellulitis, abscess, or both [1-3,39].

Cellulitis and erysipelas — Cellulitis and erysipelas manifest as areas of skin erythema, edema, and warmth; they develop as a result of bacterial entry via breaches in the skin barrier [4]. Petechiae and/or hemorrhage can be seen in erythematous skin, and superficial bullae can occur. Fever and other systemic manifestations of infection may also be present. Cellulitis and erysipelas are nearly always unilateral, and the lower extremities are the most common site of involvement (picture 1A-B); bilateral involvement should prompt consideration of alternative causes [4,6,48]. (See 'Differential diagnosis' below.) Cellulitis involves the deeper dermis and subcutaneous fat; erysipelas involves the upper dermis and superficial lymphatics (figure 1). Cellulitis may present with or without purulence; erysipelas is nonpurulent [1-3]. Patients with cellulitis tend to have a more indolent course with development of localized symptoms over a few days. Patients with erysipelas generally have acute onset of symptoms with systemic manifestations, including fever, chills, severe malaise, and headache; these can precede onset of local inflammatory signs and symptoms by minutes to hours. In erysipelas, there is clear demarcation between involved and uninvolved tissue [49]. There may be a raised, advancing border or erythema with central clearing. Classic descriptions of erysipelas note "butterfly" involvement of the face. Involvement of the ear (Milian's ear sign) is a distinguishing feature for erysipelas, since this region does not contain deeper dermis tissue. Additional manifestations of cellulitis and erysipelas include lymphangitis and enlargement of regional lymph nodes. Edema surrounding the hair follicles may lead to dimpling in the skin, creating an appearance reminiscent of an orange peel texture ("peau d'orange"). Vesicles, bullae, and ecchymoses or petechiae may be observed. Cutaneous hemorrhage can occur in the setting of significant inflammation in the skin. Crepitant and gangrenous cellulitis are unusual manifestations

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of cellulitis due to clostridia and other anaerobes. Severe manifestations with systemic toxicity should prompt investigation for additional underlying sources of infection. (See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis" and "Staphylococcal toxic shock syndrome".) The interdigital toe spaces should be examined for fissuring or maceration; minimizing these conditions may reduce the likelihood of recurrent lower-extremity cellulitis. Other forms of cellulitis include orbital cellulitis, abdominal wall cellulitis (in morbidly obese individuals), buccal cellulitis (due to S. pneumoniae and, prior to the conjugate vaccine era, H. influenzae type b) and perianal cellulitis (due to group A beta-hemolytic Streptococcus) [50,51]. Rarely, infections involving the medial third of the face (ie, the areas around the eyes and nose) can be complicated by septic cavernous thrombosis, since the veins in this region are valveless (figure 2). (See "Orbital cellulitis" and "Septic dural sinus thrombosis".) Laboratory findings are nonspecific and may include leukocytosis and elevated inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) [4,52].

Skin abscess — A skin abscess is a collection of pus within the dermis or subcutaneous space (picture 2 and figure 1). It manifests as a painful, fluctuant, erythematous nodule, with or without surrounding cellulitis [40]. Spontaneous drainage of purulent material may occur. Regional adenopathy may be observed. Fever, chills, and systemic toxicity are unusual. A skin abscess may develop via deep infection of a hair follicle (known as a furuncle or boil), which reflects extension of purulent material through the dermis into the subcutaneous tissue. Multiple furuncles can coalesce to form carbuncles (picture 3), which may be associated with systemic symptoms. Common areas of involvement include the back of the neck, face, axillae, and buttocks.

Complications — Complications of cellulitis and abscess include bacteremia, endocarditis, septic arthritis or osteomyelitis, metastatic infection, sepsis, and toxic shock syndrome [4].

DIAGNOSIS

The diagnosis of cellulitis, erysipelas, and skin abscess is usually

based upon clinical manifestations. Cellulitis and erysipelas manifest as areas of skin erythema, edema, and warmth. Erysipelas lesions are raised above the level of surrounding skin with clear demarcation between involved and uninvolved tissue. A skin abscess manifests as a painful, fluctuant, erythematous nodule, with or without surrounding cellulitis (picture 2). Laboratory testing is not required for patients with uncomplicated infection in the absence of comorbidities or complications. Patients with drainable abscess should undergo incision and drainage [53,54]. Routine culture of debrided material is not necessary in healthy patients who do not receive antibiotics.

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Cultures of debrided material and blood cultures (prior to addition of antibiotic therapy) are warranted in the following circumstances [55,56]: ●Severe local infection (eg, extensive cellulitis) ●Systemic signs of infection (eg, fever) ●History of recurrent or multiple abscesses ●Failure of initial antibiotic therapy ●Extremes of age (young infants or older adults) ●Presence of underlying comorbidities (lymphedema, malignancy, neutropenia, immunodeficiency, splenectomy, diabetes) ●Special exposures (animal bite, water-associated injury) ●Presence of indication for prophylaxis against infective endocarditis ●Community patterns of S. aureus susceptibility are unknown or rapidly changing Blood cultures are positive in less than 10 percent of cellulitis cases [57-59]. A skin biopsy may be warranted if the diagnosis is uncertain; cultures of skin biopsy specimens yield a pathogen in 20 to 30 percent of cases [60-63]. Cultures of swabs from intact skin are not helpful and should not be performed [2,3]. Radiographic examination can be useful to determine whether a skin abscess is present (via ultrasonography) and for distinguishing cellulitis from osteomyelitis (via magnetic resonance imaging) [64-67]. Radiographic evaluation may be warranted in patients with underlying immunosuppression, diabetes, venous insufficiency, or lymphedema and in patients with persistent systemic symptoms. Radiographic examination cannot reliably distinguish cellulitis from necrotizing fasciitis or gas gangrene; if there is clinical suspicion for these entities, radiographic imaging should not delay surgical intervention [68,69]. (See "Necrotizing soft tissue infections" and "Clostridial myonecrosis".) In patients with recurrent cellulitis, serologic testing for beta-hemolytic streptococci may be a useful diagnostic tool. Assays include the anti-streptolysin-O (ASO) reaction, the anti-deoxyribonuclease B test (anti-DNAse B), the anti-hyaluronidase test (AHT), or the Streptozyme antibody assay [24]. AntiDNase B and AHT responses are more reliable than the ASO response following group A streptococcal skin infections. (See "Cellulitis and skin abscess in adults: Treatment", section on 'Recurrent infection'.)

DIFFERENTIAL DIAGNOSIS 3345

Cellulitis and erysipelas — Cellulitis is often confused with other infections or noninfectious illnesses [70,71]. Rapidly progressive erythema with signs of systemic toxicity should prompt consideration of severe infection, including: ●Necrotizing fasciitis – Necrotizing fasciitis is a deep infection that results in progressive destruction of the muscle fascia. The affected area may be erythematous, swollen, warm, and exquisitely tender. Pain out of proportion to exam findings may be observed. The diagnosis is established surgically with visualization of fascial planes. (See "Necrotizing soft tissue infections".) ●Toxic shock syndrome – Toxic shock syndrome typically presents with pain that precedes physical findings. Clinical signs of soft tissue infection consist of local swelling and erythema followed by ecchymoses and sloughing of skin. Fever is common. Patients may be normotensive on presentation but subsequently become hypotensive. (See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".) ●Gas gangrene or myonecrosis – Gas gangrene should be suspected in the setting of fever and severe pain in an extremity, particularly in the setting of recent surgery or trauma. The presence of tissue crepitus favors clostridial infection. Gas gangrene can also be detected radiographically. (See "Clostridial myonecrosis".) Cellulitis must be distinguished from other infections including: ●Erythema migrans – Erythema migrans is an early manifestation of Lyme disease; it consists of a region of erythema at the site of a tick bite, often with central clearing and a necrotic center (picture 4). The diagnosis is established based on serologic testing, although sensitivity in early disease is low. A similar lesion may occur in patients with Southern tick–associated rash illness. (See "Clinical manifestations of Lyme disease in adults" and "Southern tick-associated rash illness (STARI)".) ●Herpes zoster – The rash of herpes zoster begins as erythematous papules that evolve into grouped vesicles (picture 5). The rash is generally limited to one dermatome but can affect two or three neighboring dermatome. The diagnosis is established by polymerase chain reaction (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".) ●Septic arthritis – Cellulitis may overlie a septic joint. Clinical manifestations include joint pain, swelling, warmth, and limited range of motion. The diagnosis of septic arthritis is established based on synovial fluid examination. (See "Septic arthritis in adults".) ●Septic bursitis – Cellulitis may precede or accompany septic bursitis. Distinguishing cellulitis with and without bursitis depends on skilled palpation. Radiographic imaging is warranted if septic bursitis is suspected. (See "Septic bursitis".)

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●Osteomyelitis – Osteomyelitis may underlie an area of cellulitis. It is prudent to pursue imaging for assessment of bone involvement in the setting of chronic soft tissue infection that fails to improve with appropriate antibiotic therapy. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis".) ●Mycotic aneurysm – Mycotic aneurysm should be suspected in the setting of erythema, swelling, and tenderness at an intravenous drug injection site such as antecubital fossa [72]. The diagnosis is established via ultrasonography. (See "Overview of infected (mycotic) arterial aneurysm".) Noninfectious masqueraders of cellulitis (unilateral) include: ●Contact dermatitis – Contact dermatitis may be distinguished from cellulitis in that the contact dermatitis lesions are pruritic. Clinical features include erythema, edema, vesicles, bullae, and oozing. The reaction is generally limited to the site of contact and is associated with burning, stinging, or pain. (See "Irritant contact dermatitis in adults".) ●Acute gout – Acute gouty arthritis consists of severe pain, warmth, erythema, and swelling overlying a single joint. The diagnosis can be established by synovial fluid analysis, which should demonstrate the characteristic urate crystals of gout or the calcium pyrophosphate crystals of pseudogout. Additional clues suggestive of gout include involvement of the first metatarsophalangeal joint, prior self-limited attacks of arthritis, and presence of tophi. (See "Clinical manifestations and diagnosis of gout".) ●Drug reaction – A drug reaction presents with an erythematous maculopapular rash that involves the trunk and proximal extremities. It may be accompanied by pruritus, low-grade fever, and mild eosinophilia. The diagnosis is suspected in a patient receiving drug treatment who presents with a rash of recent onset. The clinical suspicion can be substantiated by histopathologic examination of a skin biopsy. (See "Exanthematous (maculopapular) drug eruption".) ●Vasculitis – The morphology of cutaneous lesions of vasculitis is variable. Macular and papular lesions are characteristically nonblanchable due to the presence of extravasated erythrocytes in the dermis, which occurs as a result of damaged vessel walls. The diagnosis is established by skin biopsy. (See "Evaluation of adults with cutaneous lesions of vasculitis".) ●Insect bite – An insect bite triggers an inflammatory reaction at the site of the punctured skin, which appears within minutes and consists of pruritic local erythema and edema. In some cases, a local reaction is followed by a delayed skin reaction consisting of local swelling, itching, and erythema. (See "Insect and other arthropod bites".) ●Deep venous thrombosis – Findings suggestive of cellulitis involving the lower extremity should prompt consideration of deep venous thrombosis; the evaluation consists of ultrasound evaluation. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)

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●Panniculitis – Panniculitis refers to inflammation of subcutaneous fat and may have many causes, both infectious and noninfectious (table 2). The diagnosis is confirmed via biopsy. (See "Panniculitis: Recognition and diagnosis".) ●Vaccination site reaction – A local reaction to vaccination manifests with erythema, swelling, and tenderness at the injection site; these are typically self-limited. (See "Allergic reactions to vaccines", section on 'Delayed vaccine reactions'.) ●Erythema ab igne - Erythema ab igne is an erythematous pigmented dermatosis resulting from repeated exposures to moderate heat or infrared radiation. The diagnosis is established clinically and may be confirmed by biopsy. (See "Acquired hyperpigmentation disorders", section on 'Erythema ab igne'.) Noninfectious masqueraders of cellulitis (bilateral) include: ●Stasis dermatitis – Stasis dermatitis is an inflammatory dermatosis of the lower extremities that occurs in patients with chronic venous insufficiency. It is usually bilateral but can be unilateral in the setting of anatomic asymmetry. The diagnosis is usually established clinically. (See "Stasis dermatitis" and "Clinical manifestations of lower extremity chronic venous disease".) ●Lipodermatosclerosis – Lipodermatosclerosis is a fibrosing panniculitis of the subcutaneous tissue that can develop in the setting of chronic venous insufficiency following severe cases of deep venous thrombosis or associated with lymphatic compromise. Typically the overlying skin is heavily pigmented and bound down to the subcutaneous tissues. (See "Clinical manifestations of lower extremity chronic venous disease", section on 'Lipodermatosclerosis'.) ●Lymphedema – Lymphedema is abnormal accumulation of interstitial fluid resulting from injury or anatomic abnormality of the lymphatic system. The diagnosis is usually established clinically. (See "Clinical features and diagnosis of peripheral lymphedema".)

Skin abscess — Skin lesions that should be distinguished from skin abscess include: ●Epidermoid cyst – An epidermoid cyst is a skin-colored cutaneous nodule. The diagnosis is usually clinical, based on the clinical appearance of a discrete cyst or nodule, often with a central punctum, that is freely movable on palpation. Epidermoid cysts may become secondarily infected. (See "Overview of benign lesions of the skin", section on 'Epidermoid cyst'.) ●Folliculitis – Folliculitis refers to inflammation of one or more hair follicles. The diagnosis is often established clinically; rarely, Gram stain and culture or skin biopsy may be warranted to differentiate folliculitis from other conditions. (See "Infectious folliculitis".) ●Hidradenitis suppurativa – Hidradenitis suppurativa is a chronic suppurative process involving the skin and subcutaneous tissue of intertriginous skin. The diagnosis is usually established clinically. (See "Hidradenitis suppurativa: Pathogenesis, clinical features, and diagnosis".)

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●Nodular lymphangitis – Nodular lymphangitis presents as nodular subcutaneous swellings along the course of the lymphatic channels. The differential diagnosis is broad and is summarized separately. (See "Lymphangitis", section on 'Nodular lymphangitis'.) ●Botryomycosis – Botryomycosis is a chronic, suppurative infection characterized by a granulomatous inflammatory response to S. aureus and other bacteria; it occurs most commonly in immunocompromised patients. The diagnosis is established via Gram stain, culture, or examination of pus for granules. (See "Botryomycosis".) ●Myiasis – Myiasis presents as an enlarging nodular associated with an insect bite; it is caused by penetration of fly larvae into subdermal tissue. The diagnosis is established via clinical manifestations in the setting of epidemiologic exposure to tropical and subtropical areas. (See "Skin lesions in the returning traveler", section on 'Myiasis'.) The differential diagnosis for skin and soft tissue infections in immunocompromised patients is summarized separately. (See "Clinical manifestations, diagnosis, and grading of acute graft-versushost disease", section on 'Differential diagnosis'.)

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Skin and soft tissue infections".)

SUMMARY ●Patients with skin and soft tissue infection may present with cellulitis, abscess, or both. Misdiagnosis of these entities is common, and possible alternative diagnoses should be considered carefully. (See 'Introduction' above and 'Differential diagnosis' above.) ●Risk factors for development of cellulitis and/or skin abscess include skin barrier disruption, edema, venous insufficiency, and immunosuppression. However, healthy individuals with no risk factors may also develop these infections. (See 'Epidemiology' above.) ●The most common microbiologic cause of cellulitis is beta-hemolytic streptococci (groups A, B, C, G, and F), most commonly group A Streptococcus or Streptococcus pyogenes; Staphylococcus aureus (including methicillin-resistant strains) is a notable but less common cause. The vast majority of erysipelas cases are caused by beta-hemolytic streptococci. The most common microbiologic cause of skin abscess is S. aureus; a skin abscess can be caused by more than one pathogen. (See 'Microbiology' above.) ●Cellulitis and erysipelas manifest as areas of skin erythema, edema, and warmth. Erysipelas lesions are raised above the level of surrounding skin with clear demarcation between involved and uninvolved tissue. Cellulitis and erysipelas are nearly always unilateral, and the lower extremities are

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the most common site of involvement. Cellulitis may present with or without purulence; erysipelas is nonpurulent. A skin abscess manifests as a painful, fluctuant, erythematous nodule, with or without surrounding cellulitis. (See 'Clinical manifestations' above.) ●The diagnosis of cellulitis, erysipelas, and skin abscess is usually based upon clinical manifestations. Patients with drainable abscess should undergo incision and drainage, with culture and susceptibility testing of debrided material. Blood cultures are warranted for patients in the circumstances described above. (See 'Diagnosis' above.) ●Radiographic examination can be useful to determine whether skin abscess is present (via ultrasonography) and for distinguishing cellulitis from osteomyelitis (via magnetic resonance imaging). Radiographic evaluation may be warranted in patients with underlying immunosuppression, diabetes, venous insufficiency, or lymphedema and in patients with persistent systemic symptoms. (See 'Diagnosis' above.)

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Cellulitis and skin abscess in adults: Treatment uptodate.com/contents/cellulitis-and-skin-abscess-in-adults-treatment/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Apr 01, 2019.

INTRODUCTION

Patients with skin and soft tissue infection may present

with cellulitis, abscess, or both [1-3]. Treatment of cellulitis and skin abscess are reviewed here. Issues related to clinical manifestations and diagnosis of cellulitis and abscess are discussed separately. (See "Cellulitis and skin abscess: Clinical manifestations and diagnosis".) Issues related to skin and soft tissue infections associated with specific epidemiologic factors (such as diabetes, animal bites, and water exposure) are discussed separately. (See "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities" and "Soft tissue infections following water exposure" and "Animal bites (dogs, cats, and other animals): Evaluation and management" and "Human bites: Evaluation and management".) Issues related to infection involving the gluteal area and perineum are discussed separately. (See "Perianal and perirectal abscess" and "Pilonidal disease".)

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GENERAL PRINCIPLES Overview — The approach to management of skin and soft tissue infection depends on the clinical presentation: ●Patients with nonpurulent infection (ie, cellulitis or erysipelas in the absence of abscess or purulent drainage) should be managed with empiric antibiotic therapy (algorithm 1). (See 'Nonpurulent infection' below.) ●Patients with drainable abscess should undergo incision and drainage; the technique is discussed separately (see "Technique of incision and drainage for skin abscess"). In addition, antibiotic therapy is warranted if clinical criteria are met, as discussed below (algorithm 2). (See 'Drainable abscess present' below.) ●Patients with purulent cellulitis (ie, cellulitis associated with purulent drainage in the absence of drainable abscess) should be managed with antibiotic therapy (algorithm 2). (See 'Purulent cellulitis (no drainable abscess)' below.) Issues related to choosing between oral and parenteral therapy are discussed below. (See 'Oral versus parenteral therapy' below.) Attention to antibiotic dosing is important, particularly in obese individuals; underdosing (particularly in those with morbid obesity and lymphedema) may result in higher rates of treatment failure [4]. The approach to empiric antimicrobial therapy should be modified as indicated in the setting of known pathogens, underlying conditions (such as diabetes), and special circumstances (such as animal bites and water exposure). Management of patients in these settings is discussed in detail separately. (See "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities" and "Animal bites (dogs, cats, and other animals): Evaluation and management" and "Soft tissue infections following water exposure" and "Human bites: Evaluation and management".) Other components of management include elevation of the affected area and treatment of underlying conditions (such as edema or underlying cutaneous disorders) if present [2]. Elevation facilitates gravity drainage of edema and inflammatory substances. The skin should be sufficiently hydrated to avoid dryness and cracking without interdigital maceration.

Oral versus parenteral therapy — Patients with mild infection may be treated with oral antibiotics. Treatment with parenteral antibiotics is warranted in the following circumstances: ●Systemic signs of toxicity (eg, fever >100.5°F/38°C, hypotension, or sustained tachycardia)

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●Rapid progression of erythema ●Progression of clinical findings after 48 hours of oral antibiotic therapy ●Inability to tolerate oral therapy ●Proximity of the lesion to an indwelling medical device (eg, prosthetic joint or vascular graft) The decision to initiate parenteral therapy should be based on individual clinical circumstances such as severity of clinical presentation and patient comorbidities. As an example, the presence of an immunocompromising condition (such as neutropenia, recent organ transplant, advanced HIV infection, B cell or T cell deficiency, or use of immunosuppressive agents) should lower the threshold for parenteral therapy.

CLINICAL APPROACH Nonpurulent infection — Forms of nonpurulent skin and soft tissue infection include cellulitis and erysipelas. (See "Cellulitis and skin abscess: Clinical manifestations and diagnosis", section on 'Cellulitis and erysipelas'.) Management of cellulitis and erysipelas should include elevation of the affected area and treatment of underlying conditions. (See 'Overview' above.) Many patients with cellulitis have underlying conditions that predispose them to developing recurrent cellulitis (these include tinea pedis, lymphedema, and chronic venous insufficiency). In such patients, treatment should be directed at both the infection and the predisposing condition if modifiable. As an example, patients with edema may benefit from treatment with compressive stockings and diuretic therapy.

Cellulitis — Patients with nonpurulent cellulitis (eg, cellulitis with no purulent drainage or exudate and no associated abscess) should be managed with empiric therapy for infection due to beta-hemolytic streptococci and methicillin-susceptible Staphylococcus aureus (MSSA) [1-3]. Common options are cefazolin for intravenous therapy and cephalexin for oral therapy; options and doses are summarized in the algorithm (algorithm 1). Issues related to choosing between oral and parenteral therapy are discussed above. (See 'Oral versus parenteral therapy' above.) This approach is supported by the following studies: ●A randomized trial including 496 patients with nonpurulent cellulitis (in the modified intention-totreat analysis) noted similar clinical cure rates among those treated with cephalexin plus placebo (for empiric treatment of beta-hemolytic streptococci and MSSA; 69 percent) and those treated with cephalexin plus trimethoprim-sulfamethoxazole (TMP-SMX; for empiric treatment of beta-hemolytic streptococci and methicillin-resistant S. aureus [MRSA]; 76 percent; difference 7.3 percent; 95% CI

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-1.0 to 15.5 percent; p=0.09) [5]. While these findings raise the possibility that addition of TMP-SMX may be somewhat superior to cephalexin alone, the results were likely skewed by a relatively large number of patients who did not complete the full course of therapy. ●A randomized trial including 153 patients with cellulitis without abscess noted comparable cure rates among those treated with cephalexin (for empiric treatment of beta-hemolytic streptococci and MSSA; 82 percent) and those treated with cephalexin and TMP-SMX (for empiric MRSA coverage; 85 percent) [6]. Additional empiric coverage for MRSA is warranted in the following circumstances [2,7]: ●Systemic signs of toxicity (eg, fever >100.5°F/38°C, hypotension, or sustained tachycardia) ●Prior episode of MRSA infection or known MRSA colonization ●Lack of clinical response to antibiotic regimen that does not include activity against MRSA ●Presence of risk factor(s) for MRSA infection (including recent hospitalization, residence in a longterm care facility, recent surgery, hemodialysis, and HIV infection) ●Proximity of the lesion to an indwelling medical device (eg, prosthetic joint or vascular graft) Issues related to treatment of MRSA infection are discuss further below. (See 'Approach to antibiotic therapy' below.) Deepening of erythema may be observed following initiation of antimicrobial therapy. This may be due to destruction of pathogens that release enzymes increasing local inflammation and should not be mistaken for therapeutic failure. Patients with cellulitis typically have symptomatic improvement within 24 to 48 hours of beginning antimicrobial therapy, although visible improvement of clinical manifestations in more severe cases may take up to 72 hours. Persistence of erythema and/or systemic symptoms after this period of time should prompt consideration of resistant pathogens or alternative diagnoses. In such cases, culture data should be reviewed carefully, pursuit of radiographic evaluation for deeper infection is appropriate, and broadening antibiotic therapy to include coverage for gram-negative bacilli pending further diagnostic data is reasonable. (See "Cellulitis and skin abscess: Clinical manifestations and diagnosis", section on 'Diagnosis'.) The duration of therapy should be individualized depending on clinical response. In general, five days of therapy is appropriate for patients with uncomplicated cellulitis whose infection has improved within this time period [2,8]. Extension of antibiotic therapy (up to 14 days) may be warranted in the setting of severe infection, slow response to therapy, or immunosuppression. In one study including 216 patients hospitalized with nonpurulent cellulitis, 90 percent of patients had improvement in clinical findings and serum C-reactive protein concentration 3 days after initiation of antimicrobial therapy [9,10]. More than half of patients had residual inflammation at the

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end of therapy (median 11 to 15 days), but relapse occurred in only 16 percent of these cases.

Erysipelas — Patients with erysipelas should be managed with empiric therapy for infection due to beta-hemolytic streptococci. Patients with systemic manifestations (such as fever and chills) should be treated with parenteral therapy. Appropriate choices include cefazolin, ceftriaxone, or flucloxacillin (algorithm 1). Cefazolin has activity against streptococci as well as MSSA, which is useful in settings where erysipelas cannot be reliably distinguished from cellulitis. Ceftriaxone has activity against streptococci (and may be used for activity against MSSA in some circumstances), and its once-daily dosing allows for convenient outpatient administration. Patients with mild infection or those who have improved following initial treatment with parenteral antibiotic therapy may be treated with oral penicillin or amoxicillin (algorithm 1). In the setting of beta-lactam allergy, cephalexin (if the patient can tolerate cephalosporins), clindamycin, trimethoprim-sulfamethoxazole, or linezolid may be used; data regarding use of trimethoprimsulfamethoxazole are limited [2,11]. Macrolides (such as erythromycin) may not be adequate in areas with relatively high resistance rates among beta-hemolytic streptococci [2,12]. The duration of therapy should be individualized depending on clinical response; 5 to 14 days is usually appropriate.

Recurrent infection First recurrence — Recurrent cellulitis is common; 22 to 49 percent of patients with cellulitis report at least one prior episode [3]. Recurrences occur in approximately 14 percent of cellulitis cases within one year and 45 percent of cases within three years, usually in the same location [3]. In one review of more than 447,000 index admissions for cellulitis, the readmission rates was 9.8 percent; most readmissions are due to skin and soft tissue infections [13]. Underlying conditions that predispose to recurrent cellulitis include [14-22]: ●Edema due to impaired lymphatic drainage ●Venous insufficiency ●Obesity ●Immunosuppression ●Fissuring or maceration of the interdigital toe spaces ●Tinea pedis

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Patients with suspected recurrent infection should be evaluated carefully to rule out alternative diagnoses. (See "Cellulitis and skin abscess: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.) The approach to treatment of a recurrent episode is the same as the approach for an initial episode. In addition, predisposing condition(s) should be identified and alleviated if possible [3]. As an example, patients with edema may benefit from treatment with compressive stockings and diuretic therapy. (See "Clinical staging and conservative management of peripheral lymphedema" and "Medical management of lower extremity chronic venous disease" and "Dermatophyte (tinea) infections".) For patients with recurrent infection due to S. aureus, attempting decolonization is reasonable; this is discussed further separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Prevention and control", section on 'Targeted decolonization' and "Methicillin-resistant Staphylococcus aureus (MRSA) in children: Prevention and control".)

Subsequent recurrences — For patients with three to four episodes of cellulitis per year in the setting of predisposing factors that cannot be alleviated, suppressive antibiotic therapy may be warranted (for as long as the predisposing factors persist) [2]. Serologic testing for beta-hemolytic streptococci may be a useful diagnostic tool to help guide the choice of suppressive antibiotic therapy. (See "Cellulitis and skin abscess: Clinical manifestations and diagnosis", section on 'Diagnosis'.) Antibiotic options for suppressive therapy include: ●For patients with known or presumed beta-hemolytic streptococcal infection [23,24]: •Penicillin V (250 to 500 mg orally twice daily) •Erythromycin (250 mg orally twice daily) •Penicillin G benzathine intramuscular injections (1.2 million units for patients who weigh >27 kg; 600,000 units for patients who weigh ≤27 kg) administered every two to four weeks ●For patients with known or presumed staphylococcal infection [25]: •Cefadroxil (500 mg orally twice daily; for treatment of MSSA infection) •Clindamycin (150 mg orally once daily) •Trimethoprim-sulfamethoxazole (one double-strength tablet orally twice daily) Suppressive therapy may be continued for several months with interval assessments for efficacy and tolerance. If recurrent cellulitis occurs, the patient should be reevaluated promptly; patients may be given instructions to self-initiate antibiotic therapy at onset of symptoms prior to seeking immediate medical attention.

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Support for suppressive antibiotic therapy for prevention of recurrent infection comes from the following studies: ●In a study of 209 cases of cellulitis, recurrences were observed in 17 percent of patients; among 143 patients with erysipelas, 29 percent had recurrent infection [14,26]. Early episodes of cellulitis cause lymphatic inflammation, and repeated infection can lead to lymphedema. Supportive care with elevation of the affected area and treatment of underlying predisposing conditions are paramount. (See "Clinical staging and conservative management of peripheral lymphedema".) ●In a systematic review and meta-analysis of five trials with a total of over 500 patients with at least one prior episode of cellulitis, prophylactic antibiotic use reduced the risk of subsequent cellulitis (relative risk [RR] 0.46, 95% CI 0.26-0.79) [27]. Findings from two of the included studies also demonstrated that antibiotic prophylaxis is cost-effective [28]. ●In a subsequent randomized trial that included 274 patients with two or more episodes of lower extremity cellulitis, penicillin (250 mg orally twice daily) nearly halved the risk of recurrence during 12 months of prophylaxis (hazard ratio 0.55; 95% CI 0.35 to 0.86; p = 0.01), but the protective effect diminished rapidly after the prophylaxis period ended [23]. A lower likelihood of response was observed among patients with a body mass index ≥33, multiple previous episodes of cellulitis, or lymphedema of the leg. These findings warrant further investigation since patients in these categories are most likely to receive long-term prophylaxis.

Purulent infection — Purulent infection refers to presence of a drainable abscess or cellulitis associated with purulent drainage (in the absence of drainable abscess) (algorithm 2). An infection involving purulence (whether the process began as an abscess [with secondary cellulitis] or as a cellulitis [with secondary purulence]) is potentially attributable to S. aureus, which should be reflected in the choice of empiric antimicrobial therapy.

Drainable abscess present — Patients with drainable abscess should undergo incision and drainage (algorithm 2) [29,30]. The technique for incision and drainage and the role of culture are discussed separately. (See "Technique of incision and drainage for skin abscess".) Individuals at risk for endocarditis warrant empiric antibiotic therapy prior to incision and drainage; an oral antibiotic with activity against MRSA and beta-hemolytic Streptococcus should be administered one hour prior to procedure (algorithm 2) [31,32]. (See "Antimicrobial prophylaxis for the prevention of bacterial endocarditis".)

Role of antibiotic therapy — For patients undergoing incision and drainage of a skin abscess, we suggest antibiotic treatment. In particular, we favor antibiotic treatment for patients with any of the following: ●Single abscess ≥2 cm [33-35] ●Multiple lesions

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●Extensive surrounding cellulitis ●Associated immunosuppression or other comorbidities ●Systemic signs of toxicity (eg, fever >100.5°F/38°C, hypotension, or sustained tachycardia) ●Inadequate clinical response to incision and drainage alone ●Presence of an indwelling medical device (such as prosthetic joint, vascular graft, or pacemaker) ●High risk for adverse outcomes with endocarditis (these include a history of infective endocarditis, presence of prosthetic valve or prosthetic perivalvular material, unrepaired congenital heart defect, or valvular dysfunction in a transplanted heart) ●High risk for transmission of S. aureus to others (such as in athletes or military personnel) However, because many abscesses can be treated successfully with incision and drainage alone, expert opinion varies, and it is reasonable to forgo antibiotic therapy in otherwise healthy patients who have small abscesses (eg, 12 years of age (median 35 years) with abscess 2 to 5 cm in diameter who underwent incision and drainage, treatment with TMP-SMX (320 mg/1600 mg twice daily) resulted in higher cure rates 7 to 14 days after treatment than placebo (80.5 versus 73.6 percent) [33]. Wound cultures were positive for MRSA in 45 percent of cases. A subsequent subgroup analysis of this cohort also demonstrated improved outcomes among the TMP-SMX recipients [35]. ●In another randomized trial including more than 780 patients with skin abscess ≤5 cm (45 percent were ≤2 cm) who underwent incision and drainage, treatment with TMP-SMX or clindamycin each resulted in higher cure rates at 10 days than placebo (82 or 83 percent versus 69 percent) [34]. MRSA was isolated in 49 percent of cases. The above randomized trials were included in a systematic review and meta-analysis of more than 2400 patients with drained abscess treated with antibiotics or placebo [39]. The rate of treatment failure was lower among patients who received antibiotics (7 versus 16 percent); the odds ratio for clinical cure was 2.3 (95% CI 1.7-3.1). A separate systematic review and meta-analysis including

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more than 400 patients concluded treatment with TMP-SMX or clindamycin reduced the risk of treatment failure compared with placebo, albeit with some risk of drug-adverse (primarily gastrointestinal) events; cephalosporins failed to reduce treatment failure rates [40]. Antimicrobial therapy may also decrease the risk of recurrent skin abscess. In one randomized trial, new infections at one month of follow-up were less common among those who received clindamycin than those who received TMP-SMX or placebo [34]. In another randomized trial, the likelihood of recurrent abscess formation was lower in patients who received TMP-SMX than in patients who received placebo [38]. The approach to empiric antibiotic selection and duration of therapy is as described below. (See 'Approach to antibiotic therapy' below.)

Purulent cellulitis (no drainable abscess) — Patients with cellulitis associated with purulent drainage (in the absence of drainable abscess) should be managed with antibiotic therapy (algorithm 2). The approach to empiric antibiotic selection and duration of therapy is as described below. (See 'Approach to antibiotic therapy' below.)

Approach to antibiotic therapy — The approach to empiric antibiotic selection is the same for all patients with purulent infection, including: ●Patients with drainable abscess and relevant clinical criteria (see 'Role of antibiotic therapy' above) ●Patients with cellulitis and associated purulent drainage, in the absence of a drainable abscess (see 'Purulent cellulitis (no drainable abscess)' above) It is useful to document the baseline appearance of the physical findings at the start of antibiotic therapy. A baseline digital image should be taken to monitor progress.

Pathogens to cover — Patients with purulent infection (as defined in the preceding section) should be managed with empiric therapy for infection due to MRSA, pending culture results (algorithm 2) [1,2]. Empiric therapy for infection due to beta-hemolytic streptococci is usually not necessary. Empiric therapy selection should be tailored to culture and susceptibility results when available. This approach is supported by findings of a study including 422 patients with purulent soft tissue infection in which MRSA was the dominant organism (isolated from 59 percent of patients), followed by MSSA (isolated from 17 percent of patients); beta-hemolytic streptococci accounted for a much smaller proportion of these infections (2.6 percent) [41]. Initial management of patients with purulent infection in association with a pressure ulcer, a perioral or peri-rectal site of infection, or prominent skin necrosis consists of antimicrobial therapy that includes empiric coverage for MRSA as well as gram-negative and anaerobic organisms (pending culture and susceptibility results) (algorithm 2).

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Choosing an antibiotic agent — Issues related to choosing between oral and parenteral therapy are discussed above. (See 'Oral versus parenteral therapy' above.) Options for empiric oral therapy of purulent infection (ie, with activity against MRSA) include clindamycin, TMP-SMX, or tetracyclines (doxycycline or minocycline) (table 1 and algorithm 2). The efficacy of clindamycin and TMP-SMX for treatment of uncomplicated skin infection may be considered comparable; this was illustrated in a randomized trial that included 524 patients with uncomplicated skin infections, including both cellulitis and abscesses (cure rates for clindamycin and TMP-SMX were 80 and 78 percent, respectively) [42]. For oral anti-MRSA coverage, however, we generally favor TMP-SMX, doxycycline, or minocycline; clindamycin is less frequently chosen due to its greater risk of Clostridioides (formerly Clostridium) difficile infection [43]. In addition, in vitro susceptibility of MRSA to clindamycin must be confirmed [44,45]. Oxazolidinones (linezolid or tedizolid), delafloxacin, and omadacycline are additional agents with activity against MRSA; they should be reserved for circumstances in which none of the other regimens listed can be used. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections".) For patients who are at high risk of an adverse outcome if infective endocarditis occurs (eg, individuals with prior infective endocarditis, prosthetic heart material, unrepaired congenital heart defect, and valvular dysfunction in a transplanted heart), we favor covering beta-hemolytic streptococci in addition to MRSA pending culture data because of the possibility (albeit small) of streptococcal involvement. In such patients who are undergoing incision and drainage, antibiotics should be administered 60 minutes prior to the incision. Antimicrobial therapy with activity against MRSA and beta-hemolytic streptococci may be achieved with clindamycin or TMP-SMX monotherapy; there may be regional differences in MRSA susceptibility to these agents [11,46]. In one systematic review that included 10 randomized trials evaluating the utility of TMP-SMX for treatment of skin and soft tissue infection due to betahemolytic streptococci or S. aureus, eight studies demonstrated efficacy of TMP-SMX for these conditions, although the number of nonpurulent cellulitis cases in these trials due to beta-hemolytic streptococci was limited [11]. In vitro susceptibility data support the notion that TMP-SMX is active against Streptococcus pyogenes [46]. Because of uncertain streptococcal coverage with doxycycline or minocycline, we add amoxicillin to each of these agents to ensure adequate antistreptococcal activity. Options for empiric parenteral therapy of MRSA include vancomycin and daptomycin (algorithm 2); alternative parenteral agents with activity against MRSA are summarized in the table (table 2) and are discussed in detail separately. These agents also have activity against beta-hemolytic Streptococcus. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections", section on 'Parenteral antibiotic therapy'.)

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Duration of therapy — The appropriate duration of therapy for treatment of skin and soft tissue infection depends on the nature of the clinical presentation, and the clinical response should guide duration of therapy. Patients with mild infection who warrant outpatient management with oral antibiotic therapy should have repeat evaluation after 24 to 48 hours to verify clinical response [2]. Patients with MRSA responsive to oral therapy are typically treated for 5 days; extension of the duration (up to 14 days) may be warranted in the setting of severe infection, slow response to therapy, or immunosuppression. Lack of response may be due to infection with resistant organism(s), inadequate adherence, or presence of a deeper, more serious infection than previously realized. Patients with infection warranting parenteral therapy (in the absence of bacteremia or involvement beyond soft tissue) are typically treated for a total duration of 5 to 14 days. Once there are signs of clinical improvement with no evidence of systemic toxicity, antibiotics may be transitioned from parenteral to oral therapy. For patients with abscess that was detected radiographically, follow-up imaging may be useful for assessing response to therapy. (See "Cellulitis and skin abscess: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Recurrent infection — The approach to management of recurrent purulent cellulitis is the same as the approach to management of the initial episode. A recurrent abscess at a site of previous infection should prompt consideration of additional causes such as pilonidal cyst, hidradenitis suppurativa, or presence of foreign material [2]. Surgical exploration and debridement may be warranted, and suppressive antibiotics may be reasonable if no drainable collection or treatable underlying condition is found. In patients with recurrent abscess beginning in early childhood, evaluation for a neutrophil disorder is warranted. (See "Primary disorders of phagocyte number and/or function: An overview".) For patients with recurrent infection due to S. aureus, attempting decolonization is reasonable; this is discussed separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Prevention and control", section on 'Targeted decolonization' and "Methicillin-resistant Staphylococcus aureus (MRSA) in children: Prevention and control".)

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Skin and soft tissue infections".)

SUMMARY AND RECOMMENDATIONS 3361

●Patients with skin and soft tissue infection may present with cellulitis, abscess, or both. The approach to management depends on the nature of the clinical presentation. (See 'General principles' above.) ●In general, patients with mild infection may be treated with an oral antibiotic regimen. The decision to initiate parenteral antibiotic therapy should be based on individual clinical circumstances such as severity of clinical presentation and patient comorbidities. We recommend that patients with signs of systemic toxicity or rapid progression of erythema be treated initially with parenteral antibiotics (Grade 1B). Parenteral therapy is also appropriate for patients with persistence or progression of symptoms despite 48 hours of oral antibiotic therapy, inability to tolerate oral therapy, or proximity of the lesion to an indwelling medical device (eg, prosthetic joint or vascular graft). (See 'Oral versus parenteral therapy' above.) ●The management of patients with nonpurulent infection (ie, cellulitis or erysipelas in the absence of abscess or purulent drainage) consists of antibiotic therapy (algorithm 1). (See 'Nonpurulent infection' above.) •Patients with nonpurulent cellulitis (eg, cellulitis with no purulent drainage or exudate and no associated abscess) should be managed with empiric therapy for infection due to beta-hemolytic streptococci and methicillin-susceptible Staphylococcus aureus (MSSA); additional empiric coverage for methicillin-resistant S. aureus (MRSA) is warranted in the circumstances summarized above (algorithm 1). (See 'Cellulitis' above.) •Patients with erysipelas should be managed with empiric therapy for infection due to betahemolytic streptococci. (See 'Erysipelas' above.) •The duration of antibiotic therapy for treatment of nonpurulent infection should be individualized depending on clinical response. In general, 5 days of therapy is appropriate for patients with uncomplicated infection who have improved within this time period. Extension of the duration (up to 14 days) may be warranted in the setting of severe infection and/or slow response to therapy. ●For patients with recurrent nonpurulent cellulitis, we suggest administration of suppressive antibiotic therapy (Grade 2B). Predisposing factors that can be alleviated should be addressed whenever possible. (See 'Recurrent infection' above.) ●The management of patients with purulent infection depends on whether a drainable abscess is present (see 'Purulent infection' above): •Patients with drainable abscess should undergo incision and drainage (algorithm 2). (See 'Drainable abscess present' above and "Technique of incision and drainage for skin abscess".) •The role of antimicrobial therapy in the setting of drainable abscess depends on individual clinical circumstances.

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-In general, we recommend antibiotic therapy for patients with multiple lesions, extensive surrounding cellulitis, associated comorbidities or immunosuppression, signs of systemic infection, or inadequate clinical response to incision and drainage alone (Grade 1B), and we suggest antibiotic therapy for patients with skin abscess ≥2 cm (Grade 2A), an indwelling device, or high risk for transmission of S. aureus to others (Grade 2B). (See 'Role of antibiotic therapy' above.) -For otherwise healthy patients with no risk factors, we suggest administering antimicrobial therapy (Grade 2C). However, because many abscesses can be treated successfully with incision and drainage alone, expert opinion varies, and it is reasonable to forgo antibiotic therapy in otherwise healthy patients who have small (eg, 30,000/microL; band neutrophils >10 percent ●Serum creatinine >2.0 mg/dL (177 mmol/L) ●Age >60 years ●Streptococcal toxic shock syndrome ●Clostridial infection ●Delay in surgery for more than 24 hours ●Infection involving the head, neck, thorax, or abdomen

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SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Skin and soft tissue infections".)

INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topic (see "Patient education: Gangrene (The Basics)")

SUMMARY AND RECOMMENDATIONS ●Necrotizing soft tissue infections (NSTIs) include necrotizing forms of fasciitis, myositis, and cellulitis. These infections are characterized clinically by fulminant tissue destruction, systemic signs of toxicity, and high mortality. They may be categorized based on microbiology and presence or absence of gas in the tissues (table 1). Risk factors for NSTI include skin or mucosal breach, traumatic wounds, and diabetes or other immunosuppressing conditions. (See 'Introduction' above and 'Risk factors' above.) ●Necrotizing fasciitis is an infection of the deep soft tissues that results in progressive destruction of the muscle fascia and overlying subcutaneous fat. Infection may be polymicrobial (type I) or monomicrobial (type II) (see 'Necrotizing fasciitis' above): •Polymicrobial (type I) necrotizing infection is caused by aerobic and anaerobic bacteria. It usually occurs in older adults and/or in individuals with underlying comorbidities including diabetes. •Monomicrobial (type II) necrotizing infection is most commonly caused by group A Streptococcus (GAS)(and other beta-hemolytic streptococci). It may occur in any age group and in individuals with no underlying comorbidities.

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●Necrotizing myositis is an infection of skeletal muscle typically caused by GAS(and other betahemolytic streptococci). Necrotizing cellulitis is typically caused by anaerobic pathogens and may be divided into two types: clostridial (usually caused by Clostridium perfringens) and nonclostridial (caused by polymicrobial infection). (See 'Necrotizing myositis' above and 'Necrotizing cellulitis' above.) ●Clinical manifestations of NSTI include erythema, edema extending beyond the visible erythema, severe pain (out of proportion to exam findings in some cases), fever, crepitus, and skin bullae, necrosis, or ecchymosis. Systemic toxicity may be observed. Necrotizing infection most commonly involves the extremities (lower extremity more commonly than upper extremity) and usually presents acutely. Other presentations of necrotizing fasciitis include involvement of the perineum (Fournier gangrene), head and neck region, and neonatal infection. (See 'Clinical manifestations' above.) ●NSTI should be suspected in patients with soft tissue infection (erythema, edema, warmth) and signs of systemic illness (fever, hemodynamic instability) in association with crepitus, rapid progression of clinical manifestations, and/or severe pain (out of proportion to skin findings in some cases) (algorithm 1). The diagnosis of necrotizing infection is established via surgical exploration of the soft tissues in the operating room, with physical examination of the skin, subcutaneous tissue, fascial planes, and muscle. (See 'Diagnosis' above.) ●Radiographic imaging studies can be useful to help determine whether necrotizing infection is present but should not delay surgical intervention when there is crepitus on examination or rapid progression of clinical manifestations. The best initial radiographic imaging exam is computed tomography scan. Presence of gas in the tissues (seen most frequently in the setting of polymicrobial [type I] necrotizing fasciitis or clostridial infection) is highly specific for NSTI and should prompt immediate surgical intervention. (See 'Radiographic imaging' above.) ●Treatment of necrotizing infection consists of early and aggressive surgical exploration and debridement of necrotic tissue, together with broad-spectrum empiric antibiotic therapy and hemodynamic support. (See 'Treatment' above.) In general, empiric antibiotic treatment of necrotizing infection should consist of broad-spectrum antimicrobial therapy, including activity against gram-positive, gram-negative, and anaerobic organisms. Acceptable empiric antibiotic regimens include (see 'Antibiotic therapy' above): •A carbapenem or piperacillin-tazobactam plus •An agent with activity against methicillin-resistant Staphylococcus aureus plus •Clindamycin (for its antitoxin effects against toxin-elaborating strains of streptococci and staphylococci) Antibiotic treatment should be tailored to Gram stain, culture, and sensitivity results when available.

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Issues related to surgical management of NSTI and hemodynamic support are discussed separately (See "Surgical management of necrotizing soft tissue infections" and "Evaluation and management of suspected sepsis and septic shock in adults".) ●For patients with NSTI in the setting of streptococcal toxic shock syndrome, we suggest administering intravenous immune globulin (Grade 2C). (See 'Intravenous immune globulin' above.) ●Close contacts of a patient with necrotizing infection due to GAS can become colonized with a virulent strain. For highly susceptible individuals (such as immunocompromised individuals or patients with recent surgery) who are close contacts of a patient with necrotizing infection due to GAS, we suggest postexposure prophylaxis with oral penicillin (Grade 2C). (See 'Prevention' above.)

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Trichomycosis (trichobacteriosis) - UpToDate uptodate.com/contents/trichomycosis-trichobacteriosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Oct 03, 2018.

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INTRODUCTION

Trichomycosis is a superficial bacterial infection of hair

that is also known more appropriately as trichobacteriosis. The primary causative agents are Corynebacterium species (usually Corynebacterium flavescens). Trichomycosis presents with yellow-white (occasionally red or black), soft, malodorous nodules and sheath-like structures on hair shafts (picture 1A-C). The infection most often affects the axillary hair (trichomycosis axillaris) but can also involve other sites, such as pubic (trichomycosis pubis), scrotal, and intergluteal hair. The clinical features, diagnosis, and management of trichomycosis will be reviewed here. Trichomycosis should be distinguished from other disorders that present with nodules on hair shafts, such as piedra and pediculosis. These disorders are reviewed separately. (See "Piedra" and "Infections due to Trichosporon species and Blastoschizomyces capitatus (Saprochaete capitata)", section on 'Superficial infection' and "Pediculosis pubis and pediculosis ciliaris" and "Pediculosis capitis".)

MICROBIOLOGY

Trichomycosis typically results from infection with

Corynebacterium spp, which are gram-positive and rod-shaped bacteria. Examples of identified species include C. flavescens (most common) and Corynebacterium propinquum [1,2]. Dermabacter hominis has also been reported to cause trichomycosis [3].

EPIDEMIOLOGY AND RISK FACTORS

Trichomycosis is a relatively common but under-recognized condition.

Poor hygiene, hyperhidrosis, obesity, and high humidity are predisposing factors [1,4-6]. The infection tends to be more prevalent in humid and tropical climates than in temperate climates. Trichomycosis is most often diagnosed in adolescent boys and young men but may occur in both sexes and at any age, including infancy [4]. The lower incidence in women may be related to a higher prevalence of axillary shaving. In a retrospective study in Mexico City, 53 of 56 patients (95 percent) with clinically and microbiologically confirmed trichomycosis were men, and the average age was 32.5 years [1]. Person-to-person transmission has been reported but is not considered a major mode of transmission. It is most likely to occur in groups that live in close quarters, such as soldiers and athletes [1].

PATHOGENESIS

Infection is limited to the free hair shaft; the hair root

and follicle are unaffected. The nodules and sheath-like structures surrounding hairs contain high numbers of bacteria and are postulated to result from a combination of dried and hardened apocrine

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sweat, proliferating corynebacteria, and bacterial products. The associated odor may be partially due to bacterial metabolism of testosterone in apocrine sweat into malodorous compounds. The occurrence of red and black, sheath-like structures in the trichomycosis rubra and trichomycosis nigra clinical variants may result from symbiosis with chromogenic bacteria. Examples include Micrococcus castellani, Micrococcus nigricans, and Serratia marcescens [1,7]. (See 'Clinical presentation' below.)

CLINICAL PRESENTATION

Trichomycosis is

characterized by creamy, opaque, soft in consistency, and easily scraped off nodules and sheath-like structures on the hair shaft, most often on the axillary hair (picture 1A-C) [1]. The structures are typically yellow-white (trichomycosis flava). Less frequently, the structures are red (trichomycosis rubra) or black (trichomycosis nigra). Less common sites include pubic and intergluteal hair, and there are rare reports of eyebrow and scalp hair involvement [1,8]. In the report of eyebrow involvement, infection was attributed to autoinoculation from axillary hair [1]. Early infection may be more easily palpated (as irregular thickening of the hair shaft) than visualized. As infection progresses, the deposits become more visible and extend along the entire length of the hair shaft, forming a sheath and causing the hair to appear thickened [1]. A rancid, acidic odor is common. Symptoms, such as pruritus or pain, are generally absent.

ASSOCIATED DISORDERS

Trichomycosis often occurs

in association with hyperhidrosis. In addition, patients may have concomitant cutaneous corynebacterial infections, including erythrasma and pitted keratolysis [1,9,10]. A study of a cohort of 108 male Korean soldiers with pitted keratolysis found 22 (20 percent) with concomitant physical findings consistent with trichomycosis axillaris and 14 (13 percent) with both trichomycosis axillaris and erythrasma [9].

DIAGNOSIS

The diagnosis of trichomycosis is usually made clinically. Findings

that strongly support the diagnosis include soft; yellow-white, red, or black; irregular masses attached to hair shafts, particularly when located in the axilla or pubic region. Patients may be unaware of the infection or present with a complaint of texture change of the hair or malodor. Findings that should prompt consideration of other disorders include involvement of nonintertriginous sites and hair with adherent, firm, immobile structures. (See 'Differential diagnosis' below.) Although not typically necessary, dermoscopy, Wood's light examination, or a potassium hydroxide preparation can provide additional support for the diagnosis through demonstrating expected findings. Typical dermoscopic findings are irregular, golden yellow to pale yellow-white accretions around hairs, some with a brush-like or feathery appearance (picture 2). Wood's light examination often reveals faint to bright, yellow-white or yellow-green fluorescence, and a potassium hydroxide

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preparation will show an opaque sheath surrounding hair shafts [11-13]. Examination of trichomycosis with reflectance confocal microscopy, a less widely available technique for in vivo microscopy, reveals lobulated structures with heterogenous refractility attached to the hair shaft [14]. Laboratory tests to identify bacteria can confirm the diagnosis but are not necessary. Gram stain of affected hair will show hair shafts heavily colonized with gram-positive coccobacillary structures. Corynebacteria can be cultured on brain-heart infusion agar or chocolate-blood agar and identified with biochemical testing.

DIFFERENTIAL DIAGNOSIS

Trichomycosis should be

distinguished from piedra and pediculosis: ●Piedra – Piedra is an asymptomatic fungal infection of the hair shaft that is also known as trichomycosis nodularis [15-17]. White piedra typically manifests as white to beige, soft nodules or sheaths that are loosely adhered to hair shafts on the face, axillae, or genitals (picture 3). Nodules and sheaths of white piedra tend to be more discrete and well defined than trichomycosis and lack a creamy appearance. Trichosporon asahii is the primary causative organism. Faint Wood's light fluorescence is occasionally noted but may reflect the concomitant presence of bacteria. (See "Piedra" and "Infections due to Trichosporon species and Blastoschizomyces capitatus (Saprochaete capitata)".) Black piedra is caused by Piedraia hortae and should be distinguished from the nigra variant of trichomycosis. Black piedra classically presents with hard, firmly attached, brown to black nodules in contrast to the soft, creamy sheaths of trichomycosis (picture 4). Unlike trichomycosis, black piedra most often occurs on scalp hair. (See "Piedra".) A potassium hydroxide preparation of hair shaft nodules will demonstrate fungal forms and is useful for confirming a diagnosis of piedra. ●Pediculosis – Patients with pediculosis capitis or pediculosis pubis present with tiny, nonmobile, oval eggs on hair shafts, sometimes yellowish in coloration (picture 5) [18-20]. Adult lice and nymphs may also be visualized. Unlike trichomycosis, pruritus is a characteristic feature. Dermoscopic or microscopic examination of hair shafts aids in confirming the presence of nits. (See "Pediculosis capitis" and "Pediculosis pubis and pediculosis ciliaris".)

TREATMENT

Given the benign nature of infection, treatment is not required.

However, many patients desire treatment because of the abnormal appearance of hair and malodor associated with this condition. In the absence of treatment, the infection tends to persist. Data on treatment options for trichomycosis are limited. Randomized trials have not been performed, and evidence for treatment efficacy is primarily limited to case reports, case series, and expert opinion. Typical treatments include shaving of hair in the affected area and topical

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antimicrobial agents. Common choices for topical antimicrobial therapy include sulfur soap, benzoyl peroxide, erythromycin, clindamycin, and fusidic acid [1,21,22]. In addition, resolution of trichomycosis pubis with naftifine hydrochloride 1% cream, an antifungal agent with concomitant antibacterial properties, has been reported [23]. Shaving should be sufficient but is often combined with topical antimicrobial therapy in an attempt to augment efficacy and reduce risk for recurrence. Topical antimicrobial therapy alone may also be sufficient [22]. Our suggested therapeutic approach consists of both of the following measures: ●Patients should bathe daily and shave hair in affected area daily for two to three weeks. ●Patients should wash affected area daily with sulfur soap or apply a topical antimicrobial agent (eg, benzoyl peroxide 5%, erythromycin 2%, clindamycin 1%) once to twice daily. For patients who comply with shaving, we suggest continuing topical antimicrobial therapy for one week. A typical treatment course for patients who do not shave the affected area is two to four weeks [22]; for these patients, we suggest continuing antimicrobial therapy for at least three days after visible signs of trichomycosis disappear. Treatment is usually successful, leading to resolution of the characteristic nodules and sheaths on hair shafts by the end of treatment. Resolution of associated odor usually occurs within a few weeks.

INDICATIONS FOR REFERRAL

Apparent

treatment failure (ie, persistence or rapid recurrence of clinical findings) warrants assessment for adherence to therapy and accuracy of the diagnosis. If the cause of treatment failure remains uncertain, referral to a dermatologist may be helpful.

PREVENTION

Suggested methods to reduce risk for recurrence of

trichomycosis include good hygiene, regular shaving of hair in affected areas, control of hyperhidrosis, and weight loss. (See 'Epidemiology and risk factors' above.)

SUMMARY AND RECOMMENDATIONS ●Trichomycosis is a corynebacterial infection of hair shafts. Predisposing factors include poor hygiene, hyperhidrosis, and obesity. The infection is most common in young men. (See 'Microbiology' above and 'Epidemiology and risk factors' above.)

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●Characteristic clinical findings in trichomycosis are creamy, opaque, soft nodules and sheath-like structures on hair shafts (picture 1A-C). The color is typically yellow-white and occasionally red or black. Odor is often present. Pain and pruritus are typically absent. (See 'Clinical presentation' above.) ●Trichomycosis can be diagnosed based upon recognition of the characteristic clinical findings during a physical examination. In challenging cases, additional studies may be helpful for confirming the diagnosis and ruling out other conditions. (See 'Diagnosis' above.) ●Data on the treatment of trichomycosis are limited. We suggest treating with a combination of shaving of hair in the affected area and application of a topical antimicrobial agent (Grade 2C). Hair should be shaved for two to three weeks. Common choices for topical antimicrobial therapy include sulfur soap, benzoyl peroxide, erythromycin, and clindamycin. (See 'Treatment' above.) ●Treatment of trichomycosis is usually successful. Treatment failure may indicate poor adherence to therapy or an incorrect diagnosis. (See 'Indications for referral' above.) ●Good hygiene practices and regular shaving of affected hair may help to reduce risk for recurrence of trichomycosis. (See 'Prevention' above.)

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Botryomycosis - UpToDate uptodate.com/contents/botryomycosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Oct 18, 2019.

INTRODUCTION

Botryomycosis is a chronic suppurative infection

characterized by a granulomatous inflammatory response to bacterial pathogens; it may present with cutaneous or, less commonly, visceral involvement [1]. Botryomycosis was first described in a horse in 1870 by a German pathologist. The name "botryomycosis" was coined in 1884, but its bacterial nature was not discovered until 1919 [2]. The term "botryomycosis" is derived from the Greek word "botrys" (meaning "bunch of grapes") and "mycosis" (a misnomer, due to the presumed fungal etiology in early descriptions). Other terms used to describe botryomycosis include bacterial pseudomycosis, staphylococcal actinophytosis, granular bacteriosis, and actinobacillosis.

EPIDEMIOLOGY

Botryomycosis is a relatively uncommon disease, and its

description is limited to case reports in children and adults. It occurs more commonly among immunocompromised patients, although infection in immunocompetent patients has also been described [3-5]. The specific role of the host immune response is not fully understood [6-8]. Risk factors associated with botryomycosis include [6,7,9-13]: ●Alcoholism ●Diabetes mellitus

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●HIV infection ●Cystic fibrosis ●Chronic granulomatous disease ●Trauma ●Surgery

MICROBIOLOGY AND PATHOGENESIS

The most common organism causing botryomycosis is

Staphylococcus aureus. Less common pathogens include gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli, Serratia, and Proteus), gram-positive cocci (coagulase-negative staphylococci, streptococci, micrococci), and anaerobes (Actinobacillus, Peptostreptococcus, and Cutibacterium [formerly Propionibacterium] acnes) [3,14]. The pathogenesis of botryomycosis is not fully understood; it is thought to involve a combination of potential factors including an inciting event (such as trauma), the number of organisms inoculated, the virulence of the infecting pathogen, and host susceptibility to infection [1,6,15,16]. Visceral botryomycosis is more likely to occur in patients who are immunosuppressed [2].

CLINICAL MANIFESTATIONS

Botryomycosis may

present as cutaneous or visceral disease. Cutaneous botryomycosis involves the skin and subcutaneous tissue; visceral botryomycosis involves internal organs such as lungs, liver, or brain.

Cutaneous disease — Cutaneous botryomycosis is the most common form of botryomycosis and usually occurs following cutaneous inoculation of bacteria due to trauma, surgery, or the presence of a foreign body [17-19]. Lesions characteristically develop slowly and may evolve and enlarge for several months and, rarely, even years. Most patients present with subcutaneous nodules, but others may develop verrucous lesions or nonhealing ulcers associated with draining sinuses or fistulae (picture 1). Drainage from these lesions is usually purulent and may contain small yellowish "grains" resembling the sulfur granules seen in actinomycosis. (See "Cervicofacial actinomycosis".) Occasionally, infection may involve contiguous soft tissues such as the subcutaneous tissue, muscles, tendons, and bone. Mucosal involvement of areas such as the tongue and nasal septum, lymph nodes or visceral involvement has also been described [5,20,21]. Disseminated infection can follow cutaneous disease in the setting of severe immunosuppression [22].

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Patients infected with HIV may present with atypical lesions resembling conditions such as prurigo nodularis, lichen simplex chronicus, or sporotrichosis [7,23]. No correlation between CD4 count and susceptibility to botryomycosis has been described. (See "Fever and rash in HIV-infected patients".)

Visceral disease — Visceral botryomycosis occurs most commonly in the lung, although involvement of other organs including liver, spleen, kidney, and brain has also been described [2]. Systemic symptoms such as fever, fatigue, or weight loss may or may not be present. Symptoms associated with pulmonary botryomycosis include chronic cough, dyspnea, hemoptysis, and chest wall pain [14,24]. Clinical examination may be normal or demonstrate diminished breath sounds or rhonchi over the consolidated lung. Given the prolonged duration and nature of the symptoms, pulmonary botryomycosis may be mistaken for malignancy [24]. Botryomycosis involving the liver, spleen, or kidney tends to present with chronic abdominal pain and local tenderness to palpation [9,25]. Ultrasonography or computerized tomography reveals a mass lesion of the abdomen suspicious for an abscess or malignancy. Cerebral botryomycosis has been described in association with dental caries or after oral surgery [25-27]. Focal neurological deficits, seizures, or signs of meningitis may occur, and some patients develop a fulminant course [25].

DIFFERENTIAL DIAGNOSIS

Conditions that mimic

botryomycosis are summarized below; in general, the diagnoses are distinguished by histopathology and culture. ●Actinomycosis – Both actinomycosis and botryomycosis can present with cutaneous or visceral involvement. Cutaneous disease due to both actinomycosis and botryomycosis can be associated with drainage containing small "grains." (See "Nonresolving pneumonia", section on 'Nocardia and Actinomyces'.) ●Nocardia – Like botryomycosis, nocardiosis may present with cutaneous or visceral involvement; it is generally observed in immunocompromised patients. (See "Clinical manifestations and diagnosis of nocardiosis".) ●Fungal infection – A number of fungal infections present with cutaneous lesions resembling botryomycosis; these include mycetoma, chromoblastomycosis, and phaeohyphomycosis. (See "Eumycetoma".) ●Mycobacterial infection – Cutaneous tuberculosis, tuberculous lymphadenitis, and atypical mycobacterial infection may present with skin lesions and draining sinus tracts resembling botryomycosis. (See "Cutaneous manifestations of tuberculosis" and "Overview of nontuberculous mycobacterial infections in HIV-negative patients".)

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●Sporotrichosis – Sporotrichosis occurs following cutaneous inoculation and presents with lymphocutaneous spread; in rare cases, pulmonary involvement may be observed. (See "Clinical features and diagnosis of sporotrichosis".) ●Cutaneous leishmaniasis – Cutaneous leishmaniasis causes a spectrum of cutaneous disease and can resemble botryomycosis. Epidemiologic exposure is an important component of the clinical history. (See "Cutaneous leishmaniasis: Clinical manifestations and diagnosis".) ●Skin cancer – Botryomycosis can mimic the appearance of squamous cell carcinoma or the violaceous lesions of Kaposi sarcoma; these are distinguished by histopathology. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis" and "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment".)

DIAGNOSIS

Laboratory evaluation including biopsy for histopathology and

culture are needed to differentiate botryomycosis from other diagnoses listed above [20]: ●Evaluation of drainage for grains – Pus from draining sinuses should be collected on sterile gauze or aspirated and transferred to a sterile container. Granules should be picked up using a needle or forceps and crushed between two slides. Anecdotal reports associate certain pathogens with a characteristic grain color. S. aureus is classically associated with pale yellow or white granules. •The presence of granules itself does not establish diagnosis of botryomycosis since they can be present in actinomycosis and nocardiosis. •Botryomycosis may be distinguished from actinomycosis and mycetoma in that botryomycosis granules are of variable size and shape up to 500 microns in diameter. ●Gram staining (using traditional methods or the Brown-Brenn stain) or silver nitrate staining (using the Grocott-Gomori method) of crushed granules or biopsy specimens to identify nonfilamentous bacteria – Rarely, gram-positive cocci ≤1 micron in diameter are present in the exudate surrounding the granule and occur singly, in pairs, or in small clumps. In contrast, actinomycetes are branching filamentous bacteria ≤1 micron in diameter, while fungi causing mycetoma have hyphae that are at least 2 microns wide. These distinctions are important for guiding clinical management. ●Routine bacterial, fungal, and mycobacterial cultures – Growth of bacterial pathogens would support diagnosis of botryomycosis. ●The histopathologic appearance of botryomycosis is characterized by a central focus of necrosis surrounded by a chronic inflammatory reaction containing histiocytes, epithelioid cells, multinucleated giant cells, and fibrosis [25]. Unlike the sulfur granules seen in actinomycosis (which contain filamentous branching organisms), the granules seen in botryomycosis (Bollinger granules) contain bacteria surrounded by an eosinophilic matrix containing club-like projections. This histologic appearance is commonly referred to as the Splendore-Hoeppli phenomenon, although it may not always be present (picture 2) [22,28,29].

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●Radiographic studies may be useful to evaluate the size and extent of involvement. Pulmonary lesions may be present as a consolidation or mass lesion (picture 3), while other forms of visceral botryomycosis usually present as a mass lesion.

TREATMENT

In general, patients should receive antibiotic therapy until signs

and symptoms of infection have resolved. A few weeks of therapy may be sufficient for those with superficial infection; patients with deep infections and/or those with underlying immunodeficiency may require months of therapy. Prolonged antibiotic therapy may be necessary in cases for which debridement is incomplete or not feasible. In such situations, antibiotic penetration to the organisms sequestered in the granules may be poor or limited [20]. Selection of antibiotics should be tailored to culture and susceptibility results. There is no conclusive evidence regarding the appropriate duration of therapy; most information on the duration of treatment of botryomycosis is anecdotal [20]. The duration of therapy described in case reports has ranged from weeks to months. In general, antibiotic therapy is continued until the clinical and radiographic (if applicable) signs of infection have resolved.

Cutaneous disease — Treatment of cutaneous disease requires antibiotic therapy and, in most cases, surgical debridement. Antibiotic therapy alone may be sufficient for patients with superficial disease if a bacterial pathogen has been identified and malignancy has been excluded. For gram-positive infections, including S. aureus, oral trimethoprim-sulfamethoxazole (two double-strength tablets twice daily) or oral clindamycin (600 mg orally three times daily) can be used. Depending on culture and susceptibility data, other alternative agents include doxycycline (100 mg twice daily), minocycline (100 mg twice daily), erythromycin (500 mg four times daily), cephalexin (500 mg four times daily), or dicloxacillin (500 mg every six hours). For pseudomonal infections, we recommend initiating therapy with ceftazidime (2 g intravenously [IV] every 8 hours), ciprofloxacin (400 mg IV every 12 hours), aztreonam (2 g IV every 8 hours), or imipenem (500 mg IV every 6 hours). If the isolate is fluoroquinolone sensitive, therapy may be switched to oral ciprofloxacin (750 mg twice daily). For infections due to other gram-negative organisms (E. coli, Serratia, Proteus), ceftriaxone (1 to 2 g once daily), ciprofloxacin (400 mg IV every 12 hours), imipenem (500 mg IV every 6 hours), or ertapenem 1 gm IV every 24 hours can be used initially until susceptibility data is available; oral ciprofloxacin (500 mg twice daily) can be used if the isolate is susceptible. In patients with superficial infection, antibiotic therapy is usually continued for one to two months or until all signs of infection have resolved. Surgical debridement together with antibiotic therapy is appropriate for lesions that extend into deep tissues such as muscle or bone, for lesions that do not improve with antibiotics alone, and for immunocompromised patients.

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Visceral disease — Treatment of visceral disease requires a combination of surgical and antimicrobial therapy. Resection of the mass often occurs prior to diagnosis given concern for malignancy in most cases of visceral disease. For S. aureus and other gram-positive infections, we recommend initiating therapy with IV vancomycin (15 to 20 mg/kg/dose every 8 to 12 hours). For S. aureus isolates sensitive to methicillin, a beta-lactam agent such as nafcillin (2 g IV every 4 to 6 hours) should be used. Patients can be switched to oral antibiotics once the infection is debrided surgically and susceptibility data are available. Antibiotic selection for pseudomonal and other gram-negative infections is similar to the recommendations for cutaneous infections. Therapy is usually continued for several months until all signs of infection have resolved.

SUMMARY AND RECOMMENDATIONS ●Botryomycosis is a chronic suppurative infection characterized by a granulomatous inflammatory response to bacterial pathogens that is observed most commonly among immunocompromised patients. (See 'Introduction' above and 'Epidemiology' above.) ●The most common pathogen is Staphylococcus aureus; other pathogens have also been implicated. The pathogenesis of botryomycosis is not fully understood; it is thought to involve a combination of factors including an inciting event (such as trauma), the number of organisms inoculated, the virulence of the infecting pathogen, and host susceptibility to infection. (See 'Microbiology and pathogenesis' above.) ●Cutaneous botryomycosis may present with subcutaneous nodules, verrucous lesions, or nonhealing ulcers associated with draining sinuses or fistulae. Drainage from the lesion is usually purulent and contains small yellowish grains resembling the sulfur granules seen in actinomycosis. (See 'Cutaneous disease' above.) ●Visceral botryomycosis occurs most commonly in the lung, although involvement of other organs including liver, spleen, kidney, and brain has also been described. (See 'Visceral disease' above.) ●Botryomycosis may be difficult to distinguish from mycetoma, actinomycosis, malignancy, and other conditions. (See 'Differential diagnosis' above.) ●The diagnosis of botryomycosis may be established by identifying nonfilamentous bacteria in granules in pus from draining sinuses, identifying nonfilamentous bacteria in granules in biopsy specimens, or culturing bacteria from ulcers or exudates in patients with clinical findings of botryomycosis. (See 'Diagnosis' above.)

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●Treatment of cutaneous disease requires antibiotic therapy and may also require surgical debridement, while treatment of visceral disease requires both surgical and antimicrobial therapy. (See 'Treatment' above.) ●There is no conclusive evidence regarding the appropriate duration of therapy. In general, patients should receive antibiotic therapy until signs and symptoms of infection have resolved. For superficial infection, a few weeks may be sufficient, while patients with deep infection and/or immunodeficiency may require a prolonged course of therapy. (See 'Treatment' above.)

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Yaws, bejel, and pinta - UpToDate uptodate.com/contents/yaws-bejel-and-pinta/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Sep 19, 2019.

INTRODUCTION

The endemic treponematoses include yaws (Treponema

pallidum subsp pertenue), bejel (T. pallidum subsp endemicum), and pinta (Treponema carateum) [1]. These are bacterial infections caused by organisms that are morphologically and serologically indistinguishable from Treponema pallidum subsp pallidum, which is the causative organism of venereal syphilis [2,3]. They may be differentiated by clinical manifestations, geographic distribution, and molecular diagnostic testing [4,5]. Yaws and bejel affect skin and bones; pinta affects the skin only. Other terms for yaws include buba, bouba, framboesia, parangi, paru, and pian [6,7]. Other terms for bejel include endemic syphilis, dichuchwa, sklerjevo, belesh, bishel, firjal, and loath. Other terms for pinta include enfermedad azul, carate, cute, and mal de pinto.

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EPIDEMIOLOGY Historic perspective — Between 1952 and 1964, the number of endemic treponematoses cases was reduced from an estimated 50 million to 2.5 million as a result of mass treatment campaigns led by the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) in 46 countries. In some regions, disease was eliminated; bejel was eliminated in Bosnia [8], and yaws was eliminated in Malaysia and Brazil [9,10]. Endemic treponematoses began to reemerge in the late 1970s. Efforts to eradicate yaws were renewed in 1978 by the WHO; however, endemic treponematoses have not been prioritized in many regions, and surveillance and reporting have been sporadic; one exception is the WHO South Asia region, which kept yaws on its agenda [11].

Geographic distribution — The nonvenereal treponematoses are endemic in rural areas among communities living in overcrowded conditions with poor hygiene (figure 1). Imported cases of yaws from Ghana and Congo have been reported in the United States and the Netherlands [12,13]. In addition, cases of bejel imported from Pakistan, Mali, and the Republic of Senegal have been reported in France [14,15] and Canada [16]. There is also evidence of genital ulcer cases allegedly caused by T. p. endemicum (on the basis of genetic findings) that were transmitted in Cuba and Japan via sexual contact [17,18]. Yaws is the most prevalent nonvenereal treponematosis. It is endemic mainly in warm, humid equatorial regions of Africa, Southeast Asia, and the Pacific (table 1) [19-33]. In 2013, approximately 89 million people lived in at-risk areas of the 13 countries known to be endemic for yaws [34]. In 2017 to 2019, two additional countries reported confirmed yaws cases (Liberia and Philippines) and three countries reported suspected yaws cases (Colombia, Ecuador, and Haiti). Of the 96 countries known to have been endemic in the 1950s, 76 need to be reassessed by the WHO to determine whether transmission has been interrupted. West Africa is an important reservoir for yaws, particularly in Ghana (1481 cases in 2016) and Cote d'Ivoire (1581 cases in 2016). There is also a growing number of cases in the Pacific region, including Papua New Guinea (33,891 cases in 2016), the Solomon Islands (18,082 cases in 2016), and Indonesia (2762 cases in 2016). India reported elimination of yaws in 2006 [35], and the WHO officially declared India free of yaws in May 2016. Elimination of yaws has also been reported in Ecuador, although this has not yet been certified by the WHO [32]; additional data on yaws in the Americas are limited. Bejel occurs mainly in the arid areas of the Sahel (southern border of the Sahara desert), including Senegal [36], Burkina Faso [37], Mali [38], and Niger [39,40]. In these areas, high rates of seropositivity (10 to 20 percent of children under 15 years) have been reported. Bejel has also been described among the nomadic people of the Arabian Peninsula (Saudi Arabia, Iraq, and Syria) [41,42]. There was a report of three cases of bejel in Turkey in 1995 (where the disease was considered to be eliminated) [43], as well as one case report from Iran in 2012 and one from Pakistan in 2013 [15,44].

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Data on the distribution of pinta are limited; there is the perception that the disease has sustained a marked decline over the past century. Pinta might remain endemic in remote regions of Mexico (states of Oaxaca, Guerrero, Michoacan, and Chiapas) [45,46] and Central and South America (among Indian tribes in the Amazon region of Brazil [47], Colombia [48], Venezuela [49], and Peru [50]). A survey in Panama in the 1980s noted evidence of active or inactive pinta among 20 percent of the population [51].

Transmission — Yaws and bejel usually occur in children; 65 to 75 percent of new cases arise in individuals between 1 and 15 years (peak between 5 and 10 years), the infection is uncommon in children less than 1 year of age [52-54]. The age range for pinta is 15 to 50 years (median 30 to 34 years) [55]. Data on the incubation period of endemic treponematoses are limited; the range is 9 to 90 days (mean 21 days) [56,57]. Infected individuals may develop immunity to reinfection, which may be strain specific [58,59]. Yaws is transmitted by direct skin-to-skin, nonsexual contact with infectious lesions. Because T. p. pertenue is temperature and humidity dependent, the incidence of skin lesions is higher in the wet season; high humidity promotes exuberant growth of papillomata and survival of treponemes in serous exudates [52]. Transmission may be facilitated by a breach in the skin of the recipient, such as a scratch or insect bite [60]. Cases of yaws are often seen in temporal clusters within neighboring households or communities as transmission occurs between children in the community, schools, and other public places [61]. Yaws is generally transmitted during childhood, and infectious lesions usually resolve before sexual maturity; sexual transmission might be possible but is not frequently described. Bejel is transmitted by direct skin-to-skin or mouth-to-mouth contact and by indirect contact through sharing of communal eating or drinking utensils [8,62]. Initial lesions are often in or around the mouth; infection can be spread by older children kissing younger siblings. In addition, bejel has been detected in primary genital lesions and may be transmitted sexually [15,17,62]. Pinta is transmitted by direct skin-to-skin contact. Inoculation of fluid from a pinta lesion can reproduce skin lesions in previously uninfected individuals [63]. Transmission is thought to occur frequently within families; in the absence of infection among adults in a household, the likelihood of infection among children is extremely low [63]. Indirect transmission of endemic treponematoses by nonbiting flies has been suggested on the basis that Musca spp could transmit yaws to monkeys in the laboratory [57,60,63]. Molecular studies have demonstrated that wild-caught flies from a yaws-endemic setting harbor T. pallidum DNA but could not demonstrate that fly-associated bacteria were viable and present in sufficient numbers for transmission [64,65].

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MICROBIOLOGY

The causative organisms of endemic treponematoses

include Treponema pallidum subsp pertenue (yaws), T. pallidum subsp endemicum (bejel), and T. carateum (pinta). T. pallidum belongs to a family of gram-negative spiral-shaped bacteria, the Spirochaetaceae,and has a length ranging from 10 to 15 microns and a diameter of 0.2 microns, making it invisible to light microscopy except under dark field illumination [66,67]. Electron microscope studies have shown that there are not significant differences in morphology or structure between T. pallidum subspeciesor with T. carateum [66-68]. The organismsare easily killed by drying, elevated temperature, and exposure to oxygen. They multiply slowly (once every 30 to 33 hours) [69] and cannot survive outside the mammalian host [69]. Since T. pallidum species could not be grown in culture, testing for antibiotic resistance has been performed only by indirect molecular methods, experimental infection of animals, or polymerase chain reaction (PCR) detection of mutations to antibiotic target sites [70]. A novel cell culture-based cultivation system able to support long-term in vitro propagation of T. p. pallidum was described in 2018 [71], which will allow investigators to perform in vitro susceptibility studies. One in vitro assay to assess the effect of antibiotics on treponemal protein synthesis (as measured by the incorporation of radiolabeled 35S-methionine) demonstrated sensitivity of T. p. pallidum and T. p. pertenue to penicillin, chloramphenicol, tetracycline, and erythromycin [72]. Penicillin, cephalosporins, monobactams, and macrolides have shown curative results in animal models [73]; tests on experimentally infected patients showed that benzylpenicillin levels >0.03 units/mL of serum maintained for at least seven days were treponemicidal [74]. In contrast, in vitro and in vivo studies have demonstrated lack of sensitivity to streptomycin (up to 500 mcg/mL), rifampin (up to 100 mcg/mL), or quinolones (up to 10 mcg/mL) [75-77]. Azithromycin resistance has been described in yaws [78]. Macrolide resistance in T. pallidum is associated with alteration of the target site due to a mutation of the 23S ribosomal RNA gene and was previously reported in patients with syphilis [79-81]. Detection of a mutation causing macrolide resistance in 23S rRNA genes of T. p. pertenue has been observed in five patients who presented with treatment failure in a mass azithromycin treatment trial [78]. A real-time PCR assay for detection of mutations has been developed, enabling molecular surveillance for detection of macrolide resistance in T. p. pertenue [82,83].

PATHOPHYSIOLOGY Virulence — Treponemes penetrate the human host through the skin, move through epithelial cells via tight junctions, and attach to fibronectin-coated surfaces on the extracellular matrix of host cells [84]. In the hamster model, the rate of appearance and resolution of cutaneous lesions varies with the size of the inoculum, and the minimum infective dose has been estimated to be 103 to 104 bacteria [85,86]. Clinical lesions appear when a concentration of approximately 107 organisms per mg of tissue is reached.

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After invasion, the organisms appear in lymph nodes within minutes and disseminate widely within hours, reaching and surviving in distal skin and mucosal sites to enhance opportunities for subsequent transmission [86]. Treponemes are extracellular pathogens that exhibit characteristic corkscrew motility due to endoflagella [87], with rapid rotation about the longitudinal axis, and are able to swim efficiently in a gel-like environment such as connective tissue [88]. This virulence factor plays a role in the widespread dissemination of treponemal infections and the establishment of chronic disease [89]. In the face of a hostile host environment and a strong specific immune response (including macrophage phagocytosis due to opsonization) [86,90], the bacterium utilizes several survival mechanisms. T. pallidum may stimulate trafficking of T cells out of the peripheral blood circulation [91,92]. The organism may also exploit its low metabolic rate in order to maintain infection with very few viable cells, avoiding the stimulation of an immune response [58]. Antigenic variation in candidate outer membrane protein antigenic targets (eg, TprK) may be important in immune evasion and persistence of infection [93].

Immunology — New skin lesions are rarely found in adults, suggesting that immunity to reinfection can develop in humans. Studies in the experimental model designed to identify resistance to infection and immunologic correlates of resistance suggest that acquired resistance to the yaws bacteria can develop in untreated animals and persist after treatment [94].

Genetics — Whole-genome analysis for several pathogenic treponemes has been performed, and several genetic differences between T. p. pallidum, T. p. pertenue,and T. p. endemicum have been identified. The overall sequence identity between genomes of the three subspecies is 99.8 percent [5,95], but the regions of sequence divergence are used for the molecular detection and discrimination of syphilis and yaws strains, which is not possible with other tests [4,13,96-102]. Laboratory isolates from patients with syphilis and yaws genetically cluster according to subspecies classification, and there is a robust correlation between clinical presentation and genetics. However, because data for bejel strains are limited, it is uncertain whether genetic tests can accurately differentiate T. p. endemicum.

HISTOPATHOLOGY

Yaws and bejel affect skin and bones; pinta is

unique in that it affects the skin only. The skin pathology in endemic treponematoses is largely similar to that of venereal syphilis. Early yaws lesions consist of epidermal hyperplasia and papillomatosis, often with focal spongiosis and intraepidermal collections of neutrophils. In contrast with syphilis, skin biopsies from yaws patients show numerous plasma cells in the dermis but few T and B cells [103], and vascular changes are less marked [104,105]. The treponemes are found mostly in extracellular clusters in the

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upper regions of the proliferative epidermis, unlike subspecies pallidum, which primarily localizes in the dermis and dermal-epidermal junction (picture 1) [67,106]. These differences are relative, so they cannot be used to differentiate yaws from venereal syphilis. The histopathology of bejel closely resembles that of venereal syphilis. The inflammatory infiltrate is mainly perivascular and is composed of lymphocytes and plasma cells. Granulomas consisting of epithelioid cells and multinuclear giant cells may be present [107]. In pinta, there is no ulcer formation comparable with that in yaws [105]. In the early lesion, there is loss of melanin in basal cells and liquefaction degeneration. A superficial and perivascular mixed infiltrate primarily composed of lymphocytes and plasma cells develops in the dermis [108]. In the late stage, there is epidermal atrophy and many melanophages are present in the dermis [107]. Absence of treponemes and inflammatory cells in the achromic lesions are typical findings [109].

YAWS Clinical manifestations — Yaws consists of primary, secondary, and tertiary phases [110]. Most patients present in childhood with a primary cutaneous lesion on the lower extremity; some develop arthralgias due to joint involvement. The cutaneous lesions begin as a painless papule and, if left untreated, progress over weeks to months into an ulcerating nodule; bony involvement can occur as a late complication. The clinical manifestations are summarized in the table (table 2). Issues related to transmission and incubation period are described above. (See 'Transmission' above.) The primary lesion ("mother yaw") appears at the site of initial infection [110]. It is usually a localized papule that may develop into a typically large yellow nodule (2 to 5 cm in diameter, often called papilloma) that ulcerates (picture 2). The lesion is not painful but may be pruritic. Ulcers characteristically have a red base consisting of granulation tissue, and the edges are commonly indurated and elevated (picture 3) [6]. The primary lesion is most commonly found on the legs and ankles (65 to 85 percent of cases) [111,112] but can also occur on the buttocks, arms, hands, or face. It usually spontaneously heals after three to six months, regressing into a hyperpigmented pitted scar [113]. Sometimes the primary lesion is present at the onset of the secondary stage [56]. Secondary lesions are the result of lymphatic and hematogenous spread of organisms; they appear a few weeks to two years after the primary lesion. Secondary skin lesions consist of a solitary papillomatous nodule or ulcer resembling the primary lesion or an eruption of multiple smaller excrescences that cover a region of the body (picture 4) [114]. Multiple scaly patches or plaques with discoid or irregular shapes also may develop (picture 5). Arthralgia occurs commonly in the setting of secondary yaws; in one study including 233 children in Papua New Guinea with suspected yaws, up to 75 percent presented with arthralgia [112].

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Other manifestations of secondary yaws include palmar and plantar papilloma or hyperkeratotic plaques (which may be so painful that the affected individual favors weight bearing on the side of the foot, producing a characteristic crab-like gait) (picture 6) [114], and nocturnal bone pain due to osteoperiostitis of the proximal phalanges of the fingers (dactylitis) (picture 7) or long bones (forearm, tibia, or fibula) (picture 8). Yaws is a polyostotic disorder; the mean number of affected bones is three. Involvement of the hands and feet is common [115]. In general, primary and secondary lesions are reversible with treatment. If untreated, the manifestations spontaneously regress due to host's immune response against the pathogen, and a stage of latency begins. Latent yaws is characterized by absence of physical signs but persistence of serological evidence of the infection. Relapse of symptomatic infection can occur and is most common in the first 1 to 2 years after the initial exposure but may occur for up to 5 to 10 years. Tertiary yaws is not common; it occurs in approximately 10 percent of untreated patients and consists of late lesions that develop after five or more years of infection [52]. This stage is characterized by gummatous lesions of skin, bones, and overlying tissues. Manifestations include: ●Malformation of long bones (eg, anterior bowing of the tibia) (picture 9) ●Juxta-articular subcutaneous nodules ●Hyperostosis of the nasal processes of the maxillae ("goundou") ●Ulceration of the palate and nasopharynx (rhinopharyngitis mutilans) with secondary infection resulting in foul-smelling discharge ("gangosa") Yaws can spread systemically via the lymphatics or hematogenously. Yaws has been associated with neurologic and ophthalmologic abnormalities, but there is no definitive evidence of a causal relationship [116-119]. An association between tertiary yaws and cardiovascular disease has been postulated; among 3645 autopsies performed in Ghana between 1921 and 1953, aortitis was the most common cardiovascular disease (and the incidence of syphilis was relatively low) [120]. Yaws is not known to cause congenital infection; this may be because most new infections occur in children rather than in women of child-bearing age.

Diagnosis — Diagnosis of endemic treponematoses requires correlation of clinical manifestations, epidemiology, and demographic characteristics with serologic testing, if available (table 1 and table 2).

Clinical approach — The diagnosis of yaws should be suspected based on clinical manifestations (cutaneous papule on lower extremity that may develop into an ulcerating nodule, as well as joint and bone involvement in secondary disease; most commonly occurs in children) and the geographic distribution (tropics).

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The diagnosis of yaws may be definitively established by serology, polymerase chain reaction (PCR) or via direct visualization of the organism in a clinical specimen [4,5]. Serologic testing is the mainstay of diagnosis due to complexities of direct visualization techniques and lack of access to molecular techniques in endemic countries. In the absence of access to serology, empiric therapy for patients with suspected infection based on clinical grounds is reasonable.

Diagnostic tools Serologic tests — The serological tests used to diagnose endemic treponematoses are the same as those used to diagnose syphilis; the tests cannot differentiate between endemic treponematoses and syphilis [121]. Serologic testing requires detection of two distinct antibodies: one against a treponemal antigen and one against a nontreponemal antigen. (See "Syphilis: Screening and diagnostic testing".)

Nontreponemal tests — Nontreponemal agglutination tests (rapid plasma reagin [RPR] or Venereal Disease Research Laboratory [VDRL]) are positive in untreated patients and can be used as a test of cure since the quantitative titers fall following treatment. The RPR can be read with the naked eye, whereas the VDRL requires a microscope. Two automated RPR assays have been cleared by the US Food and Drug Administration. The nontreponemal tests may give rise to false positives in patients with other conditions, including malaria, leprosy, and rheumatologic diseases [122]. They are often performed on serial dilutions of serum to give a quantitative titer, defined as the highest dilution that yields a positive result. Nontreponemal tests become positive within two to four weeks after appearance of the primary lesion [123]. Nontreponemal tests yield false-negative results in about 10 percent of patients with early infections (eg, window period). In the setting of clinical suspicion for yaws and a negative RPR result, we favor repeat testing with a nontreponemal test within two to four weeks or, if available, we use PCR for identification of the organism. There is a negative correlation between the duration of yaws infection and the nontreponemal titer; in end-stage disease, nontreponemal tests may be nonreactive. Large serologic cohort surveys of yaws have reported an association between low nontreponemal titers (55 years, there was a similar rise in herpes zoster incidence through 2006, but this rate subsequently decelerated. The reason for the overall increase in herpes zoster incidence, as well as these age-specific findings, is unclear. Some experts raised the possibility that widespread varicella immunization in childhood may increase the age-specific incidence of herpes zoster in adults [30]. Their concern was based on evidence that exposure to endemic varicella boosts VZV-specific immunity in adults and that cessation of varicella in the community would result in a decline in the T cell-mediated immunity required to maintain latency of VZV in neurons [31]. However, numerous epidemiologic studies have failed to document this effect [26,28,30,32]. In addition, the rise in herpes zoster incidence has occurred equally in countries without varicella immunization, and, in the United States, has occurred equally in states with or without good uptake of the varicella vaccine. There have also been concerns that varicella immunization might lead to an increased risk of vaccine-associated herpes zoster, particularly in immunocompromised children. The incidence of post-vaccination herpes zoster was examined in a study of 346 children with acute lymphocytic leukemia who received the Oka live attenuated varicella vaccine. Herpes zoster developed in five subjects (1.45 percent) after 10,878 months of observation [33]. In a substudy that matched 84 vaccinated subjects to those who had prior natural varicella infection, herpes zoster was less frequent in the immunized group (3 versus 11 cases). Reductions in herpes zoster among children have also been reported in a population-based study evaluating persons vaccinated in a communitybased setting [34,35]. In a database analysis of 13,084,793 children aged 50 years compared with those 500 cells/microL, 47.2 per 1000 person-years for CD4 count 200 to 499 cells/microL, and 97.5 per 1000 person-years for CD4 count 72 hours after onset' above.) ●The nucleoside analogues acyclovir, valacyclovir, or famciclovir can be used for treatment of acute herpes zoster infection. We prefer valacyclovir (1000 mg three times daily) or famciclovir (500 mg three times daily) because of their lower dosing frequency compared with acyclovir (800 mg five times daily). All regimens should be given for seven days. (See 'Choice of agent' above.) ●Analgesic drugs are often needed to control mild to severe pain associated with acute neuritis. There is no clear role for the use of glucocorticoids or tricyclic antidepressants in patients with uncomplicated herpes zoster since clinical benefit has not been demonstrated and there are significant risks associated with these medications. (See 'Analgesia for acute neuritis' above and 'Adjuvant therapies' above.) ●We treat pregnant women with early herpes zoster to hasten healing of cutaneous lesions and reduce the severity and duration of pain. Although there are no clinical trials examining the role of antiviral therapy in pregnant woman with herpes zoster infection, experience with acyclovir therapy in both herpes simplex infection and varicella pneumonia suggests that this drug is safe in pregnancy. (See 'Pregnant women' above.) ●Should secondary bacterial infection be suspected at the time of the initial evaluation, or at any time during the course of treatment, the patient should receive appropriate staphylococcal and streptococcal antibiotic coverage in addition to antiviral therapy. (See 'Secondary bacterial infection' above.) ●On occasion, immunocompetent patients with herpes zoster can present with ocular, otic, or neurologic manifestations. Such patients may require intravenous and/or prolonged antiviral therapy. In addition, there may be a role for adjunctive glucocorticoids in certain conditions. (See

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'Complicated zoster' above.) ●Patients with herpes zoster can transmit VZV to individuals who have not had varicella and have not received the varicella vaccine. Until the rash has crusted, patients should be advised to keep the rash covered, if feasible, and to wash their hands often to prevent the spread of virus to others. They should also avoid contact with pregnant women who have never had chickenpox or the varicella vaccine, premature or low birth weight infants, and immunocompromised individuals. (See 'Preventing transmission to others' above.)

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Molluscum contagiosum - UpToDate uptodate.com/contents/molluscum-contagiosum/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jan 24, 2020.

INTRODUCTION

Molluscum contagiosum virus (MCV) is a poxvirus that

causes a chronic, localized infection, consisting of flesh-colored, dome-shaped papules on the skin of an infected individual. The epidemiology, clinical features, diagnosis, and management of MCV infection will be reviewed here.

VIROLOGY

Molluscum contagiosum virus (MCV) is a double-stranded DNA virus

and member of the poxvirus family. MCV is in a different genus (Molluscipoxvirus) than the orthopoxviruses (variola, vaccinia, and monkeypox viruses). (See "Variola virus (smallpox)" and "Vaccinia virus as the smallpox vaccine" and "Monkeypox".) Four major genotypes of MCV have been identified, with MCV1 and MCV2 as the most common genotypes [1]. MCV causes a chronic, localized infection with small papules on the skin. Similar to the virus that causes smallpox, the only known host for MCV is humans. Information about MCV at the molecular level has been hampered by the inability to grow the virus in standard cell culture or in an animal model of infection. While there are reports of some success in growth using human foreskin xenograft fragments [2], a major advance in understanding the biology of the virus came when the entire 190,000 base pair genome of the MCV was sequenced [3,4].

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Like variola and vaccinia viruses, MCV replicates in the cytoplasm of cells, and more than one-half of the MCV genes are similar to those found in variola and vaccinia viruses [3,4]. Molluscum contagiosum contains many unique genes that encode proteins responsible for novel viral defense mechanisms; these mechanisms inhibit the host inflammatory and immune responses to the infection [5-10].

EPIDEMIOLOGY

Molluscum contagiosum virus (MCV) infection has been

reported worldwide. Although four distinct genotypes have been identified, genotype 1 (MCV1) predominates and represents 90 percent of cases in the United States [11]. A population-based Australian seroepidemiology study in 357 people revealed an overall seropositivity rate of 23 percent [12]. The data also indicated that very mild or subclinical cases may be more common in the general community than previously suspected. It is estimated that fewer than 5 percent of children in the United States have clinical evidence of MCV infection [11]. The number of cases in adults has varied over time. In the 1980s, the number of molluscum contagiosum cases increased, apparently as a result of the AIDS epidemic [13]; however, since the introduction of potent antiretroviral therapy (ART), the number of molluscum contagiosum cases in AIDS patients has decreased substantially [14].

RISK FACTORS

Molluscum contagiosum is a common disease of

childhood. The disease also occurs in healthy adolescents and adults, often as a sexually transmitted disease or in relation to participation in contact sports [11]. Molluscum contagiosum is also associated with immunodeficient states. It can occur in the setting of underlying cellular immunodeficiency, such as in inherited immunodeficiencies [15], during HIV infection, or following treatment with immunosuppressive drugs. Although it has been proposed that atopic dermatitis is a risk factor for molluscum contagiosum (picture 1F), data conflict on the relationship between these diseases. An increased risk is suggested by studies that report prevalence rates for atopic dermatitis between 18 and 45 percent among patients with molluscum contagiosum, rates that exceed the estimated prevalence of atopic dermatitis in the general pediatric population (10 to 20 percent) [16]. It is theorized that the relative suppression of T-helper cell type 1 responses in acute skin lesions of atopic dermatitis could contribute to a predisposition for molluscum contagiosum in the atopic dermatitis population. A nursery school-based study of over 1100 children in Japan did not find a statistically significant association between a history of molluscum contagiosum and a history of atopic dermatitis (odds ratio 1.64, 95% CI 1.00-2.68) [17]. Thus, the relationship between atopic dermatitis and molluscum contagiosum remains uncertain.

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TRANSMISSION

Like many viruses in the poxvirus family, molluscum

contagiosum virus (MCV) is spread by direct skin-to-skin contact and thus can occur anywhere on the body. The virus can be transmitted via autoinoculation by scratching or touching a lesion. For example, if the lesions develop on the face, shaving may spread the virus. The only known host for MCV is humans. Infection can also be spread via fomites on bath sponges or towels or through skin contact during participation in contact sports [11]. An association of molluscum contagiosum with swimming pool use also has been reported [18]. When it occurs in the genital region in sexually active individuals, molluscum contagiosum is classified as a sexually transmitted disease. In contrast to adults and adolescents, autoinoculation, rather than sexual contact, is responsible for most anogenital lesions in children [19]. Estimates for the incubation period of the virus vary from one week to six months, but it is typically between two and six weeks [18].

CLINICAL FEATURES

The molluscum contagiosum virus (MCV)

causes a chronic, localized infection characterized by firm, dome shaped papules on the skin (picture 1A-F). Lesions are often 2 to 5 mm in diameter, with a shiny surface and central indentation or umbilication. Occasionally, the growths can be polypoid with a stalk-like base. Pruritus may be present or absent, and lesions sometimes become visibly inflamed. Molluscum contagiosum may appear anywhere on the body except the palms and soles. The most common areas of involvement include the trunk, axillae, antecubital and popliteal fossae, and crural folds. Lesions on the eyelid can cause conjunctivitis (picture 2A-B) [20]. Oral mucosal involvement is rare [21]. Sexually transmitted molluscum contagiosum typically involves the groin, genitals, proximal thighs, and lower abdomen. In HIV-infected and other immunocompromised patients, lesions can be large (aka giant molluscum) and widespread (picture 3A-B).

ASSOCIATED CLINICAL FINDINGS Molluscum dermatitis — Molluscum dermatitis, which is characterized by the development of eczematous patches or plaques surrounding molluscum contagiosum lesions, is a common phenomenon (picture 4). Estimates of the proportion of patients with molluscum who develop molluscum dermatitis have ranged from 9 to 47 percent [16]. Whether the use of topical corticosteroid therapy for molluscum dermatitis impacts the prognosis of molluscum contagiosum is unclear. Although there is some concern that local immunosuppression from topical corticosteroids could inhibit clearance of the infection, this has not been proven [22,23]. On the other hand, it is conceivable that untreated molluscum dermatitis could contribute to spread of the infection through scratching.

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A short course (eg, up to two weeks) of a low or medium potency topical corticosteroid (table 1) can be used to treat sites of molluscum dermatitis in patients in whom the condition is pruritic. Emollients may be used for the management of asymptomatic patients [23].

Inflamed lesions — Inflamed molluscum contagiosum, which is characterized by erythema and swelling of individual lesions, is a clinical finding that may portend a higher likelihood of impending clinical improvement [16,24]. In a retrospective study of 696 children with molluscum contagiosum, children with inflamed lesions were less likely to develop an increase in the number of lesions over the course of three months than patients who had neither inflamed lesions nor molluscum dermatitis [16]. In a case series of seven children with inflamed molluscum, the duration from onset of inflammation to resolution ranged from three weeks to five months [24]. Inflamed molluscum should not be mistaken for secondary bacterial infection. Antibiotic treatment is not needed.

Other — Gianotti-Crosti syndrome (also known as papular acrodermatitis) is a pruritic inflammatory skin condition that may occur in association with viral infections in children (picture 5). The face, buttocks, and extremities are common sites for lesion development. (See "GianottiCrosti syndrome (papular acrodermatitis)".) Gianotti-Crosti like eruptions have been reported in patients with molluscum contagiosum. In one large retrospective study, this phenomenon was diagnosed in 5 percent [16]. Gianotti-Crosti like reactions may portend a higher likelihood of forthcoming clinical improvement [16].

DIAGNOSIS

The diagnosis of molluscum contagiosum is usually made by the

characteristic appearance of the lesions (picture 6). When necessary, histologic examination can confirm the clinical diagnosis. Hematoxylin and eosin staining of a molluscum contagiosum lesion typically reveals keratinocytes containing eosinophilic cytoplasmic inclusion bodies (also known as molluscum bodies or Henderson-Paterson bodies) (picture 7) [25]. Dermoscopic examination can be useful for supporting a clinical diagnosis of molluscum contagiosum. Visualization of a central umbilication with polylobular, white to yellow, amorphous structures is typical (picture 8) [26,27]. A peripheral crown of radiating or punctiform vessels is also present [28]. (See "Dermoscopy of mucosal lesions", section on 'Molluscum contagiosum'.) Although usually not indicated, electron microscopy of biopsies demonstrates typical brick-shaped poxvirus particles. Electron microscopy can also identify infected cells that appear normal on light microscopy [29].

DIFFERENTIAL DIAGNOSIS

Skin lesions due to

cryptococcosis, histoplasmosis, or Penicillium marneffei infection may resemble molluscum lesions (picture 9A-E) [30]. The possibility of these disorders should be considered in immunosuppressed

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patients. Other lesions that may be mistaken for molluscum contagiosum include flat warts, condyloma acuminatum, condylomata lata (picture 10), pyogenic granuloma (picture 11), adnexal tumors, Langerhans cell histiocytosis (picture 12), basal cell carcinoma (picture 13), and amelanotic melanoma. Skin biopsy is useful for distinguishing molluscum contagiosum from other disorders. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis" and "Cryptococcus neoformans infection outside the central nervous system", section on 'Nonmeningeal, nonpulmonary cryptococcosis' and "Epidemiology and clinical manifestations of Talaromyces (Penicillium) marneffei infection", section on 'Clinical manifestations'.)

NATURAL HISTORY

In immunocompetent patients, individual

lesions usually spontaneously resolve within two months and the infection often clears completely within six to twelve months [19,24,31]. In a minority of cases, disease persists for three to five years [19,24,31]. Although scarring can occur after spontaneous resolution, most molluscum contagiosum lesions do not resolve with scars.

LABORATORY TESTS

Laboratory studies usually are not

indicated in children with molluscum contagiosum. Sexually active adolescents and adults with genital lesions should be evaluated for the presence of other sexually transmitted diseases. Patients with extensive lesions should be tested for HIV infection, and the possibility of other immune system disorders should also be considered. (See "Screening and diagnostic testing for HIV infection" and "Approach to the child with recurrent infections".)

OVERVIEW OF MANAGEMENT

The self-limited

nature of molluscum contagiosum and the paucity of evidence that definitively supports therapeutic intervention have led to debate over the need for treatment [32,33].

Decision to treat — Potential advantages of successful treatment include limitation of lesion spread to other sites, reduction of the risk of transmission to others, resolution of pruritus when present, and the prevention of scarring that can result from lesions that become inflamed, traumatized, or secondarily infected. Treatment may also reduce patient or parental psychologic stress over the appearance of lesions. However, depending on the chosen therapy, treatment can be time consuming or can result in adverse effects such as pain, irritation, dyspigmentation, or scarring. In general, adolescents and adults with sexually-transmitted molluscum contagiosum should be treated to avoid spread of the disease to others. Early treatment is also indicated in the setting of immunocompromised individuals, in whom infections can become severe.

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For immunocompetent children with molluscum contagiosum, treatment is optional. One retrospective study utilizing a telephone survey and medical chart review found similar rates of molluscum contagiosum resolution among 46 treated and 124 untreated children; approximately 50 percent of children in both groups had complete resolution within 12 months [32]. We typically inform parents and guardians of the expected course of the disease without treatment and the potential adverse effects of each treatment option. When parents or guardians desire intervention, we proceed with therapy. Prior to treatment, a full skin examination should be performed on patients with molluscum to identify all lesions. Incomplete treatment may result in continued autoinoculation and failure to achieve cure.

Periocular lesions — The destructive methods and topical agents reviewed below should not be utilized on lesions involving the ocular mucosa or eyelids. Patients with symptomatic ocular lesions should be referred to an ophthalmologist for management.

FIRST-LINE THERAPIES

Strong evidence for the efficacy of

any treatment for molluscum contagiosum is lacking. A systematic review of randomized trials that investigated the efficacy of treatments for nongenital molluscum contagiosum in healthy individuals found insufficient evidence to conclude that any treatment was definitively effective [33]. Despite the absence of large placebo-controlled trials to support the efficacy of cryotherapy, curettage, and cantharidin, the rapid, clinically evident response associated with their use offers some support for their utility for the removal of individual lesions. The efficacy of podophyllotoxin is supported by data from a placebo-controlled randomized trial. Thus, when a trial of treatment is desired, we consider cryotherapy, curettage, cantharidin, and podophyllotoxin as first-line therapeutic options. The efficacy and safety of podophyllotoxin for molluscum contagiosum in young children have not been definitively established.

Cryotherapy — Liquid nitrogen is used to perform cryotherapy. A cotton-tipped swab dipped in liquid nitrogen and applied to individual lesions for 6 to 10 seconds can be used [19]. (See "Minor dermatologic procedures", section on 'Cryotherapy (cryosurgery)'.) Cryotherapy was shown to be a rapidly effective therapy in a randomized trial (see 'Comparative studies' below) [34]. Treatment is often well tolerated in adolescents and adults; however, the pain associated with cryotherapy can limit its use in young children, particularly if multiple lesions are present. Scarring and temporary or permanent hypopigmentation are potential adverse effects of cryotherapy. Hypopigmentation can be prominent in individuals with dark skin.

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Curettage — Curettage involves the physical removal of the molluscum contagiosum lesion with a curette. The immediate resolution of lesions has led some clinicians to use this method as their preferred therapy for molluscum contagiosum [35]. Support for the use of curettage comes from a retrospective study that found that 70 percent of 1878 children treated with curettage were cured after a single treatment session [36]. In addition, a trial in which 124 children with molluscum contagiosum were randomly assigned to one of four treatment modalities found that 81 percent of 31 children treated with curettage were cured after a single session [35]. (See 'Comparative studies' below.) In contrast, a prospective study of 73 children and adults treated with curettage found that 42 out of 64 patients (66 percent) were not cured after a single session, and 25 out of 55 (45 percent) failed to clear after two sessions [37]. Risk factors for treatment failure included a high number of lesions and concomitant atopic dermatitis. The discomfort and minor bleeding associated with this procedure can be disturbing for some children, and the possibility of the development of small, depressed scars should be discussed with patients or their guardians prior to proceeding. Treatment may be time-consuming due to the need to ease children's fears about the procedure. Topical anesthetics applied prior to curettage can reduce discomfort and facilitate therapy. (See "Clinical use of topical anesthetics in children".)

Cantharidin — Cantharidin is a topical blistering agent that is commonly used for the treatment of molluscum [38]. Treatment should be performed by a clinician; patients should not be given cantharidin to apply at home. The expected response is the development of a small blister at the treatment site, followed by disappearance of the molluscum lesion and healing without scarring. A trial in which 94 children with molluscum contagiosum were randomly assigned to a single treatment of cantharidin without occlusion, cantharidin with occlusion, placebo without occlusion, or placebo with occlusion found a nonstatistically significant trend towards better outcomes with cantharidin [39]. Total clearance of molluscum lesions at week 6 occurred in 10 of 24 children (42 percent) in the cantharidin with occlusion group, 7 of 23 children (30 percent) in the cantharidin without occlusion group, 2 of 25 children (8 percent) in the placebo with occlusion group, and 3 of 22 children (14 percent) in the placebo without occlusion group. A post-hoc analysis that compared the combined cantharidin groups with the combined placebo groups found the response to cantharidin superior (36 versus 11 percent of patients achieved complete clearance, respectively). In a retrospective study of 300 children treated with cantharidin (without occlusion) for molluscum, 90 percent of children had lesion clearance, and an additional 8 percent demonstrated improvement without complete clearance [40]. On average, 2.1 clinician visits were necessary to achieve complete clearance. The parents of the patients appeared satisfied with treatment; 95 percent stated that they would be willing to have their child treated again with cantharidin.

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Cantharidin is applied directly to lesions; the blunt wooden end of a cotton swab can be used for application. The site may be then covered, such as with a bandage, to avoid inadvertent spread of the vesicant to other areas. Cantharidin should be washed off with soap and water two to six hours after application or at the first sign of blistering [19]. Occasionally blistering can be exuberant, and it is reasonable to treat a small number of lesions at the first visit. The duration of application can be adjusted based upon the initial response. Treatments can be repeated every two to four weeks until all lesions have resolved [40]. In general, treatment with cantharidin should be avoided on the face, genital, or perianal areas. Common adverse effects include transient burning, pain, erythema, and pruritus [40]. Postinflammatory dyspigmentation may occur, but typically resolves over several months. While uncommon, scarring can occur as a consequence of cantharidin treatment [41].

Podophyllotoxin — Podophyllotoxin is an antimitotic agent that is commercially available as podofilox 0.5% (Condylox) in a solution or gel. The efficacy of podophyllotoxin was explored in a randomized trial of 150 males (ages 10 to 26 years); most lesions were located on the thighs or genitalia. Patients in the trial applied 0.5% podophyllotoxin cream, 0.3% podophyllotoxin cream, or placebo twice daily for three consecutive days per week [42]. Treatment was continued for up to four weeks. By the end of treatment, the superiority of 0.5% podophyllotoxin was evident; 92, 52, and 16 percent of patients in the 0.5% podophyllotoxin, 0.3% podophyllotoxin, and placebo groups were cured, respectively. Local erythema, burning, pruritus, inflammation, and erosions can occur with the use of this agent. The safety and efficacy of podophyllotoxin for molluscum contagiosum have not been definitively established in young children.

OTHER INTERVENTIONS

Although topical therapies such

as imiquimod and potassium hydroxide (KOH) have been used for the treatment of molluscum, sufficient data to support a recommendation for the use of these and several other treatments are lacking.

Imiquimod — Imiquimod is a topical immunomodulator that induces the local production of proinflammatory cytokines. Although favorable responses to imiquimod have been reported in uncontrolled studies and case series [43-45], the drug has not been proven more effective than placebo in randomized trials, suggesting that spontaneous resolution may account for some observations of efficacy. Because of the lack of clarity regarding the effect of imiquimod on molluscum contagiosum, we are unable to recommend the routine use of this drug for therapy. Imiquimod did not appear to be effective in two large, unpublished randomized trials of children who were treated with imiquimod 5% cream or vehicle three times weekly for up to 16 weeks [46]. In the first study, complete clearance of molluscum occurred in 52 of 217 children in the treatment group

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(24 percent) versus 28 of 106 children in the vehicle group (26 percent). In the second trial, clearance occurred in 60 of 253 children (24 percent) and 35 of 126 children (28 percent) in the treatment and vehicle groups, respectively. A small, published, placebo-controlled randomized trial (n = 23) also was unable to demonstrate a benefit of imiquimod [47]. Although significantly more patients treated with imiquimod 5% cream (applied three times weekly for up to 12 weeks) achieved partial clearance by week 12 (defined as a ≥30 percent decrease in lesion count) than patients in the placebo group (67 versus 18 percent), the difference in the complete clearance rate (33 versus 9 percent, respectively) was not statistically significant. The small size of the trial may have contributed to the lack of statistical significance. A few trials have compared imiquimod with other treatments for molluscum. In a small randomized trial, once weekly cryotherapy was associated with a faster rate of lesion clearance than imiquimod 5% cream applied five days per week, but a similar rate of complete cure was observed [34]. Trials that have compared imiquimod with other treatments are reviewed below. (See 'Comparative studies' below.) Imiquimod is usually applied at night and washed off in the morning. Erythema and pruritus at application sites are common adverse effects [48]. Flu-like symptoms may also occur.

Potassium hydroxide — Potassium hydroxide (KOH), in concentrations of 5 or 10%, has been used for molluscum contagiosum [49-52]. Application frequency reported in the literature ranges from three times per week to twice daily. In a trial in which 53 young children with molluscum contagiosum were randomly assigned to oncedaily application of 10% KOH, 15% KOH, or placebo until complete clearance or a maximum of 60 days, more children in the 10% and 15% KOH groups achieved complete clearance than in the placebo group at day 60 (59, 64, and 19 percent, respectively) [53]. Common side effects included stinging and burning at the site of application. In a subsequent trial by the same research group in which 91 children (ages 2 to 16) were randomly assigned to application of either 10% KOH or placebo once daily until clearance of lesions or up to a maximum of 30 days, 55 percent of children in the KOH group achieved at least a 75 percent reduction in the number of molluscum lesions within 33 days compared with only 16 percent in the placebo group [52]. Adverse events were more frequent in the KOH group, with local effects at the application site and infections as the most common adverse events. Approximately one-third of children in the KOH group discontinued treatment due to adverse events compared with none in the placebo group. Lower concentrations of KOH might also be of benefit. In a series of 20 children treated twice daily with 5% KOH in an aqueous solution, all patients cleared within six weeks [51]. Treatment with KOH also has been compared with other therapies for molluscum in randomized trials [54-56]. (See 'Comparative studies' below.)

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Stinging or burning sensations often accompany application of KOH [54], and may be reduced with the use of the 5% concentration [50]. Temporary dyspigmentation is another potential adverse effect of this therapy.

Salicylic acid — Salicylic acid is a widely available keratolytic that has been used in the treatment of molluscum contagiosum. In a randomized trial of 124 children, an agent containing salicylic acid 16.7% and lactic acid 16.7% (Duofilm) applied with a tooth pick at home three times per week was compared with three other treatments (see 'Comparative studies' below) [35]. Compared with curettage, patients treated with salicylic acid were more likely to return to the office, which they were instructed to do if lesions persisted. Adverse effects were frequent; 54 percent of patients treated with salicylic/lactic acid experienced side effects. Local irritation is common with the use of salicylic acid. Use of salicylic acid in combination with sodium nitrite [57] or povidone iodine solution [58] has also been reported.

Topical retinoids — Tretinoin (0.5% cream, 0.1% cream, or 0.025% gel), adapalene, and tazarotene have been used for the treatment of molluscum [59-62]. The mechanism of action is thought to involve the induction of local irritation that damages the viral protein-lipid membrane [63]. Data on the efficacy of these agents are limited to reports of clinical experiences [59-62]. Treatment with topical retinoids can begin every other day and can be increased to twice daily as tolerated [19]. Application is discontinued once local erythema develops [19]. Irritation and xerosis are expected side effects. Topical retinoids should not be used during pregnancy.

Other topical agents — Limited data suggest potential benefit of other agents, such as ingenol mebutate, berdazimer sodium, and silver nitrate paste, for molluscum contagiosum. An unblinded trial in which 19 patients with molluscum contagiosum were randomly assigned to topical ingenol mebutate 0.015% gel applied once daily for three consecutive days per week until resolution or imiquimod 5% cream applied once daily for five days per week until resolution found complete clearance in 9 of 10 patients in the ingenol mebutate group compared with 3 of 9 patients in the imiquimod group at week 12 [64]. A phase 2, vehicle-controlled, randomized trial in which 256 patients with molluscum contagiosum were randomly assigned to different regimens of berdazimer sodium coadministered with hydrogel, an investigational nitric oxide releaser, or vehicle suggests benefit of this agent for molluscum contagiosum [65].

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A paste containing 40% silver nitrate was reported to be effective in a series of 389 patients [66]. Topical phenol [67] and trichloroacetic acid [68,69] also have been used for molluscum contagiosum, but high risks for pain and scarring make these agents unfavorable options. A nonprescription topical homeopathic agent that contains argentum nitricum, Echinacea angustifolia, Fucus vesiculosus, and Thuja occidentalis is marketed for the treatment of molluscum contagiosum. No published studies have evaluated the efficacy and safety of this product for molluscum contagiosum.

Other physical interventions — Pulsed dye lasers have shown efficacy in case reports and small uncontrolled studies [70-76]. In a prospective study of 19 children treated with a 585 nm pulsed dye laser, a single treatment led to disease resolution in 84 percent of patients [70]. Use of topical anesthetics prior to pulsed dye laser treatment may help to reduce pain associated with laser therapy. Potassium titanyl phosphate (KTP) lasers [77], carbon dioxide lasers [78,79], and photodynamic therapy have also been used to treat lesions. Additional physical interventions that have been reported in the treatment of molluscum contagiosum include electrodessication, manual extrusion of the central core by squeezing [67], removal with sterilized tweezers [80], needle penetration in combination with topical tretinoin [81], intralesional injection with Candida antigen [82], topical 20 to 35% trichloroacetic acid [83], and hyperthermia [84]. The efficacy and safety of these interventions have not been studied in randomized trials.

Oral cimetidine — Cimetidine is an H

2

antihistamine that has also been found to

have immunomodulatory properties. Data conflict on the efficacy of this agent for molluscum contagiosum [85,86]. In a series of 13 children with molluscum contagiosum who had failed to respond to other therapies, treatment with cimetidine (40 mg/kg/day for two months) was associated with clearance of all lesions [86]. However, in a separate series of 14 children treated with cimetidine 40 mg/kg/day, only four children cleared within three months, and seven children showed no improvement [85]. Three children who did not take cimetidine due to the taste of the medicine or treatment cost spontaneously improved within three months, raising questions about the efficacy of treatment. Additional studies are necessary to investigate the efficacy of cimetidine in the management of molluscum.

COMPARATIVE STUDIES

There are relatively few trials

that compare the efficacy of treatments for molluscum. Examples of the available data include: ●Multiple therapies – A randomized trial of 124 children (ages 1 to 16 years) compared the safety and efficacy of curettage with topical anesthesia, cantharidin 0.7% (applied for two to four hours), a combination product with 16.7% salicylic acid and 16.7% lactic acid (three times per week), and imiquimod 5% cream (three times per week) [35]. Ten lesions on each patient were treated according to protocol, and the remaining lesions on all patients were treated with curettage. Telephone follow-

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up was performed on days 7, 21, 84, and 180 and follow-up visits were scheduled for patients with residual lesions. Curettage required the fewest follow-up visits for resolution of all 10 lesions, with 81 percent of patients requiring only one visit. Cantharidin, salicylic/lactic acid, and imiquimod required only one visit 37, 54, and 57 percent of the time, respectively. Parent and patient satisfaction with treatment was highest in the curettage group (87 percent), followed by cantharidin (60 percent), imiquimod (45 percent), and salicylic/lactic acid (32 percent). Adverse effects were most common in the group treated with salicylic acid (53 percent of patients). ●Imiquimod versus cryotherapy – Imiquimod (applied five days per week) was compared with cryotherapy (once weekly) in a randomized trial of 74 children with molluscum contagiosum [34]. Treatment with either regimen was continued until lesion resolution or for up to 16 weeks. Cryotherapy led to complete cure in all patients and more rapid resolution than imiquimod; the majority of children (26 out of 37; 70 percent) were cured within three weeks. In the imiquimod group, 34 of 37 (92 percent) achieved complete cure, with the majority (22 out of 37; 59 percent) clearing within six weeks. The difference in complete cure rates between the two groups was not statistically significant. However, adverse effects (pain, bullae, dyspigmentation, mild scarring) were more common in cryotherapy group. ●Imiquimod verus potassium hydroxide –Two randomized trials have compared the efficacy of imiquimod 5% cream and 10% potassium hydroxide (KOH). The trials did not find significant differences in efficacy. •In a randomized trial of 30 patients with molluscum contagiosum (ages 1 to 36 years), patients were treated with either agent three nights per week until lesion clearance or for up to 12 weeks [55]. Statistically significant reductions in lesion counts were observed in both groups, but a statistically significant difference in efficacy between the two treatments was not detected. In the trial, 8 out of 14 patients treated with imiquimod (57 percent) and 10 out of 13 patients treated with KOH (77 percent) achieved complete clearance. All patients who achieved complete responses cleared within eight weeks. •Imiquimod and 10% KOH were found to be equally effective for achieving disease clearance in another randomized trial in which patients (ages 2 to 32 years) were treated with either agent three times weekly; all lesions resolved within 12 weeks in 8 out of 18 patients given imiquimod (44 percent) and 8 out of 19 of patients given KOH (42 percent) [54]. Compared with imiquimod, KOH appeared to have a more rapid onset of action and a higher rate of adverse effects (56 versus 78 percent developed side effects). The most common side effects observed were erythema and crusting. ●Cryotherapy versus potassium hydroxide – Cryotherapy and KOH were similarly effective in a fourweek trial in which 30 patients (ages 1 to 24) were randomly assigned to once weekly cryotherapy or twice daily applications of 10% KOH [56]. After four weeks, 14 of 15 patients in the cryotherapy group (93 percent) and 13 of 15 patients in the KOH group (87 percent) had complete clearance of molluscum lesions. Side effects of transient hyperpigmentation and hypopigmentation occurred in both groups.

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IMMUNOCOMPROMISED PATIENTS

Immunocompromised patients can develop severe, persistent cases of

molluscum contagiosum. Therapies that result in wounds, such as curettage, may be a less favorable option for immunocompromised patients because of an elevated risk for infection. Case reports have described the successful treatment of severe, refractory molluscum contagiosum in a few immunocompromised patients with imiquimod [44,62,87-89]. However, randomized trials in nonimmunocompromised patients with molluscum contagiosum have failed to find benefit of imiquimod therapy. (See 'Imiquimod' above.) In addition to the treatments above, immunocompromised patients with refractory disease have been treated with agents such as interferon alfa and cidofovir.

Interferon alfa — Immunodeficient children and adults have attained resolution of severe, refractory lesions with subcutaneous interferon alfa [90-92]. The use of intralesional interferon alfa has also been reported [93]. Influenza-like symptoms are common adverse effects of interferon therapy.

Cidofovir — Intravenous cidofovir [94-96] and topical cidofovir (1% or 3%) [95,97-100] have been used in immunocompromised patients with severe, refractory molluscum. Renal toxicity is a significant concern with the use of systemic cidofovir. Local irritation and painful cutaneous erosions can occur after application of the topical form [99]. Due to the absence of a commercial product, preparation of topical cidofovir must be entrusted to a compounding pharmacy. The stability, bioavailability, and optimal dosing regimen of such extemporaneous mixtures are unknown.

HIV therapy — Recovery of immune function may result in improvement. In HIVinfected patients, there have been multiple reports of recalcitrant molluscum contagiosum lesions resolving only after initiation of effective antiretroviral therapy [14,101]. However, the development of molluscum contagiosum has also been reported in association with immune reconstitution inflammatory syndrome (IRIS) following antiretroviral therapy in patients with HIV infection [100]. (See "Immune reconstitution inflammatory syndrome".)

SCHOOL AND SPORTS

It is not necessary to remove children

with molluscum contagiosum from daycare or school; however, care should be taken to reduce the risk of transmission to others. Lesions in areas that are likely to come in contact with others should

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be covered with clothing or a watertight bandage. Bathing with other children should be avoided and towels and sponges should not be shared. Affected individuals do not need to be excluded from contact sports activities provided lesions can be covered with clothing or bandages. Individuals with molluscum contagiosum should not be restricted from the use of public swimming pools.

PREGNANCY

Molluscum contagiosum in pregnancy is not common and the

vertical transmission rate is not known. Only a small number of cases of congenital transmission have been documented in the literature [102]. Since molluscum contagiosum is spread by direct contact, a woman with genital lesions at the time of a vaginal delivery could theoretically transmit molluscum to her newborn, as is seen with genital warts. However, studies that have examined the incidence of molluscum contagiosum in children reveal that it is extremely uncommon to find molluscum contagiosum in children under the age of one [103,104]. The lack of many cases in this age group may indicate that infants are protected by passive maternal antibodies or that the infection has a very long incubation period. There are scant data regarding the management of molluscum contagiosum in pregnancy since it is uncommonly encountered. Due to the toxicity of the chemicals commonly used to treat molluscum contagiosum (eg, podophyllotoxin or imiquimod), we do not recommend their use during pregnancy. Other options include cryotherapy or curettage or no treatment, since molluscum contagiosum is a self-limited disease. Dressings to cover visible lesions during delivery (eg, Tegaderm) may be considered to avoid skin-to-skin contact and hopefully lessen the risk of transmission.

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Molluscum contagiosum".)

INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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●Beyond the Basics topics (see "Patient education: Molluscum contagiosum (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS ●Molluscum contagiosum virus (MCV) is a poxvirus that causes localized skin infections. (See 'Virology' above.) ●Molluscum contagiosum is commonly seen in children, but can also occur in adults. The virus is transmitted through direct skin contact or fomites. Molluscum contagiosum infection in the genital region may result from transmission during sexual activity. (See 'Epidemiology' above and 'Transmission' above.) ●The incubation period for molluscum contagiosum is uncertain, but has been estimated to be between two and six weeks. (See 'Transmission' above.) ●Molluscum contagiosum most commonly presents as single or multiple small, flesh-colored papules with central umbilication (picture 1A-F). Immunosuppressed individuals have an increased risk for larger lesions and more widespread disease (picture 3A-B). (See 'Clinical features' above.) ●The diagnosis of molluscum contagiosum typically is based upon the clinical appearance of skin lesions. Biopsy can confirm the diagnosis when necessary. Histopathologic examination of a lesion of molluscum contagiosum reveals eosinophilic cytoplasmic inclusion bodies within keratinocytes (picture 7). (See 'Diagnosis' above.) ●Molluscum contagiosum infection is usually self-limited in immunocompetent individuals, and electing not to treat is a satisfactory option. In general, molluscum in the genital region should be treated due to the potential for sexual transmission. (See 'Overview of management' above.) ●Inflammation of molluscum is common and can be a sign of impending regression. Inflammation should not be mistaken for bacterial infection. (See 'Inflamed lesions' above.) ●High quality data on the efficacy of treatments for molluscum contagiosum are limited. When a trial of treatment is desired, we suggest the use of cryotherapy, curettage, cantharidin, or podophyllotoxin over other therapies (Grade 2B). The use of cantharidin should be avoided in the genital area. The efficacy and safety of podophyllotoxin for molluscum contagiosum in children has not been definitively established. (See 'First-line therapies' above.) ●Prominent hypopigmentation may result from treatment with cryotherapy in patients with dark skin. The risks and benefits of cryotherapy should be considered carefully in these patients. (See 'Cryotherapy' above.)

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●Imiquimod, potassium hydroxide (KOH), salicylic acid, and topical retinoids have also been used for the treatment of molluscum contagiosum. However, data in support of the efficacy of these treatments are insufficient for a recommendation for the routine use of these therapies. (See 'Other interventions' above.) ●The efficacy of cimetidine for molluscum contagiosum is uncertain. Cimetidine should not be used as a first-line therapy for molluscum contagiosum. (See 'Oral cimetidine' above.) ●Immunocompromised patients are at risk for extensive and persistent disease. Improvement in molluscum contagiosum may occur in patients with HIV infection after the initiation of antiretroviral therapy. (See 'Immunocompromised patients' above.) ●Children with molluscum contagiosum should not be excluded from daycare or school. Lesions should be covered with clothing or a bandage to reduce the risk of transmission to others. (See 'School and sports' above.)

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Orf virus infection - UpToDate uptodate.com/contents/orf-virus-infection/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Aug 15, 2018.

INTRODUCTION

Orf is a highly contagious, zoonotic, self-limited viral

infection that threatens individuals who handle sheep and goats. The cause of orf is the orf virus. Other terms for orf include ecthyma contagiosum, infectious pustular dermatitis, and contagious pustular dermatitis [1-4]. In humans, orf usually presents as an evolving, erythematous nodule on the hand (picture 1A). The infection typically resolves spontaneously within six to eight weeks. The risk factors, clinical features, diagnosis, and management of orf virus infection will be reviewed here. Other zoonotic infections are reviewed separately. (See "Zoonoses from pets other than dogs and cats" and "Zoonoses from dogs" and "Zoonoses from cats".)

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VIROLOGY

The epitheliotropic orf virus is the prototype of the Parapoxvirus genus

of Poxviridae family [1-4]. The virus has a linear double-stranded DNA genome and replicates within the host cell cytoplasm. The genome consists of a central core containing highly conserved genes that encode transcription and replication machinery; genes encoding factors associated with virulence, immune modulation, and pathogenesis are located outside the core region at both ends of the genome [3].

TRANSMISSION

Orf virus is highly contagious. Loss of epithelial barrier

integrity (ie, abrasion or other skin break) is the most important predisposing factor for infection [14].   Transmission to humans can occur through direct contact with an infected lesion on a living or deceased goat or sheep. Infected animals usually exhibit scabbed sores on or around the mouth, and the infection is commonly known as sore mouth or scabby mouth disease in sheep or goats [5]. Infections may also occur on the legs or udder teats, particularly in female animals that are nursing infected young. In addition, infection can occur through contact with fomites previously contaminated by infected animals, such as farm buildings, wool, knives, buckets, equipment, and fences [4,6]. Orf virus is resilient and resistant to drying and freezing and can remain viable for months to years [4,7]. Autoinoculation and human-to-human transmission are rare [6].

RISK FACTORS

Orf is most often an occupational hazard. Populations

most at risk include shepherds, wool shearers, butchers, farmers, and veterinarians [1,2,4,7]. Less often, infection occurs in individuals with nonoccupational contact with sheep and goats, such as zoologic garden visitors and people who slaughter sheep or goats for traditional rituals [4,6-10].

PATHOGENESIS

Orf virus causes a vesiculoulcerative infection of

keratinized skin and mucosa that replicates in regenerating epidermal keratinocytes [1-4]. Multiple virulence factors contribute to immune evasion and the establishment of infection [3,4]. Host immunity, especially the cell-mediated immune response, plays a major role in limiting the severity of infection. Virulence factors of the orf virus include proteins with anti-inflammatory functions (eg, viral-vascular endothelial growth factor, orf virus interleukin-10, ovine interferon resistance protein, granulocytemacrophage colony-stimulating factor, inhibitory factor, and chemokine binding protein) and proteins that promote virus survival and host cell manipulation or exploitation (eg, orf virus-encoded deoxyuridine triphosphate [dUTP]ases, nuclear factor kappa-B modulatory factors, ankyrin repeat proteins, and gene 125-encoded proteins).

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CLINICAL MANIFESTATIONS

In

immunocompetent patients, orf typically presents as a single asymptomatic lesion (approximately 1 cm in diameter) on the dorsa of hands or fingers that evolves in appearance over time (picture 1A-B) [1,2,4]. Examples of less frequent sites include the head [11], axilla [12], and genitals [13]. Multiple lesions may also occur (picture 2). Orf lesions commonly appear three to seven days after inoculation and progress through six clinical stages over the course of six to eight weeks, ending in resolution. The duration of each stage is approximately one week [1-4,6-8]: ●Maculopapular stage (solitary erythematous papule) (picture 1B) ●Target stage (papule or nodule with gray-white, necrotic center and red outer halo) (picture 3) ●Acute-nodular weepy stage (draining papule or nodule) (picture 1A) ●Regenerative-nodular dry stage (firm, crusted papule or nodule) (picture 4) ●Papilloma stage (papule or nodule with a papillomatous surface and dry crust) (picture 2) ●Regression stage (lesion progressively shrinks in size and resolves, generally without residual scar) (picture 4) Rarely, fever, malaise, and lymphadenopathy accompany the skin lesion [4,14]. Immunocompromised patients, especially patients with inherited or acquired T cell dysfunction, may develop atypical, painful, persistent giant orf lesions up to several centimeters in diameter [15-21]. Tumor-like and pyogenic granuloma-like morphologies may occur in these patients. Rarely, giant orf occurs in immunocompetent individuals [22].

COMPLICATIONS

Potential complications include secondary bacterial

infections and lymphangitis. In addition, orf is occasionally associated with the induction of secondary immunologic reactions, such as erythema multiforme [23,24], widespread papulovesicular eruptions [14,25], id reactions [26,27], and autoimmune blistering disorders [24,2831].

HISTOPATHOLOGY

Microscopic findings may vary depending on

the clinical stage of the lesion. Characteristic features of orf include (picture 5) [3,4,32]: ●Overlying crust ●Parakeratosis

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●Irregular epidermal hyperplasia ●Keratinocyte ballooning and degeneration ●Intraepidermal vesiculation ●Intracytoplasmic and intranuclear inclusions within vacuolated keratinocytes (picture 6) ●Increased dermal vascularity ●Papillary dermal edema ●Mixed inflammatory cell infiltrate

DIAGNOSIS

The patient history and physical examination are usually sufficient

for diagnosis. The collection of findings that strongly support the diagnosis include: ●Acute development of a papule or nodule exhibiting features consistent with one of the stages of orf ●Recent exposure to an infected sheep or goat or objects contaminated by an infected sheep or goat When the diagnosis is in doubt, a biopsy or molecular testing can aid in confirming the diagnosis [24]. A shave or punch biopsy can either reveal features supportive of viral infection (eg, intracytoplasmic and intranuclear inclusions within vacuolated keratinocytes) and other supportive features of orf or identify findings that are more consistent with other diseases. (See 'Histopathology' above.) Although not available in all settings, both standard and real-time polymerase chain reaction (PCR) testing are rapid and sensitive methods for diagnosing orf, with real-time PCR being highly sensitive [4,33,34]. A skin biopsy provides an adequate specimen. Other less widely used methods for confirming the diagnosis include cell culture and electron microscopy [2,4].

DIFFERENTIAL DIAGNOSIS

The clinical differential

diagnosis is extensive. In particular, orf should be distinguished from milker's nodule and cutaneous anthrax, infections that may also result in vesiculoulcerative lesions following contact with animals: ●Milker's nodule – Milker's nodule (also known as paravaccinia) is a parapoxvirus infection humans can acquire from dairy cows. Milker's nodule usually appears as one or more red-blue, smooth, verrucous, or vesicular nodules on the hand or arms and may be clinically indistinguishable from orf lesions (picture 7). Like orf, milker's nodule typically spontaneously resolves over the course of several weeks. The history of acquisition from contact with cows rather than sheep or goats is helpful for distinguishing these diseases.

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●Cutaneous anthrax – Cutaneous anthrax is an infection that may result from contact with infected animals, animal meat, hides, or wool. Bacillus anthracis, a gram-positive bacillus, is the causative organism. Affected patients typically present with a nonpainful papule that subsequently vesiculates and evolves into an ulcer with black eschar (picture 8). Gram stain, culture, and polymerase chain reaction (PCR) tests can confirm the diagnosis. (See "Clinical manifestations and diagnosis of anthrax", section on 'Cutaneous anthrax'.) Other infections that may present with papules or nodules that may be mistaken for orf virus infection include giant molluscum, atypical mycobacterial infections, paronychia (picture 1B), cutaneous leishmaniasis, herpetic whitlow, tularemia, and sporotrichosis. Neoplastic entities, such as keratoacanthoma and pyogenic granuloma, are also in the differential diagnosis [4,17,35,36]. The patient history and clinical findings are often sufficient for differentiating orf from these disorders.

TREATMENT

In immunocompetent patients, treatment is not necessary since

the infection spontaneously resolves within several weeks. Topical antiseptics can be used to minimize risk for secondary bacterial infections [1,4]. Immunocompromised patients may develop giant persistent lesions and may require intervention for resolution. Case reports describe successful treatment with cryotherapy, electrocautery, curettage, imiquimod, intralesional interferon injections, or topical cidofovir [4,17,19-21,37]. Wide local excision has been performed for refractory infections that cannot be managed with less invasive therapies, but recurrence after excision is common [4]. No randomized trials evaluating the efficacy of therapies have been performed.

PREVENTION

Reinfection with orf virus can occur. However, reinfection is

commonly characterized by decreased lesion size and faster resolution [1,2,4]. Use of nonpermeable gloves when handling infected animals may reduce risk for human infection. Orf virus vaccines have been used in animals but appear only partially effective and are not available for use in humans [38,39].

SUMMARY AND RECOMMENDATIONS ●Orf is a cutaneous viral infection caused by infection with the orf virus, a parapoxvirus that infects sheep and goats. Humans may acquire the infection from contact with infected animals or contaminated fomites. Populations most at risk for orf include shepherds, wool shearers, butchers, farmers, and veterinarians. (See 'Virology' above and 'Transmission' above and 'Risk factors' above.)

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●Orf usually manifests as a solitary papule or nodule that evolves through six clinical stages over the course of six to eight weeks (picture 1A-B). Multiple and giant lesions may also occur, particularly in immunocompromised patients. (See 'Clinical manifestations' above.) ●The six clinical stages of orf include the maculopapular stage, target stage, acute-nodular weepy stage, regenerative-nodular dry stage, papilloma stage, and regression stage. Fever, malaise, or lymphadenopathy occasionally accompany the skin lesion. (See 'Clinical manifestations' above.) ●Orf usually can be diagnosed based upon the patient history and physical examination. A biopsy or molecular testing can aid in confirming the diagnosis in difficult cases. (See 'Diagnosis' above.) ●Orf generally spontaneously resolves within several weeks. Persistent infection may occur in immunocompromised patients. Data on treatment of persistent infection are limited. Treatments that have seemed beneficial in case reports include cryotherapy, electrocautery, curettage, imiquimod, intralesional interferon injections, or cidofovir. Recurrence is common after wide local excision. (See 'Treatment' above.)

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HIV-associated eosinophilic folliculitis - UpToDate uptodate.com/contents/hiv-associated-eosinophilic-folliculitis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jan 11, 2019.

INTRODUCTION

Eosinophilic folliculitis (EF) is a pruritic skin eruption

consisting of follicular papules or pustules, predominantly located on the scalp, face, neck, and upper chest (picture 1A-B). EF is a relatively common skin eruption in patients with advanced human immunodeficiency virus (HIV) disease [1,2]. A clinically distinct form of EF (Ofuji's disease) has also been described in otherwise healthy individuals, particularly in Japan [3]. Other rare types of non-HIV-associated EF include infantile EF and EF associated with bone marrow transplantation [4,5]. Non-HIV-associated EF has also been described as a rare side effect of medication, including chemotherapy [6].

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This topic reviews the presentation and management of HIV-associated EF. Bacterial folliculitis and eosinophilic pustular folliculitis of infancy are discussed separately. (See "Infectious folliculitis" and "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Eosinophilic pustular folliculitis of infancy'.)

EPIDEMIOLOGY

HIV-associated EF most commonly occurs in patients

with late-stage disease or low CD4 counts [1]. EF has been reported in HIV-infected men, women, and children [7-9]. The prevalence is uncertain, although one series of HIV patients reported folliculitis in 9 percent [10]. In our experience, since the advent of antiretroviral therapy, EF has become less common.

PATHOGENESIS

The etiology of EF is unknown. Clinical characteristics

of EF suggest that it may be an inflammatory disease related to immune dysregulation, perhaps in association with an underlying infection [11,12]. Etiologic hypotheses include: ●Demodex mites – It has been suggested that Demodex may play a role in the pathogenesis of EF [13,14]. However, a case series of 18 patients found Demodex in only four, and in those four cases the mite was not associated with a surrounding inflammatory response, suggesting that it was not the cause of the folliculitis [15]. ●Pityrosporum yeast – It has been hypothesized that HIV-infected persons with immunodysregulation could develop a hypersensitivity reaction to commensal follicular Pityrosporum organisms; however, histopathologic examination in 70 cases demonstrated appreciable yeast forms in just one case [15,16]. ●Bacteria – Responses to antibiotics such as metronidazole have raised the possibility of a bacterial infection; however, bacteria are not consistently found in patients who respond to antibiotic treatment [17]. Additionally, most patients do not get prolonged benefits from antibiotic therapy [15]. ●Autoimmunity – Based on the known association of autoimmune disease with HIV infection, and the sebaceous distribution of lesions in EF, it has been suggested that EF might be an autoimmune reaction to sebocytes or a constituent of sebum [15].

RISK FACTORS

HIV-associated EF was first described in patients with

acquired immune deficiency syndrome (AIDS) [18], and it typically occurs in late-stage disease. Patients typically have CD4 cell counts below 250 cells/mm3 [1], with a mean CD4 count of 64 cells/mm3 in a series of 18 patients [15], and a mean CD4 count of 116 cells/mm3 in a series of 57 patients [19].

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CLINICAL MANIFESTATIONS

HIV-associated EF is

characterized by recurrent, pruritic crops of discrete, erythematous, urticarial follicular papules and rare pustules, with a diameter of 3 to 5 mm (picture 1A-B). The most common areas of involvement are the scalp, face, neck, and upper trunk; all are areas with a high concentration of sebaceous glands. In a series of 13 patients, all 13 had lesions on the trunk, 11 had lesions on the head and neck, and 8 had lesions on the proximal aspects of their extremities [1]. Two main patterns of distribution were identified: lesions concentrated on the trunk with a few on the face; lesions predominantly on the forehead and beard areas with limited truncal involvement. Facial involvement may be particularly common in women with EF [20]. Intense, intractable pruritus is typical [15]. True pustules are rarely observed, as the lesions are typically so pruritic that the lesions are excoriated [1,21]. Peripheral eosinophilia and elevated serum IgE are seen in about 25 to 50 percent of patients with HIV-associated EF [15,21]. Because of this low sensitivity, these tests are not routinely performed for diagnosis.

HISTOPATHOLOGY

Common histopathologic findings of EF include

perifollicular infiltrates of lymphocytes and eosinophils along with spongiosis of follicular epithelium [16]. The lymphocytic and eosinophilic infiltrate is often focused at the level of the isthmus, where the sebaceous gland and duct enter the follicle [15,16]. Lysis of sebaceous ducts can be seen.

DIAGNOSIS

Although the diagnosis can be strongly suspected clinically in

patients with a low CD4 count and a pruritic follicular papular eruption on the upper body, skin biopsy is needed to confirm the diagnosis [22]. Aside from HIV testing, serologic studies are not useful for diagnosis. (See "Infectious folliculitis".)

Biopsy — A 4 mm punch biopsy of an inflamed papule or pustule usually provides a sufficient specimen for evaluation. Key histopathologic findings that support EF include eosinophilic spongiosis involving the follicular epithelium and perifollicular inflammatory infiltrate containing lymphocytes and eosinophils. (See 'Histopathology' above and "Skin biopsy techniques", section on 'Punch biopsy'.)

DIFFERENTIAL DIAGNOSIS

The differential diagnosis

of EF includes other follicular or pruritic disorders. The main distinction is between EF and infective folliculitis. In a prospective study of 51 HIV-positive patients with pruritic folliculitis, histopathologic examination revealed evidence for EF in 23 (45 percent), bacterial folliculitis in 21 (41 percent),

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Pityrosporum folliculitis in 5 (10 percent), and Demodex folliculitis in 2 (4 percent) [23]. In addition, in a series of 23 HIV-infected patients with itchy folliculitis, 18 (78 percent) had EF and 5 (22 percent) had infective folliculitis [15]. ●Bacterial folliculitis – Bacterial folliculitis typically presents with erythematous papules and pustules at the sites of hair follicles (picture 2A-B). In contrast to bacterial folliculitis, intact pustules are rare in EF and EF pustules are typically smaller than pustules in bacterial folliculitis. Unlike the sterile pustules of EF, Gram stain and culture of bacterial folliculitis will demonstrate a causative organism. (See "Infectious folliculitis", section on 'Bacterial folliculitis'.) Biopsy is not usually necessary to distinguish EF from bacterial folliculitis. However, in a series that compared 52 specimens from 50 patients with HIV-associated EF with 6 specimens of suppurative folliculitis in patients with HIV infection, biopsies of EF were distinct from those of suppurative folliculitis in that suppurative folliculitis demonstrated a predominance of neutrophils and macrophages within the infiltrate, microorganisms were easily identified, and there was often rupture of the involved follicle (picture 3A-B) [16]. ●Pityrosporum folliculitis – Pityrosporum folliculitis presents with follicle-based erythematous papules and pustules distributed on the upper body, but unlike EF, rarely involves the face. A potassium hydroxide (KOH) preparation demonstrating yeast forms supports the diagnosis (picture 4). (See "Infectious folliculitis", section on 'Fungal folliculitis' and "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.) Additional common disorders requiring differentiation from EF include: ●Acne vulgaris – Acne vulgaris is a common condition that, like EF, presents with papules and pustules that are primarily distributed on the upper body (picture 5A-B). Clinical features that suggest a diagnosis of acne vulgaris over EF include the presence of comedones and the absence of prominent pruritus. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris".) ●Pruritic papular eruption – Pruritic papular eruption (PPE) is an intensely pruritic skin condition seen commonly in people infected with HIV in Sub-Saharan Africa. Although the etiology is uncertain, there is some evidence that it involves an exaggerated reaction to arthropod bites (picture 6) [24]. Patients present with skin-colored papules on the extremities, face, and trunk that are often excoriated [25]. Postinflammatory hyperpigmentation may also be present. The results of a small retrospective study suggest that histologic features and immunohistochemical stains may be of value for distinguishing EF from PPE [26]. Patients with EF demonstrated more intense inflammatory infiltrates, higher counts of tissue mast cells, and higher expression levels of CD15, CD4, and CD7. Additional studies are necessary to confirm these findings. ●Scabies – Scabies can present as a widespread pruritic papular eruption (picture 7A-B). Recognition of classic areas of involvement (eg, interdigital areas), scabies burrows, or detection of the mite on a skin scraping are useful for the diagnosis of scabies. (See "Scabies: Epidemiology, clinical features, and diagnosis".)

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Other pruritic or pustular disorders such as atopic dermatitis, steroid folliculitis (also known as steroid acne (picture 8A-B)), papular urticaria, and drug eruptions may also enter the differential diagnosis. (See "Insect and other arthropod bites", section on 'Papular urticaria'.)

TREATMENT

Unlike Ofuji's disease (EF in otherwise healthy individuals),

human immunodeficiency virus (HIV)-associated EF does not normally respond to indomethacin [11]. Various treatments have been tried for HIV-associated EF, but there are no controlled trials comparing treatments with each other or with placebo, precluding definitive conclusions about the best approach to treatment.

First-line therapy — Antiretroviral treatment is our preferred first-line treatment for HIV-associated EF because patients in whom HIV infection responds to antiretroviral therapy generally show improvement or resolution of their EF. We also usually prescribe topical corticosteroids to aid with improvement in pruritus. We have not had much personal success with oral antihistamines for EF pruritus; however, other clinicians utilize this therapy.

Antiretroviral therapy — Although not formally studied in clinical trials, there is widespread recognition that HIV-associated EF improves or resolves in most patients treated with antiretroviral therapy (ART). (See "Selecting antiretroviral regimens for the treatment-naïve HIVinfected patient".) However, there are case reports of EF flaring during the first two to six months of ART, consistent with immune reconstitution inflammatory syndrome (IRIS) [19,27]. In a series of 34 cases of EF in patients on ART, 28 (82 percent) occurred within six months of initiating ART [19] (see "Immune reconstitution inflammatory syndrome"). Patients who appear to have a flare of EF as a manifestation of IRIS are typically treated with another therapy for EF for a period of several weeks to months. (See 'Second-line therapy' below and 'Third-line therapies' below.)

Topical corticosteroids — Potent topical corticosteroids (table 1) are common first-line therapies for EF. However, data on the efficacy of topical corticosteroids are limited. Of the 38 patients with topical corticosteroid-treated HIV-associated EF identified in a review of articles published between 1965 and 2013, 47 percent had documentation of at least partial improvement with topical corticosteroid treatment [28]. In general, topical corticosteroids can decrease pruritus and improve inflammation of existing lesions but do not suppress the development of new lesions and may not fully control symptoms [11,29]. We typically instruct patients to apply a potent topical corticosteroid (eg, group 2 or group 3 (table 1)) to affected areas on the trunk and extremities twice daily for two to three weeks, after which the patient returns for reassessment. For facial involvement we prefer to use a lower-potency agent (eg, group 6 (table 1)) to reduce the risk for local corticosteroid side effects. If satisfactory improvement in pruritus is achieved, we then instruct patients to taper the topical steroid. One example of a taper

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is to use the agent every other day, then every third day, and so on until the topical treatment is no longer needed. If improvement is insufficient, we then add a second-line therapy. (See 'Second-line therapy' below.) Cutaneous atrophy is a common side effect of topical corticosteroid treatment that is particularly likely to occur with the use of potent topical corticosteroids. The adverse effects of topical corticosteroids are reviewed in greater detail separately. (See "Topical corticosteroids: Use and adverse effects".)

Antihistamines — A variety of H1 and H2 blocking agents, including hydroxyzine and doxepin, are also used as first-line treatments to control pruritus. A single case report of a patient successfully treated with cetirizine led the authors to hypothesize that antieosinophilic properties possessed by cetirizine may result in increased efficacy [30]. In our experience, the efficacy of systemic antihistamines in patients with HIV-associated EF has been disappointing.

Second-line therapy — Phototherapy is a well-tolerated therapy that may improve EF in affected patients.

Phototherapy — Data from an uncontrolled study suggest that phototherapy with broadband ultraviolet B (UVB) is effective for HIV-associated EF [31-33]. In the study, which included 14 HIV-positive patients with eosinophilic folliculitis and 7 HIV-positive patients with primary pruritus, treatment of intractable pruritus with UVB phototherapy three times per week resulted in a reduction in pruritus severity scores [34]. In addition, in a series of six patients with EF who were treated with thrice-weekly broadband UVB phototherapy sessions after not responding to other therapies, all patients reported a decrease in pruritus within the first nine treatment sessions [31]. Narrowband UVB also appeared to improve HIV-associated EF in a case report; a woman who failed to respond to multiple other treatments experienced resolution of papules and pruritus with twiceweekly narrowband UVB treatments [35]. Improvement occurred within the first several treatments. However, recurrence of EF is likely after discontinuation of UVB treatment [31,35]. When treating with UVB phototherapy, we typically administer broadband or narrowband UVB two to three times per week. A response is expected within the first two to three weeks. Once sufficient improvement is achieved, we attempt to taper treatments to the lowest effective frequency. If no response is evident within two months of treatment, we discontinue UVB phototherapy and consider other treatments. (See 'Third-line therapies' below.) UV phototherapy is known to suppress T-cell mediated processes and also to induce activation and replication of HIV, leading some to question its safety in HIV-infected individuals [36]. However, most evidence suggests such treatment is not associated with clinical deterioration and that it can be safely used in HIV-infected patients [37,38]. Examples of other potential adverse effects are erythema, skin dryness, pruritus, and blistering. (See "UVB therapy (broadband and narrowband)", section on 'Short- and long-term adverse effects'.)

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Although treatment with a systemic psoralen-based photosensitizer plus ultraviolet A (PUVA) has also been used successfully to treat HIV-associated EF, the increased toxicity profile of PUVA makes UVB preferable initially [11]. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Adverse effects'.)

Third-line therapies — Patients who cannot be managed effectively with the interventions above are candidates for systemic therapy. Itraconazole and oral isotretinoin are our preferred next-line therapies based upon limited data that suggest efficacy.

Itraconazole — Itraconazole may be of benefit in patients with HIV-associated EF. In an open study, 28 HIV-positive men were treated with itraconazole 100 to 400 mg daily [39]. Complete response was seen in 17 patients and partial improvement in 4 patients. All patients who improved responded within two weeks. Some patients were able to discontinue itraconazole during the threeto six-month follow-up period, while others required continued therapy with itraconazole or topical corticosteroids to maintain the response to treatment. The effects of itraconazole on EF may be related to an anti-inflammatory effect of the drug rather than an antimycotic effect. In the study above, a patient who was switched to fluconazole had a relapse of EF, and two other patients received fluconazole without improvement, one of whom improved with itraconazole [39]. This differential response to fluconazole raises the possibility that the effect of itraconazole is due to suppression of inflammation. Patients treated with itraconazole should have liver function tests monitored, and drug-drug interactions should be considered.

Oral isotretinoin — Data supporting the efficacy of isotretinoin in HIV-associated EF are limited to case reports and small, uncontrolled studies [23,40,41]. Isotretinoin is most commonly administered in doses of 0.5 to 1.2 mg/kg/day and typical treatment durations range from a few weeks to a few months. Responses to treatment are usually evident within the first few weeks [40]. The risk for relapse after isotretinoin therapy may be high. In a pilot study in which seven patients were treated with courses of isotretinoin ranging from 2 to 17 weeks, relapse occurred within nine months of the discontinuation of therapy in all patients, including three patients who were given multiple courses of therapy secondary to rapid initial relapses [40]. Isotretinoin is a drug that can virtually halt sebum production, and proponents of an autoimmune reaction to sebum as the etiology of HIV-associated EF suggest that this may be the explanation for its efficacy [15]. The drug is teratogenic and also can induce a variety of cutaneous and systemic adverse effects. Due to the limited data in support of the efficacy of isotretinoin, the possibility of relapse upon the cessation of therapy, and the potential adverse effects of this drug, the use of isotretinoin for HIV-associated EF should be considered carefully. In the United States, isotretinoin

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must be prescribed through the iPLEDGE program, an internet-based registry that was created to reduce the incidence of fetal exposure to isotretinoin. (See "Oral isotretinoin therapy for acne vulgaris".)

Other therapies — Additional topical and systemic therapies have been reported to improve EF in small numbers of patients.

Topical permethrin — Topical permethrin 5% applied daily was effective in six patients with treatment-resistant HIV-associated EF who were found to have increased numbers of Demodex mites on skin biopsy [14]. Lesions recurred when therapy was discontinued. It is uncertain whether the effect of permethrin was due to reducing numbers of Demodex mites or to other antiinflammatory properties. We sometimes utilize permethrin in combination with systemic therapy (eg, itraconazole); however, the efficacy of such combination therapy is not established.

Topical calcineurin inhibitors — Topical tacrolimus and pimecrolimus have been reported to have some benefit in patients with Ofuji's disease [42-44]. A case series reported rapid improvement in eight patients with HIV-associated EF who were treated with once-daily topical tacrolimus 0.1%; three of the patients had developed EF in the setting of recently initiating ART [45]. The authors reported that they have not had similar success treating EF with either tacrolimus 0.03% or with pimecrolimus. However, concerns have been raised about the safety of topical calcineurin inhibitors, with a recommendation by the United States FDA to avoid their use in patients with compromised immune systems (see "Treatment of atopic dermatitis (eczema)", section on 'Topical calcineurin inhibitors'). We suggest not treating EF with topical calcineurin inhibitors until further information on safety and efficacy is available.

Oral metronidazole — In a series of five patients with severe HIV-associated EF unresponsive to other therapies, metronidazole 250 mg three times daily for three to four weeks resulted in complete clearing [17]. Two patients had recurrences within a few months and responded to retreatment with oral metronidazole.

Oral dapsone — Dapsone has demonstrated variable success in treating Ofuji's disease and has been used in HIV-associated EF as well [11,46,47]. Dapsone suppresses the activity of myeloperoxidase within neutrophils, and there is evidence to suggest it may suppress eosinophil peroxidase within eosinophils as well [48]. The typical dose is 50 to 100 mg, once or twice a day [11].

Oral glucocorticoids — Oral glucocorticoids are occasionally used to treat HIVassociated EF [11]. Data are insufficient to determine the ideal regimen. A short treatment course beginning with 70 mg (or 1 mg/kg) of prednisone per day tapered by 5 or 10 mg per day to treatment cessation over 7 to 14 days may be effective [49].

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Although oral glucocorticoids can improve HIV-associated EF, relapses are common within a few weeks after treatment is discontinued and long-term treatment is associated with risk for serious side effects. Patients with severe disease requiring continued therapy have been treated with everyother-day dosing or weekly dosing [49]. However, long-term treatment with oral glucocorticoids should be avoided whenever feasible. (See "Major side effects of systemic glucocorticoids".) The decision to use systemic glucocorticoids must take into account the adverse effects of oral glucocorticoids, particularly in immunocompromised patients.

Other — A patient treated for Pneumocystis jirovecii pneumonia (PCP) with intravenous trimethoprim-sulfamethoxazole reportedly showed improvement in his EF [41]. Other treatments that have been reported to show benefit in Ofuji's disease, though not necessarily in HIV-associated EF, include oral minocycline, clofazimine, cyclosporine, and nicotine patches [11,28,50].

SUMMARY AND RECOMMENDATIONS ●HIV-associated EF is a chronic pruritic skin eruption of uncertain etiology associated with low CD4 counts and later-stage disease. (See 'Clinical manifestations' above.) ●Diagnosis depends upon clinical suspicion, an appropriate presentation (intensely pruritic follicular lesions generally on the upper trunk, face, neck, or scalp), and histologic confirmation via skin biopsy of an unexcoriated lesion. (See 'Diagnosis' above.) ●There are no controlled trials of therapy for HIV-associated EF. (See 'Treatment' above.) ●Patients who are treated with antiretroviral therapy (ART) typically show improvement or resolution of EF. We suggest use of ART as the primary therapy for EF (Grade 2C). During the initial two to six months of ART, there may be a flare of EF (immune reconstitution inflammatory syndrome). (See 'Antiretroviral therapy' above.) ●Topical corticosteroids are useful for pruritus associated with EF. However, topical corticosteroids do not alter the course of the disease and may not fully control symptoms. Oral antihistamines are also frequently used for EF-associated pruritus. Our personal experience with antihistamines has been disappointing. (See 'Topical corticosteroids' above and 'Antihistamines' above.) ●For patients who cannot be managed with ART, topical corticosteroids, or oral antihistamines, we suggest treatment with UVB phototherapy (Grade 2C). Responses to phototherapy are usually evident within the first few weeks of treatment. Oral itraconazole and oral isotretinoin are additional treatment options for patients who fail to respond to phototherapy. (See 'Second-line therapy' above and 'Third-line therapies' above.)

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Fever and rash in the immunocompetent patient uptodate.com/contents/fever-and-rash-in-the-immunocompetent-patient/print

Fever and rash in the immunocompetent patient Authors: Fred A Lopez, MD Charles V Sanders, MD Section Editor: Peter F Weller, MD, MACP Deputy Editor: Allyson Bloom, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Dec 13, 2019.

INTRODUCTION

Fever with an accompanying rash is a common symptom constellation in

patients presenting to clinicians' offices and emergency departments. Skin manifestations may provide the only early clue to an underlying infection, may be the hallmark of contagious disease, and/or may be an early sign of a lifethreatening infection or serious noninfectious disorder. The differential diagnosis of fever and rash is extremely broad, but this symptom complex provides an opportunity for the diligent clinician to establish a probable etiology through a careful history and physical examination. A systematic approach is crucial for establishing a timely diagnosis, determining early therapy when appropriate, and considering isolation of the patient if necessary. Epidemiologic clues are important to pursue, such as [1-6]: ●Age of the patient ●Season of the year ●Travel history ●Geographic location ●Exposures, including to insects (especially ticks and mosquitoes), animals (both wild and domestic), and ill contacts ●Medications ●Immunizations and history of childhood illnesses ●Immune status of the host Features of the rash are also important to consider, including: ●Characteristics of the lesions ●Distribution and progression of the rash ●Timing of the onset in relation to fever ●Change in morphology, such as papules to vesicles or petechiae

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●Symptoms associated with the rash (eg, pain, pruritus, numbness) Despite the strong association between the syndrome of fever and rash and infectious diseases, a variety of noninfectious processes can also cause similar presentations, including deep venous thrombosis, superficial thrombophlebitis, erythromelalgia, relapsing polychondritis, foreign body reactions, drug reactions, gouty arthritis, cutaneous lupus erythematosus, cutaneous vasculitis, and erythema nodosum [7]. The approach to the immunocompetent patient with fever and rash and selected presentations that constitute emergencies will be reviewed here. Fever and rash in immunocompromised patients are discussed separately. Skin lesions in the returning traveler are also discussed separately. (See "Fever and rash in immunocompromised patients without HIV infection" and "Fever and rash in HIV-infected patients" and "Skin lesions in the returning traveler".)

EPIDEMIOLOGY AND ETIOLOGY

Epidemiologic features are

extremely helpful in the approach to a patient with a fever and rash [1-4].

Diseases that present in childhood — The age of the patient often assists in narrowing the differential diagnosis. Exanthems associated with a variety of viral illnesses are classically seen in the pediatric age group [8]. The constellation of symptoms and a characteristic rash often allow for a clinically based diagnosis, as illustrated by the following disorders. ●Measles (rubeola) – Measles is associated with a blanching erythematous "brick-red" maculopapular rash beginning in the head and neck area and spreading centrifugally to the trunk and extremities (picture 1A-D); patients also typically have fever, cough, coryza, conjunctivitis, and Koplik's spots (picture 2). (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention".) ●Chickenpox (varicella) – Chickenpox is characterized by classic vesicular lesions on an erythematous base that appear in crops and are present in different stages from papules through vesicles to crusting (picture 3A-D). (See "Clinical features of varicella-zoster virus infection: Chickenpox".) ●Rubella – Rubella has a rash that resembles measles; however, the patient does not appear to be sick (picture 4). Prominent postauricular, posterior cervical, and/or suboccipital adenopathy may also assists in the diagnosis. Forchheimer spots, or punctate soft palate macules, can represent a helpful clue. ●Erythema infectiosum (fifth disease) – Erythema infectiosum is due to human parvovirus B19. Children, unlike adults, often develop a characteristic rash with a "slapped cheeks" appearance followed by an erythematous maculopapular rash that spreads from arms to trunk and rash in a reticular pattern (picture 5A-B). (See "Clinical manifestations and diagnosis of parvovirus B19 infection".) ●Roseola infantum (exanthem subitum; sixth disease) – Roseola infantum, an illness of infants most commonly caused by human herpesvirus 6, is characterized by high fever for three to four days, followed by seizures and a generalized maculopapular rash that starts on the neck and trunk and spreads to the face and extremities. (picture 6). (See "Roseola infantum (exanthem subitum)" and "Human herpesvirus 7 infection", section on 'Primary infection'.) Other infections accompanied by rash also occur primarily in children: ●Scarlet fever – Scarlet fever is an exotoxin (erythrogenic toxin)-mediated diffuse erythematous rash occurring most commonly in the setting of pharyngitis from group A Streptococcus (GAS) infection. Scarlet fever is manifested by a coarse, sandpaper-like, erythematous, blanching rash, which ultimately desquamates (picture 7A-B). This is accompanied by circumoral pallor and a strawberry tongue. (See "Complications of streptococcal tonsillopharyngitis".)

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●Acute rheumatic fever – Acute rheumatic fever (ARF) is another potential sequela of group A streptococcal pharyngeal infection. The classic dermatologic manifestations of ARF are erythema marginatum (transient macular lesions with central clearing found on the extensor surfaces of the proximal extremities and trunk) and subcutaneous nodules often located over bony prominences (picture 8). (See "Complications of streptococcal tonsillopharyngitis" and "Acute rheumatic fever: Clinical manifestations and diagnosis".) ●Kawasaki syndrome – Kawasaki syndrome, a disease of unknown etiology, is usually seen in children less than four years of age. In addition to fever lasting >5 days, some of the criteria for this syndrome are bilateral conjunctival injection; erythematous fissured lips; injected oropharynx or "strawberry tongue"; edema and erythema of the hands or feet and/or subsequent periungual desquamation (picture 9A-B); rash (picture 10A-B); and cervical lymphadenopathy [9]. (See "Kawasaki disease: Clinical features and diagnosis".) ●Enteroviruses – Nonpolio enteroviruses (coxsackievirus, echovirus) can cause a variety of rashes and should always be included in the differential diagnosis of a young child with fever and rash of undetermined etiology. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention".) ●Mononucleosis – An evaluation for Epstein-Barr virus (EBV)–associated infectious mononucleosis should be undertaken in older children and adolescents who present with fever, malaise, sweats, anorexia, nausea, chills, sore throat, posterior cervical lymphadenopathy, splenomegaly, and a maculopapular rash, especially after the administration of ampicillin (picture 11). The rash is usually over the trunk but can involve the extremities, including the hands and feet. Other causes of infectious mononucleosis are discussed below. (See 'Selected diseases that present in adulthood' below and "Infectious mononucleosis".) ●Arcanobacterium haemolyticum – Adolescents and young adults with pharyngitis, fever, lymphadenopathy, and/or maculopapular/scarlatiniform rash whose work-up is negative for group A Streptococcus and viral-associated mononucleosis may be infected with A. haemolyticum, a gram-positive rod that appears to be more susceptible to erythromycin than to penicillin [10]. This infection is seen primarily in adolescents and young adults, and the rash, which can be pruritic, is typically seen first over the extensor surfaces before spreading centrally (picture 12) [10]. The rash usually spares the face. ●Mycoplasma pneumoniae – M. pneumoniae infection may be accompanied by skin findings, which include a mild erythematous maculopapular or vesicular rash, erythema multiforme, or the Stevens-Johnson syndrome. (See "Mycoplasma pneumoniae infection in children", section on 'Mucocutaneous disease'.)

Selected diseases that present in adulthood — Exanthems associated with a variety of viral illnesses can be seen in adults. Several to consider include: ●Measles (rubeola) – Measles (rubeola) is associated with a blanching erythematous "brick-red" maculopapular rash beginning in the head and neck area and spreading centrifugally to the trunk and extremities (picture 1D-E); patients also complain of fever, cough, coryza, and conjunctivitis. Despite the availability of an effective measles vaccine, measles outbreaks continue to occur [11,12]. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention" and "Measles: Epidemiology and transmission".) ●Mononucleosis – Infectious mononucleosis syndromes can be caused by several different pathogens (eg, EBV, cytomegalovirus, HIV, human herpesvirus 6, Toxoplasma gondii). Young adults who present with fever, malaise, sweats, anorexia, nausea, chills, sore throat, posterior cervical lymphadenopathy, splenomegaly, and a maculopapular rash, especially after the administration of ampicillin, should undergo an evaluation for Epstein-Barr virus–associated infectious mononucleosis (picture 11). The rash is usually over the trunk but can involve the extremities, including the hands and feet. About half of all college freshmen have EBV-associated antibodies, and up to 20 percent of those who do not are expected to seroconvert annually during these years. Importantly, these cases are usually asymptomatic [13]. (See "Infectious mononucleosis".)

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Cytomegalovirus should be considered in the heterophile antibody-negative patient with infectious mononucleosis, although lymphadenopathy and pharyngitis may not be as prominent. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'CMV mononucleosis'.) The acute retroviral syndrome that may occur approximately two to four weeks after primary HIV infection is a mononucleosis-like illness characterized by fever, sore throat, malaise, headache, lymphadenopathy, mucocutaneous ulceration, and rash. The rash, seen in more than 50 percent of patients, is usually transient, maculopapular, nonpruritic, and truncal or facial in location. (See "Acute and early HIV infection: Pathogenesis and epidemiology".) Adolescents and young adults with pharyngitis, fever, lymphadenopathy, and/or a maculopapular/scarlatiniform rash whose evaluation is negative for group A Streptococcus and viral causes of mononucleosis may be infected with Arcanobacterium haemolyticum, a gram-positive rod that appears to be more susceptible to erythromycin than to penicillin [10]. This infection is seen primarily in adolescents and young adults, and the rash, which can be pruritic, is typically seen first over the extensor surfaces before spreading centrally (picture 12) [10]. The rash usually spares the face. ●Erythema infectiosum – Approximately 20 percent of cases of erythema infectiosum occur in adults [14]. Constitutional symptoms in primary infection are more pronounced in adults and typically include lymphadenopathy, arthritis, and fever. The rash, when present, is often described as first macular and then lacy and reticulated, spreading initially from the limbs to the trunk and buttocks (picture 5B). (See "Clinical manifestations and diagnosis of parvovirus B19 infection".) ●Herpes zoster (shingles) – Individuals who did not have chickenpox during childhood may develop it later in life. Those who did have chickenpox may develop herpes zoster, which is caused by reactivation of latent varicella zoster virus. Incidence and severity increases with age and with increasing immunosuppression. In immunocompetent individuals, herpes zoster is typically manifested as vesicular lesions distributed along a dermatome and ending at the midline. (See "Clinical features of varicella-zoster virus infection: Chickenpox" and "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".) ●Mycoplasma pneumoniae – M. pneumoniae infection may be accompanied by skin findings, which range from a mild erythematous maculopapular or vesicular rash to the Stevens-Johnson syndrome. (See "Mycoplasma pneumoniae infection in adults", section on 'Mucocutaneous disease'.)

Season — A number of infections characterized by fever and rash have a distinct seasonal pattern. As examples, nonpolio enteroviral infections occur in the summer and fall months; Kawasaki syndrome, meningococcal infection, and parvoviral infections present most commonly in the winter or early spring months; measles and rubella are more frequent in the spring; tickborne diseases such as Lyme disease, ehrlichiosis/anaplasmosis, and Rocky Mountain spotted fever (RMSF) primarily occur in the spring and summer; tularemia and plague are usually seen in the summer. Vibrio vulnificus infections occur between the months of April and October, when warmer ocean waters facilitate propagation of this organism. Septicemia due to this organism typically occurs after consumption of raw seafood (usually oysters). V. vulnificus– and Vibrio parahaemolyticus–associated wound infections can occur after injury to skin in contaminated ocean water (eg, after natural disasters) [15,16]. (See "Vibrio vulnificus infections".)

Geography — Travel to or residence in specific areas of the continental United States or other parts of the world can provide important clues for the diagnosis of fever and rash [17-19]. Examples associated with principal locations (but not necessarily the only locations) in the United States include: ●Rocky Mountain spotted fever – South-central and Atlantic states (see "Clinical manifestations and diagnosis of Rocky Mountain spotted fever") ●Human monocytic ehrlichiosis and anaplasmosis – Midwestern, south-central, and southeastern states (see "Human ehrlichiosis and anaplasmosis")

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●Lyme disease – The northeast, midwest, and Pacific northwest (see "Epidemiology of Lyme disease" and "Clinical manifestations of Lyme disease in adults" and "Lyme disease: Clinical manifestations in children") ●The tick vectors for tularemia – Western, southeastern, and south-central states (see "Tularemia: Microbiology, epidemiology, and pathogenesis" and "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention") ●Plague – Western states (see "Epidemiology, microbiology and pathogenesis of plague (Yersinia pestis infection)" and "Clinical manifestations, diagnosis, and treatment of plague (Yersinia pestis infection)") ●Relapsing fever due to Borrelia hermsii – Mountainous areas of the western United States (see "Microbiology, pathogenesis, and epidemiology of relapsing fever" and "Clinical features, diagnosis, and management of relapsing fever") ●Endemic fungal infections – Endemic fungal infections including Blastomyces dermatitidis (southeastern states), Coccidioides immitis (southwestern states), and Histoplasma capsulatum (Mississippi and Ohio River valleys) (see "Clinical manifestations and diagnosis of blastomycosis" and "Primary pulmonary coccidioidal infection" and "Pathogenesis and clinical features of pulmonary histoplasmosis" and "Pathogenesis and clinical manifestations of disseminated histoplasmosis") Skin lesions in the returning traveler are discussed in greater detail separately. (See "Skin lesions in the returning traveler".)

Incubation period — Knowledge of the incubation period for infectious agents is particularly helpful to the physician trying to determine the significance of a rash in a patient exposed to another individual with a similar exanthem. A range of incubation periods exists for selected infectious agents that may be associated with fever and rash (table 1).

Exposure history — The category of exposures is a broad one in the differential diagnosis of fever and rash. Exposures to food, water, plant materials, animals, and infected human secretions can lead to rashes and can be associated with both occupational and nonoccupational contacts. As an example, the herpetic whitlow, seen in dental workers exposed to herpes simplex virus–infected mucous membranes and secretions, is a classic occupationassociated infection (picture 13). Animal handlers, pet owners, and laboratory workers are more vulnerable to such infections, including [20-22]: ●Toxoplasmosis and cat scratch disease from cats and kittens (picture 14) (see "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease") ●Psittacosis from poultry, finches, or parrots (see "Psittacosis") ●Cryptococcosis from pigeon, dog, or cat feces (see "Cryptococcus neoformans infection outside the central nervous system") ●Plague from goats, rabbits, dogs, squirrels, or coyotes (see "Clinical manifestations, diagnosis, and treatment of plague (Yersinia pestis infection)") ●Rat bite fever or leptospirosis from rats (see "Rat bite fever" and "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis") ●Tularemia in sheep handlers, wild game cooks, pelt dealers, and veterinarians, which can result in ulceroglandular, oculoglandular, glandular, oropharyngeal, typhoidal, or pneumonic syndromes (picture 15) [23] (see "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention") ●Pasteurella-associated wound infections secondary to cat and dog bites [24] (see "Pasteurella infections")

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Other environmental occupational exposures include: ●Papular or nodular lymphocutaneous lesions that develop on the extremities after trauma associated with an aquarium or swimming pool or after handling seafood are consistent with Mycobacterium marinum infections ("fish tank granuloma") (picture 16)[25,26]. ●Percutaneous injuries inflicted while handling the fish tilapia have been reported to cause Streptococcus iniae cellulitis of the hand [27]. ●Erysipelothrix rhusiopathiae, a gram-positive rod whose major host is swine, can produce a localized violaceous, cellulitic process involving primarily the hands or fingers in fish and meat handlers (picture 17). (See "Erysipelothrix infection".) ●A gram-negative rod known as Edwardsiella tarda can cause fresh water–associated wound infections. Skin and soft tissue infections caused by this organism include abscesses, bullae, myonecrosis, necrotizing fasciitis, and cellulitis [28]. ●Pseudomonas aeruginosa folliculitis can occur following exposure to hot tubs or whirlpools (picture 18) [29]. ●Whirlpool footbaths have been associated with Mycobacterium fortuitum–associated furuncles in individuals who had pedicures [30]. ●Swimming in contaminated lake water has been associated with the development of hemolytic-uremic syndrome with thrombocytopenia-associated petechial skin lesions [31]. ●Herpes gladiatorum skin infections caused by herpes simplex virus type 1 have been described in athletes who engage in contact sports like rugby and wrestling [32,33], and outbreaks of group A streptococcal and staphylococcal skin infections can occur in American and European football players after competition [34-36]. ●In one report, a cutaneous larva migrans infection secondary to Ancylostoma braziliense was observed in a beach volleyball player [37]. ●Individuals who work with plants and soil (ie, florists, gardeners, farmers) are at risk for developing sporotrichosis, an infection of the extremities caused by the dimorphic fungus Sporothrix schenckii (picture 19). (See "Clinical features and diagnosis of sporotrichosis".)

Arthropod exposures — A variety of conditions accompanied by fever and rash result from arthropod exposures. As examples, black flies are associated with onchocerciasis; deer flies with loiasis; fleas with plague and endemic typhus; mosquitoes with malaria-associated parasites, dengue virus, chikungunya virus, West Nile virus, and Zika virus; assassin or reduviid bugs with Chagas disease; and sand flies with leishmaniasis. (See "Onchocerciasis" and "Loiasis (Loa loa infection)" and "Epidemiology, microbiology and pathogenesis of plague (Yersinia pestis infection)" and "Murine typhus" and "Malaria: Epidemiology, prevention, and control" and "Dengue virus infection: Epidemiology" and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis" and "Zika virus infection: An overview" and "Cutaneous leishmaniasis: Epidemiology and control" and "Chagas disease: Epidemiology and prevention".) A report from the United States described 15 patients with West Nile virus fever who presented with a generalized maculopapular rash. A tingling and burning sensation was reported by four patients (27 percent) and pruritus by five patients (33 percent) [38]. (See "Clinical manifestations and diagnosis of West Nile virus infection".) Tickborne diseases seen in the United States include: ●The spirochete Borrelia burgdorferi is the etiologic agent of Lyme disease, an ixodid tick-associated infection seen in the United States. The classic skin lesion in this infection is erythema migrans (EM), a red expanding plaque-like lesion with central clearing that develops at the site of the tick bite (picture 20). (See "Clinical manifestations of Lyme disease in

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adults".) ●Ehrlichiosis/anaplasmosis can present as human monocytic ehrlichiosis (HME) caused by Ehrlichia chaffeensis or human granulocytic anaplasmosis (HGA) due to Anaplasma phagocytophilum [39]. Rash may or may not accompany this infection, which has also been termed "spotless Rocky Mountain spotted fever" [40]. A rash is much more likely to be seen in cases of HME than HGA [41]. (See "Human ehrlichiosis and anaplasmosis".) ●Rickettsia rickettsii, the etiologic agent of RMSF, can be transmitted by the dog or wood tick and is primarily seen in the south-central and south Atlantic United States (see below). (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".) ●Southern tick-associated rash illness (STARI), presumably caused by a spirochete carried by lone star ticks (Amblyomma americanum), is characterized by a flu-like illness and an erythema migrans–like rash (picture 21). STARI should be considered in areas where A. americanum ticks are present but where Lyme disease is absent or uncommon [42]. (See "Southern tick-associated rash illness (STARI)".)

Medication history — Although drugs can cause a plethora of skin lesions, the relationship between drug fever and rash may not be as strong as many physicians believe. In one systematic analysis of 148 episodes of drug fever, fewer than 20 percent were associated with rash, and fewer than 50 percent of the rashes were urticarial in nature [43]. Hypersensitivity or allergic-type skin reactions (rash, itching, or hives) were evaluated in over 20,000 hospitalized patients in the Boston Collaborative Drug surveillance program, and, though associated fever was not evaluated, only about 2 percent of patients receiving drugs developed cutaneous reactions [44]. Antibiotics such as penicillins, cephalosporins, and trimethoprim-sulfamethoxazole were associated with high rates of allergic skin reactions. (See "Drug eruptions".) Skin lesions accompanied by fever (often relatively high fever) are a feature of severe drug reactions, particularly drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. These rare reactions typically develop one to three weeks after the initiation of the culprit agent. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Immunization history — Inadequately immunized individuals are susceptible to the traditional childhood viral infections and serve as an often overlooked reservoir of disease. Recommended immunizations for children in the United States include hepatitis A and B; diphtheria, tetanus and pertussis; Haemophilus influenzae type b; rotavirus; poliovirus; measles-mumps-rubella; varicella; influenza; human papillomavirus; pneumococcus; and meningococcus. Follow-up of older children with their primary care physicians provides an opportune time for confirming appropriate immunizations. (See "Standard immunizations for children and adolescents: Overview".) Similarly, zoster vaccination is recommended for adults 50 years of age and older to decrease the incidence of zoster and postherpetic neuralgia. (See "Vaccination for the prevention of shingles (herpes zoster)".)

Sexual history — A thorough sexual history is essential in evaluating the patient with a rash of unknown etiology. Genital or rectal ulcerations may be caused by a variety of infectious agents, including syphilis (picture 22), herpes simplex, lymphogranuloma venereum (picture 23), chancroid (picture 24), and donovanosis (picture 25 and table 2). These infections may not be associated with fever. Syphilis can have a variety of cutaneous manifestations. The primary stage is characterized by the chancre, a painless, often solitary, indurated genital ulceration with elevated, well-defined borders. The skin lesions of secondary syphilis include a generalized papular or maculopapular rash (rarely pustular) that also affects the palms and soles (picture 26A-

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B). Other lesions seen during this stage include condylomata lata: flat, moist condylomata-like lesions that are gray, infectious, and located around the genitals, mouth, anus, and other moist areas (picture 27). Approximately 15 to 30 percent of infected patients will manifest mucous membrane ulcerations that are sharply demarcated and covered with a gray exudate (ie, mucous patches) (picture 28). Patchy alopecia resulting in a "moth-eaten" appearance of the scalp can also be seen during this stage (picture 29). Following treatment of syphilis with appropriate antibiotics, patients may experience a worsening of preexisting skin lesions accompanied by fever (so-called Jarisch-Herxheimer reaction) in response to rapid release of endotoxin-like proteins from dying spirochetes. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients".) Classic skin lesions of late, or tertiary, syphilis include the gumma, generally a solitary granulomatous subcutaneous skin or mucous membrane lesion that is initially nodular before ulcerating (picture 30). Enlargement of these lesions can result in local tissue destruction. Also seen in tertiary syphilis are noduloulcerative lesions arranged in characteristic ringlike patterns known as lues maligna (picture 31). Resolution of these lesions results in hyperpigmented scars. Disseminated gonococcal infection causes a rash in as many as 90 percent of patients. The rash consists of fewer than 20 to 30 papular, nodular, and/or petechial lesions that develop a vesiculopustular component and then, finally, a necrotic, hemorrhagic appearance (picture 32) [45]. The rash contains lesions that, like those of primary varicella infection, are in different stages of evolution and favor distal anatomic sites. (See "Disseminated gonococcal infection" and "Cutaneous manifestations of gonorrhea".) The acute retroviral syndrome that occurs approximately two to six weeks after primary HIV infection is characterized by fever, sore throat, malaise, headache, lymphadenopathy, mucocutaneous ulceration, and rash. The rash, seen in more than 50 percent of patients, is usually transient, maculopapular, nonpruritic, and truncal or facial in location [46]. This presentation can often be confused for infectious mononucleosis [47]. (See "Acute and early HIV infection: Pathogenesis and epidemiology".)

Immunocompetence of the host — The possible etiologies of fever and rash are quite different if the host is immunosuppressed. Thus, determining the underlying immunologic status of the host is essential in assessing any patient with fever and rash [48]. (See "Fever and rash in immunocompromised patients without HIV infection" and "Fever and rash in HIV-infected patients".)

SELECTED FEVER AND RASH EMERGENCIES

Several infections associated with fever and rash constitute emergencies that

must be recognized promptly by the evaluating clinician. Such infections include meningococcal infection, bacterial endocarditis, Rocky Mountain spotted fever (RMSF), necrotizing fasciitis (including Fournier gangrene), toxic shock syndrome, and miliary tuberculosis.

Meningococcal infection — The gram-negative diplococcus N. meningitidis can cause lifethreatening infection in children and young adults; outbreaks of infection can occur, especially among groups with confined living conditions, such as military bases, daycare centers, and dormitories. The infection can also develop in individuals with congenital deficiency of a terminal complement component, an acquired complement deficiency (ie, nephrotic syndrome, systemic lupus erythematosus), or splenectomy. (See "Epidemiology of Neisseria meningitidis infection".) Meningococcal infection can result in a number of different clinical presentations, but meningococcemia and/or meningitis are the most common. In addition to fever, myalgia, somnolence, headache, and nausea, rash occurs in most patients with meningococcemia. Early lesions may be macular, but rapidly increasing numbers of petechial or purpuric

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lesions can develop on the distal extremities and trunk, usually sparing the palms and soles (in contrast to RMSF) (picture 33A-B). An urticarial rash can also be seen [49]. Lesions on mucosal surfaces are also common. (See "Clinical manifestations of meningococcal infection".) In one review of 151 patients with meningococcal infection, 75 percent had petechial/maculopapular lesions, 11 percent purpuric/ecchymotic lesions, and 14 percent no skin lesions [50]. Mortality was considerably higher in those with purpuric/ecchymotic lesions. Meningococcemia may be rapidly fatal, with mortality rates of approximately 10 to 25 percent. Prompt recognition, supportive therapy to maintain adequate blood pressure and oxygenation, and pathogen-directed therapy with parenteral antibiotics (usually high doses of penicillin or a third-generation cephalosporin) are essential. Purpura fulminans, a particularly severe complication of meningococcemia, refers to the fulminant hemorrhagic skin necrosis that can be seen in association with disseminated intravascular coagulation (DIC) and shock. (See "Treatment and prevention of meningococcal infection".)

Bacterial endocarditis — Skin lesions may offer a clue to the underlying diagnosis of infective endocarditis (IE). Associated peripheral cutaneous or mucocutaneous lesions include petechiae, splinter hemorrhages, Janeway lesions, Osler's nodes, and Roth spots. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".) Petechiae are not specific for infective endocarditis but are its most common skin manifestation. They may be present on the skin, usually on the extremities, or on mucous membranes such as the palate or conjunctivae, the latter usually as hemorrhages best seen with eversion of either upper or lower eyelids (picture 34). Splinter hemorrhages, also nonspecific for endocarditis, are nonblanching, linear reddish-brown lesions found under the nail bed (picture 35). Janeway lesions, Osler's nodes, and Roth spots are more specific for IE but are also less common; Roth spots are particularly rare. Janeway lesions are macular, nonblanching, nonpainful, and erythematous lesions on the palms and soles (picture 36). By contrast, Osler's nodes are painful, violaceous nodules found in the pulp of fingers and toes and are seen more often in subacute than acute cases of IE (picture 37). Roth spots are exudative, edematous hemorrhagic lesions of the retina. Of note, conjunctival hemorrhage, Janeway lesions, Osler's nodes, and Roth spots are included as minor criteria in the Duke criteria for the diagnosis of infective endocarditis [51]. It is important to recognize the skin manifestations of endocarditis in order to obtain blood cultures and initiate appropriate therapy. A prospective cohort study reported that S. aureus is the most common cause of infective endocarditis in many locations worldwide [52]. Similar data have been reported from a retrospective observational cohort study in the United States using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample [53]. Despite improvements in therapy and the availability of surgical intervention, there is still an appreciable mortality rate of 25 to 40 percent for patients with S. aureus IE who are not injection drug users [54] (see "Clinical manifestations of Staphylococcus aureus infection in adults"). Significantly, the incidence of infective endocarditis has remained unchanged in the last 20 years [55].

Rocky Mountain spotted fever — RMSF is a tickborne disease caused by Rickettsia rickettsii. After an incubation period of as little as two days, fever, headache, malaise, conjunctival suffusion, and myalgia usually develop. In most patients, a rash appears within the following week, initially on the wrists and ankles and later on the palms and soles, before spreading centripetally to include the arms, legs, face, and trunk. The differential diagnosis includes meningococcemia, infective endocarditis, measles, secondary syphilis, and other rickettsial diseases. The rash is at first erythematous and maculopapular. Progression to a petechial rash is often noted and, in severe cases of RMSF, purpura and hemorrhagic necrosis can occur (picture 38A-C). Associated thrombocytopenia can make the diagnosis of RMSF difficult to distinguish from meningococcemia. However, several

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clinical clues favor the diagnosis of RMSF, including a history of tick bite or visits to areas where RMSF-associated ticks are present, occurrence of the rash a median of three to four days following the onset of fever, relative leukopenia, and elevated aminotransferases. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)

Necrotizing fasciitis — Necrotizing fasciitis is a rare, life-threatening, rapidly spreading infection that involves subcutaneous tissue and superficial fascia and typically spares muscle tissue. Conditions commonly associated with the development of necrotizing fasciitis include diabetes mellitus, peripheral vascular disease, injection drug use, obesity, and immunosuppression. The precipitating event is typically infection or trauma to the skin including abrasion, laceration, needle puncture, bite wound, ulcer, or surgical wound; hematogenous spread may also be responsible. These infections are often categorized as type I or type II [56]. Type I necrotizing fasciitis refers to a polymicrobial infection consisting of aerobic and anaerobic bacteria including facultative streptococci, enterococci, aerobic gram-negative bacilli including Escherichia coli, Proteus, Klebsiella, and/or Pseudomonas (less commonly) and anaerobes including Clostridium, Peptostreptococcus, and Bacteroides. Fournier gangrene refers to a type I necrotizing fasciitis of the male (or female) perineum, usually due to disruption of the urethral or gastrointestinal mucosa, often in patients with diabetes mellitus [57]. Type II necrotizing fasciitis is usually monomicrobial and is usually due to Streptococcus pyogenes or other beta-hemolytic streptococci, methicillin-resistant S. aureus, V. vulnificus, Aeromonas hydrophila, or Clostridium species. Initially, patients present with a cellulitis that can progress rapidly with associated fever, warmth, swelling, edema, and pain out of proportion to the findings on the physical examination. Crepitus and a firm "woody" induration are classically described upon palpation of affected tissues. As the infection evolves, systemic toxicity can become prominent, cutaneous manifestations may include bullae and ecchymoses with necrosis, and cutaneous anesthesia may develop. Toxic shock syndrome develops in about 50 percent of patients with group A streptococcal necrotizing fasciitis. (See "Necrotizing soft tissue infections" and 'Toxic shock syndrome' below.)

Toxic shock syndrome — Initially used in the late 1970s to describe a disease syndrome in children infected with S. aureus, toxic shock syndrome (TSS) became a well-known entity in the early 1980s when its association with young menstruating women and tampon use was described [58-60]. Nonmenstrual toxic shock syndrome has been associated with surgical wounds, burns, skin ulcerations, catheters, and nasal packings. (See "Staphylococcal toxic shock syndrome".) Criteria for the diagnosis of TSS include a temperature above 38.9ºC, hypotension, a desquamating rash, involvement of at least three organ systems, and exclusion of clinical mimics such as RMSF, leptospirosis, and measles [61]. Multiple toxins have been described in association with this syndrome, particularly TSS toxin (TSST-1) in menstrual-associated TSS [62]. The rash seen in TSS is diffuse and erythematous and can resemble a sunburn (picture 39A-B). The conjunctivae are also often involved (picture 40). Fever, diarrhea, muscle aches, and nausea/emesis are commonly present. Desquamation, usually of the palms and soles or at the sites of the original rash, is classically described one to three weeks later. Group A streptococci (GAS) can also produce a toxic shock–like syndrome, most often in association with a skin or soft tissue infection. (See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".) Streptococcal pyrogenic exotoxins that cause cytokine production, analogous to staphylococcal TSST-1, appear to be responsible for initiating this syndrome. Several general differences are noted between TSS caused by GAS and by S. aureus. In GAS TSS, mortality is higher (30 versus 3 percent with S. aureus), bacteremia and tissue necrosis are more common, and generalized erythema is less common [61]. (See "Invasive group A streptococcal infection and toxic shock syndrome: Treatment and prevention".)

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Miliary tuberculosis — Miliary tuberculosis (TB) may not always be considered in the differential diagnosis of patients who have a nonspecific presentation of fever, rash, night sweats, anorexia, weight loss, weakness, and respiratory complaints. In one series, almost 20 percent of cases with miliary tuberculosis in the United States were diagnosed postmortem [63]. Miliary TB resulting from widely disseminated hematogenous infection can affect any organ including the lung, lymph nodes, joints, bones, liver, central nervous system, pericardium, adrenal glands, genitourinary tract, eye, and skin. Usually seen in immunocompromised patients, the most common cutaneous manifestation (TB cutis miliaris disseminata) consists of small, erythematous to violaceous, macular, papular, purpuric, or vesicular lesions that can break down and become umbilicated with crust formation. These lesions subsequently heal with resultant hypopigmented depressed scars [64,65]. Biopsy of these lesions reveals microabscesses with numerous acid-fast bacilli and possible granulomas. The tuberculin skin test is typically negative as a result of anergy. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis" and "Cutaneous manifestations of tuberculosis".)

DIAGNOSTIC APPROACH

The diagnostic approach to the patient with fever

and rash should focus on the appearance of the rash in addition to the detailed epidemiologic history listed above.

Characteristics of the rash — A history of the rash should include the following questions [5]: ●Was a prodrome present? ●Where and when did the rash start? ●How has the rash progressed anatomically? ●What symptoms are associated with the rash? ●Has the rash changed in appearance? ●Has any treatment been instituted for the rash? In examining a rash, it is essential to characterize the lesions, both individually and collectively, according to morphology and arrangement (eg, annular, linear, serpiginous, dermatomal), distribution (eg, isolated versus generalized, bilateral versus unilateral, symmetric, occurring on exposed areas), and evolution (centrifugal versus centripetal) [5,66]. In addition, a differential diagnosis for fever and rash can be based upon the appearance of the rash and its accompanying signs (table 3A-C and table 4A-B). The following definitions are useful in interpreting the tables and characterizing lesions and rashes [67]: ●Macule – Nonpalpable, circumscribed lesion that is flat and ≤1 cm in diameter ●Papule – Palpable lesion that is solid, elevated, and ≤5 mm in diameter ●Maculopapular – Confluent, erythematous rash made up of both macular and papular lesions ●Purpura – Papular or macular nonblanching lesions that are due to extravasation of red blood cells; 1 to 2 mm lesions are called petechiae ●Nodule – Deep-seated, roundish lesion ≥5 mm in diameter that can involve the epidermal, dermal, and/or subcutaneous tissue ●Plaque – A palpable elevated lesion ≥5 mm in diameter ●Vesicle – A distinct, elevated skin lesion that contains fluid and is 1 year

Zika virus

2 to 14 days

M. marinum

14 to 56 days

Chlamydia psittaci

5 to 21 days

Coccidioides immitis

Adapted with permission from Sanders CV. Diagnosis of the patient with fever and rash. In: The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT (Eds), Williams & Wilkins, Baltimore, 1995. Graphic 66762 Version 5.0

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Herpetic whitlow In addition to erythema, swelling, and pain, herpetic whitlow is characterized by the presence of vesicular or pustular lesions. Patients may also experience fever, lymphadenitis, and epitrochlear or axillary lymphadenopathy. Reproduced with permission from: Nikkels AF, Peirard GE. Treatment of mucocutaneous presentations of herpes simplex virus infections. Am J Clin Dermatol 2002; 3:479. Copyright © 2002 Adis International. Graphic 75510 Version 6.0

Cat scratch disease

This patient with cat scratch disease has a primary inoculation lesion and prominent cervical lymphadenopathy (arrow). Courtesy of Joy D Jester. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 59249 Version 3.0

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Ulceroglandular tularemia

The primary inoculation site in this patient with ulceroglandular tularemia is an ulcerated nodule that is accompanied by lymphadenopathy. Courtesy of Charles V Sanders. (The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 75954 Version 3.0

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Mycobacterium marinum infection

Erythematous nodules and ulceration on the hand. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 122553 Version 1.0

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Erysipeloid

Erysipeloid is the localized cutaneous form of the infection caused by Erysipelothrix rhusiopathiae. In this patient, violaceous maculopapular lesions of the fingers developed after cleaning fish. Courtesy of Lee T Nesbitt, Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 55885 Version 4.0

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Pseudomonas folliculitis (hot tub folliculitis)

Multiple erythematous papules and pustules. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 98255 Version 2.0

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Sporotrichosis

Nodular lymphangitis in sporotrichosis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 98278 Version 2.0

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Erythema migrans

An erythematous plaque with central clearing on the leg. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 118894 Version 2.0 Erythema migrans-like rash of STARI Circular erythema migrans-like lesion with central clearing on the lower leg of a patient with STARI. The central papule was the site of a recent tick bite. STARI: Southern tick-associated rash illness. Courtesy of Edwin Masters, MD. Graphic 60256 Version 4.0

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Primary syphilis

Primary chancre on the labia majora. Chancres are painless and frequently can be missed, especially in women. Courtesy of Lee T Nesbitt, Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 50385 Version 5.0 Lymphogranuloma venereum A dramatic case of lymphogranuloma venereum shows chronic ulcerating lymph nodes and prominent edema. Courtesy of Lee T Nesbitt, Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 73707 Version 3.0

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The genital lesions of chancroid

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 60163 Version 4.0 Donovanosis Numerous ulcerogranulomatous, friable lesions are visible in the inguinal area and on the scrotum in a patient with donovanosis. Courtesy of Lee T Nesbitt, Jr.; The Skin and Infection: A Color Atlas and Text, Sanders, CV, Nesbitt, LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 58925 Version 3.0

Characteristics of sexually transmitted genital ulcers

 

Primary syphilis

Genital herpes

Chancroid

Lymphogranuloma venereum

Donovanosis

Etiology

Treponema pallidum.

Herpes simplex.

Haemophilus ducreyi.

Chlamydia trachomatis.

Klebsiella granulomatis.

Incubation period

9 to 90 days; average 2 to 4 weeks.

2 to 7 days.

1 to 35 days; average 3 to

3 days to 3 weeks; average 10 to 14 days.

Precise data unavailable; probably a few

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g 7 days.

y

p y days to several months.

Number of lesions

Usually single lesion, but multiple lesions may occur.

Multiple; may coalesce; more lesions appear in primary episodes than in recurrences.

Usually 1 to 3, but multiple lesions may occur.

Usually single.

Single or multiple.

Appearance of genital ulcers

Sharply demarcated round or oval ulcer with slightly elevated edges; may be irregular or symmetrical ("kissing chancre").

Small superficial grouped vesicles and/or erosions; lesions may coalesce, forming bullae or large areas of ulceration; lesions have irregular borders.

Deep, sharply demarcated ulcer; irregular ragged undermined edge; ranges in diameter from a few mm to 2 cm.

Papule, pustule, vesicle, or ulcer; discrete and transient; frequently overlooked.

Sharply defined irregular ulcerations or hypertrophic, verrucous, necrotic, or cicatricial granulomas.

Base

Red, smooth and shiny, or crusted; serous exudate occurs when squeezed.

Bright, red, and smooth.

Rough, uneven, yellow to gray in color.

Variable.

Usually friable, rough, beefy granulations; can be necrotic, verrucous, or cicatricial.

Induration

Firm; does not change shape with pressure.

None.

Soft; changes shape with pressure.

None.

Firm granulation tissue.

Pain

Painless; may become tender if secondarily infected.

Common; more prominent with initial infection than with recurrences.

Common.

Variable.

Rare.

Inguinal lymphadenopathy

Unilateral or bilateral; firm, movable, and nontender; do not suppurate.

Usually bilateral, firm, and tender; more common in primary episodes than in recurrences.

Unilateral (rarely bilateral); overlying erythema; matted, fixed, and tender; may suppurate.

Unilateral or bilateral; initially movable, firm, and tender; later indolent; fixed and matted; "sign of Groove" may suppurate; fistulas.

Pseudobuboes; subcutaneous perilymphatic granulomatous lesions that produce inguinal swelling.

Constitutional symptoms

Rare.

Common in primary episode; less likely in recurrences.

Rare.

Frequent.

Rare.

Course of disease if untreated

Slowly resolves to latency (2 to 6 weeks).

Typically recurs.

May progress to erosive lesions

Local lesions heal; systemic disease may progress; disfigurement; late

Worsens slowly.

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Diagnostic tests

Darkfield exam, direct immunofluorescence, FTA-ABS, VDRL, RPR.

Culture, PCR, direct immunofluorescence, serology, Tzanck smear, Pap smear, electron-microscopy, direct immunoperoxidase staining.

lesions.

disfigurement; late complications.

Culture, biopsy (rarely done); Gram stained smears have low specificity.

LGV complement fixation test; isolation of the microorganism by culture.

"Donovan bodies" in tissue smears; biopsy.

FTA-ABS: fluorescent treponemal antibody absorption; VDRL: Venereal Disease Research Laboratory; RPR: rapid plasma reagin; PCR: polymerase chain reaction; LGV: lymphogranuloma venereum. Adapted with permission from: Martin DH, Mroczkowski TF. Sexually transmitted diseases. In: The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT (Eds), Williams & Wilkins, Baltimore 1995. p.95. Graphic 60432 Version 5.0 Secondary syphilis

Maculopapular rash on the palms, which rarely can be pustular, in a patient with secondary syphilis. Patients can be quite contagious at this stage. Courtesy of David H Martin and Tomasz F Mroczkowski. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 65500 Version 6.0

3893

Secondary syphilis Multiple slightly scaly, erythematous papules are present on the trunk of this patient with papular secondary syphilis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 60313 Version 5.0

Condylomata lata Flat condylomata lata lesions which are moist in a woman with secondary syphilis. Courtesy of David H Martin and Tomasz F Mroczkowski. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 56162 Version 7.0

3894

Secondary syphilis

Multiple erosions (mucous patches) are present on the oral mucosa in this patient with secondary syphilis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 72680 Version 5.0 Patchy alopecia in secondary syphilis

Scalp hair loss associated with secondary syphilis is usually patchy, producing a so-called "moth-eaten" appearance. Courtesy of Charles Hicks, MD. Graphic 52213 Version 2.0

3895

Gummatous syphilis

Gumma on the leg of a patient with tertiary syphilis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 104182 Version 2.0

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Tertiary syphilis

Noduloulcerative lesions in a ring-like distribution on the posterior thigh, known as lues maligna, in a patient with tertiary syphilis. Courtesy of David H Martin and Tomasz F Mroczkowski. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 51169 Version 5.0 Skin lesions in disseminated gonococcal infection

This woman developed a fever, several painful joints, and exquisitely tender necrotic acral pustules. A culture from her cervix grew Neisseria gonorrhoeae. Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org. Graphic 59399 Version 5.0

3897

Meningococcemia

Erythematous macules and papules resembling a viral exanthem may be the early manifestation of meningococcemia in some patients. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 94769 Version 2.0 Acute meningococcemia Skin lesions in acute meningococcemia can begin as papules but quickly progress to petechiae and purpura. As seen here, the purpuric lesions can coalesce. Courtesy of Charles V Sanders. (The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt, LT Jr [Eds], Williams & Wilkins, Baltimore, 1995). Graphic 52107 Version 6.0

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Subconjunctival petechiae in infective endocarditis

Subconjunctival petechiae are prominent in this case of bacterial endocarditis caused by Staphylococcus aureus. Courtesy of Jan V Hirschmann. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 59982 Version 6.0 Splinter hemorrhages in infective endocarditis Splinter hemorrhages, linear reddish-brown lesions, are seen in the nail bed of this patient with bacterial endocarditis due to group B Streptococcus. Courtesy of Gene Beyt. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore 1995.

http://www.lww.com Graphic 72076 Version 9.0

3899

Janeway lesion in infective endocarditis

A Janeway lesion (arrow) occurred on the palm in this patient with bacterial endocarditis due to Streptococcus bovis. These lesions are macular, nonpainful, and erythematous; they are located on the palms and soles. Courtesy of Jan V Hirschmann. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore 1995.

http://www.lww.com Graphic 58380 Version 15.0 Osler nodes in infective endocarditis Osler nodes are tender papulopustules located on the pulp of the finger in a patient with bacterial endocarditis caused by Staphylococcus aureus. Courtesy of Charles V Sanders. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore 1995.

http://www.lww.com Graphic 68796 Version 9.0

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Rocky mountain spotted fever

Discrete and confluent petechiae forming purpura on the dorsal hands, fingers, and abdomen. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 122556 Version 1.0

3901

Rocky mountain spotted fever

Numerous petechiae on the foot. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 122557 Version 1.0

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Rocky Mountain spotted fever

Extensive maculopapular and petechial lesions on the trunk and thigh in a patient with Rocky Mountain spotted fever. The rash characteristically begins on the wrists and ankles and spreads centripetally. Courtesy of Harold G Muchmore. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams &Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 67850 Version 6.0 Toxic shock syndrome

Macular erythema in toxic shock syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 82561 Version 4.0

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Toxic shock syndrome

Macular erythema is present on the arm. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 61786 Version 5.0 Conjunctival suffusion in staphylococcal toxic shock syndrome

Conjunctival suffusion in a patient with staphylococcal toxic shock syndrome. Courtesy of Charles V Sanders. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 66457 Version 6.0 Differential diagnosis of fever and rash based upon appearance of the rash

Macules, papules, nodules, or plaques

Vesicles, bullae, or pustules

Purpuric macules, purpuric papules, or purpuric vesicles

Bacterial

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Followed widespread erythema with or without edema by desquamation

Bacterial Arcanobacterium haemolyticum

Bacillus anthracis

Bacillus anthracis

Ehrlichia canis

Bartonella bacilliformis

Listeria monocytogenes

Bartonella henselae (cat scratch disease) Bartonella quintana (trench fever) Borrelia burgdorferi (Lyme disease)* Borrelia spp (relapsing fever) Brucella spp (brucellosis)* Calymmatobacterium granulomatis (donovanosis)* Chlamydia psittaci (psittacosis) Ehrlichiosis* Ehrlichia chafeensis (HME) Human granulocytic erlichiosis Erysipelothrix rhusiopathiae (erysipeloid)

BacteremiaΔ Borrelia spp Clostridium spp Infective endocarditis (many species)

Mycoplasma pneumoniae

Haemophilus influenzae type B

Neisseria gonorrhoeae*

Neisseria gonorrhoeae (disseminated gonococcal infection)*¶

Neisseria meningitidis*

Neisseria meningitidis (acute or chronic meningococcemia)*¶

Pseudomonas aeruginosa

Pseudomonas aeruginosa

Rickettsia akari

Rickettsia prowazekii

Rickettsia rickettsii*

Rickettsia rickettsii¶

Staphylococcus aureus (TSS, SSSS) Streptococcus group A Treponema pallidum (secondary syphilis) Vibrio vulnificus

Spirillum minor Staphylococcus aureus (bacteremia) Streptobacillus moniliformis Streptococcus group A (streptococcal toxic shock syndrome, scarlet fever) Streptococcus pneumoniae (asplenic patient) Vibrio vulnificus Yersinia pestis

Francisella tularensis (tularemia) Listeria monocytogenes Leptospira spp (leptospirosis)* Mycobacterium leprae* Mycobacterium marinum* Mycobacterium tuberculosis Mycoplasma pneumoniae

3905

Streptococcus group A (scarlet fever, streptococcal toxic shock syndrome) Stapylococcus aureus (TSS, SSSS)

pneumoniae Neisseria gonorrhoeae (gonorrhea)* Neisseria meningitidis (meningococcemia)* Pseudomonas aeruginosa Rickettsia akari (rickettsialpox) Rickettsia prowazekii (epidemic/louse-borne typhus) Rickettsia rickettsii (RMSF-early lesions)*¶ Rickettsia orientalis/tsutsugamushi (scrub typhus) Rickettsia typhi (endemic/murine typhus) Salmonella typhi (typhoid fever)* Spirillum minor (rat-bite fever)

Adapted with permission from: Sanders CV. Diagnosis of the patient with fever and rash. In: The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT (Eds), Williams & Wilkins, Baltimore, 1995. Originally modified with permission from Fitzpatrick TB, et al: Color Atlas & Synopsis of Clinical Dermatology - Common and Serious Diseases. Fitzgerald TB, et al (Eds), McGraw-Hill, New York, 1992. Graphic 52167 Version 8.0 Differential diagnosis of fever and rash based upon appearance of the rash

Macules, papules, nodules, or plaques

Vesicles, bullae, or pustules

Purpuric macules, purpuric papules, or purpuric vesicles

Widespread erythema with or without edema followed by desquamation

Histoplasma capsulatum

 

 

Fungal Blastomyces dermatitidis* Candida spp Coccidioides immitis Cryptococcus neoformans

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Histoplasma capsulatum Other disseminated deep fungal infections in immunocompromised patients Viral Adenovirus

Colorado tick fever

Adenovirus (rare)

Atypical measles*

Atypical measles* Coxsackie A5, 9, Chikungunya virus 10, 16, B2, 7

Chikungunya virus

Echoviruses

Colorado tick fever

Colorado tick fever

Eczema herpeticumΔ

Congenital cytomegalovirus

Herpes simplex (disseminated)Δ

Coxsackie A and B (rare, types A-9, B2-5)

Varicella (chickenpox)Δ

Dengue fever

Arbovirus

Coxsackieviruses A and B Cytomegalovirus, primary infection Dengue virus Epstein-Barr virus, primary infection

Varicella-zoster (disseminated)Δ

Epstein-Barr virus (rare)

Echoviruses

Echoviruses (rare, types 3, 4, 9)

Hepatitis B (urticaria)*

Rubella*

Human herpesvirus 6 (exanthem subitum)*

Varicella-zoster virus

Human immunodeficiency virus (HIV-1)*

West Nile virus Yellow fever

Kawasaki syndrome (presumed viral) Molluscum contagiosum Orf Parvovirus B19 (erythema infectiosum [fifth disease]) Rubella (German measles)*¶ Rubeola (measles)* Varicella (chickenpox)* Varicella-zoster (disseminated) Viral hemorrhagic fevers (many) West Nile virus Zika virus

3907

Kawasaki syndrome (presumed viral)

Zika virus

* Reportable disease. ¶ May have arthralgia or musculoskeletal pain. Δ Umbilicated papule or vesicle a characteristic of these exanthems. Adapted with permission from: Sanders CV. Diagnosis of the patient with fever and rash. In: The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT (Eds), Williams & Wilkins, Baltimore, 1995. Originally modified with permission from Fitzpatrick TB, et al: Color Atlas & Synopsis of Clinical Dermatology - Common and Serious Diseases. Fitzgerald TB, et al (Eds), McGraw-Hill, New York, 1992. Graphic 63955 Version 6.0 Differential diagnosis of fever and rash based upon appearance of the rash

Macules, papules, nodules, or plaques

Vesicles, bullae, or pustules

Purpuric macules, purpuric papules, or purpuric vesicles

Widespread erythema with or without edema followed by desquamation

 

Plasmodium falciparum (blackwater fever)*

 

Protozoal/parasitic Leishmania braziliensis Leishmania mexicana Leishmania tropica

Trichinella spiralis (trichinosis)

Necator americanus

Toxoplasma gondii

Onchocerca volvulus Schistosoma Strongyloides stercoralis Toxoplasma gondii (toxoplasmosis) Trichinella spiralis (trichinosis) Trypanosoma spp Noninfectious Erythema multiforme Systemic lupus erythematosus Dermatomyositis Drug hypersensitivities Gianotti-Crosti syndrome Inflammatory bowel di

Erythema multiforme bullosum

"Allergic" vasculitis¶

Erythroderma

Erythroderma

Drug hypersensitivities

Toxic epidermal necrolysis

Cholesterol embolization

Graft-versus-host reaction

Disseminated intravascular coagulation (purpura fulminans)Δ

Stevens-Johnson syndrome

Drug hypersensitivities

von Zumbusch pustular psoriasis

Dermatitis from plants Drug hypersensitivities

F t

b li

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Toxic epidermal necrolysis

disease

Fat embolism

Pityriasis rosea (fever rare)

Henoch-Schönlein purpura

Sarcoidosis "Serum sickness"¶ Sweet syndrome (acute febrile neutrophilic dermatosis)

Immune thrombocytopenic purpura Granulomatosis with polyangiitis (Wegener's)

Still's disease (juvenile idiopathic arthritis)

* Reportable disease. ¶ May have arthralgia or musculoskeletal pain. Δ Often present as infarcts. Adapted with permission from: Sanders CV. Diagnosis of the patient with fever and rash. In: The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT (Eds), Williams & Wilkins, Baltimore, 1995. Originally modified with permission from: Fitzpatrick TB, et al: Color Atlas & Synopsis of Clinical Dermatology - Common and Serious Diseases. Fitzgerald TB, et al (Eds), McGraw-Hill, New York, 1992. Graphic 71663 Version 10.0

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Differential diagnosis of fever and rash based upon accompanying signs

Arthritis or arthralgia

Desquamation

Lymphadenopathy

Meningitis

Acute meningococcemia

Arcanobacterium haemolyticum infection

Cervical

Acute meningococcemia

Kawasaki syndrome

Cryptococcosis

Allergic purpura Disseminated gonococcal infection Erythema marginatum (acute rheumatic fever) Hepatitis B virus, prodromal phase

Drug hypersensitivity Graft-versus-host reaction

Rubella Scarlet fever

Kawasaki syndrome Measles

Generalized Infectious mononucleosis

Lyme disease

Rocky Mountain spotted fever

Parvovirus B19

Scarlet fever

Reiter's syndrome

Staphylococcal scaldedskin syndrome

Sarcoidosis

Stevens-Johnson syndrome

Systemic lupus erythematosus

Toxic epidermal necrolysis

Toxoplasmosis

Rocky Mountain spotted fever Roseola (especially in adults) Rubella Serum sickness Still's disease Systemic lupus erythematosus

Secondary syphilis Serum sickness

Enterovirus (Coxsackieviruses, echoviruses) Leptospirosis Lyme disease Rocky Mountain spotted fever Secondary syphilis

Hilar

Toxic shock syndrome von Zumbusch pustular psoriasis

Atypical measles Sarcoidosis Local Cat-scratch disease Tularemia

Adapted with permission from Adapted with permission from Sanders CV. Diagnosis of the patient with fever and rash. In: The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT (Eds), Williams & Wilkins, Baltimore, 1995. With permission from Hurst JW (Ed). Medicine for the Practicing Physician., 3rd ed, Butterworth-Heinemann, Boston, 1992, p. 273. Graphic 78412 Version 2.0

3910

Differential diagnosis of fever and rash based upon accompanying signs

Mucosal membrane lesions (enanthems)

Palm-sole involvement

Pulmonary infiltrate

Herpes simplex

Acute meningococcemia

Atypical measles

Infectious mononucleosis (palatal petechiae)

Atypical measles

Coccidioidomycosis

Dengue

Cryptococcosis

Drug rash

Fat embolism

Erythema multiforme

Histoplasmosis

Hand-foot-mouth disease

Mycoplasma pneumoniae

Kawasaki syndrome

North American blastomycosis

Measles (Koplick's spots) Strawberry tongue Atypical measles Kawasaki disease Scarlet fever Toxic shock syndrome Varicella zoster Ulcerative or vesicular stomatitis Hand-foot-mouth disease Herpes simplex Histoplasmosis Inflammatory bowel disease Secondary syphilis Systemic lupus erythematosus

Measles Rocky Mountain spotted fever

Psittacosis

Secondary syphilis

Rocky Mountain spotted fever

Staphylococcus aureus endocarditis

Sarcoidosis

Rash predominantly on extremities

Varicella zoster

Allergic purpura Brucellosis Disseminated gonococcal infection Ecthyma gangrenosum Erythema nodosum Sporotrichosis (fever rare)

Adapted with permission from Sanders CV. Diagnosis of the patient with fever and rash. In: The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT (Eds), Williams & Wilkins, Baltimore, 1995. With permission from Hurst JW (Ed). Medicine for the Practicing Physician, 3rd ed, Butterworth-Heinemann, Boston, 1992, p. 273. Graphic 54445 Version 2.0

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Erythema multiforme Characteristic target lesions of the palm in erythema multiforme begin with a central vesicle. Courtesy of Nesbitt LT Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore 1995.

http://www.lww.com Graphic 74095 Version 6.0

Causes of erythema multiforme

Contact reactions Tadania ignis (fire sponge) Drugs Allopurinol Antituberculous agents Barbiturates Carbamazepine Oral hypoglycemic agents NSAIDs Phenytoin Sulfonamides Endocrine factors Pregnancy Idiopathic >50 percent Infections Epstein-Barr virus

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Francisella tularensis Hemolytic streptococci Herpes simplex 1 and 2 Histoplasma capsulatum Mycoplasma pneumoniae Mycobacterium tuberculosis Proteus spp Salmonella spp Staphylococcus spp Vibrio parahaemolyticus Yersinia spp Physical Sunlight Radiograph therapy NSAIDs: nonsteroidal anti-inflammatory drugs. Adapted with permission from Sanders CV, Diagnosis of the Patient with Fever and Rash. In: The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT (Eds), Williams & Wilkins, Baltimore, 1995. Originally modified with permission from Dermatology in General Medicine, Fitzpatrick TB, et al (Eds), McGraw-Hill, New York, 1993. Graphic 72248 Version 3.0

3913

Erythema nodosum

Multiple erythematous nodules on the lower leg. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 108925 Version 3.0

3914

Toxic epidermal necrolysis

Multiple bullae and areas of denuded epidermis are present. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 59418 Version 9.0 Causes of toxic epidermal necrolysis

Drugs

Infections

Abacavir 

Aspergillosis (pulmonary)

Acetaminophen  Aspirin/citric acid/sodium bicarbonate (Alka-Seltzer)

Escherichia coli (septicemia)

Allopurinol*

Herpes simplex virus

Amiodarone

Measles virus

Antibiotics, especially tetracyclines, aminopenicillins, cephalosporins, and sulfonamides*

Varicella-zoster virus Miscellaneous

Anticonvulsants* Barbiturates*

Graft-versus-host disease

Brompheniramine

Idiopathic

Capecitabine 

Neoplasia

Chlorpromazine

Hodgkin's disease

Dapsone

Leukemia

Ethambutol

Non-Hodgkin's lymphoma

Sulfadoxine and pyrimethamine

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Vaccinations

Gold

BCG

Griseofulvin

Diphtheria toxoid

Ipecac

Measles

Isoniazid

Poliomyelitis

Nevirapine 

Tetanus antitoxin

NSAIDs Pentamidine Phenolphthalein Quinine Streptomycin Tamoxifen  Thalidomide  Tolbutamide Trimethoprim Vemurafenib  NSAIDs: nonsteroidal anti-inflammatory drugs; BCG: Bacillus Calmette-Guérin. * Most commonly associated with toxic epidermal necrolysis (TEN).

Adapted with permission from Sanders CV. Diagnosis of the patient with fever and rash. In: The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT (Eds), Williams & Wilkins, Baltimore, 1995. With permission from Rohrer TE, Ahmed AR. Toxic epidermal necrolysis. Int J Dermatol 1991; 30:457. Graphic 65062 Version 6.0 Infectious agents and illnesses associated with urticaria

Agent

Illness

Bedbugs, kissing bugs, ants, fleas, flies, and mosquitoes

Bites and stings

Coxiella burnetii

Q Fever

Coxsackieviruses A9, A16, B4, B5

Rash

Echinococcus sp

Echinococcosis

Echovirus 11

Rash

Epstein-Barr virus

Infectious mononucleosis

Entamoeba histolytica

Amebiasis

Enterobius vermicularis

Pinworm infestation

3916

Enterobius vermicularis

Pinworm infestation

Giardia lambdia

Giardiasis

Hepatitis B virus

Hepatitis B

Mites

Bites

Mumps virus

Mumps

Mycoplasma pneumoniae

Atypical pneumonia

Necator americanus

Hookworm disease

Neisseria meningitidis

Meningococcemia

Plasmodium spp

Malaria

Pediculus humanus

Pediculosis

Sarcoptes scabiei

Scabies

Schistosoma spp

Schistosomiasis

Shigella sonnei

Shigellosis

Trichinella spiralis

Trichinosis

Trichobilharzia spp

Swimmer's itch; collector's itch

Trichomonas vaginalis

Vulvovaginitis

Trombicula irritans

Chigger bites

Wuchereria bancrofti

Filariasis

Yersinia enterocolitica

Yersiniosis

Adapted with permissiom from Sanders CV, Diagnosis of the Patient with Fever and Rash. In: The Skin and Infection: A Color Atlas and Text. Sanders CV, Nesbitt LT (Eds), Baltimore, Maryland: Williams & Wilkins, 1995. Originally modified from Textbook of Pediatric Infectious Diseases, 3rd ed, Vol 1, Feigin RD and Cherry JD (Eds), Philadelphia, WB Saunders, Philadelphia 1992, p. 771. Graphic 74764 Version 3.0

3917

Urticaria

Annular, edematous, mildly erythematous plaques are present on the trunk. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 60454 Version 5.0 Giant urticaria Very large erythematous annular lesion of the shoulder with central clearing. This patient had several large lesions of this type, which could be confused with erythema migrans. Courtesy of Lee T Nesbitt, Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 81678 Version 4.0

3918

Genital herpes

Multiple grouped vesicles of genital herpes on the shaft of the penis. These lesions are frequently painful. Courtesy of Larry Millikan. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 78603 Version 5.0 Chancroid ulcer on penis Penile ulcer due to chancroid which is accompanied by marked inguinal lymphadenitis Graphic 76843 Version 1.0

Contributor Disclosures Fred A Lopez, MDNothing to discloseCharles V Sanders, MDEquity Ownership/Stock Options: Baxter International.Peter F Weller, MD, MACPGrant/Research/Clinical Trial Support: GlaxoSmithKline [Anti-IL5 mAb for EGPA]. Consultant/Advisory Boards: Knopp Biosciences [Hypereosinophilic syndrome treatment]; GlaxoSmithKline [Eosinophilic diseases]; Genzyme [Eosinophilia]. Other Financial Interest: AstraZeneca [Hypereosinophilic syndrome].Allyson Bloom, MDNothing to disclose Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

3919

Conflict of interest policy

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Gianotti-Crosti syndrome (papular acrodermatitis) - UpToDate uptodate.com/contents/gianotti-crosti-syndrome-papular-acrodermatitis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Aug 14, 2019.

INTRODUCTION

Gianotti-Crosti syndrome (GCS), also known as papular

acrodermatitis, papular acrodermatitis of childhood, and infantile papular acrodermatitis, is a selflimited skin disorder that most often occurs in young children. Viral infections are common precipitating factors for GCS. GCS typically manifests as a symmetric, papular eruption. Classic sites of involvement include the cheeks, buttocks, and extensor surfaces of the forearms and legs (picture 1A-F). GCS may be pruritic or asymptomatic, and papules typically resolve spontaneously within two months. Occasionally, GCS persists for longer periods. The etiology, clinical manifestations, diagnosis, and management of GCS will be reviewed here. Other uncommon exanthems that primarily occur in children and in association with viral infections are reviewed separately. (See "Atypical exanthems in children".)

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HISTORY AND TERMINOLOGY

Features

consistent with GCS were first described by Gianotti and Crosti in the 1950s [1,2]. The disorder was initially considered limited to infants and children but has since been recognized in adolescents and adults [3-5]. The original description of GCS consisted of three cardinal manifestations [1,2,6-8]: ●Nonrelapsing erythemato-papular dermatitis localized to the face and limbs, lasting approximately three weeks ●Paracortical hyperplasia of lymph nodes ●Acute hepatitis, usually anicteric, which could last for months and progress to chronic liver disease However, it is now accepted that neither lymphadenopathy nor hepatitis is mandatory for the diagnosis of GCS, and the duration of the condition can vary. Some authors have utilized the term "Gianotti-Crosti disease" to refer to GCS that occurs specifically in association with hepatitis B virus infection [9].

EPIDEMIOLOGY

GCS occurs worldwide. The incidence and prevalence

are unknown. Because many children with GCS are likely diagnosed with a "viral rash" or "nonspecific viral exanthem," GCS is probably underdiagnosed [10]. (See 'Differential diagnosis' below.) GCS primarily affects children younger than five years of age. During childhood, there does not appear to be a sex predilection [11,12]. In contrast, case reports suggest that, among adults, females may be more likely to develop GCS than males [9]. Most reports of GCS describe isolated cases. However, outbreaks have been described in association with hepatitis B virus infection, Epstein-Barr virus infection, and idiopathic cases [13-18].

ETIOLOGY

The epidemiologic features (eg, young age of onset, equal sex

distribution in children, and occurrences of outbreaks) support an infectious etiology for GCS [19]. Viral infections are considered the most common etiologic agents.

Viral infections — GCS usually occurs in association with a viral illness, most often Epstein-Barr virus (EBV) or hepatitis B virus (HBV) infection [20]. Case reports, case series, and retrospective studies support the association between EBV [11,21-30] and HBV infection [13-15,3135]. Of note, HBV is an uncommon cause of GCS in locales where vaccination against HBV infection

3922

during infancy is routine, such as the United States [9]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents".) GCS is less commonly reported in association with other viral pathogens. Examples include enteroviruses [36,37], cytomegalovirus [38-41], parvovirus [42,43], parainfluenza virus [44,45], hepatitis A virus [46,47], rotavirus [48,49], molluscum contagiosum [42,50], respiratory syncytial virus [37], HIV [51], and human herpesvirus 6 [52-54].

Other associations — Occasionally, GCS occurs in association with vaccination or bacterial infections. GCS has occurred following the administration of various antiviral vaccines, including vaccination against influenza [55-58], measles-mumps-rubella [59], hepatitis B [60,61], polio [62,63], hepatitis A [64], Japanese encephalitis [65], and varicella zoster virus infections [66]. One of the largest studies to evaluate the relationship between GCS and vaccination assessed 116 children diagnosed with GCS in close proximity to scheduled national days for receipt of the oral polio vaccine [63]. The study found that GCS was more often present one month after scheduled vaccination days (105 children, 90 percent) than one month prior to these days (11 children, 10 percent). Additional study is necessary to clarify the relationship between GCS and vaccines. Associations between the development of GCS and bacterial infections have been documented in case reports, including Mycoplasma pneumoniae [67,68], beta-hemolytic streptococci [37], Bartonella henselae [69], and Borrelia burgdorferi [70].

PATHOGENESIS

The pathogenesis of GCS, including the reason for the

acral distribution, is unknown. One hypothesis suggests that the clinical manifestations result from a delayed hypersensitivity reaction to viral infections [71]. The significance of immunoglobulin E (IgE)-mediated immunity in the pathogenesis of GCS and other viral exanthems is an area of investigation. GCS appears to be associated with atopy, which is characterized by the production of specific IgE following allergen exposure. A case-control study found that children with GCS were more likely to have had atopic dermatitis and to have a family history of atopy than control children who were being evaluated for recurrent infections (24 versus 7 percent for atopic dermatitis and 52 versus 31 percent for family history of atopy) [72]. In another case-control study with 37 children with GCS and matched controls, atopic dermatitis was more common among children with GCS than without GCS (76 versus 24 percent), and children with GCS were more likely to have at least one atopic disorder (84 versus 51 percent) [73]. (See "The relationship between IgE and allergic disease".)

CLINICAL FEATURES

The clinical manifestations of GCS

typically consist of the cutaneous eruption and findings related to the associated infection.

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Cutaneous manifestations — GCS classically presents as an acute, symmetric eruption of flat-topped, skin-colored or pink-brown papules or papulovesicles 1 to 10 mm in diameter that may coalesce into plaques (picture 1A-F) [9,74]. Although the face, buttocks, extensor aspects of forearms and legs, and feet are the predominant sites of involvement, involvement of the trunk does not exclude a diagnosis of GCS [75]. Truncal lesions are often more transient and fewer in number than acral lesions. The mucosal surfaces and nails are not involved [76,77]. Pruritus is usually mild to moderate but may be absent or severe. The development of lesions at sites of skin trauma (ie, the Koebner phenomenon) may occur early in the course of GCS [11,77]. In addition, hemorrhagic lesions occasionally occur, particularly in areas subject to trauma [9,74,77,78]. It has been suggested that patients with petechial lesions are more likely to have hepatitis B virus infection [79]. However, the cutaneous findings of GCS are not a reliable indicator of the etiologic agent [31]. A vesiculobullous variant has also been reported in a child with Epstein-Barr virus (EBV) infection [80]. (See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents".) Mucocutaneous features of certain associated viral infections may accompany the cutaneous manifestations of GCS. As an example, patients with enterovirus-associated GCS may have oral mucosal or palmoplantar skin lesions. (See "Hand, foot, and mouth disease and herpangina".)

Extracutaneous manifestations — Patients with GCS may experience symptoms of an upper respiratory or gastrointestinal illness during the week before the onset of the rash [9]. The initial illness may have resolved by the time the child presents with cutaneous manifestations. Patients may also present with concurrent malaise, low-grade fever, or diarrhea [9]. Lymphadenopathy occurs in 25 to 35 percent of patients, usually in the cervical, axillary, or inguinal regions [11,81]. The frequency of hepatic involvement is not known [9]. When hepatitis is present, it usually is anicteric (without clinically recognized jaundice) [8,82]. Splenomegaly may occur but is uncommon [9]. (See 'Diagnosis' below.)

Laboratory findings — There are no laboratory features characteristic of GCS. Patients may have modest lymphocytosis or lymphopenia [9]. Liver enzymes may be elevated in patients with EBV, cytomegalovirus, or hepatitis-associated disease.

COURSE

Most children with GCS have an excellent prognosis, although the course

may be prolonged [9]. Spontaneous remission without active intervention is the rule. During the initial two to three weeks, new papules and papulovesicles continue to occur, and the areas of involvement expand. The distribution is most classic in the middle phase of the disease.

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GCS usually persists for 10 days to 6 months; however, durations ranging from 5 days to 12 months have been reported [81]. Most patients achieve resolution of papules and associated pruritus within two weeks to two months. Near the end of the course, slow resolution of the skin lesions occurs. Recurrences are rare [83]. When present, lymphadenopathy and hepatomegaly (or hepatosplenomegaly) usually take longer to resolve than the cutaneous lesions [33,77].

COMPLICATIONS

Postinflammatory hypopigmentation or

hyperpigmentation often follows resolution of the skin lesions in children with highly pigmented skin and can persist for up to six months, but eventually resolves [9,84]. Permanent scarring is uncommon. Other potential complications are related to the underlying etiology. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Complications' and "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents".)

HISTOPATHOLOGY

The histopathologic findings of GCS are

nonspecific. Typical findings include focal, epidermal spongiosis and parakeratosis with perivascular, lymphocytic infiltrates in the upper dermis [85].

DIAGNOSIS

GCS can usually be diagnosed based upon the history and physical

examination. A skin biopsy is not usually necessary but may be useful in challenging cases. (See 'Differential diagnosis' below.) The establishment of diagnostic criteria would help to facilitate the clinical diagnosis of GCS and future studies of the disease. It remains to be determined whether diagnostic criteria proposed by the author and others are the ideal criteria for the diagnosis of this disease [86]. More studies are necessary to assess the criteria-rated validity, test-test intraclinician reliability, and interclinician reliability [87].

History and physical examination — The history and physical examination should include an assessment of preceding or concurrent constitutional symptoms as well as the time course, distribution, and morphology of the eruption. A full skin examination should be performed. A diagnosis of GCS is strongly suggested by the acute onset of a symmetrically distributed, papular or papulovesicular eruption in a young child that primarily involves the face, buttocks, and/or extensor surfaces of the extremities and does not have another identifiable cause (picture 1A-F). The presence of extracutaneous signs and symptoms (eg, malaise, fever, diarrhea, lymphadenopathy) is variable.

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Skin biopsy — The histopathologic findings of GCS are nonspecific and cannot confirm the diagnosis. However, a skin biopsy may be necessary to exclude other diagnoses in atypical presentations (eg, atypical lesion morphology or distribution, or lack of spontaneous resolution within six months). A 4 mm punch biopsy is usually sufficient. (See 'Histopathology' above and 'Differential diagnosis' below and "Skin biopsy techniques".)

EVALUATION FOR UNDERLYING DISORDERS

The decision to proceed with laboratory tests to identify an

etiologic agent for GCS should be made on an individual basis. Laboratory testing to identify an etiologic agent is not necessary for many patients. (See 'Etiology' above.) However, testing of patients with GCS for specific viral infections is warranted in some scenarios, such as to identify patients who may benefit from close monitoring or treatment of a suspected underlying condition. GCS may be the only clinical manifestation of acute hepatitis B virus (HBV) infection in infants and young children; therefore, testing for HBV infection is particularly appropriate for patients with risk factors for HBV infection. Laboratory testing to screen for Epstein-Barr virus (EBV) infection is generally unnecessary in the absence of other indications for EBV testing, as supportive therapy is often sufficient. (See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents", section on 'Epidemiology' and "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents", section on 'Screening'.) Testing to identify an etiologic agent may also be of value in immunocompromised patients or in patients with close contact with immunocompromised individuals or pregnant women [88]. Moreover, investigative testing may also be warranted when extracutaneous clinical findings (eg, hepatomegaly) require further work-up. The clinical presentation directs the approach to evaluation.

DIFFERENTIAL DIAGNOSIS

The constellation of

clinical features in GCS usually allows the diagnosis to be made relatively easily [9]. However, other conditions may warrant consideration, particularly in the setting of atypical presentations. Assessment of the course, associated symptoms, and lesion morphology and distribution is usually helpful for distinguishing GCS [77]: ●Erythema infectiosum − Erythema infectiosum (EI, also known as "fifth disease") is a common childhood exanthem caused by parvovirus B19. Like GCS, EI begins with nonspecific prodromal illness and acral eruption. However, the rash of EI, which begins on the cheeks (picture 2) and spreads to the extremities (picture 3), often has a lacy, reticulated appearance. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Erythema infectiosum'.)

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●Erythema multiforme − Erythema multiforme (EM) typically affects adolescents and young adults, but may also occur in children [74]. EM is often caused by herpes simplex virus or Mycoplasma infection. Although target lesions are characteristic of EM (picture 4), the lesions may be papular early in the course. Mucosal lesions are present in some children with EM and may help to distinguish it from GCS. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".) ●Hand, foot, and mouth disease − Hand, foot, and mouth disease (HFMD) is a common childhood illness that is usually caused by the group A coxsackieviruses. HFMD is characterized by fever; oral vesicles on the buccal mucosa and tongue; and peripherally distributed, small, tender, cutaneous macules, papules, or vesicles on the hands, feet, buttocks, and (less commonly) genitalia (picture 5A-C). The mucosal lesions and relatively short clinical course of HFMD distinguish it from GCS. (See "Hand, foot, and mouth disease and herpangina", section on 'Hand, foot, and mouth disease' and "Hand, foot, and mouth disease and herpangina".) ●Scabies − Scabies is an infestation of the skin by the mite Sarcoptes scabiei that results in an intense pruritus and small, erythematous papules, pustules, or vesicles, often in a characteristic distribution (picture 6A-B). The degree of pruritus distinguishes scabies from GCS; pruritus associated with GCS is not usually severe. Characteristic scabies mite burrows may also be visible in patients with scabies. (See "Scabies: Epidemiology, clinical features, and diagnosis".) ●Papular urticaria − Papular urticaria (also known as insect bite-induced hypersensitivity reaction) is defined by chronic or recurrent eruptions of papules, vesicles, target lesions, or wheals caused by hypersensitivity to insect bites (eg, fleas, mosquitoes, bedbugs, mites) in children. The lesions are symmetric, usually grouped in crops or clusters on exposed areas, and may take weeks to years to resolve. (See "Insect and other arthropod bites", section on 'Papular urticaria'.) Less common conditions to consider in the differential diagnosis of GCS include lichen planus, drug eruptions, papular-purpuric gloves and socks syndrome (PPGSS), and immunoglobulin A (IGA) vasculitis (Henoch-Schönlein purpura (picture 7)). Petechial or purpuric lesions should prompt consideration of PPGSS and IgA vasculitis. (See "Atypical exanthems in children", section on 'Papular-purpuric gloves and socks syndrome' and "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)

MANAGEMENT

GCS is a self-limited condition that can typically be

managed with supportive therapy to minimize pruritus, when present. In addition, patients or caregivers of patients of GCS often benefit from a discussion of the diagnosis, expected course, and prognosis of GCS. (See 'Course' above.)

Pruritus — Interventions for GCS have not been evaluated in randomized trials. Clinical experience suggests that topical emollients provide adequate relief for most individuals. For patients with significant pruritus, lotions containing ingredients such as calamine, pramoxine, menthol, or camphor may help to alleviate pruritus. Low- or medium-potency topical corticosteroids have also been utilized. However, the ability of topical corticosteroids to alter the disease course has not been

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confirmed (table 1) [44]. The administration of a sedating antihistamine may be helpful when the pruritus interferes with sleep. (See "Pruritus: Overview of management", section on 'Nonpharmacologic interventions'.)

Return to daycare or school — Exclusion from daycare, school, or other activities is unnecessary for most children with GCS. The need for any infection precautions is based upon the risks of transmission of the underlying infectious disease. (See 'Etiology' above.)

Indications for referral — Referral to a pediatric dermatologist may be beneficial if the diagnosis is uncertain or the disease course is exceptionally prolonged (eg, longer than six months).

SUMMARY AND RECOMMENDATIONS ●Gianotti-Crosti syndrome (GCS) is a self-limited cutaneous disorder that typically presents as a symmetric, papular eruption with an acral distribution. GCS primarily affects children younger than five years but can also occur in adolescents and adults. (See 'Epidemiology' above.) ●GCS usually occurs in association with a viral illness, such as infection with Epstein-Barr virus, hepatitis B virus, or other viruses. GCS associated with antiviral vaccines or bacterial infections and idiopathic GCS have also been reported. (See 'Etiology' above.) ●The diagnosis of GCS usually can be made based upon the patient history and physical findings. The characteristic presentation of GCS consists of symmetric, monomorphous, flat-topped, pinkbrown or skin-colored papules or papulovesicles on the face, buttocks, feet, and extensor aspects of forearms and legs (picture 1A-F). Pruritus may be present. (See 'Clinical features' above.) ●Noncutaneous findings in patients with GCS may include malaise, low-grade fever, and diarrhea. Lymphadenopathy is present in a subset of patients. Hepatitis, when present, is usually anicteric. (See 'Extracutaneous manifestations' above.) ●GCS typically resolves spontaneously within two months. Supportive care for associated pruritus, such as emollients, topical antipruritic agents, and oral sedating antihistamines, is usually sufficient. Exclusion from daycare or school is not necessary for most children with GCS. (See 'Management' above.)

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Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities uptodate.com/contents/clinical-manifestations-diagnosis-and-management-of-diabetic-infections-of-the-lowerextremities/print

Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Oct 03, 2018.

INTRODUCTION

Diabetic foot infections are associated with substantial

morbidity and mortality [1]. Important risk factors for development of diabetic foot infections include neuropathy, peripheral vascular disease, and poor glycemic control. In the setting of sensory neuropathy, there is diminished perception of pain and temperature; thus, many patients are slow to recognize the presence of an injury to their feet. Autonomic neuropathy can cause diminished sweat secretion resulting in dry, cracked skin that facilitates the entry of microorganisms to the deeper skin structures. In addition, motor neuropathy can lead to foot deformities, which lead to pressureinduced soft tissue damage. Peripheral artery disease can impair blood flow necessary for healing of ulcers and infections. Hyperglycemia impairs neutrophil function and reduces host defenses. Trauma in patients with one or more of these risk factors precipitates development of wounds that can be slow to heal and predispose to secondary infection. The microbiology, clinical evaluation, diagnosis, and management of diabetic foot infections will be reviewed here. The general evaluation of the diabetic foot and management of uninfected diabetic foot lesions are discussed separately. (See "Evaluation of the diabetic foot" and "Management of diabetic foot ulcers".)

GUIDELINES

In 2012, the Infectious Disease Society of America updated

guidelines on the diagnosis and management of diabetic foot infections, which were originally published in 2004 [2]. Practical guidelines are also published regularly by the International Working Group on the Diabetic Foot [3]. The information reviewed in this topic is largely consistent with these guidelines. Links to these and other guidelines related to care of diabetes mellitus are found below. (See 'Society guideline links' below.)

MICROBIOLOGY

Most diabetic foot infections are polymicrobial, with up

to five to seven different specific organisms often involved. The microbiology of diabetic foot wounds is variable depending on the extent of involvement [4-8]:

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●Superficial diabetic foot infections (including cellulitis and infected ulcers in antibiotic-naïve individuals) are likely due to aerobic gram-positive cocci (including Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pyogenes, and coagulase-negative staphylococci). ●Ulcers that are deep, chronically infected, and/or previously treated with antibiotics are more likely to be polymicrobial. Such wounds may involve the above organisms in addition to enterococci, Enterobacteriaceae, Pseudomonas aeruginosa, and anaerobes. ●Wounds with extensive local inflammation, necrosis, malodorous drainage, or gangrene with signs of systemic toxicity should be presumed to have anaerobic organisms in addition to the above pathogens. Potential pathogens include anaerobic streptococci, Bacteroides species, and Clostridium species [9-13]. The typical microbiological spectrum also differs by geographic location, with gram-negative pathogens predominating in the sub-tropical climates of Africa and Asia, in contrast to the predominantly gram-positive organisms seen in the Western hemisphere [14,15].

Risk of specific organisms Resistant Staphylococcus aureus — Methicillin-resistant S. aureus (MRSA) is a common pathogen in diabetic foot infections, particularly in those who have had previous MRSA infections or known colonization. Other risk factors for MRSA infection include prior antibiotic use, previous hospitalization, and residence in a long-term care facility. (See "Methicillinresistant Staphylococcus aureus (MRSA) in adults: Epidemiology", section on 'Risk factors'.) It is also important to note that diabetic patients with chronic foot wounds who receive repeated and prolonged courses of antibiotics represent an important risk group for development of vancomycinintermediate S. aureus infections. (See "Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin".)

Pseudomonas aeruginosa — P. aeruginosa is a particularly prevalent organism in diabetic foot infections reported from regions with warm climates. As an example, in a study of 434 patients with infected diabetic foot ulcers in Northern India, P. aeruginosa was the most common isolate, found in 20 percent of initial cultures [16]. Macerated ulcers, foot soaking, and other exposure to water or moist environments also likely increases the risk of involvement with P. aeruginosa. However, in temperate climates and in the absence of the preceding findings and exposures, P. aeruginosa is a relatively uncommon pathogen [17]. Furthermore, its role as a pathogen in routine clinical practice is often hard to assess. As an example, when P. aeruginosa was isolated from participants of clinical studies of diabetic foot infections, most patients improved on antibiotic regimens that did not cover Pseudomonas, suggesting that it was not the primary pathogenic organism [18,19].

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Resistant enteric gram-negative rods — Gram-negative bacilli that express an extended-spectrum beta-lactamase (ESBL) are increasing in prevalence worldwide. These pathogens are more common in patients with prolonged hospital stays, prolonged catheterization, prior antibiotic use, or residence in a long-term care facility (see "Extended-spectrum beta-lactamases", section on 'Epidemiology'). The involvement of ESBL-producing organisms in diabetic foot infections in particular is also increasingly reported [20,21].

CLINICAL MANIFESTATIONS Spectrum of involvement — Diabetic foot infections can develop as a result of neuropathic or ischemic ulcers, traumatic wounds, skin cracks or fissures, or other defects in the skin of the foot or nail beds (paronychia) [2,22]. Thus, infection can present as localized superficial skin involvement at the site of a preexisting lesion or as infection of the skin or deeper skin structures that has spread beyond the site of local trauma. Such infections can subsequently extend to joints, bones, and the systemic circulation [23].

Skin and soft tissue infection — Diabetic foot infections are often accompanied by the cardinal manifestations of inflammation (erythema, warmth, swelling, and tenderness) and/or the presence of pus in an ulcer or sinus tract [4]. However, these local signs of infection may not be evident in all cases. Infections may not manifest with warmth and erythema in the setting of severe ischemia. Diabetics with sensory neuropathy may have diminished sensation in the involved area and therefore may not complain of tenderness nor, in some cases, even realize that infection is present. In such instances, infection may progress to involve deeper tissues before the patient seeks clinical attention. Other local signs that may be present in diabetic foot infections are nonspecific and include nonpurulent drainage, friable or discolored granulation tissue, and undermining of wound edges [2]. Cutaneous bullae, soft tissue gas, skin discoloration, or a foul odor may occur in necrotizing infections. Findings of gangrene, severe ischemia, or tissue necrosis may denote the presence of a limb-threatening infection. Systemic signs such as fever, chills, hypotension, and tachycardia may accompany local signs of infection, and their presence indicates an increased severity of infection. (See 'Determining severity of infection' below.)

Osteomyelitis — Osteomyelitis can occur in the setting of a diabetic foot wound with or without evidence of local soft tissue infection. Clinical features associated with underlying osteomyelitis in patients with diabetic foot ulcers include ulcer size >2 cm2 and depth allowing visibly exposed bone or ability to probe to bone [24-27]. The presence of a "sausage" toe, with

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erythema and nonpitting edema that obliterates the normal contour of the digit, has also been associated with underlying osteomyelitis in patients with diabetes, but the frequency of this finding is not known [28]. Although not specific or highly sensitive, the erythrocyte sedimentation rate (ESR) may be useful in evaluating whether osteomyelitis is present. The finding of an ESR of 70 or greater increases the clinical probability that osteomyelitis is present [26]. On plain radiographs, findings characteristic of osteomyelitis include cortical erosion, periosteal reaction, mixed lucency, and sclerosis [2,26]. There is often also evidence of soft tissue swelling. However, radiographs may be normal or have only subtle non-specific findings early in infection. Magnetic resonance imaging (MRI) findings of osteomyelitis include cortical destruction, bone marrow edema, and soft tissue inflammation. (See "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis", section on 'Conventional radiography' and "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis", section on 'Magnetic resonance imaging'.)

DIAGNOSIS Evaluation — The evaluation of a patient with a suspected diabetic foot infection involves three key steps: 1) determining the extent and severity of infection, 2) identifying underlying factors that predispose to and promote infection, and 3) assessing the microbial etiology. The clinical history should focus on the details related to recent trauma, the duration of the current lesion(s), associated systemic symptoms, and prior treatment, if any. Mechanical factors that may predispose to the formation of an ulcer should be noted, and the history of blood glucose control should be assessed. Evidence of systemic toxicity should also be carefully noted. Clinical examination should note the location of the lesions, extent of infection (eg, involving skin, subcutaneous tissue, muscles, tendons and/or bone) and whether bone is grossly visible or palpable by probing. Although osteomyelitis is highly likely if bone is visible, it may be present in the absence of such findings. (See 'Diagnosis of underlying osteomyelitis' below.) Clinical examination should also include a neurologic evaluation that documents the extent of sensory loss as well as a vascular evaluation of the presence and severity of arterial and/or venous insufficiency. (See "Evaluation of the diabetic foot".) Laboratory evaluation should include complete blood count as well as measurement of blood glucose, electrolytes, and renal function. Baseline and subsequent inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be useful for monitoring response to therapy [6]. Some but not all studies have suggested that procalcitonin (PCT), a novel

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inflammatory marker, may also be useful if laboratory facilities that test this substance are locally available; further investigation is needed to determine the clinical utility of this assay [29]. (See 'Diagnosis of underlying osteomyelitis' below.) Initial evaluation should include conventional radiographs to evaluate for bony deformity, foreign bodies, and gas in the soft tissue. In select cases, magnetic resonance imaging (MRI) can be performed to better evaluate for soft tissue abnormalities and osteomyelitis. (See 'Osteomyelitis' above and "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis".) Aerobic and anaerobic cultures of deep tissue or bone biopsies should be obtained at the time of debridement if deep tissue infection or osteomyelitis is suspected. (See 'Obtaining samples for culture' below.) If surgical intervention is warranted for management of infection, formal neurological and/or vascular evaluation is important for determining the extent of surgical intervention. (See 'Surgery' below and "Evaluation of the diabetic foot".)

Diagnosis of soft tissue infection — The diagnosis of a diabetic foot infection is primarily based on suggestive clinical manifestations. The presence of two or more features of inflammation (erythema, warmth, tenderness, swelling, induration and purulent secretions) can establish the diagnosis [2,30]. (See 'Clinical manifestations' above.) As many diabetic foot wounds are colonized by bacteria, the presence of microbial growth from a wound culture in the absence of supportive clinical findings is not sufficient to make the diagnosis of infection [2,30]. (See 'Obtaining samples for culture' below.)

Diagnosis of underlying osteomyelitis — The possibility of osteomyelitis should be considered in diabetic patients with foot wounds associated with signs of infection in the deeper soft tissues and in patients with chronic ulcers, particularly those overlying bony prominences that do not heal after several weeks of wound care and off-loading. The diagnosis of osteomyelitis is definitively made through isolation of bacteria from a sterilely obtained bone biopsy sample with histologic evidence of inflammation and osteonecrosis [2,30]. However, bone biopsy is not always routinely available or practical. Furthermore, bone cultures may be negative in patients who have already received antibiotics, and bone histology may not show inflammation due to sampling error. In such instances, the presumptive diagnosis is based on clinical and radiographic assessment. Certain clinical findings can support the diagnosis of osteomyelitis. In two systematic reviews that evaluated the diagnostic accuracy of exam findings in the setting of diabetic foot ulcers, the following factors increase the likelihood of osteomyelitis [26,27]: ●Grossly visible bone or ability to probe to bone ●Ulcer size larger than 2 cm2

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●Ulcer duration longer than one to two weeks ●Erythrocyte sedimentation rate (ESR) >70 mm/h If bone is grossly visible, supportive radiographic findings may not be necessary to make a diagnosis of osteomyelitis. However, for diabetic patients with one or more of the other above factors, a conventional radiograph with consistent changes can be helpful in making the diagnosis of osteomyelitis and providing a baseline image useful for subsequent management decisions. If the radiograph is indeterminate or normal and the diagnosis remains uncertain, such patients should undergo magnetic resonance imaging (MRI), which is highly sensitive and specific for osteomyelitis and superior to radiographs, three-phase bone scans, and white blood cell scans [2,26,27,30,31]. MRI is generally unnecessary if the plain radiograph is consistent with osteomyelitis. (See 'Osteomyelitis' above.) In cases of diagnostic uncertainty based on clinical or radiographic features, failure of empiric antibiotic therapy, planned hardware placement in potentially infected bone, and mid- or hindfoot lesions that could lead to high-level amputations if inadequately treated, obtaining a bone sample to establish diagnosis is recommended [2]. Culture of such bone biopsy specimens is also important for identifying the causative organisms and their susceptibilities in order to guide antimicrobial therapy. (See 'Obtaining samples for culture' below.) A detailed approach to the diagnosis of osteomyelitis in general is outlined separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis" and "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis".)

Determining severity of infection — Assessment of the severity of diabetic foot infections is important for prognosis and to assist with management decisions (eg, need for hospitalization, surgical evaluation, or parenteral versus oral antibiotic therapy). In its 2004 guidelines on the diagnosis and treatment of diabetic foot infections, the Infectious Diseases Society of America (IDSA) first outlined a clinical classification scheme to define levels of severity (table 1) [6]. Briefly, it classifies diabetic foot changes as uninfected, mild, moderate, and severe based on the extent of inflammatory findings, the tissue depth involved, and the presence of signs of systemic toxicity. The International Working Group on the Diabetic Foot published a nearly identical classification system in 2012 [30]. The prognostic value of such classification schema was assessed in a longitudinal study of 1666 persons with diabetes; there was a trend toward increased amputation risk among patients with more severe infections [32].

DIFFERENTIAL DIAGNOSIS

Other processes that lead

to inflammatory changes in the skin of the lower extremities can mimic an infection. These include trauma, crystal-associated arthritis, acute Charcot arthropathy, fracture, thrombosis, and venous stasis. Usually, infection can be distinguished from these based on history, exam, and imaging

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findings. However, infection may co-exist with other inflammatory processes, and empiric antimicrobial therapy may be warranted in some cases when the diagnosis is unclear. (See "Clinical manifestations and diagnosis of gout" and "Diabetic neuropathic arthropathy" and "Clinical manifestations of lower extremity chronic venous disease" and "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)

MANAGEMENT

Management of diabetic foot infections requires attentive

wound management, good nutrition, appropriate antimicrobial therapy, glycemic control, and fluid and electrolyte balance. Although severe infections (table 1) warrant hospitalization for urgent surgical consultation, antimicrobial administration, and medical stabilization, most mild infections and many moderate infections can be managed in the outpatient setting with close follow-up [10,19]. Hospitalization may be needed for mild or moderate infections if the patient cannot manage glycemic control at home, is unable to obtain or comply with proper wound care or offloading, needs parenteral antibiotics and is unsuitable for outpatient parenteral antimicrobial therapy, or needs more urgent diagnostic studies or surgical consultation [10,19]. Several studies have reported improved outcomes with a multidisciplinary approach to diabetic foot infections. This includes involvement of specialists in wound care, infectious diseases, endocrinology, and surgery [2,33-35].

Wound management — Local wound care for diabetic foot infections typically includes debridement of callus and necrotic tissue, wound cleansing, and relief of pressure on the ulcer [2,30]. Sharp debridement, with the use of a scalpel or scissors to shear off necrotic tissue, is the preferred method to remove callus and nonviable tissue. Such debridement promotes wound healing and removes pathogens that are present in nonviable tissues [2]. However, enzymatic debridement may be preferable in patients with significant vascular compromise that might impede the ability to heal new wounds created by sharp debridement [36]. As a general rule, surgical intervention is needed for patients with extensive infection of subcutaneous or deeper structures. (See "Management of diabetic foot ulcers", section on 'Debridement' and 'Surgery' below.) The purpose of wound dressing is to absorb exudate and create a moist environment to promote healing. A wide array of dressing and wound healing products for ulcer management has been developed. These products include enzymes, gels, hydrocolloids, honey and antiseptics containing iodine or silver salts. However, the efficacy of these agents has not been evaluated or compared in carefully designed studies [22,37]. Avoidance of weight bearing is generally more important than the specific type of wound dressing or ointment applied. (See "Management of diabetic foot ulcers", section on 'Dressings'.) Off-loading the pressure on the diabetic foot wound is essential to wound care. Various devices to relieve pressure on the foot are available, including casts and special shoes. The choice of device should be based on the wound location, the severity of infection, and the presence of peripheral

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arterial disease. (See "Management of diabetic foot ulcers", section on 'Mechanical offloading'.)

Obtaining samples for culture — Because microorganisms often colonize lower extremity wounds regardless of the presence of a true infection, cultures should be performed only in selected patients. If the clinical suspicion for infection is low, samples from the wound should not be submitted for culture. In patients with mild infection (table 1) in whom there is low suspicion for resistant organisms (eg, no recent antibiotic course), wound culture is often not necessary. However, wound culture is often helpful in cases of moderate or severe infection (table 1) and when the concern for multidrug-resistant organisms is high. Ideally, samples for culture should be obtained prior to the initiation of empiric antibiotics. However, in cases of systemic toxicity or limb-threatening infections, antibiotic therapy should not be withheld before surgical cultures are obtained. The preferred clinical specimens for reliable culture include aspirate from an abscess or curettage from the ulcer base following superficial debridement of necrotic tissue. Organisms cultured from superficial swabs are not reliable for predicting the pathogens responsible for deeper infection [3841]. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis".) In the setting of osteomyelitis, bone biopsy is the preferred method of sample collection for culture. If performed percutaneously, sampling through uninvolved tissue under radiographic guidance is preferred. Although sinus tract cultures may be of some use for prediction of osteomyelitis if S. aureus or Salmonella species are identified, in general, such cultures are not worthwhile [42,43]. (See 'Diagnosis of underlying osteomyelitis' above and "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Bone biopsy'.) Samples should be sent for both aerobic and anaerobic bacterial cultures.

Surgery — Consultation with a surgeon with experience in diabetic foot infections is important for cases of severe infections and in most cases of moderate infections. Surgical debridement is required for cure of infections complicated by abscess, extensive bone or joint involvement, crepitus, necrosis, gangrene or necrotizing fasciitis and is important for source control in patients with severe sepsis [2,44,45]. The utility of early surgical debridement was illustrated in a retrospective review of 112 diabetic patients with severe foot infections [44]. Those patients who underwent surgical intervention at the time of presentation had a significantly lower rate of aboveankle amputation than those who received three days of intravenous antimicrobial therapy prior to surgery. In addition to surgical debridement, revascularization (via angioplasty or bypass grafting) and/or amputation may be necessary. Determination of the extent of surgical intervention required should be guided by vascular evaluation [2,22]. (See "Lower extremity amputation", section on 'Indications for amputation' and "Techniques for lower extremity amputation" and "Management of diabetic foot ulcers", section on 'Ischemia and revascularization'.)

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Antimicrobial therapy — Empiric antibiotic therapy should be selected based on the severity of infection and the likelihood of involvement of resistant organisms. (See 'Determining severity of infection' above and 'Microbiology' above.) Subsequent antibiotic therapy should be tailored to culture and susceptibility results. However, it is not always necessary to cover all microorganisms isolated from cultures [6]. Patients with ulcerations that are not infected should not receive antibiotic therapy [46,47]. However, such patients often benefit from local wound care and measures that reduce the pressure at the site of ulceration. Our treatment approach outlined below is consistent with the Infectious Diseases Society of America (IDSA) guidelines on the diagnosis and treatment of diabetic foot infections and is based on their classification scheme for severity of infection (table 1) [2,6]. (See 'Determining severity of infection' above.) In general, the limited data on antibiotic therapy of diabetic foot infections do not allow comparison of outcomes of different regimens [2,30]. On the basis of the available observational studies and randomized trials, no single drug or combination appears to be superior to others [48-50]. In a systematic review of 12 studies comparing antibiotic regimens for lower extremity skin and softtissue infections in diabetic patients, reported clinical cure rates ranged from 48 to 90 percent [49]. None of the studies demonstrated a significant benefit for any specific antibiotic agent. However, subsequent data suggest that tigecycline, specifically, may not be effective as other regimens; it resulted in lower clinical cure rates and did not meet prespecified non-inferiority criteria compared with ertapenem with or without vancomycin in a randomized, double-blind trial of patients with diabetic foot infections [51].

Empiric therapy Mild infection — Mild diabetic foot infections can be treated with outpatient oral antimicrobial therapy. Empiric therapy of patients with mild infections should include activity against skin flora including streptococci and S. aureus. Agents with activity against methicillin-resistant S. aureus (MRSA) should be used in patients with purulent infections and those at risk for MRSA infection (see 'Resistant Staphylococcus aureus' above). Appropriate agents are outlined in the table (table 2). We typically follow such patients for about a week. By that time, patients who have failed to respond to treatment with agents active against streptococci and methicillin-susceptible S. aureus should receive extended antimicrobial coverage to include activity against MRSA, aerobic gram-negative bacilli, and anaerobes (table 2).

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Moderate infection — Empiric therapy of deep ulcers with extension to fascia should include activity against streptococci, S. aureus (and MRSA if risk factors are present), aerobic gramnegative bacilli and anaerobes and can be administered orally in many cases. Appropriate regimens are outlined in the table (table 2). Patients presenting with extensive infections that involve deep tissues should receive empiric parenteral therapy with activity against the above pathogens (table 3). Empiric coverage for P. aeruginosa may not always be necessary unless the patient has particular risk for involvement with this organism, such as a macerated wound or one with significant water exposure. (See 'Pseudomonas aeruginosa' above.)

Severe infection — Limb-threatening diabetic foot infections and those that are associated with systemic toxicity should be treated with broad-spectrum parenteral antibiotic therapy. In most cases, surgical debridement is also necessary. Empiric therapy should include activity against streptococci, MRSA, aerobic gram-negative bacilli, and anaerobes. Appropriate regimens are outlined in the table (table 3) [52].

Targeted therapy — If appropriate wound cultures were submitted, antimicrobial therapy should be tailored to culture and susceptibility results when available. However, it is not always necessary to cover all microorganisms isolated from cultures [2,30]. Virulent species such as S. aureus and streptococci (group A or B) should always be covered, but in polymicrobial infections, less virulent organisms (such as coagulase negative staphylococci and enterococci) may be less important. Furthermore, if isolates are resistant to an empiric regimen to which the patient is clearly responding well, broadening the spectrum to include those isolates may not be necessary. On the other hand, if the patient is not responding, expanding therapy to target all isolated organisms may be warranted. For those patients who were initiated on parenteral therapy, a switch to an oral regimen is reasonable following clinical improvement.

Duration of therapy — The duration of antibiotic therapy should be tailored to individual clinical circumstances. Patients with mild infection should receive oral antibiotic therapy in conjunction with attentive wound care until there is evidence that the infection has resolved (usually about one to two weeks). Antibiotics need not be administered for the entire duration that the wound remains open [2,30]. Patients with infection also requiring surgical debridement should receive intravenous antibiotic therapy perioperatively. In the absence of osteomyelitis, antibiotic therapy should be administered in conjunction with attentive wound care until signs of infection appear to have resolved (two to four weeks of therapy is usually sufficient). If there is a good response to parenteral therapy, oral agents can be used to complete the course of treatment [53]. Patients requiring amputation of the involved limb should receive intravenous antibiotic therapy perioperatively. If the entire area of infection is fully resected, a brief course of oral antibiotic therapy (about a week) following surgery is usually sufficient [53].

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Considerations for osteomyelitis — Similar to other types of diabetic foot infections, no data support the superiority of specific antimicrobial agents for osteomyelitis [49]. Appropriate regimens for empiric therapy are similar to that for moderate to severe diabetic foot infections (table 3). Targeted antimicrobial therapy should be tailored to culture and sensitivity results, ideally from bone biopsy. In one retrospective study of diabetic patients with osteomyelitis of the toe or metatarsal head, remission (absence of signs of infection and no need for surgery after one year) was more likely in the 22 patients treated with regimens guided by bone biopsy data compared with the 28 treated based on swab culture data (82 versus 50 percent) [54]. Of note, those who had bone culture were also more likely to be treated with a rifampicin-containing regimen, which likely was a confounding variable and limits the interpretation of this finding. Directed antimicrobial therapy for osteomyelitis is discussed in detail elsewhere. (See "Osteomyelitis in adults: Treatment", section on 'Definitive therapy'.) Many patients with osteomyelitis of the foot benefit from surgical resection. In a systematic review of studies evaluating treatment of diabetic foot osteomyelitis, there was no study that directly compared surgical intervention to nonsurgical management [55]. However, studies of prolonged antibiotic therapy without resection reported success rates comparable to those reported with surgery, about 60 to 90 percent. Furthermore, partial amputations of the foot (eg, ray or transmetatarsal amputations) may adversely alter the biomechanics of the foot, increasing the risk of future ulceration. Thus, in certain cases, limited surgical debridement combined with prolonged antibiotic therapy may be appropriate [2,30]. However, extensive surgical debridement or resection is preferable in the following clinical circumstances [2]: ●Persistent sepsis without an alternate source ●Inability to receive or tolerate appropriate antibiotic therapy ●Progressive bone deterioration despite appropriate antibiotic therapy ●Mechanics of the foot are compromised by extensive bony destruction requiring correction ●Surgery is needed to achieve soft tissue wound or primary closure The duration of antibiotic therapy of osteomyelitis depends on the extent of residual affected tissue. This is discussed in detail elsewhere. (See "Osteomyelitis in adults: Treatment", section on 'Antibiotic therapy'.)

Adjunctive therapies — Adjunctive therapies for treatment of diabetic foot infections include vacuum-assisted wound closure, hyperbaric oxygen and granulocyte colonystimulating factor (G-CSF) [56-58].

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Of these, vacuum-assisted wound closure is used most frequently. In a randomized trial evaluating vacuum-assisted wound closure including 342 patients with diabetic foot ulcers, complete ulcer closure was achieved more often among those who used vacuum-assisted closure than those who did not (43 versus 29 percent, respectively) [56]. Vacuum-assisted closure and hyperbaric oxygen therapy are discussed in detail separately. (See "Management of diabetic foot ulcers" and "Hyperbaric oxygen therapy", section on 'Infection' and "Hyperbaric oxygen therapy", section on 'Nonhealing ulcers, skin grafts, and wound healing'.) The role of G-CSF in managing diabetic foot infections is not clear. In a meta-analysis of five trials that included 167 patients, there was a reduction in the rates of surgical intervention and amputation, specifically, associated with the use of G-CSF (relative risks 0.38 [95% CI 0.21 to 0.70] and 0.41 [95% CI 0.18 to 0.95], respectively, compared with no G-CSF) and no significant difference in adverse effects [59]. There was no clear benefit to G-CSF with regards to infection resolution or improvement. The included studies were all of small size, and there was substantial clinical heterogeneity across studies, including variable antibiotic regimens used, G-CSF formulations and doses, and severity of underlying infection. Additional data are needed before G-CSF can be recommended or its high cost can be justified for use in diabetic foot infections.

Follow-up — Close follow-up is important to ensure continued improvement and to evaluate the need for modification of antimicrobial therapy, further imaging, or additional surgical intervention. Wound healing and a decrease in previously elevated inflammatory markers can be signs of clinical resolution, and may be particularly helpful in cases of osteomyelitis. If clinical evidence of infection persists beyond the expected duration, issues of patient adherence to therapy, development of antibiotic resistance, an undiagnosed deeper infection (eg, abscess or osteomyelitis), or ischemia should be evaluated [6]. If infection in a clinically stable patient fails to respond to more than one antibiotic course, some favor discontinuing antimicrobial therapy a few days (eg, 48 to 72 hours) in order to obtain a biopsy for culture of antibiotics and optimize the yield [6]. In general, this is a safe and reasonable approach, although deep cultures are often positive even if therapy is continued up to the time of debridement.

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults".)

INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the

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Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topics (see "Patient education: Diabetes and infections (The Basics)")

SUMMARY AND RECOMMENDATIONS ●Hyperglycemia, sensory and autonomic neuropathy, and peripheral arterial disease all contribute to the pathogenesis of lower extremity infections in diabetic patients. These infections are associated with substantial morbidity and mortality. (See 'Introduction' above.) ●Evaluation of a patient with a diabetic foot infection involves determining the extent and severity of infection through clinical and radiographic assessment, identifying and addressing underlying factors that predispose to and promote infection, assessing the microbial etiology, and determining the need for surgical intervention. (See 'Evaluation' above.) ●Laboratory testing should include blood work to evaluate for leukocytosis as well as blood glucose, electrolytes, and renal function values so that glycemic control and acid base status can be evaluated and monitored. Baseline and subsequent inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be useful for monitoring response to therapy. Conventional radiographs should be done to evaluate for bony and soft tissue deformity or abnormalities. Formal vascular evaluation is warranted in cases where peripheral arterial insufficiency is suspected. (See 'Evaluation' above.) ●The presence of two or more features of inflammation (erythema, warmth, tenderness, swelling, induration, or purulent secretions) can establish the diagnosis of a diabetic foot infection. The definitive diagnosis of osteomyelitis is made through histologic and microbiologic evaluation of a bone biopsy sample. However, certain clinical factors can support the presumptive diagnosis of osteomyelitis in the absence of biopsy: •Grossly visible bone or ability to probe to bone •Ulcer size larger than 2 cm2 •Ulcer duration longer than one to two weeks •Erythrocyte sedimentation rate (ESR) >70 mm/h

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Those with one or more of the above factors whose radiographs are normal or indeterminate for osteomyelitis should undergo magnetic resonance imaging (MRI). (See 'Diagnosis' above.) ●Management of diabetic foot infections requires attentive wound management, good nutrition, antimicrobial therapy, glycemic control, and fluid and electrolyte balance. Wound management includes attentive local wound care including debridement of callus and necrotic tissue, wound cleansing, and relief of pressure on the ulcer. Consultation with a surgeon with experience in diabetic foot infection is important for cases of severe infections and most cases of moderate infections. Prompt surgical debridement is critical for cure of infections complicated by abscess, extensive bone or joint involvement, crepitus, necrosis, gangrene or necrotizing fasciitis and is important for source control in patients with severe sepsis. (See 'Wound management' above and 'Surgery' above.) ●The microbiology of diabetic foot wounds varies with the severity and extent of involvement (table 1). Superficial infections are likely due to aerobic gram-positive cocci whereas deep, chronically infected, and/or previously treated ulcers are more likely to be polymicrobial. Anaerobic organisms may also be involved in wounds with extensive local inflammation, necrosis, or gangrene. When there is concern for multidrug-resistant organisms or in cases of moderate or severe infection (including deep infections and osteomyelitis), aerobic and anaerobic cultures of deep tissue or bone biopsies should be obtained at the time of debridement. Organisms cultured from superficial swabs are not reliable for predicting the pathogens responsible for deeper infection. (See 'Microbiology' above and 'Obtaining samples for culture' above.) ●Empiric antibiotic therapy should be selected based upon the severity of infection and the likelihood of involvement of resistant organisms: •For patients with mild infections, we suggest an empiric antimicrobial regimen (table 2) with activity against skin flora including streptococci and Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA] if risk factors are present) (Grade 2C). (See 'Mild infection' above.) •For patients with deep ulcers, we suggest an empiric antimicrobial regimen with activity against streptococci, S. aureus (and MRSA if risk factors are present), aerobic gram-negative bacilli and anaerobes (Grade 2C). Oral antibiotics (table 2) may be appropriate for ulcers that extend to the fascia, whereas parenteral regimens (table 3) should be used for deeper infections. (See 'Moderate infection' above.) •For patients with limb-threatening diabetic foot infections or evidence of systemic toxicity, we suggest treatment with a broad-spectrum parenteral antibiotic regimen (table 3) with activity against streptococci, MRSA, aerobic gram-negative bacilli, and anaerobes (Grade 2C). (See 'Severe infection' above.) ●Antimicrobial therapy should be tailored to culture and susceptibility results when available, and a switch to an oral from parenteral regimen is reasonable following clinical improvement. Antibiotics need not be administered for the entire duration that the wound remains open. Close follow-up is

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important to ensure continued improvement and to evaluate the need for modification of antimicrobial therapy, further imaging, or additional surgical intervention. (See 'Targeted therapy' above and 'Duration of therapy' above and 'Follow-up' above.) ●Many patients with osteomyelitis of the foot benefit from surgical resection. However, in certain cases, limited surgical debridement combined with prolonged antibiotic therapy may be appropriate. The duration of antibiotic therapy of osteomyelitis depends on the extent of residual affected tissue. (See 'Considerations for osteomyelitis' above and "Osteomyelitis in adults: Treatment".)

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Infectious folliculitis - UpToDate uptodate.com/contents/infectious-folliculitis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Aug 30, 2019.

INTRODUCTION

Folliculitis refers to inflammation of the superficial or

deep portion of the hair follicle. The classic clinical findings of superficial folliculitis are follicular pustules and follicular erythematous papules on hair-bearing skin. Nodules are a feature of deep follicular inflammation. Folliculitis may be infectious or, less frequently, noninfectious. Various bacteria, fungi, viruses, and parasites are causes of infectious folliculitis. The etiology, clinical manifestations, diagnosis, and management of infectious folliculitis will be reviewed here. Noninfectious causes, such as human immunodeficiency virus (HIV)-associated eosinophilic folliculitis and drug-induced folliculitis, are reviewed separately. (See "HIV-associated

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eosinophilic folliculitis" and "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors" and "Approach to the patient with pustular skin lesions".)

BACTERIAL FOLLICULITIS

Bacterial infection is the

most common cause of infectious folliculitis.

Etiology and risk factors — Frequent causes of bacterial folliculitis include Staphylococcus aureus and gram-negative bacteria. ●Staphylococcus aureus – S. aureus, a gram-positive bacterium, is the most common cause of bacterial folliculitis. "Impetigo of Bockhart" and "Bockhart impetigo" are alternative terms for superficial staphylococcal folliculitis. Both methicillin-sensitive and methicillin-resistant S. aureus (MRSA) can cause folliculitis. Folliculitis is among the infections contributing to the increasing prevalence of community-acquired MRSA infections [1]. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Epidemiology" and "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum".) ●Gram-negative folliculitis – Pseudomonas aeruginosa is a gram-negative bacterium and the cause of "hot tub folliculitis," a form of folliculitis attributed to contact with water contaminated with Pseudomonas as a result of inadequate chlorine, bromine, or pH levels in whirlpools, hot tubs, or swimming pools [2]. Bathing with contaminated sponges or nylon towels and use of contaminated rubber gloves are additional potential modes of acquisition [3-5]. (See "Pseudomonas aeruginosa skin and soft tissue infections", section on 'Hot tub-associated eruptions'.) Other organisms responsible for gram-negative folliculitis include Klebsiella, Enterobacter, and Proteus species. These bacteria are common causes of gram-negative folliculitis associated with long-term treatment with oral antibiotics (eg, tetracyclines) for acne vulgaris [6]. Aeromonas hydrophila, another gram-negative organism, can cause folliculitis after recreational water exposure [7]. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Gram-negative folliculitis'.) Bacterial folliculitis can occur in infants, children, or adults. Factors that may increase risk include [8]: ●Nasal carriage of S. aureus ●Occlusion of hair follicles ●Hyperhidrosis ●Scratching secondary to pruritic skin disease (eg, atopic dermatitis)

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●Prolonged application of topical corticosteroids ●Long-term oral antibiotic therapy for acne ●Shaving against the direction of hair growth ●Exposure to hot tubs or heated swimming pools ●Male sex (for gram-negative folliculitis associated with oral antibiotic therapy for acne vulgaris) [6]

Clinical manifestations — The classic clinical findings in bacterial folliculitis are follicular pustules and follicular erythematous papules (picture 1A-D). Pruritus is the most common symptom associated with folliculitis. Patients may also experience painful pustules. Folliculitis can occur on any hair-bearing area; however, certain etiologies often correlate with particular distributions [8]. S. aureus folliculitis is most common on the scalp and face [9]. Other common sites include the upper trunk, buttocks, and legs, as well as the axillae in infants and children [8]. Community-acquired MRSA folliculitis may be more likely to occur on the chest, flanks, scrotum, and periumbilical region than methicillin-sensitive S. aureus infections [1]. Folliculitis barbae (also known as sycosis barbae) is a bacterial folliculitis involving deep portions of the hair follicles in the beard areas of the face and neck. S. aureus is a frequent causative organism. Folliculitis barbae is often characterized by tender pustules within erythematous plaques involving multiple hair follicles [8,9]. "Hot tub folliculitis" induced by P. aeruginosa presents with pruritic follicular macules, papules, or pustules (picture 2A-B). The eruption appears 8 to 48 hours after exposure and primarily occurs on the trunk and buttocks in the distribution of the wet bathing suit or other areas exposed to contaminated water [2]. (See "Pseudomonas aeruginosa skin and soft tissue infections", section on 'Hot tub-associated eruptions'.) Gram-negative folliculitis due to Klebsiella, Enterobacter, or Proteus and associated with long-term oral antibiotic treatment for acne vulgaris typically occurs on the face, most commonly in the perinasal region. Deep infection of the hair follicle can lead to development of a furuncle (or "boil"). Multiple furuncles can coalesce to form carbuncles. In most cases, S. aureus is the cause [10]. Furuncles and carbuncles are reviewed separately. (See "Cellulitis and skin abscess: Clinical manifestations and diagnosis".)

Diagnosis — Bacterial folliculitis is usually diagnosed by means of the patient history and physical examination. The diagnosis should be suspected in patients with follicularly-based papules or pustules who lack additional features suggestive of another follicular or inflammatory skin disorder. (See 'Differential diagnosis' below.)

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The patient history may offer clues to the etiology of folliculitis. For example, Pseudomonas folliculitis should be suspected in patients reporting an acute eruption following exposure to hot tubs or heated swimming pools, and gram-negative folliculitis should be considered in patients with a recent history of prolonged oral antibiotic therapy for acne. Immunosuppressed patients may have increased risk for fungal or viral folliculitis, warranting stronger consideration of these disorders in the differential diagnosis of bacterial folliculitis. (See 'Fungal folliculitis' below and 'Viral folliculitis' below.) Recognition of the distribution of folliculitis may also be useful. Folliculitis limited to the scalp and/or face is often secondary to S. aureus. Pseudomonas folliculitis typically occurs on areas of skin exposed to contaminated water. Further work-up is primarily reserved for patients with an unclear diagnosis or treatment-resistant disease. A Gram stain and culture of the contents of a pustule can confirm the presence of infection and identify the causative organism. Infrequently, a skin biopsy is necessary to differentiate folliculitis from other skin conditions. Histopathologic examination of bacterial folliculitis shows neutrophils infiltrating a hair follicle (picture 3) [9].

Differential diagnosis — The differential diagnosis of infectious folliculitis includes the various forms of infectious folliculitis (eg, bacterial, fungal, viral, Demodex) and other papular, pustular, or follicular eruptions. Common eruptions on the face or scalp that may be confused with infectious folliculitis include: ●Acne vulgaris – The characteristic clinical features of acne vulgaris are open and closed comedones and inflammatory papules and pustules on the face, chest, shoulders, or back (picture 4). The presence of comedones and a lack of pruritus are more consistent with acne vulgaris than folliculitis. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris".) ●Papulopustular rosacea – Papulopustular rosacea primarily affects adults and presents with pustules and erythematous papules on the central face (picture 5). Exacerbating factors such as alcohol, spicy foods, sun exposure, and temperature changes are common. (See "Rosacea: Pathogenesis, clinical features, and diagnosis".) ●Perioral (periorificial) dermatitis – Perioral dermatitis presents with small erythematous papules around the mouth, nose, or periorbital areas (picture 6). There may be associated mild scale. Perioral dermatitis is most common in young women. (See "Perioral (periorificial) dermatitis".) ●Acne keloidalis nuchae – Acne keloidalis nuchae is a chronic, scarring folliculitis that primarily affects males of African descent. Papules, pustules, and keloid-like papules and plaques develop on the posterior scalp (picture 7). (See "Acne keloidalis nuchae".) ●Pseudofolliculitis barbae – Pseudofolliculitis barbae is an inflammatory reaction to hair penetrating interfollicular skin. Patients develop inflamed papules and pustules following hair removal in the beard area of the face or neck (picture 8). Pseudofolliculitis barbae is most common

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in patients of African descent. (See "Pseudofolliculitis barbae".) Common eruptions in the differential diagnosis that most frequently affect the trunk or extremities include: ●Drug-induced folliculitis – A monomorphic papulopustular eruption on the trunk and arms known as "steroid folliculitis" or "steroid acne" may occur after administration of systemic glucocorticoids (picture 9A-B) [11]. Other drugs that may cause folliculitis-like eruptions include phenytoin, lithium, isoniazid, cyclosporine, halogens, and epidermal growth factor receptor inhibitors (picture 10). (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors" and "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Acneiform eruptions'.) ●Keratosis pilaris – Keratosis pilaris is a common disorder of follicular keratinization that presents with asymptomatic, keratotic follicular papules on the upper arms, face, thighs, and buttocks (picture 11). Keratosis pilaris is most commonly seen in children and young adults. (See "Keratosis pilaris".) ●Hidradenitis suppurativa – Hidradenitis suppurativa is a chronic inflammatory skin disorder characterized by the development of inflamed nodules, abscesses, and sinus tracts (picture 12). Involvement occurs primarily in the axillary, mammary, and inguinal areas. (See "Hidradenitis suppurativa: Pathogenesis, clinical features, and diagnosis".) ●Scabies – Sarcoptes scabiei infestation often presents with intensely pruritic pustules and papules in the axillae, inguinal areas, interdigital web spaces, waistline, and volar wrists (picture 13). (See "Scabies: Epidemiology, clinical features, and diagnosis".) ●Grover's disease (transient acantholytic dermatosis) – Grover's disease most commonly presents as erythematous papules on the chest and back in men in their fifth decade or older (picture 14). Histopathology demonstrates focal acantholytic dyskeratosis that is not centered upon hair follicles. (See "Grover's disease (transient and persistent acantholytic dermatosis)".) Other disorders in the differential diagnosis include irritant folliculitis, actinic folliculitis, and perforating folliculitis.

Treatment — The etiology of folliculitis influences the approach to treatment. Because S. aureus folliculitis is the most common form of bacterial folliculitis, patients are often empirically treated for this infection provided the history and physical examination do not suggest another type of folliculitis. An evaluation to confirm the diagnosis is prudent when patients fail to respond to treatment. (See 'Diagnosis' above.)

Staphylococcal folliculitis — Treatment of staphylococcal folliculitis is not always necessary; mild folliculitis with few pustules often resolves spontaneously. Patients with numerous papules or pustules or with involvement of more than one body area are good candidates

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for medical treatment. Folliculitis that does not resolve spontaneously after several weeks also should be treated. ●Medical therapy – Topical antibiotic therapy is sufficient for many cases of bacterial folliculitis [12]. Our preferred first-line agents are topical mupirocin and topical clindamycin [12]. Topical fusidic acid is an additional first-line treatment option; however, increasing resistance of S. aureus to fusidic acid has been observed in areas where fusidic acid use is common, and the drug is not available in the United States [13]. Topical erythromycin may also be effective; however, topical erythromycin has fallen out of favor as a first-line treatment in many locations due to increasing prevalence of erythromycin-resistance and community-acquired MRSA infections [1]. Patients with extensive skin involvement, patients with staphylococcal folliculitis that is recurrent or refractory after topical therapy, and patients with folliculitis barbae are usually treated with oral antibiotics. A 7- to 10-day course is usually sufficient. Due to the high frequency of resistance to penicillin, other beta-lactam antibiotics such as dicloxacillin (250 to 500 mg four times per day) or cephalexin (250 to 500 mg four times per day) are first-line systemic treatments [9,14]. (See "Penicillin, antistaphylococcal penicillins, and broad-spectrum penicillins".) However, if MRSA is cultured or suspected, the patient should be treated with a 7- to 10-day course of oral trimethoprim/sulfamethoxazole (1 to 2 DS tablets twice daily), clindamycin (300 to 450 mg four times per day), or doxycycline (100 mg twice daily). Occasionally, treatment for more than two weeks is required for resolution of MRSA folliculitis [1]. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections".) Another treatment that may be effective for staphylococcal folliculitis is topical retapamulin ointment, an agent used for the treatment of impetigo [15]. In our experience, staphylococcal folliculitis, particularly of the scalp or trunk, is sometimes persistent or recurrent despite treatment. There are insufficient data for definitive conclusions on the best approach to refractory staphylococcal folliculitis. In clinical practice, these patients are often given extended courses of oral antibiotics (eg, up to three months). Measures to prevent recurrences may also be implemented. ●Prevention – The best approach to the prevention of recurrence has not been established. Avoidance of predisposing factors for folliculitis (eg, occlusive clothing, hyperhidrosis) may be beneficial. A decolonization regimen, such as a five-day course of topical mupirocin ointment in the nares and daily chlorhexidine body washes plus daily decontamination of personal items (eg, towels, clothing) has been suggested for patients with recurrent abscesses in an attempt to reduce recurrences [16]. However, more data are indicated to confirm efficacy of such measures for recurrent staphylococcal folliculitis. Benzoyl peroxide washes and bleach baths have also been used in attempts to reduce recurrences of staphylococcal folliculitis.

Gram-negative folliculitis — Gram-negative folliculitis due to Pseudomonas is often self-limiting and resolves within 7 to 10 days with just good skin hygiene. Avoidance of contaminated water and proper chlorination of pools and hot tubs is preventative. Oral ciprofloxacin

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(250 to 750 mg twice daily) can be used for severe cases or immunocompromised patients [8]. Selection of an antibiotic for gram-negative folliculitis due to long-term systemic antibiotic therapy should be guided by testing to determine antibiotic sensitivity of the causative organism. Ampicillin (250 to 500 mg four times daily), trimethoprim/sulfamethoxazole (1 DS tablet twice daily), or ciprofloxacin (250 to 750 mg twice daily) are common first-line treatments. Treatment with these agents is for an additional 14 days after clinical resolution [9]. Oral isotretinoin (0.5 to 1 mg/kg daily for four to five months) is the treatment of choice for recalcitrant disease [17].

FUNGAL FOLLICULITIS

After S. aureus, fungi are the most

commonly detected microorganisms in folliculitis. The recognition of fungal folliculitis is important because treatment differs from that of bacterial folliculitis [18].

Etiology and risk factors — Malassezia species, dermatophytes, and Candida albicans can cause fungal folliculitis. ●Malassezia (Pityrosporum) folliculitis – Multiple species of Malassezia, lipophilic yeasts present in the normal cutaneous flora, cause folliculitis. The most common species are M. globosa, M. sympodialis, M. furfur, and M. restricta [19]. These fungi were previously classified under the genus Pityrosporum (P. orbiculare, P. ovale, and P. pachydermatis), contributing to the alternative name "Pityrosporum folliculitis" [20]. Malassezia folliculitis is more common in males than in females. It is also most likely to occur in adolescents and among individuals in hot, humid climates. In a review of 44 patients with Malassezia folliculitis in Japan, 75 percent reported onset during the summer months [21]. High sebum production in adolescents and increased sweating are both predisposing factors for Malassezia folliculitis [19]. Other predisposing factors include topical or oral antibiotic use, topical or oral corticosteroid treatment, and immunosuppression [21-25]. ●Dermatophyte folliculitis – Trichophyton, Epidermophyton, and Microsporum species are the usual causes of dermatophyte folliculitis. Tinea capitis (dermatophyte infection of the scalp) and tinea barbae (dermatophyte infection of the beard or mustache areas) are classic forms of dermatophyte infection involving hair follicles. Dermatophyte folliculitis can also occur as a secondary feature of tinea corporis, tinea cruris, and tinea pedis. (See "Dermatophyte (tinea) infections".) Majocchi's granuloma is a clinical subtype of dermatophyte folliculitis occurring on sites other than the scalp and beard. Majocchi's granuloma is characterized by deep follicular and dermal involvement and is commonly caused by T. rubrum [8]. Predisposing factors include shaving of the legs, topical corticosteroid use, and immunocompromised status [26]. (See "Dermatophyte (tinea) infections", section on 'Majocchi's granuloma'.)

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●Candida folliculitis – CutaneousC. albicans infection may cause fungal folliculitis. Candida folliculitis has occurred in association with candidemia in intravenous drug users but may also occur in healthy individuals [8].

Clinical manifestations — Malassezia folliculitis presents with pruritic, monomorphic, follicular papules or pustules on the chest, back, and/or shoulders (picture 15A-B). Less frequent sites of involvement include the face, neck, and extensor side of the arms. In patients with facial involvement, the central face is usually spared with involvement of the forehead, chin, and sides of the face [19]. Dermatophyte folliculitis often manifests as follicular pustules surrounded by an erythematous plaque (picture 16A-D). Associated features vary depending on the location of the infection. The most common presentation of Majocchi's granuloma is a unilateral eruption on the lower extremity (picture 16C-D). The upper extremities, specifically the forearm and dorsal hand, are additional common locations. Hair loss is common and the inflammation can be suppurative and granulomatous, depending on the depth of infection [8]. (See "Dermatophyte (tinea) infections", section on 'Majocchi's granuloma'.) Candida folliculitis has been described as a widely distributed pustular folliculitis [8]. Less common sites of involvement are the face (beard or mustache area) and scalp [27]. In rare cases, Candida folliculitis mimics tinea barbae, manifesting as a fluctuant plaque on the face with follicular pustules and papules [28].

Diagnosis — To confirm fungal folliculitis, a potassium hydroxide (KOH) examination can be performed on skin scrapings from an involved area. Hyphae suggest a dermatophyte folliculitis (picture 17) [26], whereas yeast cells and pseudohyphae suggest Candida infection (picture 18) [28]. Budding spores and short, curved hyphae are suggestive of Malassezia species. (See "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.) Although a standard KOH preparation is usually sufficient, a commercial or compounded KOH solution mixed with ink can facilitate visualization of hyphae and spores. In addition, a study that included 49 patients with Malassezia folliculitis found that staining skin scrapings with a MayGrünwald-Giemsa stain was more effective than a KOH preparation in detecting Malassezia [19]. Fungal cultures can identify dermatophyte or candidal infections; however, the results are not available immediately. Cultures for Malassezia are not routinely performed because Malassezia is difficult to culture without specialized media. A skin biopsy usually is not necessary to diagnose fungal folliculitis. If performed, a biopsy may reveal yeast or hyphae in hair follicles (picture 19A-B). A periodic acid-Schiff (PAS) stain may be performed to highlight fungal elements [29]. Malassezia can be seen in normal hair follicles; therefore, clinical correlation is important.

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Differential diagnosis — The differential diagnosis for fungal folliculitis is similar to the differential diagnosis of bacterial folliculitis. (See 'Differential diagnosis' above.)

Treatment — The approach to the treatment of fungal folliculitis depends on the etiology. Oral antifungal agents such as fluconazole and itraconazole are common treatments. Oral ketoconazole should not be used for the treatment of any form of fungal folliculitis due to risks of liver injury, adrenal gland disorders, and significant drug interactions [30]. ●Malassezia folliculitis –Both systemic and topical antifungal therapies have been used for Malassezia folliculitis. Systemic therapy is often considered more effective than topical treatment based upon the concept that systemic therapy may eliminate Malassezia deep within hair follicles [30]. However, randomized trials comparing systemic and topical therapy are lacking. Benefit from itraconazole (200 mg taken orally daily for one week) was demonstrated in a randomized trial that compared itraconazole (200 mg per day for seven days) to placebo in 26 patients with Malassezia folliculitis. After five weeks, 9 of 13 patients in the itraconazole group had no visual evidence of disease and 11 of 13 had a negative KOH preparation, whereas none of 12 patients in the placebo group had complete clearance of disease and only 1 of 12 had negative KOH preparation [31]. Despite the greater evidence for efficacy of itraconazole, we most often treat with oral fluconazole based upon the drug's more favorable side effect profile and lower risk for drug interactions. Fluconazole can be given as 100 to 200 mg daily for one to four weeks or 300 mg once weekly for one to two months [30]. Data on the efficacy of topical agents as primary treatments are limited. A retrospective study in which 44 patients with Malassezia folliculitis were treated with either twice-daily application of ketoconazole 2% cream (37 patients) or 100 mg per day of oral itraconazole (7 patients), both given until papules flattened, found that all patients in both groups reached this endpoint (mean response time of 27±16 days versus 14±4 days, respectively). In addition, a small uncontrolled study documented benefit of selenium sulfide shampoo (applied for 30 minutes for three consecutive days, then once weekly), propylene glycol 50% in water (applied twice daily for three weeks, then twice weekly), or econazole cream (applied nightly for three weeks, then twice weekly) in the majority of treated patients [32]. However, poor results with econazole solution (applied twice daily for one month) and miconazole cream (applied twice daily for one month) were documented in another uncontrolled study [33]. Recurrence is common after treatment. Long-term periodic (eg, once- or twice-weekly) use of topical treatments, often selenium sulfide, ketoconazole, or ciclopirox shampoos, is often performed in an attempt to prevent recurrence of disease [33]. Although not typically indicated, successful treatment of Malassezia folliculitis with isotretinoin and photodynamic therapy have been reported [30,34,35]. Oral terbinafine is not effective for treating Malassezia.

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●Dermatophyte folliculitis –Dermatophyte folliculitis must be treated with systemic therapy. Topical antifungals can be used to decrease the spread of the disease, but are usually ineffective because they cannot penetrate into the deep hair follicle. Oral terbinafine is commonly used for treatment of tinea barbae and Majocchi's granuloma. Case reports and case series describe resolution of disease with doses ranging from 250 to 500 mg of terbinafine per day for four to six weeks or longer [26,36-39]. We typically treat adults with oral terbinafine (250 mg per day) for two to six weeks, with the precise duration of treatment determined based upon clinical response. Treatment is continued until complete clinical resolution. Oral griseofulvin, itraconazole, and fluconazole are also considered effective for dermatophyte folliculitis and are alternatives to terbinafine [8,26,40,41]. A case series of seven successfully treated patients with Majocchi's granuloma suggests efficacy of pulse therapy with itraconazole (200 mg twice daily for one week per month for two months) [40]. ●Candida folliculitis– Candida folliculitis can be treated with systemic itraconazole or fluconazole. Oral terbinafine is not effective [8,28].

VIRAL FOLLICULITIS

Viral folliculitis is most commonly

associated with herpesvirus infections. Molluscum contagiosum virus also can cause folliculitis.

Etiology and risk factors — Herpes folliculitis is a rare manifestation of herpesvirus infections. It is most commonly associated with varicella zoster virus (VZV) infection, but also can be attributed to herpes simplex virus (HSV)-1 or HSV-2. HSV is less likely than VZV to target the hair follicle [42]. Molluscum contagiosum virus (MCV) is a poxvirus that preferentially affects children and immunocompromised adults, but also occurs in healthy adults. MCV is a rare cause of viral folliculitis [43-45]. (See "Molluscum contagiosum".)

Clinical manifestations — Erythematous papules, pustules, vesicles, papulovesicles, and plaques are the most common presentations of herpes folliculitis [42,46]. These lesions are often grouped or clustered [46]. HSV folliculitis in the beard area (herpetic sycosis) is reported most commonly in immunocompromised patients, but may also occur in the absence of immunosuppression [47,48]. Papules and pustules along with characteristic umbilicated papules are typical findings in molluscum folliculitis. Presentations resembling tinea barbae and pseudolymphoma have been reported [43,47,48].

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Diagnosis — Folliculitis in a grouped or clustered distribution suggests the possibility of herpes folliculitis. Viral culture, polymerase chain reaction (PCR), or immunofluorescence testing should be performed to confirm the diagnosis if herpes folliculitis is suspected [46]. A skin biopsy is not usually necessary, but can be performed if the diagnosis is uncertain. Histopathologic examination of viral folliculitis may reveal intranuclear viral inclusions with multinucleated giant cells in and around the follicular epithelium. When present in conjunction with folliculitis, the umbilicated papules of molluscum contagiosum suggest MCV as the cause of folliculitis. In cases where the diagnosis is unclear, a skin biopsy will reveal characteristic molluscum bodies (Henderson-Patterson bodies) in the follicular epithelium [43]. (See "Molluscum contagiosum", section on 'Diagnosis'.)

Differential diagnosis — The differential diagnosis for viral folliculitis resembles the differential diagnosis for bacterial folliculitis. (See 'Differential diagnosis' above.)

Treatment — Herpes folliculitis can be treated with 5 to 10 days of oral acyclovir (200 mg five times per day), valacyclovir (500 mg three times per day), or famciclovir (500 mg three times per day). Molluscum folliculitis can be treated similarly to classic molluscum contagiosum infection. Common treatment options for molluscum contagiosum include curettage, cantharidin, and cryotherapy. Podophyllotoxin and trichloroacetic acid are additional treatments [8]. (See "Molluscum contagiosum", section on 'Overview of management'.)

DEMODEX FOLLICULITIS

Demodex folliculorum is a mite

belonging to the class of arachnids and a proposed cause of facial folliculitis. Demodex mites are also proposed to contribute to the pathogenesis of papulopustular rosacea and chronic blepharitis [11,49].

Etiology and risk factors — The role of D. folliculorum in folliculitis is controversial because the mite is a common inhabitant of the pilosebaceous unit in normal skin. Up to 80 to 90 percent of humans may harbor the Demodex organism[50]. Support for a pathogenic role in folliculitis and rosacea stems from improvement in these disorders with anti-Demodex therapies [8]. In addition, increased density of mites in the skin has been detected in patients with rosacea [51]. Demodex folliculitis is most frequently diagnosed in adults. However, Demodex folliculitis also has been implicated in facial pustules and papules in children [52]. Immunosuppression may increase risk for cutaneous manifestations of Demodex infection [53].

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Clinical manifestations — Demodex folliculitis is usually characterized by rosacea-like inflammatory papules and pustules on the face [50]. In addition, authors have described nodulocystic and conglobate (abscess-like) presentations [54].

Diagnosis — Demodex folliculitis is often first suspected when patients with a rosacealike papulopustular eruption fail to respond to antibiotic therapy for rosacea. A potassium hydroxide (KOH) preparation of a skin scraping from an involved area is typically used to detect Demodex mites. Clinical correlation is necessary for the interpretation of the KOH preparation because Demodex mites can be detected in normal skin and a definitive threshold for diagnosis has not been established. In general, the KOH preparation may be considered positive when more than a few mites are detected [50]. Although not typically performed in clinical practice, more than five mites per cm2 detected on an adhesive skin-surface biopsy utilizing a cyanoacrylic adhesive has been proposed as a threshold for use in clinical studies [55]. Demodex mites may also be detected on skin biopsy. As with a KOH preparation, visualization of Demodex is not sufficient to confirm the diagnosis in the absence of clinical correlation because Demodex mites can be present in follicles in normal skin.

Differential diagnosis — The differential diagnosis for Demodex folliculitis is similar to the differential diagnosis of facial bacterial folliculitis. (See 'Differential diagnosis' above.)

Treatment — Data on treatment options for Demodex folliculitis are limited. Topical permethrin 5% cream, topical sulfur, oral ivermectin, and oral metronidazole are reasonable treatments [51]. The findings of one randomized trial suggest that combination therapy with oral ivermectin and oral metronidazole is more effective for reducing mite counts than oral ivermectin monotherapy [49]; however, further study is necessary to confirm whether combination therapy is indicated for Demodex folliculitis. The efficacy of topical ivermectin remains to be determined. We typically treat with permethrin 5% cream or oral ivermectin. Topical permethrin can be applied to the entire face before bed and washed off after 8 to 14 hours. Oral ivermectin can be given as two 200 mcg/kg doses separated by one week.

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Skin and soft tissue infections".)

INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer

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the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topics (see "Patient education: Bacterial folliculitis (The Basics)")

SUMMARY AND RECOMMENDATIONS ●Folliculitis is inflammation of the superficial or deep portion of the hair follicle. Folliculitis may be infectious or noninfectious. Infectious folliculitis can be caused by bacteria, fungi, viruses, or parasites. The most common pathogen in infectious folliculitis is Staphylococcus aureus. Other common pathogens are Pseudomonas aeruginosa, Malassezia species, and Demodex mites. (See 'Introduction' above.) ●Follicular pustules and follicular erythematous papules are the most common clinical findings of folliculitis. (See 'Bacterial folliculitis' above and 'Fungal folliculitis' above and 'Viral folliculitis' above and 'Demodex folliculitis' above.) ●A diagnosis of folliculitis often can be made based upon the patient history and clinical findings. Further testing is necessary when the etiology is unclear. A Gram stain, bacterial culture, potassium hydroxide (KOH) preparation, viral culture, polymerase chain reaction assay, or immunofluorescence testing can aid in diagnosis. Skin biopsies are not usually necessary, but may be helpful in difficult cases. (See 'Bacterial folliculitis' above and 'Fungal folliculitis' above and 'Viral folliculitis' above and 'Demodex folliculitis' above.) ●The management of folliculitis varies based upon the etiology. Mild S. aureus folliculitis may resolve without medical treatment. For patients with known or suspected S. aureus folliculitis that persists and involves a limited area of skin, we suggest topical antibiotic therapy rather than oral antibiotic therapy as initial treatment (Grade 2C). Topical mupirocin and topical clindamycin are our preferred initial treatments. (See 'Staphylococcal folliculitis' above.) ●For patients with more extensive S. aureus folliculitis or S. aureus folliculitis that fails to resolve or recurs after topical treatment, we suggest systemic antibiotic therapy rather than topical antibiotic therapy (Grade 2C). Appropriate initial treatment options include dicloxacillin and cephalexin. If

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methicillin-resistant S. aureus is suspected, patients should be treated with trimethoprim/sulfamethoxazole, clindamycin, or doxycycline. (See 'Staphylococcal folliculitis' above.) ●Oral antifungal therapy is the mainstay of therapy for fungal folliculitis. Antiparasitic agents, such as permethrin and oral ivermectin, can be effective for Demodex folliculitis. (See 'Fungal folliculitis' above and 'Demodex folliculitis' above.)

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Soft tissue infections following water exposure uptodate.com/contents/soft-tissue-infections-following-water-exposure/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jul 12, 2019.

INTRODUCTION

Soft tissue infection can occur in patients with

traumatic injury associated with water exposure. A broad array of microorganisms can cause soft tissue infections following water exposure [1,2]. The epidemiology, microbiology, clinical manifestations, diagnosis, and treatment of soft tissue infections following water exposure are reviewed here. Issues related to jellyfish stings and marine envenomations are discussed separately. (See "Jellyfish stings" and "Marine envenomations from corals, sea urchins, fish, or stingrays".)

EPIDEMIOLOGY

The risk of soft tissue infection due to traumatic injury

with water exposure may be considered in the following hierarchy (from highest to lowest risk) (table 1) [1-3]: ●Fresh water (ponds, small lakes) ●Flowing fresh water (rivers, large lakes) ●Brackish water (water that is saltier than fresh water but less salty than sea water, found where bodies of sea water and fresh water meet) ●Sea water

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●Well-regulated treated swimming pools, hot tubs In addition to water, other relevant exposures may include mud, sand, debris, or sewage. Injuries associated with water exposure include lacerations (due to inanimate objects in water), puncture wounds due to fish hooks or fish spines, and bites from aquatic animals [4-7]. In addition, water exposure in patients with pre-existing wounds can result in infection. Individuals at risk for soft tissue infection following water exposure include recreational swimmers, fisherman, boaters, fishmongers, flooding victims and rescue workers, and those undergoing leech therapy. In addition, patients with underlying liver disease and immunosuppression are at increased risk for soft tissue infection associated with water exposure, as well as systemic infection [8-13].

MICROBIOLOGY

Organisms that can cause soft tissue infections

following water exposure include (table 1) [1,2,14-16]: ●Aeromonas spp (see "Aeromonas infections") ●Burkholderia pseudomallei (see "Melioidosis: Epidemiology, clinical manifestations, and diagnosis") ●Chromobacterium violaceum ●Edwardsiella tarda ●Erysipelothrix rhusiopathiae (see "Erysipelothrix infection") ●Mycobacterium fortuitum (see "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum") ●Mycobacterium marinum ●Plesiomonas spp (see "Plesiomonas shigelloides infections") ●Pseudomonas aeruginosa (see "Pseudomonas aeruginosa skin and soft tissue infections") ●Shewanella spp ●Streptococcus iniae ●Vibrio spp (see "Vibrio vulnificus infections" and "Vibrio parahaemolyticus infections" and "Minor Vibrio and Vibrio-like species associated with human disease") In addition, soft tissue infection following water exposure can be caused by organisms unrelated to water exposure (such as beta-hemolytic streptococci and Staphylococcus aureus). Polymicrobial infection may occur [17,18]. (See "Cellulitis and skin abscess: Clinical manifestations and diagnosis" and "Necrotizing soft tissue infections".)

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The microbiology depends on the type of water exposure as well as individual patient factors (table 1).

CLINICAL EVALUATION History and physical examination — In patients presenting for initial evaluation and management of a wound associated with water exposure, a thorough exposure history should be obtained, including occupational and home exposures, hobbies, and recent travel history. Soft tissue infection following water exposure may be superficial (eg, cellulitis, with or without abscess) or deep (abscess, septic arthritis, osteomyelitis, tenosynovitis, or necrotizing soft tissue infection) [11]: ●Clinical manifestations of cellulitis include fever, tenderness, erythema, swelling, and warmth; purulent drainage and/or lymphangitis may be present. An associated superficial abscess may present as a tender, erythematous, fluctuant nodule. ●In addition to the above manifestations, clues for deep infection include persistent or progressive pain several days following the initial injury, pain with passive movement, pain out of proportion to exam findings, crepitus, joint swelling, systemic illness (fever, hemodynamic instability), and persistent signs of infection despite initial wound care and antibiotic administration. The level of suspicion for deep infection should be increased for patients with immunosuppression (including diabetes) or neuropathy; these patients often present later in their course with increased risk of serious infection and limited pain on clinical exam. The clinical manifestations, microbiology, epidemiology, and incubation period for various infections following water exposure are summarized in the table (table 1). The range of clinical manifestations of skin and soft tissue infections following water exposure is illustrated by the following examples: ●Vibrio vulnificus is associated with rapidly progressive soft tissue infection (incubation period three to seven days). Relevant epidemiologic exposures include raw oyster ingestion and/or exposure of puncture wounds to salt water, especially in males with chronic liver disease. Clinical manifestations may include cellulitis, hemorrhagic bullae, ulcers, necrotizing infection with compartment syndrome, ecthyma gangrenosum, and septicemia (picture 1). (See "Vibrio vulnificus infections" and "Necrotizing soft tissue infections".) ●M. marinum is associated with indolent infection (mean incubation period 21 days). Relevant epidemiologic exposures include cleaning salt water aquariums and crustacean puncture during seafood preparation. Lesions usually appear as papules or nodules on an extremity (especially on the elbows, knees, and dorsum of feet and hands); subsequently, they progress to shallow ulceration

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and scar formation (picture 2). Most lesions are solitary; occasionally "ascending" lesions develop with "sporotrichoid spread" (ie, resembling sporotrichosis; also called nodular lymphangitis). In one series including 31 patients with M. marinum infection, the upper extremity was affected in 90 percent of cases; nodular lymphangitis occurred in 81 percent of cases [19]. (See "Clinical features and diagnosis of sporotrichosis", section on 'Lymphocutaneous sporotrichosis' and "Lymphangitis", section on 'Nodular lymphangitis'.) Issues related to clinical manifestations of necrotizing soft tissue infection (erythema, edema, warmth, and signs of systemic illness [fever, hemodynamic instability] in association with crepitus, rapid progression of clinical manifestations, and/or severe pain [out of proportion to skin findings in some cases]) are discussed separately. (See "Necrotizing soft tissue infections".) The likelihood of wound infection should be determined based upon physical findings.

Laboratory testing — For patients with clinically uninfected wounds, routine laboratory studies are not indicated. Similarly, wound cultures are not indicated; such results do not correlate with subsequent infection. For patients with clinically infected wounds, laboratory studies (complete blood count and serum inflammatory markers such as erythrocyte sedimentation rate, C-reactive protein) are reasonable. In addition, wound cultures (aerobic and anaerobic) should be obtained from infected wounds to establish the microbiology of the infection and to guide antibiotic therapy. For immunosuppressed patients, consideration of M. marinum is warranted and the microbiology laboratory should be notified so that acid-fast staining and mycobacterial culture can be performed; growth of M. marinum is generally restricted to lower temperatures. Other diagnostic tools that may be useful to establish a diagnosis of M. marinum infection include histopathology, immunohistochemistry (IC), and polymerase chain reaction (PCR) from full-thickness skin biopsy; IC and PCR may not be readily available in most clinical laboratories [20]. Blood cultures should be obtained in the setting of fever or hemodynamic instability, as well as in patients at increased risk for systemic infection (including underlying hepatic disease, cancer, or immunosuppression).

Imaging — Imaging is not necessary for most clinically uninfected, superficial wounds. Deep wounds, including those near joints warrant diagnostic imaging (plain radiography) to exclude retained foreign body [2].

MANAGEMENT

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Uninfected wound — Management of a wound following water exposure includes wound care and evaluation regarding need for antibiotic prophylaxis and/or tetanus prophylaxis.

Wound management — Wounds associated with water exposure should be irrigated copiously with sterile saline. Crushed or devitalized tissues should be debrided and foreign bodies should be removed if present.

Closure — The optimal approach to closure of uninfected wounds associated with water exposure is uncertain and depends in part on the nature of the exposure. (See 'Epidemiology' above.) Indications for surgical consultation are summarized below. (See 'Surgical consultation' below.) In general, closure of wounds associated with exposure to a treated swimming pool or hot tub is reasonable. In addition, closure of large wounds or wounds in cosmetically important areas associated with exposure to sea water, brackish water, or relatively clean fresh water (such as rivers or large lakes) may be reasonable. For patients with wounds in cosmetically important areas associated with exposure to ponds or small lakes who do not undergo surgical debridement, it may be reasonable to administer prophylactic antibiotics followed by return for delayed primary closure after two to three days if no signs of infection are present. Follow-up of patients with closed traumatic wounds is important, particularly in the first several days following closure. Such follow-up may be done via outpatient visits and/or via serial photographs sent by patients (depending upon the severity of the injury and available resources).

Surgical consultation — Surgical consultation is warranted in the following circumstances: ●Substantial wounds associated with exposure to a pond or small lake ●Complex facial lacerations ●Deep wounds that penetrate bone, tendons, joints, or other major structures ●Wounds associated with neurovascular compromise

Antibiotic prophylaxis — The optimal approach to prophylactic antibiotic therapy for patients with an open wound associated with water exposure (in the absence of established infection) is uncertain; there are no clinical trial data evaluating whether prophylactic therapy is beneficial [21]. In general, prophylactic antibiotic therapy is reasonable in the following circumstances:

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●Deep puncture wound or laceration (beyond the dermis) ●Wounds requiring surgical repair ●Wounds undergoing primary closure associated with any water exposure apart from well-regulated treated swimming pools or hot tubs (see 'Epidemiology' above) ●Wound with associated crush injury ●Wound in area of underlying vascular or lymphatic compromise ●Wound on the hands, feet, face, or genital area ●Wound in close proximity to a bone or joint (particularly a prosthetic joint) ●Wounds in immunocompromised patients or those with diabetes or chronic liver disease The choice of prophylactic antibiotic therapy should be based on the epidemiology of the exposure and patient factors. (See 'Empiric therapy' below.) The duration of prophylactic oral antibiotics is three to five days, with close follow-up. Signs of infection on follow-up examination should prompt further evaluation (with radiographic imaging and/or surgical consultation, if needed), an extension of the antibiotic course, and/or a switch to intravenous therapy.

Infected wound — Management of patients with soft tissue infection following water exposure includes wound debridement (with collection of microbiology specimens) and administration of empiric antibiotic therapy. In addition, patients should be evaluated regarding need for tetanus prophylaxis. (See 'Preventing tetanus' below.) Management of patients with suspected necrotizing soft tissue infection is discussed separately. (See "Necrotizing soft tissue infections" and "Surgical management of necrotizing soft tissue infections".)

Wound management — Wounds associated with water exposure should be irrigated copiously with sterile saline. Crushed or devitalized tissues should be debrided and foreign bodies should be removed if present. Specimens (eg, lesion aspirate or biopsy) should be sent for Gram stain and culture (aerobic and anaerobic) as well as acid-fast stain and mycobacterial culture. Acute infected wounds associated with water exposure should be left open with approximation of wound edges to facilitate closure by secondary intention following initial debridement. Delayed primary closure may be reasonable for facial wounds, large lacerations, and disfiguring wounds; factors to consider in this decision are discussed separately. (See "Basic principles of wound management" and "Assessment and management of facial lacerations".)

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Antibiotic therapy Route of therapy — Inpatient administration of intravenous (IV) antibiotics is warranted for patients with systemic symptoms (eg, fever, chills, rigors) and/or leukocytosis. Similarly, IV antibiotic therapy is warranted for patients with underlying hepatic disease, cancer, or immunosuppression; these groups are at increased risk for complications including bacteremia, sepsis and, death. The route of antibiotic administration may be switched from parenteral to oral once fever and soft tissue findings have begun to resolve (often three to five days). In the absence of the above factors, outpatient administration of oral antibiotic therapy is reasonable, with close follow-up within 24 to 48 hours.

Empiric therapy — Empiric antibiotic regimens are based on the most likely organisms to cause infection, in vitro susceptibility studies, and treatment case series [1-3]. For patients with soft tissue infection following water exposure, we use the following antibiotics for initial empiric therapy: ●A first-generation cephalosporin (cephalexin 500 mg orally four times daily or cefazolin 1 g IV every eight hours) OR ●Clindamycin (300 mg orally four times daily or 600 mg IV every eight hours) for patients with immediate hypersensitivity reactions to cephalosporins PLUS ●A fluoroquinolone such as levofloxacin (750 mg once daily) PLUS (if epidemiologic risk is present) ●Seawater exposure: doxycycline (100 mg twice daily) for coverage of Vibrio species ●Soil-contaminated wound or exposure to sewage-contaminated water: metronidazole (500 mg four times daily) for anaerobic coverage; not necessary if the regimen includes clindamycin (see dosing above) Issues related to empiric treatment of patients with suspected necrotizing soft tissue infection are discussed separately. (See "Necrotizing soft tissue infections".) Empiric antibiotic therapy need not include coverage for mycobacterial infection unless acid-fast staining is positive. In such cases, directed therapy should be administered as described below. (See 'Mycobacterial infection' below.)

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Directed therapy Bacterial infection — Empiric antibiotic therapy should be tailored to microbiology data when available. General information regarding antimicrobial susceptibility for organisms associated with water exposure is presented in the table (table 1). Treatment of infection due to Aeromonas spp, B. pseudomallei, E. rhusiopathiae, Plesiomonas spp, P. aeruginosa, S. aureus, Streptococcus pyogenes, and Vibrio spp is discussed in detail separately. (See "Aeromonas infections" and "Melioidosis: Treatment and prevention" and "Erysipelothrix infection" and "Plesiomonas shigelloides infections" and "Pseudomonas aeruginosa skin and soft tissue infections" and "Cellulitis and skin abscess in adults: Treatment" and "Vibrio vulnificus infections" and "Vibrio parahaemolyticus infections" and "Minor Vibrio and Vibrio-like species associated with human disease".) Issues related to treatment of patients with suspected necrotizing soft tissue infection are discussed separately. (See "Necrotizing soft tissue infections".) For most soft tissue infections due to bacteria associated with water exposure, a reasonable duration of therapy is 10 to 14 days. If local signs of infection persist after two weeks of treatment, we continue antibiotic therapy until signs of infection resolve.

Mycobacterial infection — Patients with infection due to nontuberculous mycobacteria (M. fortuitum or M. marinum) generally warrant months of therapy. Issues related to treatment of M. fortuitum infection are discussed separately. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".) Treatment of M. marinum infection is based on in vitro susceptibility testing and case reports; the optimal approach is uncertain [22,23]. M. marinum isolates are usually susceptible to rifampin, ethambutol, clarithromycin, sulfonamides, and trimethoprim-sulfamethoxazole; susceptible or intermediately susceptible to doxycycline and minocycline; intermediately susceptible to streptomycin; and resistant to isoniazid and pyrazinamide. For treatment of superficial papules due to M. marinum, monotherapy with one of the following regimens is reasonable: clarithromycin (500 mg orally twice daily), minocycline (100 mg orally twice daily), doxycycline (100 mg orally twice daily), or trimethoprim-sulfamethoxazole (one doublestrength tablet orally twice daily) [19,24-26]. For treatment of deeper or more extensive infection due to M. marinum, we favor treatment with two active agents. A reasonable regimen consists of clarithromycin (500 mg orally twice daily) combined with either ethambutol (15 mg/kg orally once daily) or rifampin (600 mg orally once daily). We continue treatment of M. marinum infection for one to two months following resolution of symptoms (total duration is typically three to four months) [22,27]. The rate of clinical response is variable; at least four to six weeks of therapy should be administered before inadequate response should be suspected.

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For disease involving the closed spaces of the hand or disease that responds poorly to drug therapy, surgical debridement may be warranted [28,29]. In one series including 63 patients with M. marinum infection, the median duration of antibiotics was 14 weeks (range 1 to 25 months) [30]. Cure was achieved in 87 percent of cases; treatment failure was associated with involvement of deeper structures (but not the antibiotic regimen). A combination regimen was administered in 63 percent of cases (most commonly clarithromycin plus rifampin); among patients treated with monotherapy, the most common regimen was minocycline or doxycycline.

PREVENTING TETANUS

The patient's tetanus

immunization status should be reviewed [31]. Tetanus toxoid, diphtheria-tetanus-acellular pertussis, booster tetanus toxoid-reduced diphtheria toxoid-acellular pertussis, or tetanus-diphtheria toxoids adsorbed should be administered as indicated (table 2). The need for tetanus immune globulin should also be assessed (table 2). (See "Tetanus".)

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Skin and soft tissue infections".)

SUMMARY AND RECOMMENDATIONS ●The risk of soft tissue infection associated with water exposure may be considered in the following hierarchy (from highest to lowest risk) (see 'Epidemiology' above): •Fresh water (ponds, small lakes) •Flowing fresh water (rivers, large lakes) •Brackish water (water that is saltier than fresh water but less salty than sea water, found where bodies of sea water and fresh water meet) •Sea water •Well-regulated treated swimming pools, hot tubs In addition to water, other relevant exposures may include mud, sand, or sewage.

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●Injuries associated with water exposure include lacerations (due to inanimate objects in water), puncture wounds due to fish hooks or spines, and bites from aquatic animals. Patients with underlying liver disease and immunosuppression are at increased risk for soft tissue infection associated with water exposure, as well as systemic infection. (See 'Epidemiology' above.) ●A broad array of skin and soft tissue infections may be caused by a number of microorganisms following water exposure; these include cellulitis, abscess formation, and necrotizing soft tissue processes (eg, fasciitis and myositis). In addition, bone and joint infection (such as septic arthritis and/or osteomyelitis) may occur. The microbiology, epidemiology, incubation period, and clinical manifestations for various infections following water exposure are summarized in the table (table 1). (See 'Clinical evaluation' above and 'Microbiology' above.) ●For patients with an injury associated with water exposure in the absence of clinical evidence for infection (on physical examination and/or imaging), components of management include local wound care as well as administration of antibiotic prophylaxis and tetanus prophylaxis, as needed. (See 'Uninfected wound' above.) •Indications for surgical consultation are summarized above. (See 'Surgical consultation' above.) •For patients who do not undergo surgical debridement, the optimal approach to closure of uninfected wounds associated with water exposure is uncertain; management depends in part on the nature of the exposure, as discussed above. (See 'Closure' above.) •We suggest administering prophylactic antibiotic therapy for patients with wounds associated with water exposure in the following circumstances (Grade 2C) (see 'Antibiotic prophylaxis' above): -Deep puncture wound or laceration (beyond the dermis) -Wounds requiring surgical repair -Wounds undergoing primary closure associated with any water exposure apart from well-regulated treated swimming pools or hot tubs (see 'Epidemiology' above) -Wound with associated crush injury -Wound in area of underlying vascular or lymphatic compromise -Wound on the hands, feet, face, or genital area -Wound in close proximity to a bone or joint (particularly a prosthetic joint) -Wounds in immunocompromised patients or those with diabetes or chronic liver disease ●For patients with established soft tissue infection associated with water exposure (on physical examination and/or imaging), components of management include surgical consultation for selected patients as described above, debridement of infected tissue, obtaining wound cultures (and

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blood cultures in patients with signs of systemic infection or immunocompromise), administration of antibiotic therapy, and providing tetanus prophylaxis as indicated. (See 'Infected wound' above.) ●The following antibiotic regimen may be administered prophylactically for prevention of soft tissue infection following water exposure or empirically for treatment of established soft tissue infection (see 'Antibiotic prophylaxis' above and 'Empiric therapy' above): •A first-generation cephalosporin OR •Clindamycin (for patients with immediate hypersensitivity reactions to cephalosporins) PLUS •Levofloxacin PLUS (if epidemiologic risk is present) •Seawater exposure: doxycycline for coverage of Vibrio species •Soil-contaminated wound or exposure to sewage-contaminated water: metronidazole (for anaerobic coverage; not necessary if the regimen includes clindamycin) ●Empiric antibiotic therapy should be tailored to microbiology data when available. General information regarding antimicrobial susceptibility for organisms associated with water exposure is presented in the table (table 1). For most soft tissue infections due to bacteria associated with water exposure, a reasonable duration of therapy is 10 to 14 days. (See 'Bacterial infection' above.) ●Treatment of Mycobacterium marinum infection is based on in vitro susceptibility testing and case reports; the optimal approach is uncertain. For treatment of superficial papules due to M. marinum, we suggest monotherapy (Grade 2C); reasonable regimens include clarithromycin, minocycline, doxycycline, or trimethoprim-sulfamethoxazole. For treatment of deeper or more extensive infection due to M. marinum, we suggest combination therapy with two active agents (Grade 2C); a reasonable regimen consists of clarithromycin combined with ethambutol or rifampin. We continue treatment of M. marinum infection for one to two months following resolution of symptoms (total duration is typically three to four months). For disease involving the closed spaces of the hand or disease that responds poorly to drug therapy, surgical debridement may be warranted. (See 'Mycobacterial infection' above.)

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Skin lesions in the returning traveler uptodate.com/contents/skin-lesions-in-the-returning-traveler/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Mar 01, 2019.

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INTRODUCTION

Skin lesions are a common reason for returned travelers

to seek medical evaluation (table 1). Among more than 17,000 ill returned travelers evaluated at one of the 30 GeoSentinel travel clinics worldwide, dermatologic disorders were the third most common problem (after systemic febrile illness and acute diarrhea) [1]. In another study of GeoSentinel network data including more than 25,000 patients evaluated following travel, a skin-related diagnosis was reported in 18 percent of patients [2]. The causes, manifestations, and diagnosis of skin lesions in the returned traveler will be reviewed here [3].

CAUSES OF SKIN LESIONS IN TRAVELERS

The differential diagnosis for skin lesions that occur during or after

travel is broad and includes infections due to pathogenic organisms (viruses, bacteria, fungi, helminths, protozoa), arthropod bites and infestations, allergic and hypersensitivity reactions [4], injury by chemicals and ultraviolet light, and trauma [5,6]. Among 269 patients in France with travelassociated skin problems, the most common diagnoses were [7]: ●Cutaneous larva migrans – 25 percent ●Pyoderma – 18 percent ●Arthropod-reactive dermatitis – 10 percent ●Myiasis – 9 percent ●Tungiasis – 6 percent ●Urticaria – 5 percent ●Fever and rash – 4 percent ●Cutaneous leishmaniasis – 3 percent Among 4594 returned travelers seen through the GeoSentinel network, the most common dermatologic disorders included cutaneous larva migrans (9.8 percent), insect bites (8.2 percent), skin abscess (7.7 percent), superinfected insect bites (6.8 percent), and allergic rash (5.5 percent). Dengue fever was diagnosed in 3.4 percent and leishmaniasis in 3.3 percent [2]. Many skin lesions associated with exotic travel are caused by the same pathogens that affect patients in non-tropical regions [8,9]. Infected bites, cellulitis, and lymphangitis in travelers returned from tropical travel are common (typically caused by Staphylococcus aureus [often methicillin resistant] [10] and Streptococcus pyogenes). Bacterial skin infections may frequently complicate bites in the tropics where good hygiene is difficult to maintain. Additional skin problems related to travel to

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tropical and developing areas include sunburn, scabies, and prickly heat. Chronic skin problems such as atopic dermatitis may worsen in a tropical environment. Exposure to tropical plants or plant products may cause immediate or delayed hypersensitivity reactions or phytophotodermatitis [11,12]. Hypersensitivity reactions to drugs taken for treatment or prophylaxis may occur.

History and exposures — Key elements of the history to help define possible diagnoses include: ●Time since travel ●Location and duration of travel ●Exposure history (eg, fresh or sea water, animals, arthropods, plants, breaks in skin including tattoos, sexual activity, occupational activities, and medications including over-the-counter drugs) ●Time of onset of skin lesion(s) and their evolution ●Associated symptoms (eg, itching or pain) ●Accompanying systemic symptoms

SYSTEMIC INFECTIONS

The initial focus should be on

infections that are treatable, transmissible, or associated with serious sequelae or death. Dermatologic manifestations may offer a valuable clue for diagnosis of systemic illness. Multiple systemic infections are associated with skin lesions (table 2). In a prospective study of 62 returned travelers to France with fever and widespread rash, the most common diagnoses were chikungunya (35 percent), dengue (26 percent), and African tick bite fever (ATBF; 10 percent) [13]. The high rate of chikungunya infection reflected frequent travel to the Indian Ocean region, where there was an ongoing epidemic.

Viral infections (dengue, chikungunya, Zika, and others) — Dengue virus, chikungunya virus, and Zika virus can all cause maculopapular rash (table 3). Among patients with dengue fever, a diffuse maculopapular rash is observed in 30 to 50 percent of patients (picture 1 and picture 2). Diffuse erythema resembling a sunburn or toxic shock syndrome may be present early in the course of infection. The rash of dengue may become petechial or hemorrhagic. Intense itching may be observed toward the end of the febrile period [14,15]. (See "Dengue virus infection: Clinical manifestations and diagnosis".)

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Chikungunya infection is characterized by intense polyarthralgia, arthritis, and tenosynovitis; diffuse rash is present in 40 to 56 percent of patients with chikungunya (picture 3) [16,17]. Zika virus infections commonly cause widespread micropapular rash, often with pruritus, dysesthesias, and conjunctivitis [18]. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis" and "Zika virus infection: An overview".) Geographic distributions of dengue, chikungunya, and Zika virus infection overlap [18]. In a study including 346 Nicaraguan patients with suspected viral infection, rash was present in 91 percent of patients with Zika virus infections, 56 percent of patients with chikungunya virus infections, and 50 percent of those with dengue virus infections [19]. Measles and rubella occasionally occur in travelers who have visited areas where these viruses circulate (picture 4). Unvaccinated travelers with measles have been a source of multiple introductions of measles into the United States.

Rickettsial infections — Rickettsial infections occur worldwide and are a relatively common, treatable cause of fever and rash in travelers [20-24]. Skin findings vary with the type of rickettsial infection and range from diffuse lesions to a single eschar (picture 5). The appearance of rash due to rickettsial infection may be delayed or absent. The most characteristic rashes for many of the spotted fever rickettsioses are macular, maculopapular, and petechial rashes (picture 6A-B). Vesicular eruptions resembling varicella have been reported in infections due to Rickettsia conorii, R. akari, and R. australis [25-27]. A diffuse rash is observed in 30 to 60 percent of patients with scrub typhus; recognition of an eschar can suggest the diagnosis [28]. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Scrub typhus: Clinical features and diagnosis" and "Murine typhus" and "Rickettsialpox".) Rash is common among travelers with African tick bite fever due to Rickettsia africae. Among 940 Norwegian travelers to rural sub-Equatorial Africa, 4 percent had serologic evidence of infection with R. africae. Among those Norwegian travelers with flu-like symptoms, 26 percent were diagnosed with ATBF [23]. In another series including 119 cases of ATBF, rash occurred in 46 percent of cases [29]. Rashes were most often maculopapular (51 percent); vesicular rashes and purpuric changes were also observed (45 and 4 percent, respectively). An eschar at the site of the tick attachment was noted in 95 percent of patients (picture 7); multiple eschars were observed in 54 percent of cases. Eschars most commonly occurred on the legs (62 percent), followed by chest, abdomen, or groin (18 percent), arms (11 percent), face, neck, or scalp (5 percent), and back or buttocks (4 percent). Regional lymphadenopathy was observed in 43 percent of patients. (See "Other spotted fever group rickettsial infections".)

African trypanosomiasis — African trypanosomiasis (sleeping sickness) is rare in travelers, though an increase in cases has been observed in some areas, including among short-term travelers to Tanzania [30,31]. Early recognition is important since therapy is more complex once central nervous system (CNS) invasion has occurred [32,33]. A

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chancre (indurated nodule) appears at the site of the tsetse fly bite in up to 70 to 90 percent of infected patients. A rash characterized by circinate erythematous patches, most prominent on the trunk, may appear later [34].

Fungal infections — Coccidioidomycosis is associated with rash. Among 20 patients with acute symptomatic coccidioidomycosis related to inhalation exposures in Mexico, 62 percent developed a rash [35]. In most patients, the manifestations were papular lesions progressing to maculopapular lesions on the trunk and sometimes on palms, soles, and buccal mucosa. Fever, headache, and chest pain were also prominent findings [35]. Other fungal infections can cause localized findings at the site of skin penetration. (See 'Nodules' below.)

Sexually transmitted infections — Sexual contact with new partners is common during travel. Several sexually transmitted diseases (STDs) can cause systemic infection and nongenital skin lesions, including syphilis, gonorrhea, and acute HIV [36]. In one study, 3 percent of returned travelers with fever and widespread rash had acute HIV [13].

CLINICAL MANIFESTATIONS Widespread pruritic papules or pustules — Direct penetration of the skin by pathogens may result in diffuse skin lesions. This frequently occurs following immersion in water during recreational or occupational activities.

Swimmer's itch — Cercarial dermatitis, also known as swimmer's itch, is an itchy maculopapular rash that follows skin penetration by cercariae of nonhuman schistosomes (often avian) [37,38]. The distribution of the rash is limited to areas of the body immersed in water. Itchy, red papules that may become vesicular develop hours to a day or so after exposure to water contaminated with schistosomes (picture 8). This infection usually arises from exposure to fresh water, but, occasionally, contact with brackish or salt water can lead to the rash. The nonhuman schistosomes are unable to complete development in the human host though elicit an intense inflammatory response that is more rapid and severe if repeat exposure occurs. Nonhuman schistosomes are widely distributed and found on all continents. Human schistosomes can also produce a rash (redness, urticaria, itchy papules) after penetration of the skin. Among 28 travelers to Mali, Africa, who developed schistosomiasis after water exposure, 10 (36 percent) had schistosomal dermatitis [39]. (See "Schistosomiasis: Epidemiology and clinical manifestations".)

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Seabather's eruption — Seabather's eruption is due to skin penetration by Linuche unguiculata, Edwardsiella lineata, and probably other larvae of the phylum Cnidaria, which are found in oceans (salt water) [40-42]. The tiny jellyfish larvae release nematocysts and inject toxin. The distribution of the lesions matches areas covered by a bathing suit, wet suit, or points of pressure (eg, wristbands of diving suits, flexural areas). Skin lesions are inflammatory papules, often becoming vesicular or pustular (picture 9A-B). Many descriptions have been reported from the Atlantic coast of North America and from the Caribbean.

Hot tub folliculitis — A diffuse folliculitis ("hot tub folliculitis") is usually caused by Pseudomonas aeruginosa that contaminates swimming pools, hot tubs, whirlpools, or water slides. An itchy maculopapular and vesiculopustular eruption develops within 48 hours of exposure and is most common in areas covered by bathing garments (picture 10A-B). (See "Fever and rash in the immunocompetent patient", section on 'Exposure history' and "Pseudomonas aeruginosa skin and soft tissue infections", section on 'Hot tub-associated eruptions'.)

Nodules — Nodules in the skin can occur as a result of a variety of parasitic infections (table 4). Nodular lesions are found in echinococcosis, dirofilariasis, cysticercosis (picture 11), and toxocariasis [43-46]. Cutaneous leishmaniasis lesions can be nodular initially. Following treatment for visceral leishmaniasis, a diffuse nodular eruption can develop (post–kala-azar dermal leishmaniasis). Onchocerciasis is a common cause of nodules among residents of endemic areas but typically causes an itchy rash among travelers who become infected [47-49]. Papular lesions can occur in the setting of schistosomiasis due to ectopic deposition of schistosome eggs years after exposure to schistosomiasis [50]. Disseminated fungal infections can also cause nodular skin lesions. Talaromyces (formerly Penicillium) marneffei has become an important cause of infection in AIDS patients, especially in Southeast Asia. Several bacterial pathogens, including Mycobacteria, Nocardia, and Bartonella, can also cause nodular skin lesions [51].

Lymphangitis — Lymphangitis may be caused by a variety of pathogens including Nocardia, tularemia, Mycobacterium marinum, Leishmania brasiliensis, and sporotrichosis (picture 12) [52]. Many of these pathogens are broadly distributed. The clear exception is leishmaniasis, which has a focal distribution. (See "Lymphangitis", section on 'Nodular lymphangitis' and "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention" and "Clinical features and diagnosis of sporotrichosis".) Lymphangitis with retrograde progression, lymphadenitis, orchitis, and epididymitis are characteristic of bancroftian filariasis [53,54]. Brugia malayi, B. timori, and other filarial parasites cause similar clinical findings. Infections with these filarial parasites are rare in short-term travelers.

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Ulcers — Causes of skin ulcers include pyoderma, tularemia, mycobacterial infection, anthrax, and others (table 5) [55-57]. Several of these pathogens initially induce nodules that progress to ulceration, usually at the site of inoculation of the organism. Cutaneous leishmaniasis typically begins as a papule that enlarges to a nodule with a central crust that drops off to expose an ulcer that is painless, chronic, and may have a raised border (picture 13). Identification of the specific leishmania cause helps to guide treatment [58]. Several sexually transmitted pathogens (such as chancroid) also cause ulcers.

Hemorrhagic lesions — Illnesses associated with petechial rashes and hemorrhage require urgent evaluation. Causes include viral hemorrhagic fevers, including Ebola virus infection, dengue fever, leptospirosis, meningococcemia, and rickettsial infections (table 6). Outbreaks of leptospirosis have occurred in travelers [59]; manifestations can be protean and have been mistaken for dengue hemorrhagic and other viral hemorrhagic fevers [60,61]. Leptospirosis can also be associated with an erythema nodosum–like rash [62]. (See "Leptospirosis: Treatment and prevention".)

Migratory lesions — Several parasites migrate in human tissues (table 7). Migrating parasites frequently cause eosinophilia. These have a restricted geographic distribution, so knowledge of travel and exposures is important in establishing the differential diagnosis.

Cutaneous larva migrans — Cutaneous larva migrans is the most common migratory skin infection in travelers [1,63-66]. It develops when infective larvae of animal hookworms (usually Ancylostoma braziliense) penetrate the skin and migrate in superficial tissues, producing a characteristic serpiginous eruption (picture 14). Humans become infected after direct skin contact with soil, sand, or other material contaminated with feces from hookworm-infected animals, usually dogs or cats. Lesions appear within several days of exposure and most often are found on the feet, buttocks, and thighs [67]. Lesions can be itchy or painful and may be papular or vesiculobullous. The lesions can be complicated by secondary staphylococcal or streptococcal infection. Cutaneous larva migrans is typically self-limited, though medical treatment can shorten the clinical course [68]. (See "Hookworm-related cutaneous larva migrans".)

Strongyloidiasis — Chronic strongyloidiasis can be associated with episodic, itchy, urticarial, or serpiginous skin lesions (larva currens). These lesions are most often located on the buttocks, groin, or trunk [69,70].

Gnathostomiasis — Migrating Gnathostoma larvae cause localized swellings that typically last one to two weeks and are associated with edema, pain, itching, and erythema (picture 15) [71,72]. Lesions begin three to four weeks after ingestion of the parasite, although the swelling

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can continue to appear months to years later. One or multiple parasites may be present and can migrate to tissues throughout the body including the central nervous system (CNS), gastrointestinal or genitourinary tracts, lungs, and eye [73].

Loiasis — Loiasis is characterized by localized areas of angioedema known as Calabar swellings. These are transient, migratory warm, itchy, or painful swellings that often recur multiple times per year (picture 16) [74-76]. Calabar swellings typically persist for several days to weeks [77]. Worms can survive for more than 10 years and can occasionally be observed crossing the conjunctiva.

Arthropod bites — Arthropod bites induce skin reactions in one of three ways (table 8): ●Transmission of a pathogen [78] ●Localized and systemic hypersensitivity reaction [79] ●Retained arthropod parts, which can cause a localized granulomatous reaction A few arthropods inhabit human tissues or infest hair and superficial layers of skin.

Myiasis — The most common presentation of myiasis in returning travelers is furuncular myiasis caused by Dermatobia hominis, the botfly (picture 17), and Cordylobia anthropophaga, the tumbu fly [80-82]. In each instance, larvae penetrate skin and develop in subdermal tissue. Typically, one larva is found in each lesion. Multiple lesions (each containing a single larva) may be present, especially with the tumbu fly [83]. Patients typically note an apparent insect bite that slowly enlarges over time to a nodule measuring 1 to 3 cm in diameter (picture 18A-B). Scant serosanguineous fluid may drain from the lesion. Patients may have a sensation of irritation, crawling, or episodic lancinating pain. Removal of the intact larva is curative, although secondary bacterial infection can complicate the infestation. A range of approaches have been successful, including occluding the opening (eg, with petroleum jelly or strips of bacon) and gentle extraction of the intact larva when it protrudes its abdomen to reach air (picture 19) [81,84].

Tungiasis — The female sand flea (Tunga penetrans) can penetrate human skin, usually on the feet and often under toenails and between toes. The flea feeds on blood and enlarges to a spherical form 5 to 8 mm in diameter and produces eggs that are expelled through the host's skin [85,86]. The flea can live in tissues for up to a month and causes itching and pain. Lesions are nodular and may be single or multiple, often demonstrating a black color centrally (picture 20). The nodules may ulcerate. The treatment is removal of the flea.

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SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Travel medicine".)

SUMMARY ●Skin lesions are a common reason for returned travelers to seek medical evaluation. The differential diagnosis for skin lesions that occur during or after travel is broad and includes infectious and noninfectious causes. The most common causes include cutaneous larva migrans, insect bites, skin abscess, allergic rash, dengue fever, and leishmaniasis. (See 'Causes of skin lesions in travelers' above.) ●Several systemic infections are associated with skin lesions (table 2). The most common include dengue, chikungunya, and African tick bite fever. (See 'Systemic infections' above.) ●Direct penetration of the skin by pathogens may result in diffuse skin lesions. This frequently occurs following immersion in water during recreational or occupational activities. (See 'Widespread pruritic papules or pustules' above.) ●Nodules in the skin can occur as a result of a variety of parasitic infections (table 4). Fungal infections can also cause nodular skin lesions. Several bacterial pathogens, including Mycobacteria, Nocardia, and Bartonella, can also cause nodular skin lesions. Lymphangitis may be caused by a variety of pathogens including Nocardia, tularemia, Mycobacterium marinum, Leishmania brasiliensis, and sporotrichosis. (See 'Nodules' above and 'Lymphangitis' above.) ●A range of pathogens can cause skin ulcers (table 5). Several of these pathogens initially induce nodules that progress to ulceration, usually at the site of inoculation of the organism. Several sexually transmitted pathogens (such as chancroid) also cause ulcers. (See 'Ulcers' above.) ●Illnesses associated with petechial rash and hemorrhage require urgent evaluation. Causes include viral hemorrhagic fevers, dengue fever, leptospirosis, meningococcemia, and rickettsial infections (table 6). (See 'Hemorrhagic lesions' above.) ●Causes of migratory lesions include cutaneous larva migrans, strongyloidiasis, gnathostomiasis, and loiasis (table 7). (See 'Migratory lesions' above.) ●Skin lesions due to arthropod bites include myiasis and tungiasis (table 8). (See 'Arthropod bites' above.)

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Drug eruptions - UpToDate uptodate.com/contents/drug-eruptions/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Apr 10, 2018.

INTRODUCTION

Adverse cutaneous reactions to drugs are common,

affecting 2 to 3 percent of hospitalized patients, and are a significant cause of outpatient morbidity [1]. It is estimated that 1 in 1000 hospitalized patients has a serious cutaneous drug reaction. Classic and uncommon cutaneous drug reactions will be reviewed here. Drug allergy, hypersensitivity reactions, and infusion reactions and cutaneous complications of antineoplastic drugs are discussed elsewhere. ●(See "Drug hypersensitivity: Classification and clinical features".) ●(See "Hypersensitivity reactions to macrolides, aminoglycosides, tetracyclines, clindamycin, and metronidazole".) ●(See "Hypersensitivity reactions to fluoroquinolones".) ●(See "Hypersensitivity reactions to clopidogrel".) ●(See "Vancomycin hypersensitivity".) ●(See "Progestogen hypersensitivity".)

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●(See "Hypersensitivity reactions to systemic glucocorticoids".) ●(See "Hypersensitivity reactions to insulins".) ●(See "Infusion reactions to systemic chemotherapy".) ●(See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".) ●(See "Cutaneous side effects of conventional chemotherapy agents".) ●(See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

CLASSIC DRUG REACTION PATTERNS Drug-induced exanthems — Drug-induced exanthems are the most common cutaneous reactions to drugs, responsible for approximately 90 percent of all drug rashes [2]. The most commonly prescribed medications (eg, antibiotics, sulfonamides) are implicated in most cases. The rashes are referred to as exanthems, morbilliform (picture 1A-B), and macular and papular eruptions [3]. The clinical features, diagnosis and management of exanthematous drug eruptions are discussed in detail separately. (See "Exanthematous (maculopapular) drug eruption".)

Symmetrical drug-related intertriginous and flexural exanthema — Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE, intertriginous drug eruption, baboon syndrome) is an infrequent type of drug-induced rash. SDRIFE occurs a few hours to a few days after the administration of the offending drug. The rash presents as a sharply demarcated V-shaped erythema in the gluteal/perianal or inguinal/perigenital areas, often with involvement of at least one other flexural or intertriginous fold, in the absence of systemic symptoms [4]. Amoxicillin, ceftriaxone, penicillin, clindamycin, and erythromycin are thought to be implied in about 50 percent of cases [4]. Iodinate contrast media, pseudoephedrine, acetyl salicylic acid, mitomycin C, phenothiazines, valacyclovir, and many other drugs have also been implicated [5]. Treatment includes discontinuing the suspected drug and the use of topical or systemic corticosteroids. (See "Exanthematous (maculopapular) drug eruption", section on 'Intertriginous and flexural localization'.)

Urticaria/angioedema — Urticaria, or hives, is characterized by an intensely pruritic, circumscribed, raised, and erythematous eruption with central pallor (picture 2). Individual lesions may enlarge, coalesce with other lesions, and typically disappear over a few hours.

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Urticaria is mediated by the cutaneous mast cell in the superficial dermis. (See "New-onset urticaria".) Angioedema is swelling of the deeper dermis and subcutaneous tissues that may coexist with urticaria in as many as 50 percent of cases. Angioedema may be disfiguring if it involves the face and lips, or life-threatening if airway obstruction occurs from laryngeal edema or tongue swelling. Angioedema can result from mast cell activation in the subcutaneous tissues, or by non-mast cellmediated mechanisms. These mechanisms include abnormalities of the complement cascade (inherited and acquired abnormalities of complement metabolism), and increased activity of vasodilatory kinin pathways. Angioedema (in the absence of urticaria) occurs in 2 to 10 per 10,000 new users of ACE inhibitors and usually affects the mouth or tongue. (See "An overview of angioedema: Pathogenesis and causes".) Reactions involving urticaria/angioedema can be immediate, accelerated (hours postexposure) or delayed (days postexposure). As with most drug eruptions, these reactions are more common during the first weeks of therapy, but can happen at any time. Urticaria and/or angioedema may be manifestations of an IgE-mediated (type I hypersensitivity) drug reaction (table 1). Antibiotics (especially penicillins, cephalosporins, and sulfonamides) are common causes of IgE-mediated drug allergy. IgE-mediated drug reactions tend to become more severe and progress toward anaphylaxis upon re-exposure to the causative agent. (See "Penicillin allergy: Immediate reactions".) Other drugs may cause urticaria due to mast cell degranulation by a non-IgE mediated mechanism. The most frequently implicated are the opiate analgesics morphine and codeine. The concomitant use of opiates and vancomycin may increase the frequency of reactions to the latter. The intense flushing of "Red man syndrome" seen after rapid vancomycin infusion also is due to direct mast cell activation and may have accompanying urticaria. (See "Vancomycin hypersensitivity".)

Anaphylaxis — The most severe form of immediate type I hypersensitivity is anaphylaxis, which is characterized by symptoms affecting multiple organ systems, including but not limited to pruritus, urticaria, angioedema, laryngeal edema, wheezing, nausea, vomiting, tachycardia, sense of impending doom, and occasionally shock. Drugs are the second or third most common cause of anaphylaxis [6,7]. (See "Anaphylaxis: Emergency treatment".)

Cutaneous small vessel vasculitis — Cutaneous small vessel vasculitis (CSVV, also called hypersensitivity vasculitis, cutaneous leukocytoclastic vasculitis, serum sickness or serum sickness-like reactions, and allergic vasculitis) is a single organ vasculitis caused in most cases by drugs [8-10]. Hydralazine, minocycline, propylthiouracil, and levamisole-adulterated cocaine are most often reported as causes of CSVV [11]; penicillins, cephalosporins, sulfonamides (including most loop and thiazide-type diuretics), phenytoin, and allopurinol have also been implicated (table 2) [12-15].

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CSVV typically presents with palpable purpura and/or petechiae (picture 3A-B); additional clinical findings include fever, urticaria, arthralgias, lymphadenopathy, low serum complement levels, and an elevated erythrocyte sedimentation rate. In most patients, the clinical manifestations begin 7 to 10 days after exposure to the offending drug [12]. However, the latent period may be as short as two to seven days with a secondary exposure or longer than two weeks with a long-acting drug such as penicillin G benzathine [13]. Discontinuation of the offending drug should lead to resolution of the signs and symptoms within a period of days to a few weeks. Patients with more severe reactions may require nonsteroidal antiinflammatory drugs or corticosteroids. (See "Overview of cutaneous small vessel vasculitis".)

Exfoliative dermatitis/erythroderma — Erythroderma is a cutaneous reactional state defined as chronic erythema and scale involving greater than 90 percent of the body surface area (picture 4). Common etiologies include drugs, primary skin disease (eg, atopic dermatitis, psoriasis), and malignancy (especially lymphoreticular malignancy and cutaneous T cell lymphoma). (See "Erythroderma in adults".) Drugs are responsible for approximately 20 percent of erythrodermas; implicated drugs include allopurinol, penicillins, barbiturates, gold salts, arsenic, and mercury (picture 5) [1]. In some patients, exfoliative dermatitis may be a manifestation of drug reaction with eosinophilia and systemic symptoms (DRESS). (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".) This disorder is associated with an increased rate of epidermal turnover, including rapid epidermal cell migration [16]. This is presumably mediated by inflammatory cells and represents the most severe manifestation of many inflammatory dermatoses. The clinical manifestations, diagnosis, and management of erythroderma are discussed separately. (See "Erythroderma in adults".)

Stevens-Johnson syndrome and toxic epidermal necrolysis — Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous eruptions that are frequently triggered by medications. These disorders are characterized by epidermal necrosis and sloughing of the mucous membranes and skin (picture 6A-E). The amount of body surface area involved is used to distinguish SJS from TEN; lesions affect less than 10 percent of the body surface in SJS and greater than 30 percent of the body surface in TEN. The clinical manifestations, diagnosis, and management of SJS and TEN are discussed elsewhere. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

Erythema multiforme — Erythema multiforme (EM) majus (or erythema multiforme major) is sometimes used as a synonym for SJS but is considered to be a different condition [1,17]. It is an acute eruption characterized by distinctive target skin lesions. Lesions tend to affect the distal extremities, including the palms and soles (picture 7). EM has diagnostic

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histology and is often caused by infections (typically herpes simplex virus or Mycoplasma pneumoniae) and has a benign clinical course [1]. However, there are reports of EM in association with medication use [18,19]. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)

Drug reaction with eosinophilia and systemic symptoms (DRESS) — Drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) is a severe idiosyncratic reaction characterized by fever (38 to 40°C [100.4 to 104°F]), malaise, lymphadenopathy, and skin eruption (picture 8A-C) [20]. Additional systemic symptoms may be related to visceral involvement (eg, liver, kidney, lung) [21,22]. In most patients, the reaction begins two to six weeks after the initiation of the offending medication. The aromatic antiepileptic agents (carbamazepine, phenytoin, lamotrigine, oxcarbazepine, and phenobarbital), allopurinol, and the sulfonamides are the most frequent causes of this disorder (table 3). The clinical presentation, diagnosis, and management of DRESS are discussed in detail separately. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Fixed drug eruption — A fixed drug eruption is a distinctive reaction characterized acutely by erythematous and edematous plaques with a grayish center or frank bullae, and chronically by a dark postinflammatory pigmentation (picture 9A-B). Favored sites include the mouth (lips and tongue), genitalia, face, and acral areas [3]. The defining features of this eruption include postinflammatory hyperpigmentation and recurrence of lesions at exactly the same sites with drug re-exposure [3]. Patients with generalized fixed drug eruption (GFDG) can be misdiagnosed as having SJS/TEN, but in GFDG mucosal involvement is usually absent or mild and the clinical course is favorable with rapid resolution in 7 to 14 days after drug discontinuation [23]. The drugs commonly involved include NSAIDs (acetylsalicylic acid, ibuprofen, naproxen, mefenamic acid), antibacterial agents (trimethoprim-sulfamethoxazole, tetracyclines, penicillins, quinolones, dapsone), barbiturates, acetaminophen (paracetamol), and antimalarials [3,23-26]. The clinical presentation, diagnosis, and management of fixed drug eruption are discussed in detail separately. (See "Fixed drug eruption".)

Photosensitivity — There are two basic types of photo eruptions, phototoxic and photoallergic, which differ in clinical appearance and pathogenesis. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity' and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.)

Phototoxic eruptions — Phototoxic eruptions are by far the most common druginduced photo eruptions. They are caused by absorption of ultraviolet light by the causative drug, which releases energy and damages cells. Ultraviolet A light (UVA) is the most common wavelength implicated; ultraviolet B light (UVB) and visible light can elicit reactions with some drugs.

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The eruption typically presents as an exaggerated sunburn, often with blisters (picture 10). NSAIDs, quinolones, tetracyclines, amiodarone, and the phenothiazines are the most frequent causes of phototoxicity [3]. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.) Molecularly targeted agents such as vemurafenib may also cause phototoxic reaction. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

Photoallergic eruptions — Photoallergy is a lymphocyte-mediated reaction caused by exposure to UVA. It is postulated that the absorbed radiation converts the drug into an immunologically active compound that is then presented to lymphocytes by Langerhans cells, causing a spongiotic dermatitis (eczema). The eruption is characterized by widespread eczema in the photodistribution: face; upper chest; and back of hands (picture 11). Most photoallergic reactions are caused by topical agents including biocides added to soaps (halogenated phenolic compounds) and fragrances such as musk ambrette and 6-methyl coumarin [27]. Systemic photoallergens such as the phenothiazines, chlorpromazine, sulfa products, and NSAIDs can produce photoallergic reactions, although most of their photosensitive reactions are phototoxic [27]. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.)

UNCOMMON DRUG ERUPTIONS Pemphigus — Pemphigus is an autoimmune bullous disease that may be drug-induced or drug-triggered (table 4) [28]. The latter term refers to unmasking of latent disease by a particular drug. The drugs most often implicated are penicillamine and other thiol (SH) compounds, including captopril or drugs such as piroxicam that are metabolized to thiols [29]; penicillin and its derivatives, but not cephalosporins, also have been implicated (table 4). (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Drug exposure'.)

Bullous pemphigoid — There are isolated case reports of drug-induced bullous pemphigoid [30-33]. Penicillamine and furosemide are most frequently implicated, although cases associated with captopril, penicillin and its derivatives, sulfasalazine, salicylazosulfapyridine, phenacetin, nalidixic acid, and topical fluorouracil also have been reported (table 5) [34-36]. Casecontrol studies have found a significant association between bullous pemphigoid and neuroleptics, loop diuretics, and spironolactone [37-39]. Drug-induced bullous pemphigoid falls into two categories. It is either an acute, self-limited illness with resolution after drug withdrawal, or a chronic type that appears to be merely precipitated by drug administration and eventually assumes all the characteristics of the typical autoimmune

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disease [30]. Clinical manifestations include tense vesicles and bullae on an inflammatory base distributed on the arms, legs, and trunk of older patients. (See "Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Infections and drugs'.)

Linear IgA bullous dermatosis — Linear IgA bullous dermatosis is an idiopathic subepidermal blistering disease characterized histologically by the linear deposition of IgA antibodies at the basement membrane zone. A spectrum of clinical features has been described. Patients with drug-induced disease may have erythema multiforme-type lesions, bullous pemphigoid-like lesions, or dermatitis herpetiformis-like lesions [40]. Mucosal or conjunctival lesions are not present in drug-induced disease but are common in the idiopathic form. Vancomycin is most commonly implicated; lithium, cefamandole, captopril, and diclofenac have also been associated with this illness. Spontaneous remission occurs in drug-induced disease once the offending agent is discontinued. (See "Linear IgA bullous dermatosis".)

Acute generalized exanthematous pustulosis — Acute generalized exanthematous pustulosis (AGEP) is a rare disorder characterized by the appearance of superficial pustules after drug ingestion or infection [41,42]. AGEP is remarkable for its short time to onset (24 hours) after the administration of the suspected drug, although in some cases, the onset of symptoms may be delayed for up to three weeks [43]. The cutaneous eruption begins on the face or intertriginous areas and disseminates within a few hours. Nonfollicular small pustules arise on edematous erythema with burning and/or itching (picture 12A-B). Antibiotics, particularly penicillins and macrolides, are thought to play a role in 80 percent of cases [42,44]. The clinical manifestations, diagnosis, and management of AGEP are discussed separately. (See "Acute generalized exanthematous pustulosis (AGEP)".)

Lichenoid drug eruption (drug-induced lichen planus) — Lichen planus is characterized by flat-topped, violaceous, pruritic papules (picture 13A-C). The drug-induced form of this disorder usually develops insidiously and can affect any area of the body surface. Oral lichenoid drug eruptions are rare and share clinical features with oral lichen planus. (See "Oral lichen planus: Pathogenesis, clinical features, and diagnosis".) Beta-blockers, methyldopa, penicillamine, quinidine, and NSAIDs may cause this disorder [45]. Lichenoid drug eruption is discussed in detail separately. (See "Lichenoid drug eruption (druginduced lichen planus)".)

Alopecia — Drugs cause hair loss by two major mechanisms: inducing an abrupt cessation of mitotic activity in rapidly dividing hair matrix cells (anagen effluvium); or precipitating the follicles into premature rest (telogen effluvium). In the former, hair loss usually occurs within

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days to weeks of drug administration; in the latter, hair loss occurs two to four months after starting treatment. Anagen effluvium is seen most commonly with antineoplastic drugs. (See "Alopecia related to systemic cancer therapy".) Telogen effluvium is seen in association with many drugs including anticoagulants, retinoids, interferons, and antihyperlipidemic drugs [46]. (See "Telogen effluvium".)

Cutaneous pseudolymphoma — Anticonvulsants, antidepressants, antihypertensives, beta blockers, calcium channel blockers, diuretics, antibiotics, nonsteroidal anti-inflammatory drugs, antihistamines, and biologics have been linked with benign hyperplastic lymphoid infiltrates of the skin (cutaneous pseudolymphoma) [47-50]. The lesions are often solitary or few in number and most often are nodular or plaque-like (picture 14). Various histologic variations are noted, including a mycosis fungoides-like pattern [51]. In most patients, the skin lesions resolve when the offending drug is discontinued. (See "Cutaneous T cell pseudolymphomas", section on 'Lymphomatoid drug reaction'.)

Acral chemotherapy reactions — Acral erythema (also called hand-foot syndrome or palmar-plantar erythrodysesthesia) occurs most often in patients with cancer treated with cytosine arabinoside, doxorubicin, capecitabine (an oral topical fluorouracil derivative), or docetaxel. (See "Cutaneous side effects of conventional chemotherapy agents", section on 'Hand-foot syndrome (acral erythema)'.) The small molecule tyrosine kinase inhibitors sunitinib and sorafenib and others that target angiogenesis are also associated with a high incidence of hand-foot skin reaction, but the clinical and histologic patterns differ from the classic acral erythema caused by conventional cytotoxic agents. (See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".) In both types of acral reactions, dysesthesia of the involved areas (eg, paresthesia, tingling, burning, painful sensation) precedes the development of the skin lesions. Acral erythema is most often characterized by a symmetric edema and erythema of the palms and soles, which may progress to blistering and necrosis (picture 15A-B). In contrast, hand-foot skin reaction is characterized by well demarcated, bean to coin sized, hyperkeratotic, painful plaques with underlying erythema localized to the pressure areas of the soles (picture 16) [52].

Drug-induced lupus — Drug-induced lupus is similar to spontaneous lupus but also has some different clinical and immunologic features (table 6). A variety of drugs can induce a lupus-like syndrome, particularly those agents that are metabolized by acetylation such as procainamide and hydralazine [53]. (See "Drug-induced lupus".)

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Anticoagulants Warfarin — Warfarin-induced skin necrosis typically occurs during the first several days of warfarin therapy, often in association with the administration of large loading doses [54]. The skin lesions occur on the extremities, breasts, trunk, and penis (in males) and marginate over a period of hours from an initial central erythematous macule (picture 17). Biopsies demonstrate fibrin thrombi within cutaneous vessels with interstitial hemorrhage. Skin necrosis appears to be mediated by the reduction in protein C levels on the first day of therapy, which induces a transient hypercoagulable state. Approximately one-third of patients have underlying protein C deficiency, although skin necrosis is an infrequent complication of warfarin therapy among patients with protein C deficiency [55]. Case reports have also described this syndrome in association with an acquired functional deficiency of protein C, heterozygous protein S deficiency, and factor V Leiden. (See "Protein C deficiency", section on 'Warfarin-induced skin necrosis'.)

Heparin — Heparin may induce several skin reactions including delayed-type hypersensitivity reactions and, rarely, immediate hypersensitivity reactions or skin necrosis [56]. Delayed-type hypersensitivity reactions may occur with both unfractionated and low-molecular-weight heparins, generally within two weeks of heparin treatment. Delayed-type reactions present most often with localized erythema at the injection site, but may progress to generalized eczematous or maculopapular eruption. Immediate hypersensitivity reactions are rare and manifest as anaphylactic (IgE mediated) or anaphylactoid (non-IgE mediated) reactions [57]. Clinical symptoms include localized or generalized urticaria, hypotension, angioedema, allergic rhinoconjunctivitis, tachycardia, or bronchospasm. Skin necrosis may develop in 10 to 20 percent of patients with heparin-induced immune-mediated thrombocytopenia, a rare and life-threatening complication of treatment with unfractionated or low molecular-weight heparins [58,59]. Cutaneous necrosis is caused by intradermal microvascular thromboses occurring locally or distantly from the injection site. Lesions appear 3 to 15 days after the initiation of therapy as erythematous patches that progress to skin necrosis. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

Gold — Dermatitis and stomatitis account for most adverse gold reactions. Gold rashes are highly variable and may mimic many other skin conditions. In a prospective study of 74 patients with rheumatoid arthritis, 39 patients developed a mucocutaneous reaction to gold [60]. A variety of morphologic features were noted, the bulk of which were characterized as nonspecific dermatitis (six of these patients had an associated stomatitis, six had a dyshidrotic eczema presentation). In three patients the reaction resembled contact dermatitis. One case each of pityriasis rosea, lichen planus, psoriasis, erythema multiforme, pigmentary purpura, and vasculitis was reported. Most patients had pruritus. Gold-associated eruptions had a median duration of two months, with a range

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of one week to two years. Most cases resolved promptly with discontinuation of gold or with dose reduction; application of topical steroids was also helpful. (See "Major side effects of gold therapy", section on 'Mucocutaneous effects'.)

Lithium — Cutaneous side effects from lithium therapy have been reported in 3 to 34 percent of patients [61]. ●Psoriasis is one of the most common reactions. It may begin for the first time during therapy, or a mild case may be exacerbated when the patient begins the drug. ●Acne and acneiform eruptions also are common. Pustular lesions may be the result of lysosomal enzyme release and increased neutrophil chemotaxis [61]. Acneiform lesions may be seen on the forearms and legs in addition to the sites commonly involved in acne vulgaris. ●Hair loss, especially in women during the first few months of therapy, has frequently been reported.

Halogenoderma — Ingestion of halogens such as iodides, bromides, and fluorides can rarely cause cutaneous drug reactions [62]. Iodides (such as those in seaweed, salt, amiodarone, and radiocontrast media) can cause acneiform lesions, typically on the face, as well as vesicular, pustular, hemorrhagic, urticarial, fungating, suppurative, nodular, and ulcerative lesions (picture 18). Swelling of the parotid and submandibular glands has been previously described as iodine mumps. Iododerma due to the administration of intravenous radiocontrast media commonly is seen as an acute eruption; with oral iodine exposure the onset is insidious [63]. Declining renal function may be a factor in radiocontrast induced iododerma. Amiodarone typically induce photosensitivity and a bluish-gray discoloration of the skin (picture 19). (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse skin reactions'.) Bromides can cause verrucous ulcerating plaques on the lower extremities [62]. Discontinuation of the causative agent is sufficient in most patients, with gradual resolution of lesions expected over four to six weeks [62].

Epidermal growth factor receptor (EGFR) inhibitors — Epidermal growth factor receptor (EGFR) inhibitors and other tyrosine kinase inhibitors used to treat cancers are known to cause an inflammatory acneiform eruption involving the face, neck, and upper trunk in the majority of patients receiving these medications (picture 20). (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

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Cytokine therapy — Hematopoietic colony stimulating factors are a heterogeneous group of cytokines that induce proliferation and differentiation of bone marrow precursor cells. They are most frequently administered in the setting of neutropenia secondary to chemotherapy (eg, recombinant human granulocyte or granulocyte-macrophage colony-stimulating factor). Serious cutaneous adverse effects of colony stimulating factors are distinctly rare but include neutrophilic dermatoses and necrotizing vasculitis [64]. Upregulation of neutrophil function and secondary release of cytokines may induce these complications.

SUMMARY AND RECOMMENDATIONS ●Adverse cutaneous reactions to drugs are common, affecting 2 to 3 percent of hospitalized patients. Drug-induced exanthems, also called morbilliform eruptions, are the most common cutaneous reactions to drugs, responsible for about 75 percent of all drug rashes. The most frequently prescribed medications such as antibiotics and sulfonamides are implicated in most cases. (See 'Introduction' above and 'Drug-induced exanthems' above.) ●Less frequently, drugs may cause urticaria/angioedema, anaphylaxis, hypersensitivity vasculitis, and phototoxic and photoallergic reactions. Severe and potentially life-threatening reactions are rare and include exfoliative dermatitis, Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS). The aromatic antiepileptic agents (carbamazepine, phenytoin, lamotrigine, oxcarbazepine, and phenobarbital), allopurinol, and the sulfonamides are most frequently implicated. (See 'Classic drug reaction patterns' above.) ●Autoimmune bullous diseases (eg, pemphigus, bullous pemphigoid, linear IgA bullous dermatosis) can be rarely induced or triggered by medications, most commonly penicillamine and other thiol compounds or drugs that are metabolized to thiols (eg, captopril, piroxicam). Other rare reactions to drugs include acute generalized pustular eruption (AGEP), lichenoid drug reaction, cutaneous pseudolymphoma, and drug-induced lupus. (See 'Uncommon drug eruptions' above.)

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Exanthematous (maculopapular) drug eruption - UpToDate uptodate.com/contents/exanthematous-maculopapular-drug-eruption/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 22, 2018.

INTRODUCTION

Exanthematous drug eruption, also called morbilliform

or maculopapular drug eruption, is the most common type of drug hypersensitivity reaction [1,2]. They are characterized by a diffuse and symmetric eruption of erythematous macules or small papules occurring approximately one week or, in previously sensitized individuals, as early as one or two days after the initiation of drug treatment. In severe forms, the mucosae (oral, conjunctival, nasal, or anogenital) and skin appendages (hair and nails) may be involved. This topic will discuss the clinical presentation, diagnosis, and treatment of exanthematous drug eruptions. Drug allergy and other types of cutaneous adverse drug reactions are discussed separately. ●(See "Drug hypersensitivity: Classification and clinical features".) ●(See "Penicillin allergy: Immediate reactions".)

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●(See "Cephalosporin hypersensitivity: Clinical manifestations and diagnosis".) ●(See "Hypersensitivity reactions to macrolides, aminoglycosides, tetracyclines, clindamycin, and metronidazole".) ●(See "Hypersensitivity reactions to fluoroquinolones".) ●(See "Sulfonamide allergy in HIV-uninfected patients".) ●(See "Fixed drug eruption".) ●(See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".) ●(See "Acute generalized exanthematous pustulosis (AGEP)".) ●(See "Lichenoid drug eruption (drug-induced lichen planus)".) ●(See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".) ●(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".) ●(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

EPIDEMIOLOGY

Cutaneous drug reactions are estimated to occur in

approximately 2 percent of individuals exposed to drugs [1]. The morbilliform exanthem accounts for approximately 95 percent of cutaneous drug reactions and drug-induced urticaria for approximately 5 percent. Drug-specific reaction rates range from 0 to greater than 5 percent among exposed patients, with the highest rates reported for antibiotics (1 to 8 percent) [2].

PATHOGENESIS Immunologic mechanisms — Many, but not all, cases of drug exanthem are thought to be delayed-type, T cell-mediated (type IV) immune reactions, which involve the activation of several other cell types, such as macrophages, eosinophils, or neutrophils [3]. The precise mechanisms by which drugs elicit a specific immune response are not completely understood and may involve different types of interaction between drugs and the immune system [4] (see "Drug allergy: Pathogenesis", section on 'Interaction of drugs with the immune system'): ●Drugs or their metabolites may act as haptens, form covalent bonds with a protein or peptide, and become antigenic. Haptenated proteins are then processed by antigen-presenting cells (APCs) to produce haptenated peptides bound to major histocompatibility complex (MHC) molecules. The

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hapten-peptide-MHC are then presented to naïve, allergen-specific T cells. ●Drugs may directly interact with immune receptors and activate specific immune cells (the "p-i concept" or pharmacologic interactions of drugs with immune receptors). According to the p-i concept, chemically inert drugs, unable to bind covalently to peptides or proteins, can activate certain T cells if they fit with sufficient affinity into T cell receptors or MHC molecules. In delayed-type immune reactions, specific T cell clones of the CD4 T helper cell type 1 (Th1) or T helper cell type 2 (Th2) and CD8 subtypes orchestrate different forms of inflammation depending upon the cytokines produced and other types of cells that become involved, leading to four subcategories of type IV reactions (IVa to IVd) (figure 1) [5]. Effector cells such as CD4 Th1 lymphocytes, CD8 cytotoxic lymphocytes, macrophages, and nonspecific effector cells such as neutrophils and eosinophils may be involved in the elicitation phase, explaining some of the variability of the clinical manifestations of drug reactions [6,7]. Exanthematous drug reactions appear to be driven by type IVc reactions, in which T cells act as effector cells. CD8 effector T cells emigrate to tissues and kill cells in a perforin/granzyme B-, granulysin-, and FasL-directed manner [8]. Type IVc reactions also may occur in other drug hypersensitivity reactions, mostly in conjunction with other type IV reactions involving the recruitment and activation of monocytes, eosinophils, or neutrophils. Immunohistochemical and functional studies of drug-reactive T cells in patients with distinct forms of exanthems reveal that distinct T cell functions lead to different clinical phenotypes [6,7]. The chronology of the onset and evolution of the skin lesions allow an approximate estimation of what type of pathomechanism and which drugs may be involved and may be helpful in clinical practice (table 1 and figure 2) [6].

Eliciting drugs — A large number of drugs may induce delayed-type, T cell-mediated immune reactions. Some drugs act as haptens, bind to macromolecules, and then become full antigens. Examples include penicillins, cephalosporins, and agents with sulfhydryl groups. Known antigens include the beta-lactam ring, aminobenzyl side chains, and methoxyimino side chains [9,10]. The exact antigenic moiety is not known for most drugs, such as antibiotics, macrolides, quinolones, antituberculous agents, calcium-antagonists, and proton pump inhibitors. For other drugs, biotransformation is necessary to form reactive metabolites. Examples include the aromatic sulfonamides (trimethoprim-sulfamethoxazole), anticonvulsant drugs such as carbamazepine and phenytoin, some nonsteroidal anti-inflammatory drugs (NSAIDs), and paracetamol. Biotransformation also may be necessary for reverse transcriptase inhibitors, such as nevirapine and abacavir. In the latter, direct binding and transformation of the MHC has been shown [11], although the exact mechanism is not known. Drugs that have been introduced within a timeframe of one to four weeks before the reaction or have been taken previously and are later reintroduced are more likely to be involved than drugs that have been taken for months or even years, at least when taken in an uninterrupted manner.

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Online resources (available by subscription) provide continuously updated, searchable lists of eliciting drugs, types of exanthemas, and approximate rates of reacting patients [12].

GENETIC PREDISPOSITION

Pharmacogenetic

studies based upon the frequency of some specific human leukocyte antigen (HLA) alleles suggest that there is a genetic predisposition to drug allergy. In some populations, individuals with HLAB*1502, HLA-B*5801, or HLA-B*5701 have an increased risk of developing severe drug reactions (eg, Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) to aromatic anticonvulsants such as carbamazepine, allopurinol, cotrimoxazole, and abacavir, respectively (table 2). In European populations, HLA-A*3101 has been associated with a higher incidence of severe drug reactions and maculopapular exanthems to carbamazepine [13,14]. Screening for the HLA-B*5701 allele prior to initiating therapy with abacavir is routinely available and recommended by the US Food and Drug Administration. ●(See "An approach to the patient with drug allergy", section on 'HLA type'.) ●(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'HLA types'.) ●(See "Abacavir hypersensitivity reaction".)

CONTRIBUTING FACTORS Underlying disorders — Concomitant diseases may predispose to the development of allergic drug reactions, presumably by altering metabolic pathways or inducing variations in the immunologic responses to drugs. Viral infections, particularly Epstein-Barr virus, cytomegalovirus, and human herpesviruses 6 and 7 are associated with an increased risk of cutaneous drug eruptions [15-17]. Patients with inborn, acquired, or iatrogenic immunodeficiency, (including human immunodeficiency virus [HIV] infection, cystic fibrosis, and, possibly, autoimmune disorders), also are prone to develop drug-induced exanthems [15,18,19].

Comedication — The concomitant administration of multiple medications may result in a more frequent occurrence of drug-induced exanthems, although the specific pathomechanism is unclear. Hypersensitivity reactions have been reported in patients treated with high doses of valproate and lamotrigine, probably due to sensitization to one molecule or metabolite [20].

HISTOPATHOLOGY

Exanthematous drug eruptions are

characterized by a subtle vacuolar interface dermatitis with scattered dyskeratotic keratinocytes along the dermoepidermal junction (picture 1) [21]. Usually, there is a superficial perivascular and interstitial infiltrate of lymphocytes, neutrophils, and eosinophils. Additional features include a

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pronounced extravasation of erythrocytes, foci of lymphocytes aligned along the dermoepidermal junction, and fibrin deposition within the blood vessel walls of the papillary plexus. Histologic patterns may support the clinical suspect of a drug-induced exanthem but are not characteristic for a particular drug.

CLINICAL PRESENTATION General features — Exanthematous drug eruptions present with erythematous macules and papules, and rarely pustules or bullae, that predominantly involve the trunk and proximal extremities (picture 2A-D). In mild forms, acral sites are most often spared, although the face, palms, and soles may be involved. Drug-induced exanthems are often described as "morbilliform" or "rubelliform" because the lesion morphology and distribution pattern closely resemble those of viral exanthems [6]. However, in some cases, there is a profuse eruption of small papules or pustules that does not resemble any infective exanthem. Purpuric lesions may develop on the legs and other dependent areas. Systemic symptoms include pruritus, low-grade fever, elevation of acute-phase proteins, and mild eosinophilia. The eruption typically develops within 5 to 14 days of treatment initiation but may occur within one or two days in previously sensitized individuals. In patients taking antibiotics, the eruption may appear up to a few days after the treatment has been stopped, depending upon the mechanism and the drug elimination half-time. Mucosal involvement is usually absent in uncomplicated drug exanthems. More severe drug hypersensitivity reactions should be suspected if constitutive symptoms are present or if the exanthem is extended and involves the face, as in drug reaction with eosinophilia and systemic symptoms (DRESS) or the ocular, oral, or genital mucosae, as in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). (See 'Differential diagnosis' below.)

Intertriginous and flexural localization — Symmetrical drug-related intertriginous and flexural exanthem (SDRIFE), formerly called baboon syndrome, is an uncommon variant of exanthematous drug eruption, most often induced in males by aminopenicillins (picture 3) [22]. In rare instances, SDRIFE can be the manifestation of systemically elicited allergic contact dermatitis to nickel or mercury [23]. SDRIFE occurs a few hours to a few days after the administration of the offending drug (figure 2). The rash presents as a sharply demarcated, V-shaped erythema in the gluteal/perianal or inguinal/perigenital areas, often with involvement of at least one other flexural area such as the axillae, elbows, or knees (picture 3) [6,22,24].

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SDRIFE should be differentiated from the so-called malignant intertrigo, an intertriginous form of acral erythema (also called hand-foot syndrome) caused by conventional chemotherapy agents [25]. (See "Cutaneous side effects of conventional chemotherapy agents", section on 'Hand-foot syndrome (acral erythema)'.)

Early signs of severe reaction — An exanthematous drug eruption rarely may be the heralding sign of a severe hypersensitivity reaction, such as acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS), or Stevens-Johnson syndrome/toxic necrolysis (SJS/TEN) [26,27]. (See "Acute generalized exanthematous pustulosis (AGEP)" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".) Warning signs of severe cutaneous hypersensitivity reaction include evolution to erythroderma, fever >38°C (100.4°F), facial edema, mucositis, skin tenderness, or blistering (table 3). Patients should be advised that, if any of these signs occur, they should seek immediate medical attention. (See 'Patient education' below.)

CLINICAL COURSE

Most exanthematous drug eruptions are of mild

to moderate severity and do not cause major morbidity. The eruption evolves rapidly, reaches the maximal extent approximately two days after the elimination of the causative drug, and resolves in 5 to 14 days (figure 2). Occasionally, a mild eruption subsides despite continuation of the medication. Resolution often occurs with some desquamation. In patients with darker skin tones, postinflammatory hyperpigmentation can occur.

DIAGNOSIS Clinical diagnosis — The diagnosis of exanthematous drug eruption is suspected in a patient receiving drug treatment who presents with a recent onset rash. The clinical suspicion can be substantiated by history (including chronology), clinical features, laboratory testing, and sometimes by histopathologic examination of a skin biopsy. Key elements for the clinical diagnosis include: ●Medication history – The patient should be questioned about current and past medications, including over-the-counter drugs and topical preparations. Establishing a chronologic relationship between drug exposure and onset of the rash is helpful for the identification of the culprit drug (table 4). Sensitization to a drug may have taken place with a past exposure to the same drug or to a crossreacting drug molecule. (See "An approach to the patient with drug allergy", section on 'Identification of the suspect drug'.)

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●Resolution of the rash after drug withdrawal – The eruption typically resolves rapidly (usually within 7 to 14 days) after the suspected drug is discontinued. In a few cases, longer periods until complete resolution are possible. Since most drug exanthems appear within the first week after starting a drug treatment, the diagnosis is often straightforward. However, some drugs, such as anticonvulsants, antibiotics, and allopurinol, may induce rashes up to three weeks after initiation of therapy. Identifying a particular drug as the cause of an eruption is difficult when the patient is taking multiple drugs. In this situation, it may be helpful to know the relative frequencies of cutaneous reactions for specific agents (table 5) [1,2,28-30]. In patients with a previous history of drug eruption, accidental re-exposure should be investigated, given the increased use of generic medications with the same active ingredients but different brand names. Also, over-the-counter medications and "natural remedies" should be considered.

Laboratory tests — Routine laboratory evaluation of patients with suspected drug-induced exanthem generally is not indicated. However, laboratory evaluation may be necessary if the clinical diagnosis is uncertain. It may include general laboratory tests, specific immunologic tests, and possibly a skin biopsy. ●General laboratory tests may include: •Complete blood cell count with differential (looking for eosinophilia, which supports the diagnosis and also occurs in patients with drug rash with eosinophilia and systemic symptoms [DRESS]), neutrophilia, as in acute generalized exanthematous pustulosis (AGEP), or to identify cytopenias •Liver and kidney function tests (looking for systemic involvement which may occur in patients with DRESS or Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) ●Antinuclear autoantibody tests should be performed if an autoimmune connective tissue disease is suspected (eg, juvenile idiopathic arthritis, lupus erythematosus). ●Specific immunologically based tests to evaluate delayed drug reactions may be performed one to six months after the complete resolution of the clinical symptoms to confirm the etiology and include: •Patch testing •Intradermal testing with delayed cutaneous readouts •In vitro tests for delayed reactions (eg, lymphocyte transformation/activation tests, upregulation of activation markers on T cells, cytokine production, and drug-induced cytotoxicity assays) Tests for delayed hypersensitivity are discussed in detail separately. (See "An approach to the patient with drug allergy", section on 'Type IV reactions'.)

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Skin biopsy — Skin biopsy is not routinely necessary to make the diagnosis of exanthematous drug eruption. However, a skin biopsy for histologic examination may be warranted if the diagnosis is uncertain or if there is concern for a severe hypersensitivity reaction. (See 'Histopathology' above and 'Early signs of severe reaction' above and 'Differential diagnosis' below.) Potential indications for skin biopsy include: ●Suspicion of a non-drug-induced skin disorder ●Multiple drugs involved without a clear-cut temporal relationship with cutaneous reaction ●Severe systemic symptoms (eg, fever >38°C [100.4°F] and/or symptoms of internal organ involvement) ●Evolution to erythroderma, blistering, purpura, or pustulation ●Mucous membrane involvement The finding of vacuolar interface dermatitis and tissue eosinophilia supports the diagnosis of exanthematous drug eruption (picture 1) but is nonspecific [21].

DIFFERENTIAL DIAGNOSIS

The differential diagnosis

of exanthematous drug eruption includes viral and bacterial exanthems, rashes associated with systemic diseases, and cutaneous diseases (table 6). The morphology, distribution, and spatial and temporal evolution of the rash and laboratory tests (eg, serologic tests) may help in distinguishing a drug-induced exanthem from viral or bacterial exanthems or rashes associated with systemic or cutaneous diseases [7,31,32]. The evolution of the rash and clinical course distinguishes exanthematous drug eruption from more severe hypersensitivity reactions, such as acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms, and Stevens-Johnson syndrome/toxic necrolysis (SJS/TEN) (table 3) [26,27]. (See "Acute generalized exanthematous pustulosis (AGEP)" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

MANAGEMENT Drug withdrawal — Prompt withdrawal of the offending drug(s) is the mainstay of treatment of exanthematous drug eruptions. In patients taking multiple drugs, nonessential drugs should be discontinued.

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Symptomatic treatment — The treatment of exanthematous drug eruptions is largely symptomatic. The efficacy of symptomatic therapies for the treatment of exanthematous drug eruptions has not been evaluated in randomized trials, and their use is based upon clinical experience. For symptomatic relief of exanthem and pruritus, we suggest topical corticosteroids and oral antihistamines. We generally use high-potency (group 1 to 3 (table 7)) topical corticosteroids one to two times per day for one week or until resolution. Antihistamines include: ●Diphenhydramine – 25 to 50 mg orally every four to six hours for adults and children ≥12 years; 12.5 to 25 mg orally every four to six hours for children 6 to 11 years; and 6.25 mg orally every four to six hours for children two to five years. Diphenhydramine is continued until pruritus subsides. ●Hydroxyzine – 25 mg orally three to four times per day for adults and children ≥6 years; 2 mg/kg per day orally divided every six to eight hours for children 7000/microL) ●Pustular smear and culture negative for bacteria ●Rapid resolution of the rash after drug discontinuation Histologic features that support the diagnosis of AGEP include (picture 2A-B) [47] (see 'Histopathology' above): ●Intra- or subcorneal spongiform pustules

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●Eosinophils in the pustules or dermis ●Necrotic keratinocytes ●Superficial, interstitial, and mid-dermal infiltrate rich in neutrophils ●Absence of tortuous, dilated blood vessels

Patch testing — Patch testing with one or multiple suspected drugs may be useful in identifying the cause of AGEP [48-52]. Patch testing is generally performed four to six weeks after the disease resolution. A positive test can confirm a suspected drug as the cause of AGEP. However, a negative result does not exclude that a certain drug is the causative agent. Positive patch testing reactions may occur from 18 to 58 percent of cases, depending on the drugs tested and the specific type of severe drug reaction [51,53,54]. A positive patch test reaction is often morphologically similar to AGEP, showing small sterile pustules on an erythematous base. Systemic reactions to patch testing rarely have been reported [52]. (See "Patch testing", section on 'Patch test interpretation'.)

Other tests — Drug-specific in vitro immunologic tests (eg, mast cell degranulation test, macrophage migration inhibition factor test, interferon gamma release test, lymphocyte proliferation response) are only performed in research settings [55-58].

DIFFERENTIAL DIAGNOSIS

The differential diagnosis

of AGEP includes [1,2]: ●Generalized acute pustular psoriasis (von Zumbusch type) – Seen at a single time point and without additional information, generalized acute pustular psoriasis (picture 3) and AGEP may be difficult to differentiate both clinically and histologically. Criteria that favor a diagnosis of generalized acute pustular psoriasis include a history of psoriasis; longer duration of fever and pustular eruption; absence of drug exposure; and histologic finding of subcorneal pustules with acanthosis and papillomatosis [1]. Although generalized acute pustular psoriasis can be elicited by drugs, the spectrum of medications known to trigger psoriasis (mainly beta-blockers or lithium) differs from the drugs associated with AGEP [7]. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis".) ●Stevens-Johnson syndrome/toxic epidermal necrolysis – Severe cases of AGEP presenting with atypical target lesions and confluent pustules mimicking a positive Nikolsky sign may be difficult to differentiate from Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) [36-38,59]. Features that favor a diagnosis of SJS/TEN include: a longer latency between drug exposure and clinical manifestations (one to four weeks); involvement of the mucous membranes (in over 90 percent of cases); more severe course; and histologic finding of full thickness epidermal necrosis with a sparse inflammatory dermal infiltrate.

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There are isolated reports of overlap cases with clinical and histologic features of both AGEP and SJS/TEN [39-41,60]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".) ●Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) – Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) is a rare, chronic, relapsing pustular eruption characterized by large, flaccid pustules that involve the trunk and the intertriginous areas (picture 4A-B) [61]. SneddonWilkinson has been reported in association with pyoderma gangrenosum, monoclonal IgA gammopathy, IgA myeloma, and other lymphoproliferative diseases. On histology, there is a subcorneal accumulation of neutrophils without spongiosis or keratinocyte damage and a perivascular infiltrate of neutrophils (picture 5A-B) [62-66]. (See "Neutrophilic dermatoses", section on 'Subcorneal pustular dermatosis'.) ●Drug reaction with eosinophilia and systemic symptoms – Pustules can occasionally occur in patients with drug reaction with eosinophilia and systemic symptoms (DRESS) [67]. However, DRESS is characterized by a long latency (two to eight weeks) between drug exposure and appearance of symptoms, a more severe and prolonged clinical course than AGEP, eosinophilia or atypical lymphocytosis in the peripheral blood, and signs and symptoms of visceral involvement (abnormal liver function tests in approximately 80 percent of cases). The histology of DRESS is characterized by mild spongiosis with a lymphocytic infiltrate containing eosinophils in the superficial dermis. However, subcorneal and intraepidermal neutrophilic microabscesses can be seen in pustular DRESS [67]. Cases with features of both DRESS and AGEP have been described [6,60,68,69]. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".) ●Bullous impetigo – Bullous impetigo generally occurs in young children. Small vesicles or pustules are usually localized to the head and neck or intertriginous areas (picture 6A-B). Pustules rupture and leave erosions with a honey-colored crust (picture 7). Gram staining of pustule smear reveals Gram-positive cocci. Culture of pustule exudate is positive for Staphylococcus aureus. (See "Impetigo", section on 'Bullous impetigo'.)

MANAGEMENT

AGEP is a self-limiting disease with a favorable

prognosis. Management includes withdrawal of the offending drug, supportive care, and symptomatic treatment of pruritus and skin inflammation.

Drug withdrawal and supportive measures — Prompt withdrawal of the causative agent is the mainstay treatment of AGEP. In patients taking multiple drugs, the drugs suspected to be the cause of AGEP (table 1A) should be discontinued. Since re-exposure to the causative agent can induce another episode of AGEP, patients should be counseled to avoid the offending drug and be provided with a written list of the generic and brand names of the offending drug [70,71].

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Patients with severe forms of AGEP usually are hospitalized for treatment. Older or compromised patients with fever and widespread eruption may require fluid, electrolyte, and nutritional support.

Symptomatic treatment — For symptomatic relief of pruritus and skin inflammation, we suggest topical rather than systemic corticosteroids. We use medium potency corticosteroids (group four (table 2)). They are applied twice a day for one week. In the desquamation phase, emollients may be helpful in restoring the skin barrier function. The use of topical corticosteroids for AGEP has not been evaluated in clinical trials. Their use is based upon small case series and clinical experience of efficacy in other pruritic or inflammatory skin conditions [72,73]. Given the natural history of rapid spontaneous resolution following withdrawal of the offending drug, we avoid systemic corticosteroids for the treatment of AGEP. In case series and case reports, systemic corticosteroids have been used to treat AGEP, but evidence that they shorten the disease course is lacking [16,44,72,74].

PROGNOSIS

AGEP resolves spontaneously without sequelae in the majority of

patients. Mortality rate of 2 percent has been reported in a pharmacovigilance study in France [17].

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

SUMMARY AND RECOMMENDATIONS ●Acute generalized exanthematous pustulosis (AGEP) is a rare, acute eruption characterized by the development of numerous nonfollicular, sterile, small pustules on a background of edematous erythema (picture 1A-C) [1,2]. In approximately 90 percent of cases, AGEP is caused by drugs, most often antibiotics, calcium channel blockers and antimalarials (table 1A-B). (See 'Introduction' above and 'Eliciting factors' above.) ●Fever above 38°C (100.4°F) and leukocytosis with a neutrophil count >7000/microL are usually present. The eruption resolves spontaneously in one to two weeks after the discontinuation of the offending drug. (See 'Clinical features' above and 'Clinical course' above.) ●The diagnosis of AGEP is based upon the clinical presentation and histologic examination of a skin biopsy (picture 2A). The rapid resolution of the eruption after drug discontinuation also supports the diagnosis. (See 'Diagnosis' above and 'Histopathology' above.)

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●Prompt withdrawal of the causative agent is the mainstay of treatment of AGEP. Since re-exposure to the causative agent can induce another episode of AGEP, patients should be counseled to avoid the offending drug and be provided with a written list of the generic and brand names of the offending drug. (See 'Drug withdrawal and supportive measures' above.) ●For symptomatic relief of pruritus and skin inflammation, we suggest topical corticosteroids (Grade 2C). We generally use medium potency topical corticosteroids (group four (table 2)). They are applied twice a day for one week. (See 'Symptomatic treatment' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like

to acknowledge Alexis Sidoroff, MD, who contributed to an earlier version of this topic review.

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Drug reaction with eosinophilia and systemic symptoms (DRESS) uptodate.com/contents/drug-reaction-with-eosinophilia-and-systemic-symptoms-dress/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Apr 08, 2020.

INTRODUCTION

Drug reaction with eosinophilia and systemic symptoms

(DRESS) is a rare, potentially life-threatening, drug-induced hypersensitivity reaction that includes skin eruption, hematologic abnormalities (eosinophilia, atypical lymphocytosis), lymphadenopathy, and internal organ involvement (liver, kidney, lung) [1-3]. DRESS is characterized by a long latency (two to eight weeks) between drug exposure and disease onset, a prolonged course with frequent relapses despite the discontinuation of the culprit drug, and frequent association with the reactivation of latent human herpesvirus infections [4]. DRESS will be reviewed in this topic. Other types of cutaneous drug reactions, drug fever, and drug allergy are discussed separately. ●(See "Drug eruptions".) ●(See "Exanthematous (maculopapular) drug eruption".)

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●(See "Lichenoid drug eruption (drug-induced lichen planus)".) ●(See "Fixed drug eruption".) ●(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".) ●(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".) ●(See "Acute generalized exanthematous pustulosis (AGEP)".) ●(See "Drug hypersensitivity: Classification and clinical features".) ●(See "Drug fever".)

TERMINOLOGY

Numerous terms are used to describe adverse drug

reactions with skin eruption, systemic symptoms, and visceral involvement, including drug reaction with eosinophilia and systemic symptoms; drug rash with eosinophilia and systemic symptoms; drug-induced hypersensitivity syndrome; or drug hypersensitivity syndrome [1,4,5]. Terms that were used in initial case reports include anticonvulsant hypersensitivity syndrome, drug-induced pseudolymphoma, dapsone syndrome, or phenytoin syndrome [6,7]. The confusing nosology reflects the large variability in the clinical manifestations of this type of adverse drug reaction and the lack of widely accepted diagnostic criteria. In this topic, we will use the term "drug reaction with eosinophilia and systemic symptoms" (DRESS).

EPIDEMIOLOGY

The incidence of drug reaction with eosinophilia and

systemic symptoms (DRESS) is unknown. A prospective seven-year study in a West Indian general population estimated an annual incidence of 0.9/100,000 [8]. DRESS may occur in children [9,10], but most cases occur in adults without sex predilection [11]. The frequency varies depending upon the type of drug and immune status of the patient. It ranges from 1 to 5 per 10,000 patients exposed to the anticonvulsants, carbamazepine and phenytoin, and appears to be higher among patients taking lamotrigine (1 per 300 adults and 1 per 100 children exposed) [12,13].

ETIOLOGY AND RISK FACTORS

Drug causality

is determined as "highly probable" in approximately 80 percent of cases of drug reaction with eosinophilia and systemic symptoms (DRESS) [11,14]. In 10 to 20 percent of cases fulfilling the diagnostic criteria for DRESS, a relationship with a drug cannot be established.

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Antiepileptic agents (eg, carbamazepine, lamotrigine, phenytoin, phenobarbital) and allopurinol are the most frequently reported causes [14]. DRESS with renal involvement has been reported in patients treated with febuxostat, a newly developed xanthine oxidase inhibitor with a chemical structure different from allopurinol and approved for the treatment of hyperuricemia [15,16]. Febuxostat-induced DRESS occurred in one patient with a history of allopurinol-induced DRESS, suggesting a possible cross-reaction between the two drugs [15]. In May 2016 the US Food and Drug Administration issued a warning that the antipsychotic drug olanzapine may cause DRESS, with 23 cases reported worldwide since 1996 [17]. Sulfonamides (particularly sulfasalazine), dapsone, minocycline, and vancomycin may also induce DRESS (table 1). Several cases of DRESS have been attributed to raltegravir [18] and kinase inhibitors, including imatinib, sorafenib, and vemurafenib [19-21]. In a series of 29 children with DRESS, trimethoprimsulfamethoxazole was the causative drug in 10 cases [9]. The osteoporosis medication strontium ranelate is also associated to a risk of DRESS close to 1 per 10,000 exposures [22].

Pharmacogenetics — Pharmacogenetic studies have found an association between human leukocyte antigen (HLA) haplotypes and susceptibility to DRESS [23,24]: ●Allopurinol– In populations of Han Chinese ancestry, HLA-B*58:01 is strongly associated with allopurinol induced severe cutaneous drug reactions, including DRESS [25-28]. A high frequency of HLA-B*58:01 has also been found in Portuguese patients with allopurinol-induced DRESS [29]. Recommendations for HLA testing prior to use are discussed elsewhere. (See "Pharmacologic uratelowering therapy and treatment of tophi in patients with gout", section on 'Allopurinol'.) ●Carbamazepine – A strong association between HLA-A*31:01 and carbamazepine-induced DRESS has been found in European and Han Chinese patients [30]. The recommendations for screening prior to initiating carbamazepine and related drugs are discussed separately. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Genetic screening' and "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine'.) ●Dapsone – An association between HLA-B*13:01 and the dapsone hypersensitivity syndrome, which has overlapping clinical features with DRESS, has been found in a genomewide Chinese study and in a case-control study in the Thai population [31,32]. ●Salazosulfapyridine– HLA-B*13:01 appears to be associated also with salazosulfapyridine-induced DRESS in the Chinese Han population [33]. ●Abacavir– Abacavir hypersensitivity, which is associated with HLA-B*57:01, does not fit the major clinical or biologic criteria for DRESS, although it has several similar features. Screening prior to use is reviewed elsewhere. (See "Abacavir hypersensitivity reaction", section on 'Screening prior to abacavir exposure'.)

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Once a patient has been identified as having a high-risk HLA profile, family members of that patient should also be advised to avoid the relevant drug, as familial occurrence of such hypersensitivity reactions has been noted. (See 'Prevention' below.)

PATHOGENESIS Drug-specific immune response — A strong, drug-specific immune response is a key factor in the pathogenesis of drug reaction with eosinophilia and systemic symptoms (DRESS). This has been demonstrated in many cases by positive patch test reactions and in vitro lymphocyte proliferation assays [34-39]. Among all phenotypes of cutaneous adverse drug reactions, DRESS is the one with strongest activation of drug-specific T cells [37,38]. During the acute phase of disease, there is an expansion of activated T lymphocytes in the blood, including both CD8 and CD4 cells that harbor activation markers and a skewed repertoire of the antigen receptor, and an expansion of regulatory T cells (see "Drug allergy: Pathogenesis" and "Drug allergy: Pathogenesis", section on 'Type IV (T cell-mediated)'). The latter has been suggested to contribute to virus reactivation [40,41].

Virus reactivation — Reactivation of several viruses of the herpes group (human herpesvirus [HHV]-6, HHV-7, Epstein-Barr virus [EBV], and cytomegalovirus) is frequent in DRESS [42,43]. In a study of 100 patients with DRESS, an increase in the antibody titer against HHV-6 was detected in approximately 60 percent of patients two to four weeks after the onset of symptoms [44]. Quantitative real-time polymerase chain reaction assay detected a significant amount of HHV-6 DNA in serum samples of approximately 30 percent of patients with increased anti-HHV-6 titers, indicating active viral replication in those patients. Disease relapses (eg, fever, hepatitis) were temporally related to the detection of HHV-6 DNA in the peripheral blood, suggesting that viral reactivation may contribute to the phenotype and severity of DRESS [44]. In another study including 40 patients with DRESS, evidence of EBV, HHV-6, or HHV-7 reactivation was found in 29 patients [45]. EBV-specific CD8+ lymphocytes were found in the blood, skin, and liver of patients with DRESS, representing the normal response of the immune system to control virus reactivation. These findings led to the hypothesis that the initial event in DRESS was a viral reactivation that induced the expansion of a T cell population cross-reacting with the drug and that tissue damage was caused by activated cytotoxic CD8+ lymphocytes directed against virus-related antigens [45,46]. However, since latent viruses can be harbored in humans by cells of the immune system (principally T lymphocytes and monocytes/macrophages), the reactivation and release of viruses may be considered an early marker of stimulation of these cells, rather than the initiating event in the pathogenesis of DRESS [47].

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Thus, DRESS is primarily a strong, drug-specific immune reaction that acts as a trigger of viral reactivation. Virus reactivation may contribute some symptoms or complications, but more studies are needed to clarify the respective role of viruses and drug-induced immune reaction in DRESS.

HISTOPATHOLOGY

Histopathologic examination of a skin biopsy

reveals a variable combination of spongiosis, acanthosis, interface vacuolization, a lymphocytic infiltrate in the superficial dermis, predominantly perivascular, variable presence of eosinophils, and dermal edema [48,49]. Occasionally, the lymphocytic infiltrate contains atypical cells or is dense enough to raise the suspicion of cutaneous lymphoma. (See "Cutaneous T cell pseudolymphomas", section on 'Drug-induced pseudolymphoma syndrome (DRESS mimicking CTCL)'.) In a review of 50 skin biopsies from 36 patients with DRESS, the most frequent histopathologic pattern was an interface dermatitis often involving the pilar units, followed by eczematous, erythema multiforme-like, and AGEP-like pustulosis [50]. Of note, more than one histologic pattern was frequently observed in a single biopsy. Atypical lymphocytes, sometimes resembling Sézary cells, were present in approximately one-third of cases. Lymphocytes phenotyping showed a predominance of CD8+ lymphocytes, with numerous cytotoxic cells expressing granzyme B. Although rarely performed, the histopathologic features of lymph node, liver, and kidney biopsies are as follows: ●Pathologic findings in lymph nodes range from benign reactive hyperplasia to presence of atypical lymphocytes that may suggest lymphoma [51]. Most often, lymph nodes demonstrate benign features similar to viral-induced lymphadenopathy, with partial or complete effacement of nodal architecture by a polymorphous infiltrate of immunoblasts, small lymphocytes, eosinophils, and plasma cells. ●Liver biopsy demonstrates an acute hepatitis injury pattern with lobular inflammation, scattered foci of necrotic hepatocytes, and granulomatous infiltrates containing eosinophils [52]. Portal inflammation and cholestasis also may be seen. Confluent hepatocyte necrosis and lobular disarray due to inflammation and regenerative changes are seen in severe cases. ●Kidney biopsy demonstrates tubulointerstitial nephritis with interstitial edema and infiltrates of lymphocytes, histiocytes, eosinophils, and plasma cells [53].

CLINICAL PRESENTATION

In most patients, the

reaction begins two to six weeks after the initiation of the offending medication [14]. The latency between drug exposure and onset of symptoms is considerably longer in DRESS than in most drug eruptions (typically, 4 to 9 days for morbilliform eruptions and 4 to 28 days for SJS/TEN) [54]. However, it cannot be excluded that asymptomatic alterations in lymphocyte blood count or liver function tests begin earlier.

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Fever (38 to 40°C [100.4 to 104°F]), malaise, lymphadenopathy, and skin eruption are the most common initial symptoms, but they are not invariably present [55].

Skin — The eruption starts as a morbilliform eruption that progresses more or less rapidly to a diffuse, confluent, and infiltrated erythema with follicular accentuation (picture 1A-C). The eruption suggests DRESS when it involves more than 50 percent of the body surface area (BSA) and/or includes two or more of facial edema, infiltrated lesions, scaling, and purpura. The face and upper part of the trunk and extremities are involved initially. Facial edema develops in approximately one-half of cases [14]. The facial edema is symmetric, persistent, and associated with erythema. Inflammation and pain of mucous membranes is present in nearly one-half of patients, usually in a single site (most often the mouth or pharynx), and does not progress to erosions. The extent of the BSA involvement is an important marker of disease severity (figure 1 and table 2). For the evaluation of limited or spotty lesions, is useful to remember that in both children and adults the surface of the patient's hand, including palm and fingers, corresponds to approximately one percent of the total body surface area. (See "Assessment and classification of burn injury", section on 'Extent of burn injury'.) In most cases, more than 50 percent of the BSA is erythematous [14]. In 20 to 30 percent of patients, erythema progresses to exfoliative dermatitis (diffuse erythema and scaling involving >90 percent of BSA). Vesicles, tension blisters induced by dermal edema, or pustules can also occur.

Systemic symptoms — Systemic symptoms include fever (38 to 40°C [100.4 to 104°F]), malaise, lymphadenopathy, and symptoms related to visceral involvement. (See 'Organ involvement' below.) Diffuse lymphadenopathy is reported in 30 to 60 percent of cases, with slightly enlarged (1 to 2 cm) and tender nodes at several sites [11]. Lymph node biopsy, occasionally performed to exclude lymphoma, demonstrates features similar to viral-induced lymphadenopathy or benign lymphoid hyperplasia. (See 'Histopathology' above.)

Laboratory abnormalities — Laboratory abnormalities detected in patients with DRESS include [11,14,45,55-58]: ●Leukocytosis with eosinophil counts >700/microL (in 50 to 90 percent of cases) [11,14] ●Atypical lymphocytosis with large activated lymphocytes, lymphoblasts, or mononucleosis-like cells (in 30 to 70 percent of cases) ●Increased serum alanine aminotransferase (in up to 80 percent of cases)

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●Reactivation of human herpesvirus-6 (HHV-6) and other viruses (in 40 to 60 percent of tested patients)

Organ involvement — Involvement of at least one internal organ occurs in approximately 90 percent of patients; in 50 to 60 percent of patients, two or more organs are involved, most frequently liver (60 to over 80 percent of cases), kidneys (10 to 30 percent of cases), and lungs (5 to 25 percent of cases) [14,59,60].

Liver — Hepatomegaly and jaundice may be present, but most often hepatitis is asymptomatic and detected by routine liver function tests (LFT). In one study of 72 patients with DRESS, 62 (86 percent) had liver involvement [60]. Liver injury was cholestatic-type in 37 percent of cases, mixed type in 27 percent, and hepatocellular-type in 19 percent. Liver biopsy demonstrates necrosis of hepatocytes with granulomatous infiltrates containing eosinophils. (See 'Histopathology' above.) There is no consensus on the definition of liver involvement. In the scoring system proposed by the Registry of Severe Cutaneous Adverse Reactions (RegiSCAR), liver involvement is defined by the finding of a serum level of alanine aminotransferase (ALT) greater than twice the upper limit of normal values and/or alkaline phosphatase greater than 1.5 times the upper limit of normal values on at least two different dates. LFT abnormalities are generally mild and transient, but severe impairment of liver function may occur. Prolongation of prothrombin time (international normalized ratio [INR] >1.5), increase in serum bilirubin, or evidence of impaired consciousness may be clues to acute liver failure. Severe hepatitis is responsible for the majority of deaths associated with DRESS. Markedly elevated aspartate aminotransferase and bilirubin with jaundice and presence of hepatic encephalopathy are the most important predictors of death or liver transplantation [61,62]. There are isolated case reports of life-saving emergency liver transplantation [35]. (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis", section on 'Idiosyncratic drug reactions'.)

Kidney — Renal involvement, manifesting as acute interstitial nephritis, occurs in 10 to 30 percent of DRESS cases, most often in those induced by allopurinol [56,58]. Older age and preexisting alterations of renal function may be predisposing factors. Renal abnormalities include a moderate increase in creatinine level, low grade proteinuria, and abnormal urinary sediment with occasional eosinophils. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Clinical features'.) A kidney biopsy would demonstrate tubulointerstitial nephritis with interstitial infiltrates of lymphocytes, histiocytes, and eosinophils [63]. (See 'Histopathology' above and "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Histology'.)

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Lung — Pulmonary involvement presents with nonspecific symptoms, including cough, fever, and tachypnea/dyspnea [64]. The measurement of hemoglobin oxygen saturation by pulse oximetry may reveal an unsuspected hypoxemia. Chest radiograph or CT scan may provide evidence of interstitial pneumonitis and/or pleural effusion. Drug-specific CD8+ T lymphocytes and eosinophils may be found in broncho-alveolar lavage fluid [36].

Other organs — Several other organs can be involved in DRESS, including [11]: ●Heart (eosinophilic myocarditis, pericarditis) ●Gastrointestinal tract (diarrhea, mucosal erosions, bleeding) ●Pancreas (pancreatitis) ●Thyroid (autoimmune thyroiditis, appearing often late, as a sequel of DRESS) ●Brain (encephalitis, meningitis) ●Muscle (myositis, increase in creatine kinase) ●Peripheral nerves (polyneuritis) ●Eye (uveitis) Rare cases of shock or multiple organ failure associated with disseminated intravascular coagulation or hemophagocytic syndrome also have been reported [65-67].

CLINICAL COURSE

The skin eruption and visceral involvement

generally resolve gradually after drug withdrawal. The average time to recovery is six to nine weeks [11]. In up to 20 percent of cases, the disease may persist for several months with a succession of remissions and relapses. Factors associated with a prolonged course include a more severe liver involvement and presence of mononucleosis-like atypical lymphocytosis [68]. Relapses have been reported concurrently with human herpesvirus 6 reactivation [44]. Although there have been case reports of relapses induced by the introduction of new drugs, particularly beta-lactam antibiotics, it is not clear whether these were relapses or evolution of the natural course of DRESS, which includes spontaneous flares [69]. It seems anyhow prudent to avoid treatment with beta-lactam antibiotics during the course of DRESS.

DIAGNOSIS 4027

When to suspect DRESS — The diagnosis of DRESS is suspected in a patient who received a new drug treatment in the previous two to six weeks and presents with the following signs and symptoms: ●Skin eruption (morbilliform or diffuse, confluent, and infiltrated) (picture 1A) ●Fever (38 to 40°C [100.4 to 104°F]) ●Facial edema ●Enlarged lymph nodes The clinical suspicion can be substantiated by a history of exposure in the previous two to six weeks to a high-risk medication (eg, allopurinol, antiepileptic drugs (table 1)), laboratory and/or imaging studies demonstrating eosinophilia with or without atypical lymphocytes in the peripheral blood and/or organ involvement, and a skin biopsy showing an interface dermatitis and a perivascular infiltrate of lymphocytes and eosinophils.

Assessment of drug causality — The latency between drug exposure and onset of symptoms (two to six weeks) is considerably longer in DRESS than in most drug eruptions (typically 4 to 9 days for morbilliform eruptions and 4 to 28 days for SJS/TEN) [54]. Medications taken for more than three months or initiated less than two weeks before the onset of DRESS are unlikely to be the causative drugs. Medication(s) known to have a high risk of inducing DRESS (table 1) and introduced two to eight weeks before the disease onset are considered plausible culprits and should be withdrawn. (See 'Drug withdrawal and supportive measures' below.) Causality may be further supported by positive patch tests and/or in vitro tests (eg, lymphocyte proliferation assay) [34,70]. Both tests have a good specificity but rather low sensitivity (50 to 70 percent for patch tests) [37].

Laboratory investigations — The initial laboratory evaluation in a patient suspected to have DRESS is aimed at confirming the diagnosis, excluding other conditions that mimic DRESS, and evaluating the extent and severity of visceral involvement (table 3). Laboratory tests include: ●Complete blood cell count with differential and peripheral blood smear – The finding of peripheral eosinophilia >700/microL suggests the diagnosis of DRESS. In some patients, lymphocytosis (absolute lymphocyte count >4500/microL) and/or the finding of atypical lymphocytes on peripheral smear also support the diagnosis of DRESS. ●Liver function tests – Serum alanine aminotransferase (ALT) greater than twice the upper limit of normal values and/or alkaline phosphatase greater than 1.5 times the upper limit of normal values on at least two different dates indicate liver involvement.

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●Serology for viral hepatitis – Serology for viral hepatitis (hepatitis A IgM antibody, hepatitis B surface antigen, hepatitis B core IgM antibody, hepatitis C viral RNA) may be useful in excluding acute viral hepatitis in patients with abnormal liver function test results. ●Serum creatinine and urinalysis – A moderate increase in creatinine level, low grade proteinuria, and abnormal urinary sediment with occasional eosinophils indicate kidney involvement. ●Skin biopsy – The histologic findings of mild spongiosis and a lymphocytic infiltrate in the superficial dermis, predominantly perivascular, with eosinophils and dermal edema, although not specific, supports the diagnosis of a drug hypersensitivity reaction. (See 'Histopathology' above.) ●Testing for herpesvirus infection – Testing for Epstein-Barr virus (EBV), cytomegalovirus, human herpesvirus (HHV)-6, or HHV-7 is increasingly performed in patients with DRESS, since viral infection reactivation is suspected to be a marker of prolonged course and increased risk of complications [44]. There are no standardized protocols for viral testing in DRESS. If a decision to test is made, serology should be performed at admission and repeated one or more times at two- to three-week intervals to detect a change in the antibody titer. Quantitative polymerase chain reaction (PCR) assay on serum or plasma is considered the best way to document active virus infection or reactivation. (See "Infectious mononucleosis", section on 'EBV-specific antibodies' and "Infectious mononucleosis", section on 'Detection of EBV virus' and "Clinical manifestations, diagnosis, and treatment of human herpesvirus 6 infection in adults", section on 'Diagnosis' and "Human herpesvirus 7 infection", section on 'Diagnosis'.) However, the detection of active infection with human herpesviruses has no or minor impact on treatment of DRESS. (See 'Role of antiviral treatments' below.)

Imaging studies — In patients presenting with nonspecific symptoms of pulmonary involvement (eg, cough, tachypnea/dyspnea), chest radiograph or CT scan may provide evidence of interstitial pneumonitis and/or pleural effusion.

Diagnosis — Given the high variability in the clinical presentation, the diagnosis of DRESS in many cases requires a high degree of suspicion and clinical judgement. (See 'When to suspect DRESS' above.) In typical cases, the diagnosis is based upon the following findings [1]: ●History of exposure to a high-risk medication, such as allopurinol or antiepileptic drugs (table 1) in the two to six weeks before the onset of symptoms. (See 'Assessment of drug causality' above.) ●Morbilliform eruption progressing to confluent and infiltrated erythema or exfoliative dermatitis involving >90 percent of the total body surface area (BSA) (picture 1A). (See 'Skin' above.)

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The extent of BSA involvement can be assessed by using tables or charts (eg, the modified LundBrowder charts (figure 1 and table 2)), the "rule of nines," or the palm method (the patient's palm and fingers account for 1 percent of BSA). (See "Assessment and classification of burn injury", section on 'Extent of burn injury'.) ●Hematologic abnormalities (eosinophilia >700/microL and/or atypical lymphocytosis). (See 'Laboratory abnormalities' above.) ●Systemic symptoms and organ involvement which may include: •Fever (38 to 40°C [100.4 to 104°F]) •Enlarged lymph nodes •Abnormal liver function tests •Renal impairment •Interstitial pneumonia and/or pleural effusion •Myocarditis •(See 'Systemic symptoms' above and 'Organ involvement' above.) The diagnosis is uncertain in patients with atypical presentations, including [11]: ●Unclear relationship to drug exposure ●Transient or absent skin eruption ●Absence of eosinophilia ●Mild or absent systemic symptoms It is possible, though uncommon, to make a diagnosis of DRESS without "D" (no patent drug cause), without "R" (rash was absent in 2 out of 176 cases included in a literature review), without "E" (eosinophilia was absent in 10 to 50 percent of cases), or even without systemic symptoms [55]. To help clinicians in confirming or excluding the diagnosis of DRESS, the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) devised a scoring system based upon clinical features, extent of skin involvement, organ involvement, and clinical course [55]. DRESS is classified as definite, probable, or possible (table 4). Since the score incorporates some information that is only available later in the disease course (eg, duration >15 days or worst value of laboratory parameters over time), it is more helpful in retrospective validation than in early diagnosis of DRESS. However, the RegiSCAR scoring system may serve as a guide for the collection of patient information.

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DIFFERENTIAL DIAGNOSES

Other severe cutaneous

drug eruptions, viral or bacterial infections, hypereosinophilic syndrome, lymphoma, and autoimmune connective tissue disease may present with skin eruption, fever, and systemic symptoms and mimic DRESS. ●Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) – SJS/TEN usually starts 4 to 28 days after drug exposure. Severe mucosal involvement with erosions and bleeding on at least two sites occurs in over 90 percent of cases of SJS/TEN. In contrast, mucosal involvement occurs in approximately 50 percent of patients with DRESS, usually involving a single site (most often the mouth or pharynx), and not progressing to erosion. Eosinophilia and atypical lymphocytosis are not observed in SJS/TEN, whereas leukopenia is frequent and lymphopenia is nearly constant. Mild elevation of liver enzymes is frequent in SJS/TEN, but definite hepatitis is present in less than 10 percent of cases, versus at least 50 percent in DRESS. In SJS/TEN, kidney involvement, when present, has the features of "prerenal azotemia," whereas kidney involvement in DRESS manifests as tubulointerstitial nephritis. Lung lesions result from necrosis of epithelial cells in SJS/TEN and from interstitial and alveolar infiltration by lymphocytes and eosinophils in DRESS [36,71]. In SJS/TEN, histology shows full-thickness epidermal necrosis due to massive keratinocyte apoptosis. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical presentation'.) ●Acute generalized exanthematous pustulosis (AGEP) – In contrast to DRESS, AGEP usually starts less than three days after drug exposure. Although pustules occasionally can occur in patients with DRESS, AGEP is characterized by hundreds or thousands pinpoint nonfollicular pustules disseminated over the body surface. Internal organ involvement is rare. Complete blood cell count shows leukocytosis with neutrophilia (>7000/microL). (See "Acute generalized exanthematous pustulosis (AGEP)".) ●Hypereosinophilic syndromes – The hypereosinophilic syndromes (HES) are associated with marked peripheral eosinophilia (≥1500/microL) and involvement of multiple organs such as the heart, gastrointestinal tract, lungs, brain, and kidneys, without an alternative explanation for the organ damage. Skin manifestations of HES include eczema (involving hands, flexural areas, or dispersed plaques), erythroderma, lichenification, dermographism, recurrent urticaria, and angioedema. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".) ●Angioimmunoblastic T cell lymphoma – Angioimmunoblastic T cell lymphoma typically presents as an acute-onset systemic illness. Common symptoms include generalized lymphadenopathy, hepatomegaly, splenomegaly, skin eruption (50 to 60 percent of patients), and systemic B symptoms (fevers, night sweats, or weight loss). The skin eruption is usually pruritic and may demonstrate lymphohistiocytic vasculitis on biopsy. Histopathologic examination of a biopsied lymph node confirms the diagnosis. (See "Clinical manifestations, pathologic features, and diagnosis of angioimmunoblastic T cell lymphoma".)

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●Sézary syndrome – Sézary syndrome typically presents with generalized erythroderma (picture 2). The diagnosis is based upon the finding of Sézary cells in the peripheral blood (absolute Sézary count of at least 1000 cells/microL), or increased number of CD4+ lymphocytes in the peripheral blood with a CD4/CD8 ratio ≥10, and a clonal T cell receptor rearrangement in the blood identified by PCR or southern blot analysis. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Diagnostic criteria'.) ●Acute cutaneous lupus erythematosus – Acute cutaneous lupus erythematosus (ACLE) may present with a generalized morbilliform eruption, often focused on sun-exposed areas, and systemic symptoms (eg, fever, fatigue, lymphadenopathy, myalgias, symmetric small joint arthralgia) (picture 3). The eruption is typically precipitated or exacerbated by exposure to UV light. Autoantibody testing demonstrates high titers of antinuclear antibodies (ANA), anti-dsDNA, or anti-Sm. Histologic examination of a skin biopsy reveals interface dermatitis with a lymphohistiocytic infiltrate and mucin in the upper dermis. Direct immunofluorescence shows a continuous band of granular fluorescence at the dermoepidermal junction. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Evaluation' and "Overview of cutaneous lupus erythematosus", section on 'Acute cutaneous lupus erythematosus'.)

MANAGEMENT Drug withdrawal and supportive measures — Identification and prompt withdrawal of the offending drug is the mainstay of treatment for patients with drug reaction with eosinophilia and systemic symptoms (DRESS). We also suggest avoidance of introducing new medications, if possible, during the course of DRESS and in patients in whom DRESS is suspected. In cases related to antiepileptic drugs, valproic acid is often used as substitution for the suspected medication. Patients with severe cutaneous adverse drug reactions usually are hospitalized for treatment. Those with exfoliative dermatitis require fluid, electrolyte, and nutritional support. Additional measures include a warm and humid environment and gentle skin care with warm baths/wet dressings and emollient. (See "Erythroderma in adults".)

Patients without severe organ involvement — Patients with DRESS without clinical, laboratory, or imaging evidence of renal or pulmonary involvement and those with only modest elevation of liver transaminases (ie, 150 percent basal level and proteinuria or hematuria). We use a moderate to high dose of systemic corticosteroids (eg, 0.5 to 2 mg/kg per day of prednisone or prednisone equivalent). Systemic corticosteroids are given until clinical improvement and normalization of laboratory parameters are obtained and then tapered over the ensuing 8 to 12 weeks. A more rapid tapering may increase the risk of relapse. The use of systemic corticosteroids for the treatment of DRESS with severe organ involvement has not been evaluated in randomized trials. However, there is general consensus among experts on the use of systemic corticosteroids for the treatment of DRESS with severe organ involvement, particularly in patients with renal and/or pulmonary involvement. The optimal dose and duration of corticosteroid therapy are not known. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Glucocorticoids' and "Treatment of acute interstitial nephritis".) In retrospective observational studies, most patients with DRESS, with or without severe organ involvement, are treated with systemic corticosteroids [11,56,72,74]. Systemic corticosteroids do not appear to be detrimental in patients with DRESS. The risk of death is related to the severity of visceral involvement and does not appear to be increased by treatment with systemic corticosteroids. In a series of 60 patients, the death rate was similar among patients treated with and without systemic corticosteroids (5 in 50 and 1 in 10, respectively) [56].

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Cyclosporine — There are a few reports of rapid resolution of DRESS with organ involvement with a short course of oral cyclosporine [76,77]. Although evidence is limited, cyclosporine may be a second-line therapy for patients with DRESS and severe organ involvement who do not respond to systemic corticosteroids and for patients in whom corticosteroids are contraindicated.  

Role of antiviral treatments — There are no studies evaluating the treatment of DRESS with antiviral agents active against HHV6 or CMV (eg, ganciclovir, foscarnet, or cidofovir). Given the substantial toxicity of the available antiviral agents and the natural course of spontaneous resolution, we generally do not use antiviral agents in the treatment of DRESS. However, they may be warranted for patients with DRESS in whom virus reactivation is demonstrated and suspected of contributing to severe complications (eg, encephalitis, hemophagocytosis, or severe erosive colitis) [78].

Intravenous immunoglobulins — Intravenous immunoglobulins (IVIG) have been reported as beneficial in a few patients with DRESS and detrimental in others [79,80]. While awaiting better evidence, we do not suggest the use of IVIG for the treatment of DRESS.

Monitoring — Patients with DRESS should be monitored for progression of the skin eruption and/or development of clinical or laboratory symptoms related to organ involvement. Laboratory monitoring may include complete blood count with differential, liver function tests (serum aminotransferases, bilirubin, prothrombin time), blood urea nitrogen (BUN), and creatinine. Laboratory tests are performed at weekly intervals in patients with favorable disease course. More frequent monitoring may be warranted in patients with severe or progressing disease. (See 'Clinical presentation' above.)

PROGNOSIS

Most patients with DRESS recover completely in weeks to months

after drug withdrawal. The prevalence of sequelae is unknown. Autoimmune diseases have been reported in some patients months or years after the resolution of the drug reaction [81,82]. In a retrospective study of 43 patients with DRESS followed-up for at least one year, four patients developed autoimmune diseases (Graves' disease, diabetes mellitus type 1, and autoimmune hemolytic anemia) and two patients developed chronic renal failure [81]. The author of this topic review suggests that patients recovering from DRESS be monitored by their primary care provider for manifestations of autoimmune diseases. Laboratory monitoring, including autoantibodies and thyroid stimulating hormone, also may be warranted based upon clinical findings.

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Patients who recover from DRESS may have an increased risk of reaction to structurally unrelated drugs [83]. The risk appears to be higher in the first few months following DRESS occurrence. Retrospective studies have reported a mortality rate for DRESS of 5 to 10 percent [11,56]. In a prospective multinational study, 2 of 117 patients (1.7 percent) died during the acute phase of the disease [14]. The main causes of death are acute liver failure, multiorgan failure, fulminant myocarditis, or hemophagocytosis [78,84,85].

PREVENTION

Patients should be educated about the need for a strict

avoidance of the offending drug as well as cross-reacting drugs. Cross-reaction to chemically related drugs has been documented in patients treated with antiepileptics [86]. (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects".) Avoidance of the causative drug should also be recommended to family members of patients with DRESS because of suspicion of genetic factors [87].

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

SUMMARY AND RECOMMENDATIONS ●Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, potentially lifethreatening drug-induced hypersensitivity reaction that includes skin eruption, hematologic abnormalities (eosinophilia, atypical lymphocytosis), lymphadenopathy, and/or internal organ involvement (liver, kidney, lung). (See 'Introduction' above.) ●Antiepileptic agents (eg, carbamazepine, lamotrigine, phenytoin, phenobarbital) and allopurinol are the most frequently reported causes. Sulfonamides (eg, sulfasalazine), dapsone, minocycline, and vancomycin may also induce DRESS (table 1). There is evidence for a genetic predisposition to DRESS when related to allopurinol, carbamazepine, or dapsone. (See 'Etiology and risk factors' above.) ●In most patients, the reaction begins two to six weeks after the initiation of the offending medication. Fever (38 to 40°C [100.4 to 104°F]), malaise, lymphadenopathy, and skin eruption are the most common initial symptoms, but they are not invariably present. The morbilliform eruption can become confluent and progress to exfoliative dermatitis in some patients (picture 1A-C). Additional

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systemic symptoms may be related to visceral involvement. Hematologic abnormalities include leukocytosis with eosinophilia >700/microL and/or atypical lymphocytosis. (See 'Clinical presentation' above.) ●Liver involvement occurs in 60 to 80 percent of patients. Kidney (tubulointerstitial nephritis), lung (interstitial pneumonitis), and other organs can also be involved. Skin eruption and visceral involvement resolve gradually in three to nine weeks after drug withdrawal. (See 'Organ involvement' above and 'Clinical course' above.) ●The diagnosis of DRESS is based upon the combination of clinical features (history of drug exposure (table 1), cutaneous findings (picture 1A-C), systemic findings, such as fever, lymphadenopathy, and visceral involvement) and laboratory findings (table 3). (See 'Diagnosis' above.) ●Identification and prompt withdrawal of the offending drug is the mainstay of treatment for patients with DRESS. (See 'Drug withdrawal and supportive measures' above.) ●Patients with DRESS without clinical, laboratory, or imaging evidence of renal or pulmonary involvement and those with only modest elevation of liver transaminases (ie, 38°C (100.4°F), mucositis, skin tenderness, and blistering (table 4) [102,103]. (See "Exanthematous (maculopapular) drug eruption", section on 'Early signs of severe reaction'.)

Cutaneous lesions — The skin lesions typically begin with ill-defined, coalescing, erythematous macules with purpuric centers, although many cases of SJS/TEN may present with diffuse erythema (picture 1A, 2A, 2C-D) [104,105]. The skin is often tender to the touch, and skin pain can be prominent and out of proportion to the cutaneous findings. Lesions start on the face and thorax before spreading to other areas and are symmetrically distributed [106]. The scalp is typically spared, and palms and soles are rarely involved [107,108]. Atypical target lesions with darker centers may be present. As the disease progresses, vesicles and bullae form, and within days the skin begins to slough. Nikolsky sign (ie, the ability to extend the area of superficial sloughing by applying gentle lateral pressure on the surface of the skin at an apparently uninvolved site) may be positive. The AsboeHansen sign or "bulla spread sign" (a lateral extension of bullae with pressure) may also be present. The ultimate appearance of the skin has been likened to that of extensive thermal injury [109]. (See "Approach to the patient with cutaneous blisters", section on 'Nikolsky sign'.)

Mucosal lesions — Mucosal involvement occurs in approximately 90 percent of cases of SJS/TEN and can precede or follow the skin eruption [110]. Painful crusts and erosions may occur on any mucosal surface [102,111].

Oral — The oral mucosa and the vermilion border are almost invariably involved, with painful hemorrhagic erosions covered with a grayish-white membrane (picture 1C-D). Stomatitis and mucositis lead to impaired oral intake with consequent malnutrition and dehydration.

Ocular — Ocular involvement is reported in approximately 80 percent of patients. The most common change in the eyes is a severe conjunctivitis with a purulent discharge (picture 1E), but bullae may develop. Corneal ulceration is frequent, and anterior uveitis or panophthalmitis may occur. Pain and photophobia are accompanying symptoms. A simple grading system based upon the presence of conjunctivitis, corneal or conjunctival epithelial defect, and pseudomembrane formation has been proposed to assess the severity of acute ocular involvement and guide the therapeutic choice [112]: ●No ocular involvement – 0 (none)

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●Conjunctival hyperemia – 1 (mild) ●Either ocular surface epithelial defect or pseudomembrane formation – 2 (severe) ●Both ocular surface epithelial defect and pseudomembrane formation – 3 (very severe) The eye changes may regress completely, but at least 50 percent of patients have late eye sequelae including pain, dryness, and scarring with the development of synechiae between the eyelids and conjunctiva [113,114]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'Long-term sequelae'.)

Urogenital — Urethritis develops in up to two-thirds of patients and may lead to urinary retention. Genital erosions are frequent. In women, vulvovaginal involvement may present with erosive and ulcerative vaginitis, vulvar bullae, vaginal synechiae, and may lead to long-term anatomic sequelae. These include labial and vaginal adhesions and stenosis, obstructed urinary stream and urinary retention, recurrent cystitis, or hematocolpos [115-119]. Vulvovaginal adenosis (presence of metaplastic cervical or endometrial glandular epithelium in the vulva or vagina) also has been reported in women with SJS/TEN [120-122].

Other — Pharyngeal mucosa is affected in nearly all patients; tracheal, bronchial, and esophageal membranes are less frequently involved [123,124]. Intestinal involvement is rare [125].

Laboratory abnormalities — Hematologic abnormalities, particularly anemia and lymphopenia, are common in SJS/TEN [106]. Eosinophilia is unusual; neutropenia is present in approximately one-third of patients and is correlated with a poor prognosis [106,126]. However, the administration of systemic corticosteroids can cause demarginalization and mobilization of neutrophils into the circulation, and this may obscure neutropenia. Hypoalbuminemia, electrolyte imbalance, and increased blood urea nitrogen and glucose may be noted in severe cases, due to massive transdermal fluid loss and hypercatabolic state. Serum urea nitrogen >10 mmol/L and glucose >14 mmol/L are considered markers of disease severity [127]. Mild elevations in serum aminotransferase levels (two to three times the normal value) are present in approximately one-half of patients with TEN, while overt hepatitis occurs in approximately 10 percent [111].

CLINICAL COURSE

The acute phase of Stevens-Johnson

syndrome/toxic epidermal necrolysis (SJS/TEN) lasts 8 to 12 days and is characterized by persistent fever, severe mucous membrane involvement, and epidermal sloughing that may be generalized and result in large, raw, painful areas of denuded skin. Re-epithelialization may begin after several days and typically requires two to four weeks [128]. Skin that remained attached during the acute process may peel gradually, and nails may be shed.

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COMPLICATIONS

In severe cases with extensive skin detachment,

acute complications may include massive loss of fluids through the denuded skin, electrolyte imbalance, hypovolemic shock with renal failure, bacteremia, insulin resistance, hypercatabolic state, and multiple organ dysfunction syndrome. Abdominal compartment syndrome secondary to excessive replacement fluid therapy has been reported in a few patients [129]. (See "Abdominal compartment syndrome in adults".)

Infections — Patients with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are at high risk of bacterial infection. Sepsis and septic shock, most often caused by Staphylococcus aureus and Pseudomonas aeruginosa, are the main causes of death in these patients. In a study of 179 patients with SJS/TEN, bacteremia was detected in 48 (27 percent) [130]. The main pathogens implicated were S. aureus, P. aeruginosa, and Enterobacteriaceae organisms. The risk of bacteremia was higher in patients older than 40 years, in those with skin detachment on more than 30 percent of body surface area (BSA), and in those with greater than 10,000 white blood cell count. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)

Pulmonary complications — Pulmonary complications (eg, pneumonia, interstitial pneumonitis) are frequent. Presenting symptoms include cough and elevated respiratory rate. Strict clinical surveillance is necessary for these patients, due to the risk of progression to acute respiratory distress syndrome. Acute respiratory failure requiring mechanical ventilation has been reported in approximately 25 percent of patients with SJS/TEN [123]. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

Gastrointestinal complications — Gastrointestinal complications may result from epithelial necrosis of the esophagus, small bowel, or colon. Diarrhea, melena, small bowel ulcerations, colonic perforation, and small bowel intussusception have been reported in a few patients [131-134].

LONG-TERM SEQUELAE

Long-term sequelae of Stevens-

Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are discussed separately. (See "StevensJohnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'Long-term sequelae'.)

PATIENT EVALUATION AND DIAGNOSIS 4057

Clinical findings and history — There are no universally accepted diagnostic criteria for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and histologic findings are neither specific nor diagnostic. Despite these limitations, the diagnosis of SJS or TEN would be appropriate in a patient with the following clinical features [135] (see 'Clinical presentation' above): ●A suggestive history of drug exposure or febrile illness. Drug exposure commonly precedes the onset of symptoms by one to four weeks (average 14 days), but re-exposure may result in onset of symptoms in as little as 48 hours [136]. ●A prodrome of acute-onset febrile illness and malaise. ●A painful rash that progresses rapidly. ●Erythematous macules, targetoid lesions, or diffuse erythema progressing to vesicles and bullae (picture 1A). ●Positive Nikolsky sign and/or "bulla spread sign." ●Oral, ocular, and/or genital mucositis with painful mucosal erosions (picture 1C, 1E). ●Necrosis and sloughing of the epidermis of varying degree (picture 2C).

Assessment of drug causality — For patients suspected to have SJS/TEN, the identification of the causative drug is essential because early withdrawal of the offending agent may improve the prognosis [137]. In addition, the identification of the culprit drug is of paramount importance to prevent re-exposure in patients recovering from SJS/TEN. The assessment of drug causality is based upon detailed history and clinical judgement. Information about the drugs that are most frequently associated with SJS/TEN is helpful (table 2). An algorithm of drug causality for epidermal necrolysis (ALDEN) has been developed as a tool for rapid assessment of drug causality in patients presenting with SJS/TEN, particularly in those exposed to multiple medications [16]. Each potentially offending drug is assigned a score from -11 to 10 based upon six parameters (table 5): ●Time delay from initial drug intake to onset of reaction ●Probability of drug presence in the body on the index day ●A previous history of exposure to the same drug, with or without reaction ●Presence of the drug beyond the progression phase of the disease ●Drug notoriety as a cause of SJS/TEN based upon previous studies ●Presence or absence of other etiologic causes

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The score is categorized as very probable (≥6), probable (4 to 5), possible (2 to 3), unlikely (0 to 1), and very unlikely (≤0).

Assessment of severity — The severity and prognosis of SJS/TEN depends upon the amount of skin detachment or "detachable" skin (ie, skin with positive Nikolsky sign). The extent of epidermal detachments should be estimated and recorded as the percentage of the body surface area (BSA) involved. The correct evaluation of the extent of lesions may be difficult in areas with spotty lesions. It is useful to remember that in both children and adults the surface of the patient's hand, including palm and fingers, corresponds to approximately 1 percent of the total BSA. (See "Assessment and classification of burn injury", section on 'Extent of burn injury'.) The prognosis of individual patients can be rapidly evaluated in the early stages of disease by applying a prognostic scoring system called SCORTEN, based upon seven clinical and laboratory variables (table 6) [127]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'SCORTEN score'.)

Skin biopsy — A skin biopsy for routine histopathologic examination and possibly direct immunofluorescence is useful in confirming the diagnosis and excluding other conditions that may mimic SJS/TEN. An appropriate sample may be obtained by performing a large (>4 mm) punch biopsy or a deep shave biopsy ("saucerization"). In the early stages of disease, apoptotic keratinocytes are scattered in the basal layer of the epidermis, and there is a perivascular, mononuclear, inflammatory infiltrate in the papillary dermis composed primarily of T lymphocytes [101]. This infiltrate is not diagnostic and may be seen in a wide variety of conditions, including a simple drug-induced exanthem. As the lesions progress, frank subepidermal bullae develop, with full-thickness epidermal necrosis (picture 3). Direct immunofluorescence is always negative.

Laboratory and imaging studies — The laboratory and imaging evaluation of patients presenting with SJS/TEN includes: ●Complete blood count with differential, metabolic panel (ie, glucose, electrolytes, blood urea nitrogen, creatinine, calcium, total protein, albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase), erythrocyte sedimentation rate, and C-reactive protein. ●Bacterial and fungal cultures should be performed from blood, wounds, and mucosal lesions. Because of the high risk of bacterial superinfection and sepsis in these patients, cultures should be repeated throughout the acute phase of the disease.

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●In children, polymerase chain reaction and/or serologies for M. pneumoniae infection should be obtained in the early stage of disease and three weeks later. (See "Mycoplasma pneumoniae infection in children", section on 'Diagnosis'.) ●A chest radiograph should be obtained in all patients, due to high risk of pneumonia and interstitial pneumonitis. (See 'Pulmonary complications' above.)

Investigational tests — Candidate serum markers of SJS/TEN, including soluble Fas ligand, soluble CD40 ligand, granulysin, interleukin (IL)-15, and high-mobility group box 1 protein (HMGB1, a nonhistone nuclear protein released by necrotic and apoptotic cells), have been evaluated in a few small studies [97,98,138-140]. However, further studies are necessary to determine whether these markers may be helpful in the early diagnosis of SJS/TEN. (See 'Pathogenesis' above.)

DIFFERENTIAL DIAGNOSIS

The differential diagnosis

of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) includes: ●Erythema multiforme – Erythema multiforme usually presents with typical target lesions or raised, atypical, targetoid lesions that are predominantly located on the extremities (picture 4). Bullae and epidermal detachment are usually limited and involve less than 10 percent of the body surface area (BSA) (table 1). In contrast with SJS/TEN, erythema multiforme is associated with infection with herpes simplex virus in approximately 90 percent of cases and only rarely with drugs. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".) ●Erythroderma and erythematous drug eruptions – The generalized and symmetric, maculopapular erythema of a drug eruption can mimic early SJS/TEN. However, exanthematous drug eruptions lack mucosal involvement and the prominent skin pain of TEN. Histology shows only a mild interface dermatitis with a perivascular, inflammatory infiltrate of lymphocytes, neutrophils, and eosinophils. (See "Erythroderma in adults" and "Exanthematous (maculopapular) drug eruption".) ●Acute generalized exanthematous pustulosis – Severe cases of acute generalized exanthematous pustulosis (AGEP) may be difficult to differentiate from SJS/TEN (picture 5). AGEP typically develops within a few days of exposure to the offending drug, most often a beta-lactam antibiotic, and resolves without treatment in one to two weeks after drug discontinuation. The histologic hallmark of AGEP is a spongiform, subcorneal, and/or intraepidermal pustule (picture 5). (See "Acute generalized exanthematous pustulosis (AGEP)".) ●Generalized bullous fixed drug eruption – Generalized bullous fixed drug eruption is an extremely rare form of fixed drug eruption characterized by widespread red or brown macules or plaques with overlying, large, flaccid bullae (picture 6). In contrast with SJS/TEN, mucosal involvement is usually absent. Resolution generally occurs in one to two weeks after drug discontinuation. (See "Fixed drug eruption".)

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●Phototoxic eruptions – Severe phototoxic eruptions may be confused with SJS/TEN. Important clues to the correct diagnosis include recent sun exposure, known phototoxic properties of certain medications, and location of the lesions on sun-exposed areas. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment".) ●Staphylococcal scalded skin syndrome – Staphylococcal scalded skin syndrome (SSSS) is caused by epidermolytic toxins produced by certain strains of staphylococci and is usually seen in neonates and young children. SSSS presents with generalized erythema rapidly followed by the development of flaccid blisters and desquamation (picture 7). The mucous membranes are not involved. Histology reveals sloughing of only the upper layers of the epidermis, in contrast with the subepidermal split with full-thickness epidermal necrosis observed in SJS/TEN. (See "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Staphylococcal scalded skin syndrome'.) ●Paraneoplastic pemphigus – Paraneoplastic pemphigus is a rare disorder that can represent the initial presentation of a malignancy or occur in a patient with a known neoplastic process, such as non-Hodgkin lymphoma in adults or Castleman's disease in children. Patients may develop severe mucocutaneous disease with ocular and oral blisters and skin lesions (picture 8A-C). (See "Paraneoplastic pemphigus".) ●Linear IgA bullous dermatosis – Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disease that may mimic TEN (picture 9). Histology reveals a subepidermal blister with an underlying, neutrophil-predominant, dermal infiltrate. Direct immunofluorescence shows linear deposits of IgA along the basement membrane. (See "Linear IgA bullous dermatosis".) ●Chikungunya fever – An atypical, SJS/TEN-like form of chikungunya fever characterized by fever and generalized, vesicobullous eruption and superficial erosions has been reported in infants and young children [141,142]. However, in contrast with SJS/TEN, mucosal involvement is generally absent, and the resolution of the skin manifestations occurs in most cases in 4 to 10 days. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the

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Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topic (see "Patient education: Stevens-Johnson syndrome and toxic epidermal necrolysis (The Basics)")

SUMMARY AND RECOMMENDATIONS ●Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions, most commonly triggered by medications, characterized by extensive necrosis and detachment of the epidermis. Cases with less than 10 percent epidermal involvement are classified as SJS; those with 30 percent or more involvement are classified as TEN, and cases with 10 to 30 percent involvement are considered overlap SJS/TEN. However, we use the term "SJS/TEN" to refer collectively to SJS, TEN, and SJS/TEN overlap syndrome. (See 'Introduction and terminology' above.) ●Medications are the leading trigger of SJS/TEN in both adults and children. Allopurinol, lamotrigine, aromatic anticonvulsants, antibacterial sulfonamides, and "oxicam" or COX-2 inhibitor nonsteroidal anti-inflammatory drugs (NSAIDS) are most commonly implicated (table 2). Mycoplasma pneumoniae infection is the next most common trigger of SJS/TEN, particularly in children. (See 'Etiology' above.) ●Risk factors for SJS/TEN include human immunodeficiency virus (HIV) infection, genetic factors, concomitant viral infections, underlying autoimmune diseases, and, possibly, physical factors. (See 'Risk factors' above.) ●SJS/TEN begins with a prodrome of fever and influenza-like symptoms one to three days before the development of mucocutaneous and skin lesions. The cutaneous eruption typically starts with ill-defined, coalescing, erythematous macules with atypical target lesions (picture 1A, 2A, 2C-D). As the disease progresses, vesicles and bullae form, and within days the skin begins to slough. Mucosal involvement occurs in approximately 90 percent of cases of SJS/TEN and can precede or follow the skin eruption. (See 'Clinical presentation' above.) ●In severe cases with extensive skin detachment, acute complications may include massive loss of fluids and electrolyte imbalance, hypovolemic shock with renal failure, bacteremia, insulin resistance, hypercatabolic state, and multiple organ dysfunction syndrome. (See 'Complications' above.)

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●The diagnosis of SJS/TEN is based upon clinical and histologic findings in a patient with a history of antecedent drug exposure or febrile illness. Histologic findings on skin biopsy are supportive but not independently diagnostic. (See 'Patient evaluation and diagnosis' above.)

ACKNOWLEDGMENT

We are saddened by the death of Milton H

Nirken, MD, who passed away in August 2017. UpToDate wishes to acknowledge Dr. Nirken's past work as an author for this topic. The editorial staff at UpToDate would like to acknowledge Jean-Claude Roujeau, MD, who contributed to an earlier version of this topic review.

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Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-management-prognosis-and-longterm-sequelae/print

Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Sep 17, 2019.

INTRODUCTION

Stevens-Johnson syndrome (SJS) and toxic epidermal

necrolysis (TEN) are severe mucocutaneous adverse reactions, most commonly triggered by medications, characterized by fever and extensive necrosis and detachment of the epidermis. SJS and TEN are considered a disease continuum and are distinguished chiefly by severity, based upon the percentage of body surface involved with skin detachment [1]: ●SJS is the less severe condition, in which skin detachment is 30 percent of the body surface area (BSA) (picture 2A-D). Mucous membranes are also involved in over 90 percent of cases.

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●SJS/TEN overlap describes patients with skin detachment of 10 to 30 percent of BSA. Mucous membranes are also involved in over 90 percent of cases. We will use the term "SJS/TEN" to refer collectively to SJS, TEN, and SJS/TEN overlap. The management, prognosis, and long-term sequelae of SJS/TEN are discussed in this topic. The pathogenesis, clinical manifestations, and diagnosis are discussed separately. (See "StevensJohnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

GENERAL PRINCIPLES

Patients with suspected SJS/TEN

require immediate in-hospital evaluation for diagnosis confirmation and evaluation of severity, referral to the most appropriate health care setting (eg, intensive care unit, burn unit, specialized dermatology unit, where present), and initiation of supportive treatment. The management of these patients requires a multidisciplinary approach by a team of clinicians experienced in treating SJS/TEN. Our approach is discussed below. It is generally consistent with the 2016 and 2018 United Kingdom guidelines for the management of SJS/TEN in adults and children [2,3].

RAPID EVALUATION OF SEVERITY AND PROGNOSIS

Patients suspected to have SJS and TEN should be

admitted to the hospital. As soon as the diagnosis of SJS or TEN has been established, the severity and prognosis of the disease should be rapidly determined to define the appropriate medical setting for management [2,4].

SCORTEN score — The prognosis of individual patients can be rapidly evaluated on admission by applying a prognostic scoring system called SCORTEN [5]. SCORTEN is based upon seven independent and easily measured clinical and laboratory variables (table 1) and has been validated for use on days one and three of hospitalization for SJS/TEN [6,7]. The SCORTEN score may be used to determine which clinical setting (intensive therapy/burn unit or nonspecialized ward) is appropriate for the management of the individual patient, as described below. The survival curves based upon the SCORTEN score at admission (figure 1) may be helpful when discussing a patient's prognosis with family members or medical staff [7]. However, it should be noted that, due to progresses in the management of SJS/TEN patients in specialized centers, including burn units, SCORTEN may overestimate the mortality risk in those settings [8].

Referral to intensive therapy or burn unit — The decision to refer the patient to an intensive care or burn unit should be made on a case-by-case basis, based upon the extent of skin involvement and the presence of comorbidities. Patients with a limited skin involvement, a SCORTEN score (table 1) of 0 or 1, and disease that is not rapidly

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progressing may be treated in nonspecialized wards [9]. Patients with more severe disease (skin detachment >30 percent of the body surface area) or a SCORTEN score ≥2 should be transferred to intensive care units, burn units, or specialized dermatology units, if available. Several studies indicate that prognosis is better for patients transferred promptly to a burn care unit or intensive care unit. In a retrospective multicenter review of 199 patients with TEN treated at burn care centers, the overall mortality was 32 percent compared with 51 percent among patients initially cared for in other settings and transferred to a burn center more than one week after disease onset [10].

PROMPT WITHDRAWAL OF CULPRIT DRUG

For patients with suspected SJS and TEN induced by

medications (table 2), early identification and withdrawal of the offending agent may improve the prognosis. In a 10-year observational study of 113 patients with TEN or SJS, early withdrawal of the causative drug reduced the risk of death by 30 percent for each day before the development of blisters and erosions (odds ratio [OR] 0.69; 95% CI 0.53-0.89) [11]. However, exposure to drugs with long half-lives was associated with an increased risk of death, independently from early or late withdrawal (OR 4.9; 95% CI 1.3-18.9).

SUPPORTIVE CARE

The main principles of supportive care are the

same as for major burns and include wound care, fluid and electrolyte management, nutritional support, temperature management, pain control, and monitoring or treatment of superinfections [1214]. (See "Treatment of superficial burns requiring hospital admission".) Ocular involvement requires immediate attention and care to reduce the risk of permanent ocular sequelae.

Wound care — The extent of epidermal detachment should be evaluated daily or every few days, depending upon the type of wound management, and may be expressed as the percentage of body surface area (BSA) that is involved (as for burns) (figure 2). However, the evaluation of the affected skin area may be difficult in patients presenting with small blisters scattered over large body areas. The optimal approach to wound care in SJS/TEN has not been determined, and different approaches are used at different centers [15-17]. ●Some centers surgically débride wounds and use whirlpool therapy to remove necrotic epidermis [18]. Other centers use "antishear" wound care, in which the detached skin is left in place to act like a biologic dressing [19]. In an observational study, these two approaches (as practiced at expert centers) were associated with equivalent rates of survival and re-epithelialization [19].

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●Nonadherent nanocrystalline gauze materials containing silver are increasingly replacing petrolatum-impregnated gauze for the coverage of the denuded skin, although controlled trials comparing the two have not been performed [20,21]. Nanocrystalline gauze dressings may be left in place for up to seven days, decreasing the frequency of painful dressing changes. Biosynthetic skin substitutes (eg, Biobrane, Aquacel AG, Suprathel) have also been used successfully [17,22]. ●Fluidized air beds are useful when the patient's backside is significantly denuded, although these beds can make examination and care of those surfaces challenging [23,24].

Fluids and nutrition — Fluid and electrolyte imbalances may occur due to increased water loss from the denuded dermis, but replacement volumes are approximately onethird lower than those needed for burn victims [25,26]. One study of 21 patients with TEN and extensive skin loss treated at a burn center estimated that fluid requirements during the first 24 hours may be accurately determined by using the formula: 2 mL/kg of body weight multiplied by percentage of body skin area skin detachment [27].   Room temperature should be increased to 30 to 32°C to prevent excessive caloric expenditures due to epidermal loss [28]. Heated-air body warmers may also be used. Oral feeding, via a nasogastric tube if necessary, should be initiated as soon as possible and continued throughout the acute phase of SJS/TEN [2,12]. Passage of a nasogastric tube should be performed with great care to minimize damage to affected mucous membranes.

Pain control — Cutaneous pain is common in patients with SJS/TEN and may be severe in those with extensive skin detachment. Pain may also be exacerbated by wound care procedures. Pain evaluation and administration of adequate analgesia is thus a central component of the initial management of patients with SJS/TEN. The principles of pain management in patients with SJS/TEN are similar to those used in burn patients. (See "Management of burn wound pain and itching".) The intensity of pain can be evaluated in older children and adults using a numeric scale, which allows a patient to describe the pain on a scale of increasing severity, typically from 0 to 10 (figure 3). This evaluation may be repeated every four hours during the acute phase and guide the choice of the type and dose of medication [29]. Mild pain (intensity 4 g/kg [66-70]. However, subsequent studies, including a large European cohort study, could not demonstrate a significant survival advantage for patients treated with either high- or low-dose IVIG compared with patients treated with supportive care only, as summarized below: ●A review of case series with at least 9 patients evaluated the outcome of 156 patients (22 with SJS and 134 with TEN or SJS/TEN overlap) treated with IVIG [59]. The mean total dose of IVIG ranged from 1.6 to 3.9 g/kg. Treatment was started 3.5 to 9.2 days after the disease onset and given for two to four days. The average mortality rate was 20.5 percent (range 0 to 42 percent), with higher rates in centers where lower doses of IVIG were used or the time to treatment was longer. ●In a series of 281 patients with SJS/TEN from the EuroSCAR cohort study, 35 patients were treated with IVIG alone and 40 with IVIG plus systemic corticosteroids [45]. The dose of IVIG ranged from 0.7 to 2.3 g/kg and was given in one to seven days. The mortality rate was 34 percent in the group

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treated with IVIG alone, 18 percent in the group treated with IVIG and corticosteroids, and 18 percent in a group of 87 patients treated with supportive measures alone. ●In a systematic review of 439 patients with SJS/TEN, the mortality rate was 24 percent among patients treated with IVIG and 27 percent among those treated with supportive measures only [55]. The observed mortality rate in the IVIG group was slightly lower than that predicted by the SCORTEN score (24 versus 29 percent). (See 'SCORTEN score' above.) ●In a series of 64 cases of TEN and SJS/TEN (mean SCORTEN score 2.6) treated with IVIG, the overall mortality rate was 31 percent [71]. Mortality was similar among patients treated with 80 percent in 41 of 45 patients treated with EGFR and TK inhibitors [78]. Pruritus did not recur in 87 percent of patients

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during the 90-day study period. However, aprepitant should be used with caution in patients receiving erlotinib, since aprepitant-induced inhibition of the liver cytochrome P450 3A4 may increase the trough levels of erlotinib [79]. GABA agonists such as gabapentin and pregabalin may be tried if oral antihistamines are ineffective. Evidence of benefit in patients with acneiform eruption secondary to EGFR inhibitors is limited [80], but they are used to treat other forms of chronic pruritus. (See "Pruritus: Overview of management", section on 'Anticonvulsants'.)

Patients with grade 1 rash — For patients with grade 1 rash (table 1), we suggest topical corticosteroids and topical antibiotics (algorithm 1). We typically use lowpotency topical corticosteroids (groups 6 and 7 (table 4)) plus clindamycin 1% or dapsone 5% gel twice a day for at least four weeks. We generally reassess patients after four weeks of treatment. If the acneiform eruption has not improved or has worsened, patients are treated in the same way as those with grade 2 rash.

Patients with grade 2 rash — For patients with grade 2 rash (table 1), we suggest topical corticosteroids and oral tetracycline antibiotics (algorithm 1). We use low potency topical corticosteroids (group six (table 4)) twice a day on the face and neck and fluocinonide 0.05% cream twice a day on chest and back for at least four weeks and either doxycycline 100 mg or minocycline 100 mg twice per day for four to six weeks. If a patient with grade 2 rash is already on an oral tetracycline, an alternative antibiotic such as a first-generation oral cephalosporin (eg, cephalexin 500 mg twice per day, cefadroxil 500 mg twice per day) or trimethoprim-sulfamethoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice per day) can be given for four weeks. If viral or bacterial superinfection is suspected, cultures of exudates should be obtained prior to the initiation of the antibiotic to determine appropriate antimicrobial therapy. We generally reassess patients after two weeks of treatment. If no improvement or worsening is noted after two weeks of treatment, patients are treated in the same way as those with grade ≥3 rash.   The use of topical corticosteroids and oral antibiotics for the treatment of the acneiform eruption has not been evaluated in randomized trials. Their use is based upon case series and case reports and clinical experience [76,77,81-85].

Patients with grade ≥3 rash — In patients with grade ≥3 rash, intolerable grade 2 rash, or rash that interferes with self-care activities of daily living or impairs the quality of life (table 1), discontinuation or interruption of EGFR inhibitor therapy is warranted. Treatment may be reinitiated after toxicity has resolved to baseline or less than or equal to grade 1, according to the instructions provided in the prescribing information for the particular agent [56,76].

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In addition to discontinuation or interruption of EGFR inhibitor therapy, we suggest treatment with oral antibiotics plus a short course of systemic corticosteroids (algorithm 1). Oral doxycycline 100 mg or minocycline 100 mg is given twice a day for at least four weeks. First-generation oral cephalosporins (eg, cephalexin 500 mg twice per day, cefadroxil 500 mg twice per day) or trimethoprim-sulfamethoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg/twice per day) given for four weeks can be used as alternatives when patients do not benefit from tetracycline antibiotics or have a culture-proven infection with organisms resistant to tetracycline antibiotics. Oral prednisone 0.5 mg/kg up to a maximum of 40 mg per day is given for seven days. Improvement should be noted within two weeks. If a viral or bacterial superinfection is suspected, cultures of exudates should be obtained prior to the initiation of the antibiotic treatment to determine appropriate antimicrobial therapy. Oral corticosteroids for the treatment of severe acneiform eruption have not been evaluated in randomized trials and their use is based upon their antiinflammatory properties and clinical experience.  

Refractory grade ≥3 rash — For patients with grade ≥3 rash that does not improve with the regimen of oral antibiotics plus systemic corticosteroids described above, lowdose isotretinoin (20 to 30 mg per day) or acitretin (25 mg a day) may be tried [81]. Oral tetracyclines are discontinued before initiating oral isotretinoin. Improvement is generally evident within four weeks [86]. Therapy is continued for at least two months after patients resume EGFR inhibitor at regular dose. In a retrospective chart review, nine patients treated with EGFR or MEK inhibitors with or without immunotherapy who developed an acneiform eruption were treated with acitretin or isotretinoin [87]. Improvement was evident within one month, and the rash remained stable at grade 1 or less without a need for dose modification of cancer therapy. Improvement of pruritus and pain was also noted following initiation of oral retinoids. Isotretinoin may aggravate some EGFR inhibitor adverse effects such as skin dryness, cheilitis, or photosensitivity. Skin dryness and cheilitis can be alleviated by the application of alcohol-free emollients multiple times per day. Patients with increased photosensitivity should adopt sun protection measures, which include limiting the exposure to the sun, wearing protective clothing, and regular use of sunscreens with SPF ≥30. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Mucocutaneous'.) If no improvement or worsening is noted despite dose modification, treatment with systemic antibiotics and systemic corticosteroids, or oral isotretinoin, interruption or discontinuation of EGFR inhibitor treatment may be necessary. Decisions regarding interruption or discontinuation of EGFR inhibitor therapy must involve the patient, the patient's oncologist, and the patient's dermatologist; the potential risks and benefits and the patient's values and preferences must be considered.

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The evidence for efficacy of oral isotretinoin for severe acneiform eruption is limited to single case reports and small case series [85,86,88,89]. Indirect evidence of efficacy is derived from studies of treatment of acne vulgaris. (See "Treatment of acne vulgaris", section on 'Oral isotretinoin'.)

PREVENTION General measures — Before initiating treatment with EGFR inhibitors, patients should be educated about adopting general skin care measures, which include [70]: ●Regularly using a broad-spectrum (UVA/UVB) sunscreen with SPF ≥15 with inorganic ingredients (zinc oxide, titanium dioxide) ●Limiting excessive sun exposure ●Using thick, alcohol-free emollients twice daily ●Avoiding over the counter anti-acne medications and alcohol-based skin care products ●Reducing the frequency and duration of hot showers ●Using tepid/lukewarm water for bathing ●Avoiding antibacterial or perfumed soaps and detergents

Preemptive therapy — We suggest prophylactic oral tetracyclines in conjunction with topical corticosteroids for patients initiating treatment with EGFR inhibitors. Treatment is started on the same day as EGFR inhibitor therapy. We typically use doxycycline 100 mg twice a day or minocycline 100 mg daily for six to eight weeks. A low-potency topical corticosteroid (eg, hydrocortisone 2.5%, alclometasone 0.05% cream) is applied twice daily to the face and chest. The efficacy of oral tetracyclines for the prevention of the acneiform eruption has been evaluated in two meta-analyses. ●In a 2012 meta-analysis of four placebo-controlled trials [90-93] including 351 patients, patients who initiated prophylactic treatment with a tetracycline on the same day or the day before initiating EGFR inhibitor therapy had a decreased incidence of moderate to severe (grade ≥2 (table 1)) folliculitis (combined odds ratio 0.19, 95% CI 0.12-0.31) [94]. However, the benefit was lost after discontinuation of treatment. The incidence of mild (grade 1 (table 1)) folliculitis was not changed by prophylactic tetracyclines. The data were insufficient to determine the optimal treatment regimen and duration.

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●A subsequent 2016 meta-analysis including nine randomized trials and four observational studies (1073 patients) confirmed the benefit of preemptive antibiotic therapy for the prevention of the acneic eruption [95]. In this meta-analysis, prophylactic treatment with doxycycline or minocycline reduced by approximately 50 percent the risk of developing a skin rash of any grade (OR 0.54, 95% CI 0.40-0.73) and by approximately 70 percent the risk of grade 2 or 3 rash (OR 0.36, 95% CI 0.220.60). The results were similar when the analysis was restricted to randomized trials.   There are a few studies evaluating the efficacy of topical treatments alone or in conjunction with oral antibiotics for the prevention of acneiform eruption: ●Tazarotene – In a randomized trial of 48 patients initiating cetuximab therapy with or without prophylactic minocycline, tazarotene 0.05% cream applied to one side of the face was not effective in preventing the acneiform eruption when used as a single agent and provided little benefit beyond that seen with minocycline alone when used in combination with oral minocycline [90]. In addition, tazarotene was associated with significant skin irritation.   ●Topical vitamin K1 – In a randomized trial including 126 colon cancer patients initiating cetuximab therapy, vitamin K1 cream given in combination with oral doxycycline was not effective in preventing the acneiform eruption compared with doxycycline and vehicle [96]. Grade 2 to 4 acneiform rash (defined according to the Common Terminology Criteria for Adverse Events [CTCAE] v.4.02) occurred in 73 percent of patients in the vitamin K1 group and 64 percent of those in the vehicle group. ●Topical dapsone 5% gel – In a small,randomized,split-face/chest study of 11 patients, dapsone 5% gel applied twice daily was associated with a nonstatistically significant reduction in lesion count compared with a moisturizer [97]. All patients were also treated with minocycline 100 mg daily. ●Topical erythromycin 2% ointment – In a randomized trial, 88 patients with colorectal cancer receiving panitumumab were treated with either doxycycline 100 mg twice daily or erythromycin ointment 2% followed by doxycycline in case of insufficient activity [98]. More patients treated with prophylactic erythromycin 2% ointment developed moderate or severe skin toxicity, as measured with the WoMo (Wollenberg and Moosmann) score [99], at an earlier time compared with those treated with doxycycline.

EXPERIMENTAL TREATMENTS Topical recombinant epidermal growth factor — Two small studies have evaluated the efficacy of an ointment containing recombinant epidermal growth factor (EGF) [100,101]: ●In an open-label study, 46 patients with grade ≥2 erlotinib-related skin effects (ERSE) were treated twice daily with an EGF ointment containing 1 part per million (ppm) of nepidermin [101]. At eight weeks, the overall response rate was 78 percent, with 31 patients (67 percent) having grade 2, 3, or 4

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ERSE downgraded to grade ≤1 and 5 patients (11 percent) having grade 3 or 4 ERSE downgraded to grade 2 and lasting for at least two weeks. ●In a randomized trial, 80 patients with grade ≥2 ERSE received EGF ointment at a concentration of 1 ppm, 20 ppm, or placebo twice daily [100]. Response was defined as reduction of ERSE from grade ≥2 to grade ≤1 or grade ≥3 ERSE downgrading to grade 2 and lasting for at least two weeks. The response rate was 61.5 percent (95% CI 40.6-79.8 percent) in the 1 ppm group, 77.8 percent (95% CI 57.7-91.4 percent) in the 20 ppm group, and 44.4 percent (95% CI 25.5-64.7 percent) in the placebo group. Adverse events related to EGF treatment occurred in three patients (skin fissure, pyogenic granuloma, and periungual overgrowth).

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of symptoms and toxicities of anticancer therapy".)

SUMMARY AND RECOMMENDATIONS ●The acneiform (papulopustular) eruption is the prototypical cutaneous adverse reaction to treatment with EGFR inhibitors. It occurs in over 80 percent of patients and is more frequent in older patients and in patients with light skin phototypes (table 2). (See 'Introduction' above and 'Epidemiology' above.) ●The eruption develops mainly in areas rich in sebaceous glands (eg, scalp, face, upper trunk) within the first two weeks of therapy (picture 1). Erythematous papules and pustules evolve to crusted lesions and eventually resolve leaving persistent erythema, telangiectasias, and skin dryness. Bacterial superinfection may occur. (See 'Clinical manifestations' above and 'Clinical course' above.) ●The diagnosis of acneiform eruption in patients receiving EGFR inhibitor therapy is usually straightforward, based upon the morphology and distribution of the skin lesions (eg, erythematous and follicular papules or pustules in areas rich in sebaceous glands with sparing of palmoplantar surfaces) (picture 1). The severity is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (table 1). (See 'Diagnosis' above.) ●We suggest prophylactic oral tetracyclines in conjunction with topical corticosteroids for patients initiating treatment with EGFR inhibitors (Grade 2A). Treatment is started on the same day as EGFR inhibitor therapy. We typically use doxycycline 100 mg twice a day or minocycline 100 mg daily for six to eight weeks; low-potency corticosteroids such as hydrocortisone 2.5% or alclometasone 0.05% cream are applied twice a day. (See 'Preemptive therapy' above.)

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●For patients with grade 1 rash (table 1), we suggest topical corticosteroids with or without topical antibiotics (algorithm 1) (Grade 2C). We use low potency topical corticosteroids (group six (table 4)) twice a day for four weeks and clindamycin 1% gel twice a day for four weeks. (See 'Patients with grade 1 rash' above.) ●For patients with grade 2 rash (table 1) who are not taking prophylactic tetracyclines, we suggest topical corticosteroids and oral tetracycline antibiotics (algorithm 1) (Grade 2C). We use low potency topical corticosteroids (group six (table 4)) twice a day for four weeks and either doxycycline 100 mg or minocycline 100 mg orally twice a day for four weeks. First-generation oral cephalosporins (eg, cephalexin, cefadroxil) or trimethoprim-sulfamethoxazole can be used as alternative antibiotics for patients who are taking prophylactic tetracyclines or do not benefit from tetracyclines. (See 'Patients with grade 2 rash' above.) ●For patients with grade ≥3 rash who are not taking prophylactic tetracyclines, we suggest treatment with oral tetracyclines plus a short course of systemic corticosteroids in addition to EGFR inhibitor dose modification (algorithm 1) (Grade 2C). We use either doxycycline 100 mg or minocycline 100 mg orally twice a day for at least four weeks and prednisone 0.5 mg/kg orally once per day for seven days. First-generation oral cephalosporins (eg, cephalexin, cefadroxil) or trimethoprim-sulfamethoxazole can be used as alternative antibiotics for patients who are taking prophylactic tetracyclines or do not benefit from tetracyclines. (See 'Patients with grade ≥3 rash' above.)

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Cutaneous side effects of conventional chemotherapy agents uptodate.com/contents/cutaneous-side-effects-of-conventional-chemotherapy-agents/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jan 15, 2019.

INTRODUCTION

Systemic and local treatments for cancer can cause a

number of changes in the skin, mucous membranes, hair, and nails [1-6]. When dermatologic lesions arise in patients being treated for cancer, they may represent a side effect of therapy, but other etiologies need to be considered. These include a cutaneous reaction to other drugs, exacerbation of a previously existing condition, infection, metastatic tumor involvement, a paraneoplastic phenomenon, graft-versus-host disease, or a nutritional disorder.

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Accurate diagnosis and management of chemotherapy-related side effects require the clinician to be knowledgeable of the most commonly reported cutaneous reaction patterns for the drugs the patient is receiving. The clinician must also be familiar with the cutaneous manifestations of certain cancers, as well as the dermatologic effects of other forms of cancer treatments. In some cases, diagnostic uncertainty can only be clarified with a rechallenge, and the clinician must determine whether rechallenge is safe and medically justifiable. The cutaneous adverse effects of conventional cytotoxic cancer therapy agents are presented here. Other mucocutaneous complications of cancer treatment are discussed separately. ●(See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".) ●(See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".) ●(See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".) ●(See "Extravasation injury from chemotherapy and other non-antineoplastic vesicants".) ●(See "Alopecia related to systemic cancer therapy".) ●(See "Oral toxicity associated with chemotherapy".)

IMMUNE-MEDIATED INFUSION REACTIONS

Virtually all chemotherapeutic agents have the potential to initiate

an infusion reaction when administered systemically, although few are immune mediated. Various types of skin eruptions can accompany infusion reactions, which may take the form of an anaphylactic reaction or a mild "standard infusion reaction." Infusion reactions to specific chemotherapy agents and issues related to prophylaxis and management are discussed separately. (See "Infusion reactions to systemic chemotherapy".) The following is a brief synopsis of the types of immune-mediated hypersensitivity reactions that can either directly or indirectly affect the skin and mucous membranes, and their clinical manifestations. ●Most infusion reactions with the platinum drugs (cisplatin, carboplatin, and oxaliplatin) are classic type I immunoglobulin E (IgE)-mediated allergic reactions (table 1). Urticaria, pruritus, angioedema, and other symptoms of anaphylaxis typically develop within one hour of drug administration, although such reactions may occur up to 24 hours following exposure. ●Type III reactions result from formation and tissue deposition of antigen-antibody complexes. Type III reactions may be responsible for the cutaneous vasculitis seen with methotrexate [7,8] and the serum sickness-like reaction following infusion of rituximab. (See "Serum sickness and serum

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sickness-like reactions" and "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".) ●Type IV reactions are mediated by activated T cells. Contact dermatitis to topical mechlorethamine (nitrogen mustard) is an example of a classic type IV allergic reaction to a chemotherapy agent [911]. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".) Other immune-mediated mechanisms that are incompletely understood are thought to underlie Stevens-Johnson syndrome/toxic epidermal necrolysis and certain allergic exanthematous drug rashes. (See 'Diffuse erythema and exfoliative dermatitis' below and 'Stevens-Johnson syndrome/toxic epidermal necrolysis' below.)

PIGMENTARY CHANGES

Pigmentary changes involving

the skin, nails, and mucous membranes are common in patients receiving cytotoxic drugs, particularly alkylating agents and antitumor antibiotics (table 2) [12]. The area of enhanced pigmentation may be localized or more diffuse, and it may affect the skin, mucous membranes, hair, and/or nails. The pigmentary changes usually resolve with drug discontinuation but may persist. As an example, the rare gingival margin hyperpigmentation seen with cyclophosphamide is usually permanent. Pigmentary changes may be diffuse or localized.

Fluoropyrimidines — Fluorouracil is one of the most ubiquitous drugs used in the treatment of malignancy. It is often associated with a hyperpigmentation reaction that may affect the skin diffusely or locally (in sun-exposed areas), in a serpentine manner (a pigmentary pattern that follows an underlying vein proximal to an infusion site), darken the nail beds, and induce mucosal pigmentation of the tongue and conjunctiva. Topical fluorouracil can induce hyperpigmentation in treated areas. The fluorouracil derivative tegafur can induce wellcircumscribed, brown to black, macular pigmentation that appears on the palms, soles, nails, and glans penis; the localization in these cases is unexplained. Hyperpigmentation associated with fluorouracil usually resolves within weeks to several months after cessation of therapy; however, in certain cases, nail hyperpigmentation may persist for years [13-17].

Other drugs Diffuse reaction — In addition to fluorouracil, many systemic medications induce pigmentary reaction patterns that affect the skin in a diffuse manner. As examples: ●Busulfan causes a generalized skin darkening (the so-called "busulfan tan") that can mimic the cutaneous manifestations of Addison's disease. Although busulfan can also cause adrenal insufficiency, the skin pigmentary change is thought instead to be secondary to a toxic effect on melanocytes [18,19]. Features that can help to distinguish cutaneous busulfan toxicity from true

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Addison's disease include normal levels of melanocyte-stimulating hormone and adrenocorticotropic hormone (ACTH). (See "Clinical manifestations of adrenal insufficiency in adults".) ●Pegylated liposomal doxorubicin can induce a macular hyperpigmentation over the trunk and extremities, including the palms and soles [20]. This reaction has not been described with unencapsulated doxorubicin. ●Hyperpigmentation due to hydroxyurea may affect the face, neck, lower arms, palms, and nails; pigmentation can also be accentuated in areas of pressure or trauma [21,22]. This pressure-induced hyperpigmentation is also reported for cisplatin [23]. ●Methotrexate can rarely induce a diffuse, brown skin hyperpigmentation [24]. ●Procarbazine has been associated with generalized melanosis [25].

Local — Local changes in skin pigmentation may be associated with intrinsic, anatomic features of the skin (eg, mucous membranes, skin creases, flexural or intertriginous areas, palms or soles, and face). However, a suspected local drug reaction may be due to other extrinsic factors that act in combination with the drug. In addition to fluorouracil, other examples include thiotepa, ifosfamide, and docetaxel (sites of adhesive placement on the skin); cisplatin, hydroxyurea, and bleomycin (sites of trauma or pressure); and daunorubicin (sun-exposed areas) [1,26]. The local hyperpigmentation seen in areas of skin exposed to adhesive may reflect secretion of the drug in sweat. Some of these reactions may represent postinflammatory hyperpigmentation rather than a local effect of the drug itself, especially if administration of the agent is associated with trauma, skin irritation, or a local allergic reaction (ie, contact dermatitis). The following are examples of local chemotherapy-induced hyperpigmentation: ●The pigmentary changes caused by bleomycin, cyclophosphamide, busulfan, and doxorubicin have a predilection for flexural areas and palmar creases. Ifosfamide hyperpigmentation can occur in flexural areas, dorsal and plantar surfaces of the feet, extensor surfaces of fingers and toes, on the scrotum, and occasionally on large areas of the trunk; it may also occur under occlusive dressings. ●Mitoxantrone hyperpigmentation can affect the face, dorsum of the hands, and nails. ●Daunorubicin may induce annular or polycyclic pigmentation of the scalp [1]. ●Mucosal hyperpigmentation has been associated with busulfan, cyclophosphamide (gingiva), tegafur (lower lip as well as glans penis), doxorubicin (tongue and buccal mucosa), and cisplatin [1] as well as fluorouracil. ●Like topical fluorouracil, topical mechlorethamine can induce hyperpigmentation in treated areas.

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Serpentine, flagellate, and reticular hyperpigmentation — Serpentine hyperpigmentation describes a supravenous pigmentary pattern that follows the course of an underlying vein proximal to an infusion site (picture 1). This phenomenon is most commonly seen with fluorouracil but has also been associated with fotemustine, vincristine, vinorelbine, and docetaxel [4]. Serpentine hyperpigmentation has also been reported with some combination regimens, such as CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) for lymphoma treatment [27,28]. Linear (flagellate) hyperpigmentation (picture 2) may be seen with bleomycin [29,30]. Multiple linear, erythematous or hyperpigmented streaks arise at sites of scratching or other minor traumas to the skin. Generalized pruritus is common and may precede the eruption. Paclitaxel, cytarabine, fluorouracil, and idarubicin may induce a reticular hyperpigmentation predominantly located on the trunk and lower extremities [31,32]. Pruritus is often an accompanying symptom.

Hair — In addition to causing alopecia, chemotherapy can also cause pigmentary changes in hair. (See "Alopecia related to systemic cancer therapy".) ●Both cisplatin and cyclophosphamide can induce hair color change; with cyclophosphamide, the range is from light red to black. ●Methotrexate may induce hyperpigmentation of scalp hair, eyebrow hair, and eyelashes; this tends to occur in bands that alternate with the normal color, a feature known as the "flag sign" [33]. This results from alternating periods of treatment and no treatment. ●One man receiving therapy with bleomycin, doxorubicin, and vincristine experienced hair color change from black to red [1].

NAIL DISORDERS

Nonspecific nail changes are commonly observed

during the course of systemic cancer treatment [34]. They include transverse grooves on the nail plate (Beau's lines) and onychomadesis (shedding of the nail), due to prolonged inactivation of the nail matrix (picture 3A-B). Fingernails grow approximately 0.1 mm per day; thus, the distance of a Beau's line from the proximal nail fold gives an approximate indication of when the acute insult occurred. (See "Overview of nail disorders", section on 'Transverse grooves (Beau lines)'.) Cytotoxic chemotherapeutic agents have also been associated with pigmentary changes (chromonychia) and onycholysis, a detachment of the nail plate from the nail bed. Other inflammatory reaction patterns involving the nail folds include pyogenic granuloma and acute exudative paronychia that may progress to subungual abscess.

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The various nail disorders that are associated with individual chemotherapy agents are summarized in the table (table 3), and some are described below. After discontinuation of chemotherapy, all of these conditions generally resolve as the nail grows out.

Pigmentary changes — Medications may induce diffuse hyperpigmentation or banding/streaking of the nail plate (melanonychia striata) or bed. Besides fluorouracil, a wide range of agents have been implicated, including alkylating agents, taxanes, antimetabolites (hydroxyurea, cyclophosphamide), anthracyclines, and antitumor antibiotics, among others (table 3) [1,34]. Melanonychia appears one to two months after the initiation of chemotherapy and may be associated with cutaneous and mucosal hyperpigmentations. Taxanes may also induce a red nail discoloration, due to subungual hemorrhages, and true leukonychia (picture 4) [35]. Leukonychia is also observed in patients treated with doxorubicin, cyclophosphamide, and vincristine [36].

Onycholysis — Onycholysis is caused by inflammation in the nail bed, which leads to detachment of the overlying nail. The cytotoxic drugs most frequently associated with onycholysis are the taxanes paclitaxel and docetaxel (picture 5) [4]. Other medications that have been reported to cause onycholysis include cyclophosphamide, doxorubicin, etoposide, fluorouracil, hydroxyurea, capecitabine, ixabepilone, and the combination of bleomycin plus vinblastine [1,37]. An intriguing association between denervation and protection from chemotherapy-induced nail changes was suggested in a report of a patient with a complete right arm nerve palsy due to advanced breast cancer who developed docetaxel-related nail changes in all extremities except the paretic hand [38]. A systematic review of 12 studies supports the pretreatment prophylactic use of frozen gloves and frozen socks for the prevention of taxane-induced nail and skin toxic effects [39]. However, the included studies were generally small and showed considerable methodologic heterogeneity regarding the cooling protocols, chemotherapy regimens, and choice of control limbs. Discomfort from cold may be reduced, without changes in efficacy, by using frozen gloves prepared at a temperature of -10 to -20°C rather than at the standard temperature of -25 to -30°C [40]. A drawback of cold therapy may be a reduced exposure of the extremity to the therapeutic agent, which in theory may permit persistence of metastatic tumor cells in that location. Thus, the use of cold therapy to mitigate skin and nail toxicity must be decided on a case-by-case basis.

Inflammatory changes — A number of infectious and noninfectious inflammatory changes of the nail folds and nail bed have been reported. ●Painful paronychial inflammation, often associated with pyogenic granulomas, may be induced by etoposide, capecitabine, methotrexate, and doxorubicin. (See "Paronychia" and "Pyogenic granuloma (lobular capillary hemangioma)".)

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●Treatment with docetaxel and paclitaxel may induce an exudative paronychia with or without progression to frank abscess [4].

PHOTOSENSITIVITY

An increased sensitivity to ultraviolet (UV)

light exposure (photosensitivity) has been associated with a variety of chemotherapy agents [1,4143]. Photosensitivity reactions can be manifested in a variety of ways: ●A phototoxic reaction, which is characterized by the onset of severe erythema within minutes to hours following light exposure. These reactions are not immunologically mediated, and they usually spare sun-protected areas. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.) ●A photoallergic reaction, which is a type IV hypersensitivity reaction (table 1) that develops at least 24 hours after light exposure. Photoallergic reactions may spread to involve non-sun-exposed areas and usually cause dermatitis rather than erythema. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.) ●Photorecall phenomenon (also called UV reactivation reaction or solar burn reactivation reaction), in which the administration of a chemotherapy drug (typically methotrexate but also taxanes) in the absence of light can trigger a sunburn-like reaction in the same distribution as a sunburn that the patient may have sustained months to years before [44-46]. ●In contrast, a photoenhancement reaction can occur when patients who receive a drug (typically high-dose methotrexate) within two to five days of exposure to UV light develop severe erythema within the sun-exposed areas. ●Photo-onycholysis, in which a drug-mediated reaction to light leads to separation of the nail bed from the nail plate, most commonly affecting the distal nail.

Phototoxic reactions — A phototoxic reaction resembles an exaggerated sunburn, with erythema, edema, pain, and tenderness in sun-exposed areas, such as the face, the "V" area of the upper chest, and the dorsa of the hands. In severe cases, blistering can occur. Postinflammatory hyperpigmentation is common. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.) The clinical diagnosis is based upon the distribution of the eruption (ie, a sharp demarcation between sun-exposed versus protected sites) (picture 6A-B) and the temporal relationship to administration of the offending agent. If the diagnosis is in doubt, photo patch testing can be used as adjunctive diagnostic measures [1].

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The pathogenesis of phototoxic chemotherapy reactions is thought to involve concentration of the drug within the skin and subsequent absorption of UV light, resulting in apoptosis of keratinocytes. On biopsy, the characteristic histologic findings include dyskeratotic keratinocytes, a vacuolar interface dermatitis, and papillary dermal edema with minimal inflammation [47]. Treatment of phototoxic reactions involves discontinuation of the offending agent and avoidance of direct exposure to sunlight through the use of protective clothing and a topical sunscreen for at least two weeks. Physical sunscreens containing titanium oxide or zinc oxide are preferred because chemical sunscreens, especially oxybenzone, can be associated with photoallergic reactions (see "Selection of sunscreen and sun-protective measures"). Symptomatic treatment with cool compresses and topical steroids may be helpful. Severe cases may require systemic steroids. Patients receiving photosensitizing drugs should be counseled regarding the risk of adverse reactions to sunlight and encouraged to use UV protection with sunscreens and protective clothing.

Photoallergic reactions — In contrast to phototoxic reactions, a photoallergic reaction is characterized by pruritus rather than burning, with a papulovesicular eruption, erythema, and/or scaling over sun-exposed areas. Photosensitivity reactions to flutamide (an antiandrogen) and ftorafur (also called tegafur, a prodrug of fluorouracil) are typically photoallergic rather than phototoxic [41,48,49]. Symptoms generally clear within four to eight weeks after drug discontinuation.

Photorecall and photoenhancement — Methotrexate can cause a phototoxic recall reaction (UV reactivation reaction or solar burn reactivation) in which drug administration in the absence of light triggers a sunburn-like reaction in the same distribution as a sunburn that the patient may have sustained months or years earlier [50-52]. Symptoms are usually reproduced with rechallenge. High-dose methotrexate is also associated with photoenhancement reactions, in which drug administration within two to five days after exposure to UV light causes severe erythema in sunexposed areas. Leucovorin rescue is ineffective at preventing these reactions. In contrast to photoreactivation, retreatment with methotrexate usually does not reproduce this reaction. (See "Therapeutic use and toxicity of high-dose methotrexate".) There are isolated reports of a similar photoenhancement phenomenon with taxanes, gemcitabine, pegylated liposomal doxorubicin, and some combination cytotoxic regimen [45,53-56].

Photo-onycholysis — Photo-onycholysis is a unique adverse light reaction caused by the combination of certain chemotherapeutic agents (eg, mercaptopurine) with UV light [57-59]. Separation of the nail bed from the nail plate most commonly affects the distal nail and occurs two to four weeks after drug administration.

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SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS AND SCLERODERMA-LIKE CHANGES

Subacute

cutaneous lupus erythematosus (SCLE), manifested by annular or polycyclic, photodistributed, erythematous, and scaling lesions (picture 7A-B), has been reported following taxanes [60-62], fluorouracil and capecitabine [63], doxorubicin plus cyclophosphamide [64], and gemcitabine [65]. While phototoxicity may play a role in initiating or sustaining active SCLE, the pathogenesis also involves autoimmunity. This is supported by the presence of deposits of immunoglobulin G (IgG) and complement components on epidermal keratinocytes, immunohistopathologic findings that are identical to those found in idiopathic disease. Another shared feature of drug-induced and idiopathic SCLE is the presence of anti-Ro/SSA antibodies in a majority of cases. (See "Overview of cutaneous lupus erythematosus", section on 'Subacute cutaneous lupus erythematosus'.) Scleroderma-like changes, consisting of edema, tightening, and induration of the skin on the trunk and extremities, have been reported in patients treated with bleomycin [66], gemcitabine [67], and docetaxel [68]. The serologic workup for scleroderma was negative in these five patients, and the changes resolved following discontinuation of the drug. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

RADIATION RECALL AND ENHANCEMENT Radiation recall dermatitis — Radiation recall dermatitis (RRD) is an inflammatory skin reaction that develops in an area of previously irradiated skin after administration of certain promoting agents; most cases have been associated with chemotherapy [69]. There may be a long interval between the administration of the causative agent and the appearance of RRD. The frequency of these reactions is unclear; in one study, RRD occurred in 8 of 91 patients (9 percent) who received chemotherapy following radiation therapy [70]. (See "Radiation dermatitis", section on 'Radiation recall reaction'.) RRD was originally described with dactinomycin [71]. Since then, a number of other drugs have also been associated with this phenomenon (table 4), particularly anthracyclines and anthracycline-like drugs [72-75].   Erythema, which may be painful, is the most common sign [76,77]. Vesiculation, desquamation, and ulceration have also been reported [1]. Histologically, epidermal dysplasia, necrotic keratinocytes, and a mixed inflammatory reaction [78] characterize involved areas, with some cases showing

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psoriasiform dermatitis. Additional dermal changes include fibrosis, vasodilatation, and atypical fibroblasts. Many of these findings mimic the histologic findings of acute, severe sunburn or radiation dermatitis. RRD typically occurs with the first dose of the chemotherapy agent or combination. Drug dose appears to be an important factor, as evidenced by one report in which the patient initially received doxorubicin 27 mg/m2 two weeks after radiation therapy with no reaction; administration of a higher drug dose 12 days later resulted in RRD [79]. In addition, RRD may also require a minimum threshold radiation dose. In two case reports, patients receiving various doses of radiotherapy with bleomycin or docetaxel had a radiation recall reaction only in those skin sites that had received the highest radiation dose [80,81]. Chemotherapy agents administered by the intravenous (IV) route usually produce RRD more rapidly (range, several minutes to 14 days) than oral agents, which have a longer lag period (range, three days to two months) [82,83]. The duration of symptoms also differs with drugs administered intravenously or orally. RRD caused by IV administration usually resolves within two weeks, whereas symptoms caused by orally administered medications may last for several months [84]. The pathogenesis of RRD is controversial. An idiosyncratic hypersensitivity reaction has been proposed, with the "trauma" of prior radiation therapy sensitizing an area of skin into manifesting an immune reaction when there is little or no systemic activation (akin to the Koebner phenomenon) [74]. However, the occurrence of many of these reactions after the first drug exposure argues against an immune mechanism, and defects in DNA repair [85] as well as toxic drug effects [74] have also been proposed as causative factors. Dose reduction and the use of corticosteroids have been used as adjunctive measures to prevent recurrence of RRD, although rechallenge with the same agent does not always lead to symptom recurrence [86].

Radiation enhancement — Enhancement of the dermatologic toxicity of radiation therapy can occur if a radiosensitizing chemotherapy drug is administered concurrently or within one week of radiation therapy [1]. The drugs that have been associated with radiation enhancement (also called radiation sensitizers) are listed in the table (table 4). The synergistic interaction between chemotherapy and radiation is exploited clinically in situations in which concurrent chemotherapy and radiation are administered to enhance antitumor effect (eg, concomitant fluorouracil and radiation therapy for many gastrointestinal tumors). Since the target of the radiation beam is typically located deep within the body, enhanced skin toxicity is usually not a significant problem. Skin toxicity is seen more commonly with more superficial radiation fields. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus".)

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Radiation enhancement involving the skin resembles RRD, with painful erythema, edema, superficial desquamation, and, if severe, erosions (wet desquamation). Similar to RRD, the eruption usually localizes to the irradiated field, but there may be local extension to unirradiated areas. Histologically, epidermal dysplasia, necrotic keratinocytes, and a mixed inflammatory reaction characterize involved areas, with some cases showing psoriasiform dermatitis [78]. (See "Radiation dermatitis".) Susceptibility to this effect decreases as the time between administration of chemotherapy and radiation therapy lengthens. In one report, superficial desquamation occurred in 50 percent of patients with lung cancer who received doxorubicin within five days of radiation therapy, while no desquamative reactions occurred when the interval between radiation and chemotherapy was increased to three weeks [87,88]. Possible explanations for the radiation-sensitizing effect of some chemotherapy drugs include increased blood supply and cellular reoxygenation to the tissue, interference with repair of radiation damage, competition for repair enzymes, and an increased percentage of cells in sensitive phases of the cell cycle [89]. For example, paclitaxel arrests cell division in the G2 and M phases of the cell cycle, when cells are the most susceptible to ionizing radiation injury [90]. The eruption is usually self-limiting, resolving over a period of days to months. Treatment of radiation enhancement reactions is symptomatic and includes the application of cold compresses, local wound care to prevent infection, and the avoidance of trauma, irritation, heat, and ultraviolet (UV) light. Long-term sequelae may include skin atrophy, fibrosis, and telangiectasias. (See "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis".)

HAND-FOOT SYNDROME (ACRAL ERYTHEMA)

Hand-foot syndrome (HFS) has been known by a variety of terms

including acral erythema, palmar-plantar erythrodysesthesia, toxic erythema of the palms and soles, Burgdorf's reaction, and toxic erythema of chemotherapy [91]. Since the original report in patients receiving high-dose cytarabine for acute leukemia, HFS has been described most often in patients receiving cytarabine, pegylated liposomal doxorubicin (PLD), capecitabine, or fluorouracil, although many other drugs have been implicated (table 5) [91-96]. Capecitabine toxicity may be associated with genetic polymorphisms of dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS), two enzymes that are involved in the metabolism of capecitabine and other fluoropyrimidines [97]. Although genetic tests are available that sequence the entire DPYD gene and identify some TYMS polymorphisms that predispose to excess hematologic and gastrointestinal toxicity, genetic testing is not considered standard of care prior to initiating fluoropyrimidine therapy. (See "Enterotoxicity of chemotherapeutic agents", section on 'Pharmacogenetic testing for DPYD and TYMS variants'.)

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Multitargeted tyrosine kinase inhibitors, such as sorafenib, sunitinib, and others that target angiogenesis, are associated with a high incidence of a hand-foot skin reaction, but the clinical and histologic patterns differ from the classic HFS that develops with conventional cytotoxic agents. This subject is discussed in detail elsewhere. (See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".)

Clinical presentation — Affected patients initially complain of a tingling sensation in the palms and/or soles. This is followed by edema and tender, symmetrical erythema, which is most pronounced over the fat pads of the distal phalanges (picture 8A-B). Skip areas may occur, as can extension to the dorsal surfaces of the extremities. Although rare, HFS involving the penis and scrotum has been reported [98]. An intertriginous form, named malignant intertrigo, that involves the axillary, antecubital, inframammary, and inguinal folds and the buttocks, similar to symmetric drug-related intertriginous and flexural exanthema, has also been reported [99,100]. (See "Exanthematous (maculopapular) drug eruption", section on 'Intertriginous and flexural localization'.) Affected areas may develop pallor, blistering, and desquamation [101-103]. A particularly severe bullous variant, progressing to full-thickness epidermal necrosis and sloughing, has been reported following cytarabine or high-dose methotrexate, particularly in children [104-109]. HFS is a painful condition, and it may limit daily activities such as walking or grasping objects. Functional impairment is a component of the grading system for severity of HFS (table 6). A presumed variant of HFS, termed fixed erythrodysesthesia plaque (FEP), is characteristic of intravenous (IV) injections of docetaxel [110,111]. This lesion develops as a fixed, solitary plaque proximal to the infusion site that does not involve the palms or soles. It usually resolves with desquamation, leaving an area of hyperpigmented skin five to six weeks later.

Fingerprint loss — One potential consequence of capecitabine-associated HFS is the loss of fingerprints [112-114]. Patients on long-term therapy should be advised of this potential adverse effect, since it may be an impediment in situations in which fingerprint identification is necessary (eg, international travel). However, an important point is that fingerprint loss is not permanent. In a prospective cohort study of 66 patients who were undergoing treatment with capecitabine or a tyrosine kinase inhibitor and who were fingerprinted at baseline, within 6 to 10 weeks after treatment initiation, and after treatment discontinuation, nine patients (14 percent) had severe loss of fingerprints; loss was unrelated to severity of HFS [115]. Complete recovery of fingerprints occurred in all three patients who were able to participate in post-treatment assessments within two to four weeks after treatment discontinuation.

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Risk factors — At least in the case of cytarabine, capecitabine, and doxorubicin, HFS is dose related. Furthermore, drug formulation and administration schedules that result in sustained serum levels of cytotoxic agents are more frequently associated with HFS, as evidenced by the following examples: ●The liposome-encapsulated form of doxorubicin (pegylated liposomal doxorubicin [PLD]) is associated with a higher incidence of HFS than the nonencapsulated form, particularly when initial doses greater than 40 mg/m2 are administered [116]. ●While HFS is uncommon when fluorouracil is administered as a bolus injection, it is often the doselimiting toxicity with prolonged infusions [117]. ●The incidence of HFS with capecitabine (an oral fluoropyrimidine that is converted in vivo to fluorouracil, providing prolonged tissue exposure) is nearly 60 percent [118].

Histopathology and pathogenesis — The histologic changes of HFS are nonspecific. A vacuolar interface dermatitis with necrotic keratinocytes is most commonly seen, with superficial dermal edema and a perivascular lymphocytic infiltrate [119,120]. The pathologic differential diagnosis includes graft-versus-host disease (GVHD, in the appropriate clinical setting) and Stevens-Johnson syndrome (SJS). The distinction of HFS from GVHD and SJS is important since the treatments are distinct. Unfortunately, a biopsy may not be able to distinguish between these entities in a clinically relevant timeframe. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Skin' and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Histopathology'.) The pathogenesis of HFS is not well understood. A direct toxic effect of the chemotherapeutic agent on eccrine coils (which are in highest density on the palms and soles) is most often proposed, although there is no direct evidence to support this theory, and microscopic evidence of damage to the eccrine sweat glands or ducts is only infrequently reported [121,122]. Others suggest that HFS represents a mild form of acute GVHD, although evidence to substantiate this viewpoint is lacking. Furthermore, HFS most often develops in patients who have neither undergone hematopoietic cell transplantation nor received blood products [1]. Finally, the occasional co-occurrence of facial erythema/edema, papular rash, and fever has led some to view this as a type I (immunoglobulin E [IgE]-mediated) allergic reaction [123]. For patients treated with capecitabine, at least some data suggest that expression of the capecitabine-activating enzyme thymidine phosphorylase is significantly greater in the skin of the palms as compared with skin on the lower back, providing higher tissue levels of the active moiety to this area [119]. Furthermore, the proliferative rate of epidermal basal cells in the palm was also higher as compared with skin from the back, suggesting that palmar skin might be more sensitive to the local action of cytotoxic drugs.

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Treatment — The main treatment for HFS is drug interruption or dose modification. Supportive treatment includes topical corticosteroids to decrease inflammation, wound care for erosions and ulcerations to prevent infection, emollients and topical keratolytics to decrease hyperkeratosis, and analgesics for pain control [91]. HFS usually resolves within two to four weeks after discontinuation of the causative agent, but healing frequently involves superficial desquamation of involved areas. There are usually no longterm sequelae, although palmoplantar keratoderma may develop as a result of long-standing HFS [124]. For patients who develop severe (grade 3 (table 6)) HFS, subsequent chemotherapy doses should be reduced to avoid recurrence. Based upon the severity of the reaction, the hazard of rechallenge, and the clinical situation, it may be necessary to discontinue therapy entirely and switch to an alternative regimen, if one is available.

Prevention Topical urea — For patients receiving capecitabine chemotherapy, we suggest topical urea 10% cream for the prevention of HFS. The topical urea cream is applied to hands and feet three times per day and should be reapplied after washing hands. At low concentrations (2 to 10%), topical urea acts as a humectant that increases the hydration of the stratum corneum and is generally well tolerated. The prophylactic benefit of topical urea treatment has not been demonstrated for other chemotherapy agents; however, given the low risk for toxic effects, a therapeutic trial is reasonable for patients at risk of developing HFS with other drugs. The efficacy of topical urea with or without lactic acid for the prevention of HFS has been addressed in a few randomized trials with conflicting results: ●In a randomized trial, a topical urea/lactic acid-based topical preparation applied twice daily for 21 days was compared with an emollient cream for the prevention of HFS in 137 patients receiving capecitabine for colon, lung, or breast cancer [125]. More patients in the topical urea/lactic acid group than in the placebo group developed HFS (40 versus 30 percent). The severity of HFS was similar in the two groups. ●In a subsequent randomized trial, topical urea 10% cream three times daily for six weeks was compared with a topical emollient preparation containing antioxidants for the prevention of HFS in 152 patients treated with capecitabine for gastrointestinal or breast cancer [126]. HFS was less common in patients treated with topical urea cream than in those treated with the antioxidant preparation (22 versus 40 percent). The severity of HFS was similar in the two groups.

Pyridoxine — Early studies suggesting symptomatic improvement from pyridoxine in patients with HFS [127,128] led to interest in the use of this vitamin as a preventive agent. However, in four separate phase III trials in which patients receiving capecitabine-based chemotherapy or PLD

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were randomly assigned to either pyridoxine (150 or 200 mg daily) or placebo, pyridoxine did not prevent this complication, lessen its severity, or permit higher doses of chemotherapy to be administered [129-132]. In addition, pyridoxine did not ameliorate symptoms among placebo-treated patients who received open-label pyridoxine after the development of grade 2 or 3 HFS [129]. Whether higher daily doses of pyridoxine might confer greater protection against HFS is uncertain. One randomized trial comparing 300 mg pyridoxine daily versus no treatment in 56 patients receiving capecitabine did not reveal any improvement in grade 2 or worse HFS with pyridoxine [133]. In contrast, another trial comparing 400 versus 200 mg of pyridoxine daily in 56 patients receiving capecitabine noted a significant reduction in HFS with the higher dose (relative risk 0.55, 95% CI 0.33-0.92) [134]. Two meta-analyses concluded that there was inadequate evidence to make any recommendation about using pyridoxine (at any dose) for prevention of chemotherapy-induced HFS [135,136]. Until further information becomes available, we suggest not using pyridoxine therapy to prevent HFS.

Celecoxib — In a 2014 meta-analysis of randomized trials (140 patients), oral celecoxib 200 to 400 mg twice daily for 12 to 18 weeks significantly decreased the risk of moderate to severe (grades 2 and 3) HFS (odds ratio 0.37, 95% CI 0.19-0.71) [136]. However, celecoxib is known for its potential cardiovascular adverse effects with long-term use and upper gastrointestinal risk of bleeding. In our view, the benefit-to-risk ratio is not favorable when considering the use of celecoxib for prevention of HFS. (See "NSAIDs: Adverse cardiovascular effects".)

Other approaches — Support for a variety of other approaches to treat or prevent HFS comes from small case series, although none has been proven in randomized trials: ●Local application of cold during therapy by applying ice packs to the wrists and ankles may help by decreasing blood flow to the hands and feet [137,138]. ●A benefit for oral corticosteroids in reducing the frequency of HFS was suggested by two small series [139,140].

NEUTROPHILIC ECCRINE HIDRADENITIS

Neutrophilic eccrine hidradenitis (NEH) is a reactive

disorder that may occur in association with malignancy (with or without chemotherapy), infections, and certain medications. The original description of drug-induced NEH was in a patient receiving cytarabine for acute myeloid leukemia [141]. Since then, a variety of chemotherapeutic agents have been associated with this entity (table 7) [1,142,143]. In addition, NEH has been reported in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), after acetaminophen use, as a paraneoplastic eruption in patients with malignancy who are not receiving

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chemotherapy (probably as a variant of Sweet syndrome), and as an idiopathic condition in children. (See "Neutrophilic dermatoses", section on 'Neutrophilic eccrine hidradenitis' and "Cutaneous manifestations of internal malignancy", section on 'Sweet syndrome'.) Patients present with the eruption one to two weeks after therapy with the offending agent. The clinical presentation is nonspecific. Lesions are typically asymptomatic, erythematous, edematous plaques but may be purpuric and painful. They can be located on the extremities (picture 9A), trunk, and face (picture 9B), including the periorbital region, where severe lesions may mimic cellulitis. Generalized, erythema multiforme-like lesions have been reported [144]. (See "Neutrophilic dermatoses", section on 'Neutrophilic eccrine hidradenitis'.) In all cases of suspected NEH, a biopsy should be performed since the clinical picture is nonspecific, while the histopathologic presentation is distinct. In most cases, neutrophils surround the eccrine glands, and a vacuolar interface dermatitis is visible in glands and ducts, along with necrosis of lining cells [145]. Epidermal keratinocyte atypia is a common associated finding in cases that are related to chemotherapy administration [146]. If chemotherapy-induced neutropenia is present, neutrophils may be absent on histologic examination. However, other characteristic findings, such as eccrine gland necrosis, are still identifiable [1]. The natural history is that of spontaneous resolution in one to two weeks [147]. While the reaction is self-limited and resolves without therapy, some studies support the use of systemic corticosteroids [148]. However, efficacy has not been established in randomized trials [148]. One case report suggests that oral dapsone may be useful for prophylaxis [149]. The majority of patients with NEH will develop the same eruption with rechallenge. The cause of NEH in patients receiving chemotherapy is unknown. It is postulated that a high concentration of the drug in sweat has a direct toxic effect on the eccrine glands [145,150].

EXANTHEMATOUS (MACULOPAPULAR) ERUPTIONS

A wide

variety of chemotherapy drugs have been associated with a mild, nonspecific, exanthematous drug eruption, including bortezomib, lenalidomide, cladribine, fludarabine, gemcitabine, pemetrexed, and cytarabine. Lesions may be "morbilliform" or may consist of a profuse eruption of small, erythematous papules showing no resemblance to any infective exanthem. Morbilliform eruptions (picture 10A-B) are characterized by monomorphic, erythematous papules and are usually classified as "drug rash" in the United States prescribing information and literature references. The similarity of these rashes to those described for many other drugs underscores the importance of evaluating all medications taken by the patient before concluding that the rash is caused by the chemotherapy agent. (See "Exanthematous (maculopapular) drug eruption".)

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Adverse skin reactions with bortezomib may include an erythematous, papular rash or erythematous nodules or plaques [68,151]. In one study, rash affected 26 of 140 patients (19 percent), in most cases during the third or fourth course of therapy [152]. Six patients underwent biopsy, which showed a small vessel necrotizing vasculitis. A morbilliform eruption occurs in approximately 30 percent of patients treated with lenalidomide [153]. The risk of rash appears to be independent from dose or whether lenalidomide is combined with dexamethasone or not. Lenalidomide has also been associated with Stevens-Johnson syndrome/toxic epidermal necrolysis (table 8) [154-156]. (See "Multiple myeloma: Treatment of relapsed or refractory disease".) The management of patients with a chemotherapy drug rash is dictated by the severity of the reaction as well as the clinical circumstances surrounding the use of the individual chemotherapy agent. Pertinent issues include whether the offending agent is being used with curative versus palliative intent and whether an adequate substitute from another drug class is available. In mild cases, treatment with topical steroids is usually recommended, without specific modification of the chemotherapy regimen. Pretreatment with corticosteroids is not usually recommended to prevent or diminish a chemotherapy-induced drug rash. One exception to this general rule is the drug pemetrexed, a folate analog used in the treatment of mesothelioma and non-small cell lung cancer. In an early phase II study, pemetrexed was associated with a papular skin rash in 66 percent of treated patients [157]. The rash was sometimes associated with edema and/or desquamation and responsive to corticosteroid treatment. Subsequent phase I, II, and III trials have noted a much lower incidence (less than 20 percent) and severity of skin rash, attributed to the routine use of dexamethasone 4 mg twice daily for three days starting the day before treatment [158-161]. As a result, premedication with this schedule of dexamethasone has become a standard practice for patients receiving pemetrexed [159]. Whether fewer doses would suffice is unknown.   At least one case of urticarial vasculitis has been attributed to pemetrexed [162]. Conjunctivitis, periorbital edema, and lower extremity edema and erythema have also been reported in patients treated with pemetrexed [163,164]. (See "Ocular side effects of systemically administered chemotherapy".)

FIXED DRUG ERUPTIONS

Fixed drug eruptions are

typically characterized by the rapid formation of a solitary macule, plaque, or bulla after drug exposure in a sensitized individual, although multiple or diffuse lesions can be observed in rare cases. The cytotoxic drugs most commonly associated with a fixed drug eruption are listed in the table (table 9). (See "Fixed drug eruption".) The characteristic early lesion is a sharply demarcated, erythematous, round to oval macule, which develops from 30 minutes to 8 hours after drug exposure and arises in the same location after each exposure (picture 11A-B). One-half occur on the oral or genital mucosa (picture 11D). Within hours,

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the lesion becomes edematous, forming a plaque, which may evolve to bulla (picture 11C) and eventually to erosion. Lesions persist if the drug is continued, but they resolve within days to weeks after the drug is discontinued. Postinflammatory hyperpigmentation may take months to resolve. No specific treatments are recommended other than discontinuation of the offending drug, although topical steroids instituted early after lesion development may help to reduce postinflammatory hyperpigmentation.

DIFFUSE ERYTHEMA AND EXFOLIATIVE DERMATITIS

Diffuse erythema has been

described with hydroxyurea, busulfan, and cladribine [165]. Many of these eruptions are mild and self-limited, and they do not proceed to exfoliation. Drugs that are more likely to be associated with exfoliative dermatitis include cisplatin, methotrexate, and, rarely, intravesical mitomycin [166-169]. At least some of these cases are thought to be immune mediated.

SEVERE CUTANEOUS DRUG REACTIONS

A number of antineoplastic agents may cause life-threatening

cutaneous adverse reactions, such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) [170]. Whether chemotherapy agents cause erythema multiforme, an immune-mediated reaction induced in most cases by infections and infrequently by drugs, remains uncertain. Similarities in clinical and histopathologic findings between SJS and erythema multiforme (ie, presence of targetoid lesions and keratinocyte necrosis) may have led to a misclassification of limited SJS as erythema multiforme in the few published cases [171]. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)

Stevens-Johnson syndrome/toxic epidermal necrolysis — SJS/TEN is a serious and potentially fatal mucocutaneous drug reaction characterized by extensive necrosis and detachment of the epidermis due to massive keratinocyte apoptosis. Its severity is related to the percentage of body surface area involved, ranging from less than 10 percent in SJS to greater than 30 percent in TEN. Several anticancer agents have been associated with SJS/TEN (table 10) [170]. Determining the drug causality in cancer patients may be difficult, due to the frequent use of multiple chemotherapy agents in combination and the concurrent use of other drugs to treat underlying conditions and comorbidities. In addition, cancer patients may have an increased risk of SJS/TEN due to the malignancy itself [172].

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Although the pathogenetic mechanisms of SJS/TEN are incompletely understood, it is now accepted that drug-specific CD8+ cytotoxic T cells, along with natural killer (NK) cells, are major inducers of keratinocyte apoptosis [173]. Among the various cytotoxic proteins and cytokines (eg, soluble Fas ligand, perforin/granzyme, tumor necrosis factor-alpha) involved in the extensive keratinocyte apoptosis, granulysin, a cytolytic protein found in cytotoxic T cells and NK cells, appears to play a key role [174]. SJS/TEN begins with a prodrome of fever and influenza-like symptoms followed in one to three days by an eruption of ill-defined, coalescing, erythematous macules with atypical target lesions (picture 12). As the disease progresses, vesicles and bullae form, and within days the skin begins to slough (picture 13). Mucosal involvement occurs in over 90 percent of cases. Acute complications may include massive loss of fluids and electrolyte imbalance, hypovolemic shock, sepsis, and multiple organ dysfunction. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".) Most patients with SJS/TEN require inpatient management, often in a burn unit, because of extensive skin detachment and subsequent risk for hyponatremic dehydration and sepsis. Immediate and permanent discontinuation of the offending agent is warranted. Patients who develop SJS/TEN should never be re-exposed to the causative drug because of the risk of a fatal recurrence. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

Drug reaction with eosinophilia and systemic symptoms — DRESS is a rare and potentially life-threatening, drug-induced hypersensitivity reaction that presents with a skin eruption, hematologic abnormalities (eosinophilia, atypical lymphocytosis), lymphadenopathy, and/or internal organ involvement (liver, kidney, lung). A few antineoplastic agents have been associated with DRESS, including chlorambucil [175] and lenalidomide [176]. In most patients, the reaction begins two to six weeks after the initiation of the offending medication. The eruption starts as a morbilliform eruption that progresses more or less rapidly to a diffuse, confluent, and infiltrated erythema (picture 14A-B). Liver involvement occurs in 60 to 80 percent of patients. Identification and prompt withdrawal of the offending drug is the mainstay of treatment for patients with DRESS. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

MISCELLANEOUS REACTIONS

Treatment-

induced leg ulcers occasionally occur in patients taking long-term hydroxyurea for myeloproliferative disorders [177-180]. Lesions are most commonly located near the malleoli and are characteristically painful. The primary mechanism of ulcer formation may involve hydroxyurea-induced inhibition of

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the synthesis (S) phase of the cell cycle, leading to basal keratinocyte damage and the suppression of collagen synthesis. Discontinuation of therapy is necessary for healing; ulcers recur if treatment is reinitiated [180]. Whether leg ulcers are more frequent in patients receiving hydroxyurea for sickle cell disease is unclear. Issues related to use of hydroxyurea in this setting are discussed in detail elsewhere. (See "Hydroxyurea use in sickle cell disease".) There are many other rare cutaneous reactions that have been attributed to chemotherapy agents, including Sjögren's syndrome, dermatomyositis, Raynaud's phenomenon, reactivation of varicellazoster infection, porphyria, and a blistering disorder characterized as a paraneoplastic pemphiguslike phenomenon with fludarabine [1]. (See "Paraneoplastic pemphigus".) A partial list of such reactions and the associated chemotherapeutic agents can be found in the following table (table 11).

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of symptoms and toxicities of anticancer therapy".)

SUMMARY AND RECOMMENDATIONS ●Systemic and local application of conventional cytotoxic chemotherapy agents in patients with cancer can cause a number of changes in the skin, mucous membranes, hair, and nails. Some of these changes are immune-mediated hypersensitivity reactions, including urticaria and angioedema, exanthematous eruptions, vasculitis, or contact dermatitis (table 1). (See 'Immune-mediated infusion reactions' above.) ●Pigmentary changes involving the skin, nails, and mucous membranes are common in patients receiving cytotoxic drugs, particularly alkylating agents and antitumor antibiotics (table 2). The hyperpigmentation can be localized or diffuse, sometimes with distinctive patterns, such as serpentine (picture 1) or flagellate (picture 2). (See 'Pigmentary changes' above.) ●Nail changes, such as hyperpigmentation and onycholysis (picture 5), sometimes associated with inflammatory involvement of the periungual tissues, may be induced by many medications, including alkylating agents, taxanes, antimetabolites, anthracyclines, and antitumor antibiotics (table 3). (See 'Nail disorders' above.)

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●Photosensitivity reactions, including photoallergic and phototoxic reactions (picture 6A), have been associated with a variety of chemotherapy agents. Photorecall and photoenhancement reactions have been reported with methotrexate and taxanes. The combination of some agents, such as mercaptopurine, with ultraviolet light may induce photo-onycholysis. (See 'Photosensitivity' above.) ●Subacute cutaneous lupus erythematosus, manifested by annular or polycyclic, photodistributed, erythematous, and scaling lesions (picture 7A-B), has been reported in a few cases following docetaxel, fluorouracil, or capecitabine. (See 'Subacute cutaneous lupus erythematosus and scleroderma-like changes' above.) ●Radiation recall dermatitis (RRD) is an inflammatory skin reaction that develops in an area of previously irradiated skin after administration of several chemotherapy agents (table 4). Some drugs may enhance the efficacy and dermatologic toxicity of radiation therapy when administered concurrently or within one week of radiation therapy. They are referred to as radiation sensitizers. This synergistic interaction may be exploited clinically in situations where chemotherapy and radiation therapy are administered together to enhance the therapeutic effect. (See 'Radiation recall dermatitis' above and 'Radiation enhancement' above.) ●Hand-foot syndrome (HFS), also called acral erythema (picture 8A-B), occurs most often in patients receiving cytarabine, pegylated liposomal doxorubicin, capecitabine, or fluorouracil, although many other drugs have been implicated (table 5). In patients who will be treated with capecitabine, we suggest initiating topical application of topical urea 10% cream for the prevention of HFS (Grade 2B). Given the low risk for toxic effects, a therapeutic trial is reasonable for those who develop moderate to severe HFS with other drugs (Grade 2C). HFS is dose related and usually resolves within two to four weeks after discontinuation of the causative agent with superficial desquamation of involved areas. ●Neutrophilic eccrine hidradenitis presents with erythematous, edematous plaques (picture 9A-B) in patients with malignancy (with or without chemotherapy), infections, or receiving a variety of chemotherapeutic agents (table 7). (See 'Neutrophilic eccrine hidradenitis' above and "Neutrophilic dermatoses", section on 'Neutrophilic eccrine hidradenitis'.) ●Exanthematous eruptions, including morbilliform rashes (picture 10A-B) and fixed drug eruptions (picture 11A-D), may occur in association with many chemotherapeutic agents (table 9). (See 'Exanthematous (maculopapular) eruptions' above and 'Fixed drug eruptions' above.) ●A number of antineoplastic agents (table 10) may cause severe cutaneous reactions, such as Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) (picture 14A-B). SJS/TEN is a rare, life-threatening cutaneous reaction characterized by extensive necrosis and detachment of the epidermis due to massive keratinocyte apoptosis (picture 13). Patients who develop SJS/TEN or DRESS should never be re-exposed to the causative drug because of the risk of a fatal recurrence. (See 'Severe cutaneous drug reactions' above.)

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●Rare reactions, including leg ulcers, Sjögren syndrome, dermatomyositis, Raynaud phenomenon, reactivation of varicella-zoster infection, porphyria, and a paraneoplastic pemphigus-like phenomenon, have been associated with several chemotherapeutic agents (table 11). (See 'Miscellaneous reactions' above.)

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Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors uptodate.com/contents/hand-foot-skin-reaction-induced-by-multitargeted-tyrosine-kinase-inhibitors/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jul 01, 2019.

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INTRODUCTION

Protein tyrosine kinase inhibitors (TKIs), which include

selective and multikinase inhibitors, are a class of targeted anticancer medications approved for treatment of a number of solid tumors. The ability of TKIs to block molecular pathways specific to the proliferation of malignant cells has decreased the incidence of many of the adverse events caused by cytotoxic chemotherapy. However, TKIs bring their own set of specific dermatologic adverse events, which include [1]: ●Hand-foot skin reaction (HFSR) ●Seborrheic dermatitis-like eruption ●Subungual splinter hemorrhages ●Keratoacanthoma and squamous cell carcinomas ●Hair changes such as alopecia and changes in hair color and/or texture ●Keratosis pilaris-like eruption HFSR is the most common cutaneous adverse event caused by TKIs. Although rarely lifethreatening, it can impair patients' quality of life and may lead to dose reductions or premature discontinuation of cancer treatment. HFSR secondary to TKIs will be reviewed in this topic. Other cutaneous adverse reactions to molecularly targeted therapy or conventional chemotherapy agents are discussed separately. ●(See "Cutaneous side effects of conventional chemotherapy agents".) ●(See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".) ●(See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

EPIDEMIOLOGY Incidence — The risk of developing HFSR varies depending upon the specific drug used and type of malignancy [2-4]. The incidence rates of all-grade and high-grade HFSR range from 4.5 and 1.8 percent, respectively, in patients treated with pazopanib (a multitargeted tyrosine kinase inhibitor [TKI] used in the treatment of advanced renal cell carcinoma) to 60.5 and 20.4 percent, respectively, in patients taking regorafenib (a potent multitargeted TKI used in the treatment of advanced colorectal cancer) (table 1) [5]. A meta-analysis of 57 studies (24,956 patients) found an overall incidence of all-grade and high-grade HFSR associated with vascular endothelial growth factor receptor (VEGFR)-TKIs of 35 percent (95% CI 28.6-41.6) and 9.7 percent (95% CI 7.3-12.3),

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respectively [6]. The highest risk of all-grade and high-grade HFSR was observed in patients with thyroid cancer and in patients receiving cabozantinib. The highest risk of high-grade HFSR was observed in patients receiving regorafenib.

Risk factors — The risk factors for the development of HFSR are largely unknown, and the reaction is generally considered unpredictable. In a study of patients with renal cell carcinoma treated with sorafenib, female gender, good performance status, presence of lung and liver metastases at baseline, involvement of two or more organs, baseline white blood cell count above 5.5 x 109 cells/L, and week of therapy (with maximum risk at week 5) were predictive of grade 2 or greater HFSR [3]. The development of hypertension has been shown to be a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib [7]. Polymorphisms of the VEGFR2 gene may also be associated with increased risk of developing HFSR [7]. Several genetic polymorphisms have been identified that increase risk of development of HFSR. Variants in the C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway have been found to predict severe HFSR in patients with metastatic colorectal cancer treated with regorafenib [8].

Association of hand-foot skin reaction with survival — Several studies have noted an association between the development of HFSR and other skin toxicities from TKIs and increased tumor response rate and overall survival rate [7,911]. A Japanese prospective study examining patients with metastatic renal cell carcinoma treated with sorafenib found that the median progression-free survival was 4.6 months in patients with HFSR versus 1.5 months in patients without [11]. In a multivariate analysis, HFSR was the only predictive factor of progression-free survival, after adjusting for major patient clinical characteristics (eg, Eastern Cooperative Oncology Group performance status, Memorial Sloan-Kettering Cancer Center risk classification, lactate dehydrogenase). Similarly, a national registry-based study from the Czech Republic including 705 patients with metastatic renal cell carcinoma treated with sunitinib showed improved overall survival and progression-free survival in patients who developed HFSR compared with those who did not [10]. These findings have been confirmed in multiple studies of patients with metastatic renal cell carcinoma treated with sunitinib [12,13]. A study from Taiwan showed that in patients with soft tissue sarcoma treated with pazopanib, HFSR was an independent predictive factor for better treatment outcome [14].

PATHOGENESIS

Although the exact mechanism leading to HFSR is

unknown, it is thought that the inhibition of both the vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors is necessary to cause HFSR. Inhibition of either one of these

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receptors alone rarely leads to HFSR [15]. Moreover, the observation that the incidence of HFSR increases when multikinase inhibitors are combined with VEGF receptor blockers such as bevacizumab and cediranib supports the theory that capillary microtrauma and/or inability to effectively repair vascular trauma at sites prone to mechanical and frictional stress results in drug extravasation and tissue damage [16]. Further supporting the importance of vascular competence in the pathogenesis of HFSR is its increased incidence in patients treated with regorafenib, which uniquely inhibits the endothelium-specific TIE-2 receptor (important for vascular remodeling) [15].

HISTOPATHOLOGY

The main histopathologic features described for

HFSR are similar to hand-foot syndrome (HFS) caused by cytotoxic chemotherapy. They include dyskeratotic keratinocytes at various stages of necrosis, vacuolar degeneration of the basal layer, and mild perivascular or lichenoid infiltrate that is predominantly lymphocytic [17]. Necrotic subepidermal, intraepidermal, or subcorneal blisters can form followed by acanthosis with hyperkeratosis or parakeratosis. Cases of mild cystic degeneration of the eccrine coil and squamous metaplasia of the sweat glands have also been described [18]. While the histologic features of HFS and HFSR can be similar, HFSR is more likely to show an increased rate of epidermal replication resulting in papillomatosis and acanthosis [17].

CLINICAL MANIFESTATIONS

HFSR appears in the

first two to four weeks of treatment with tyrosine kinase inhibitors (TKIs) [1]. It typically involves the palms and soles but can also occur in other friction-prone areas such as the interdigital web spaces and lateral aspects of the feet [16]. It has been reported in unusual areas of excessive friction such as the fingertips used to operate a mobile device and the stump of an amputee [19,20]. The typical appearance is that of focal, hyperkeratotic, callus-like lesions on an erythematous base in areas of pressure or friction such as the fingertips, heels and metatarsal areas, and over joints (picture 1A-C). These lesions can begin as bullae or blisters [15]. This clinical presentation differs from that of hand-foot syndrome (HFS) caused by cytotoxic chemotherapy, which typically presents with a diffuse erythema and scale involving the entire palm and sole (picture 2A-B) [16]. (See "Cutaneous side effects of conventional chemotherapy agents", section on 'Hand-foot syndrome (acral erythema)'.) HFSR lesions are usually painful; other symptoms may include paresthesia, tingling, burning, soreness of the palms and soles, and decreased tolerance of contact with hot objects [1]. In severe cases, HFSR can limit the patient's ability to care for or dress themselves. Long-term cutaneous sequelae have not been reported.

IMPACT ON QUALITY OF LIFE

Although HFSR is

not life-threatening and is usually self-limiting, the symptom burden may significantly reduce the patient's health-related quality of life (HRQL) and lead to dose reductions or premature drug discontinuation. One study examining the data from 23 patients receiving sorafenib or sunitinib who

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completed the Skindex-16 (a self-reported, dermatology-specific quality of life [QoL] questionnaire) found a positive correlation between scores for symptoms and emotions and severity grade of HFSR, with the highest score reported for the symptoms domain [21]. Two instruments have been developed to assess specifically the HRQL in patients with hand-foot syndrome (HFS) and HFSR, the HFS-14 [22], which assesses functional implications, and the newer HFSR and quality of life (HF-QoL) questionnaire [23]. The latter evaluates the wider symptom burden, including physical well-being, activities of daily living, role function, social activities, emotional wellbeing, and mood. Although generally used in the setting of clinical trials, these instruments may be helpful in clinical practice to assess the patient's tolerance of treatment and overall clinical status.

DIAGNOSIS

The diagnosis of HFSR is usually straightforward, based upon the

clinical appearance of hyperkeratotic plaques with painful erythema localized to areas of friction or pressure of the palms and soles (picture 1C) and history of tyrosine kinase inhibitor (TKI) use. A skin biopsy is not usually performed, due to the potential morbidity associated with this procedure on the hands or feet.

Grading of severity — Grading the severity of HFSR is important to guide the approach to treatment and to facilitate the communication between dermatologist and oncologist. In clinical trials and oncology practices, the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, is the most commonly employed scale to assess the severity of cutaneous adverse reactions to cancer treatment (table 2) [23,24]. Although HFSR is not included in CTCAE as its own category, "palmoplantar erythrodysesthesia" can be used to grade HFSR. It is also important to keep in mind the limitations of the CTCAE scale, which does not incorporate the patient's perception of severity or the potentially prolonged duration of HFSR [25].

DIFFERENTIAL DIAGNOSIS

The differential diagnosis

of HFSR includes other eruptions occurring primarily on the hands and feet. ●Hand-foot syndrome (HFS) – In patients receiving both a targeted agent and a cytotoxic chemotherapeutic agent, this distinction may be important to guide the reduction of the appropriate medication, if indicated. While both can be associated with pain and paresthesias, HFS due to cytotoxic chemotherapy typically presents with diffuse erythema and desquamation (picture 2A-B), in contrast with the more focal hyperkeratotic lesions found in HFSR [16]. (See "Cutaneous side effects of conventional chemotherapy agents", section on 'Hand-foot syndrome (acral erythema)'.) ●Contact dermatitis – Allergic or irritant dermatitis involving the hands and/or feet presents with erythema and scale that are often more diffuse than HFSR (picture 3) and are typically associated with pruritus rather than pain. (See "Irritant contact dermatitis in adults" and "Clinical features and diagnosis of allergic contact dermatitis".)

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●Tinea pedis and manuum – Skin infection from dermatophytes of the genus Trichophyton is characterized by erythema and scaling. The involvement of the hand is typically unilateral, resulting in the so-called "two-feet, one hand syndrome" (picture 4). Dermatophyte infections are usually more pruritic than painful. A skin scraping from an affected area with a potassium hydroxide preparation will reveal fungal hyphae. (See "Dermatophyte (tinea) infections", section on 'Tinea pedis' and "Dermatophyte (tinea) infections", section on 'Tinea manuum'.) ●Psoriasis – Psoriasis may present with erythema and scale of the palms and/or soles (picture 5). However, it is often associated with characteristic nail changes, such as pitting (picture 6) and oil spots (picture 7), as well as symmetric plaques on other areas of the body (picture 8). Patients often have a history of psoriasis; however, if a new presentation is suspected, a skin biopsy may be needed to differentiate psoriasis from HFSR. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".) ●Dyshidrotic dermatitis (eczema) – This type of eczema presents with deep-seated vesicles and blisters typically located on the volar aspect of the hands and feet (picture 9A-C). In contrast with HFSR, dyshidrotic eczema is intensely pruritic and is not limited to areas of friction and pressure. (See "Acute palmoplantar eczema (dyshidrotic eczema)".)

MANAGEMENT

The approach to management of HFSR should be

individualized, depending upon severity, impact on the patient's activities of daily living, and need to continue anticancer treatment with multitargeted tyrosine kinase inhibitors (TKIs). A multidisciplinary approach to care, including oncologist, dermatologist, podiatrist, and nursing care, can be helpful. There are no clinical trials specifically addressing the treatment of HFSR [26]. Treatment is generally based upon clinical experience, expert consensus, and local guidelines [15,18,26,27]. Our approach to management of HFSR is illustrated in the algorithm (algorithm 1).

General principles Treatment of hyperkeratosis and skin inflammation — Topical keratolytic agents, such as creams or ointments containing topical urea 10%, can be applied focally to hyperkeratotic areas [15]. Caution should be used as these agents can cause irritation and discomfort if applied to nonintact skin. Keratolytic medications can be used for all grades of HFSR (algorithm 1). It is imperative that health care providers seek out any causes of friction in areas of HFSR; inspection of clothing and questioning regarding daily activities may be needed to identify potential exacerbating factors. (See 'Prevention' below.) Topical corticosteroids may be helpful to reduce skin inflammation in patients with grade 2 or higher HFSR. Since palms and soles are areas at low risk of skin atrophy from topical corticosteroids, superpotent corticosteroids (group 1 (table 3)) can be safely used until cutaneous inflammation

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subsides. We typically use clobetasol propionate 0.05%, halobetasol 0.05%, or betamethasone dipropionate 0.05% in ointment, cream, or foam formulation, twice daily.

Treatment of pain — Topical analgesics such as topical lidocaine 4 to 6% in gels, creams, or patches can be used for symptomatic pain relief for grades 1 and 2 HFSR. Systemic pain medications such as nonsteroidal anti-inflammatory drugs, opioids, or gamma-aminobutyric acid (GABA) agonists (gabapentin or pregabalin) may be of use in grade 2 or higher HFSR, if no contraindications exist [15].

Prevention of infection — Although secondary infection in HFSR has not been described, given the patient's immunocompromised status, the disruption of the skin barrier by trauma or inflammation is a concern as a possible portal of entry for infection. Open or oozing areas of the skin may be treated with antiseptics (eg, potassium permanganate, chlorhexidine gluconate, diluted bleach) or topical antibiotics (eg, mupirocin 2%, gentamicin 1%) [15].

Other — Small studies and case reports suggest a beneficial effect of heparin-containing ointment [28], hydrocolloid dressing containing ceramide [29], vitamin E [30], narrowband ultraviolet B phototherapy [31], and topical sildenafil [32] in the treatment of HFSR. However, these treatments are rarely used due to the scant evidence of efficacy, costs, and limited accessibility of some of them.

Our approach — There is no evidence from randomized trials to determine the best reactive strategy for HFSR. Our approach, based upon clinical experience and expert consensus, is illustrated in the algorithm (algorithm 1) [15,18,26,27].

Patients with grade 1 hand-foot skin reaction — For mild, grade 1 HFSR (table 2), dose modifications are not needed (algorithm 1). Patients should avoid using hot water and should regularly apply keratolytic emollients containing topical urea 10% three times per day. (See 'Treatment of hyperkeratosis and skin inflammation' above.) We generally reassess patients after two weeks of treatment. If the reaction has not improved or has worsened, patients are treated in the same way as those with grade 2 rash.  

Patients with grade 2 hand-foot skin reaction — For grade 2 HFSR, topical treatment includes a superpotent topical corticosteroid (group 1 (table 3)) to be applied to the erythematous areas (algorithm 1). We use clobetasol propionate 0.05% foam or solution twice daily and lidocaine 4 to 6% cream or patches during the day. Oral analgesics, including nonsteroidal anti-inflammatory drugs, opioids, or GABA agonists (eg, gabapentin, pregabalin) may be given as needed to reduce skin pain and discomfort. (See 'Treatment of hyperkeratosis and skin inflammation' above.)

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We generally reassess patients after two weeks of treatment. If the reaction has not improved or has worsened, patients are treated in the same way as those with grade 3 rash [15,18].   For grade 2 reaction that does not respond to treatment, the TKI dose can be decreased as per the prescribing information. If the HFSR does not improve, the TKI can be temporarily discontinued as for patients with grade 3 HFSR, until symptoms improve to grade 0 or 1, and then resumed at a lower dose as per prescribing information [15,18].

Patients with grade 3 hand-foot skin reaction — For patients with grade 3 or intolerable grade 2 reaction that does not respond to treatment, a temporary interruption of the TKI is indicated (algorithm 1). The TKI should be held for at least seven days or until toxicity resolves and then resumed at a lower dose as per the prescribing information. If the adverse reaction does not recur, dose escalation can be attempted. Topical treatments and oral pain medications are continued as for grade 2.

PREVENTION

Prior to initiating treatment with multitargeted tyrosine kinase

inhibitors (TKIs), we instruct patients to adopt prophylactic measures that may reduce the likelihood or severity of HFSR (algorithm 1). These include [15,18,26]: ●Urea 10% cream three times per day to palms and soles. ●Examining hands and feet for presence of calluses. Hyperkeratotic areas and calluses should be removed through a manicure and/or pedicure, using appropriately sterilized instruments. Keratotic skin can be gently exfoliated using a pumice stone. ●Keeping skin of hands and feet well-moisturized using bland emollients or topical urea-based creams, especially after washing. ●Seeking evaluation by an orthotist for an orthotic device is encouraged for patients with evidence of abnormal weight bearing. ●Avoiding exposing hands and feet to hot water, as this is believed to exacerbate symptoms. ●Avoiding constrictive footwear and excessive friction on the skin when applying lotions, getting massages, or performing everyday tasks such as typing or using handheld electronic devices. ●Avoiding vigorous exercise that places undue stress on the palms and/or soles of the feet, particularly during the first month of therapy. ●Wearing shoes with padded insoles throughout treatment to reduce pressure on the feet. Thick cotton gloves or socks can be worn to prevent injury and keep the palms and soles dry.

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The use of a 10% topical urea cream for the prevention of HFSR has been evaluated in one randomized trial of 871 patients receiving sorafenib for advanced hepatocellular carcinoma [33]. In this study, patients were treated with 10% topical urea cream three times per day plus best supportive care or best supportive care alone excluding all creams. The incidence of any grade HFSR within 12 weeks of starting sorafenib was modestly but significantly lower with the topical urea cream (56 versus 74 percent, odds ratio [OR] 0.46, 95% CI 0.34-0.61) as was the incidence of grade (≥2) HFSR (21 versus 29 percent, OR 0.64, 95% CI 0.47-0.87). However, due to the lack of a placebo (vehicle) group, it is unclear whether the beneficial effect of treatment is associated with topical urea or the cream itself.

SUMMARY AND RECOMMENDATIONS ●Hand-foot skin reaction (HFSR) is the most common cutaneous adverse reaction to treatment with multitargeted tyrosine kinase inhibitors (TKIs). The incidence varies based upon medication, but it appears to be more common in women. (See 'Introduction' above and 'Epidemiology' above.) ●HFSR appears in the first two to four weeks of treatment with TKIs. It typically presents with focal, hyperkeratotic, callus-like lesions and erythema on the palms and soles (picture 1A-C) but can also occur in other friction-prone areas such as the interdigital web spaces and lateral aspects of the feet. (See 'Clinical manifestations' above.) ●The diagnosis of HFSR is usually straightforward, based upon the clinical appearance and history of TKI use. The severity is graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (table 2). (See 'Diagnosis' above.) ●Prior to initiating treatment with multitargeted TKIs, instruct patients to adopt prophylactic measures that may reduce the likelihood or severity of HFSR, including hand and foot care to eliminate hyperkeratoses, podiatric consultation, minimization of friction and pressure, and use of emollients or topical urea 10% three times per day. (See 'Prevention' above.) ●Reactive treatment is based upon clinical experience, consensus statements, and local guidelines. Our approach is illustrated in the algorithm (algorithm 1). (See 'Management' above.) •For patients with grade 1 HFSR (table 2), we suggest keratolytic moisturizers (Grade 2C). We use topical urea 10% creams or ointments and lidocaine 4 to 6% cream or patches. (See 'Patients with grade 1 hand-foot skin reaction' above.) •For patients with grade 2 HFSR, we suggest super high-potency topical corticosteroids (group 1 (table 3)) and oral analgesics in addition to topical therapies as for grade 1 (Grade 2C). We use clobetasol propionate 0.05% foam or solution twice daily. If the reaction does not improve, the TKI

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dose can be lowered as per the prescribing information until symptoms improve to grade 0 or 1 and then resumed at a lower dose as per prescribing information. (See 'Patients with grade 2 hand-foot skin reaction' above.) •For patients with grade 3 HFSR or intolerable grade 2 HFSR that does not respond to treatment, we suggest to hold the TKI dose for at least seven days or until HFSR resolves (Grade 2C). In addition, we continue topical medications and oral analgesics as for grade 1 and 2. Once the toxicity has resolved, treatment with the TKI can be resumed at a lower dose. If the adverse reaction does not recur, dose escalation can be attempted. (See 'Patients with grade 3 hand-foot skin reaction' above.)

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Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy uptodate.com/contents/cutaneous-adverse-events-of-molecularly-targeted-therapy-and-other-biologic-agents-used-forcancer-therapy/print

Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 04, 2020.

INTRODUCTION

Over the last three decades, novel antineoplastic therapy

strategies have evolved that exploit some of the molecular abnormalities that have been detected in certain types of cancer. While the targets of these agents differ, they are collectively referred to as molecularly targeted agents. Many of these agents, particularly those interfering with signal transduction (eg, epidermal growth factor receptor [EGFR] inhibitors, multitargeted tyrosine kinase inhibitors [TKIs], BRAF inhibitors), are associated with prominent dermatologic adverse events that may impact quality of life and dosing [1].

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This topic will review the dermatologic toxicities seen with several classes of molecularly targeted agents. Cutaneous reaction patterns seen with conventional cytotoxic agents and checkpoint inhibitor immunotherapies used for advanced melanoma and other solid and hematologic tumors are discussed elsewhere. Infusion reactions to monoclonal antibodies used for cancer therapy and conventional chemotherapy agents are also discussed separately. ●(See "Cutaneous side effects of conventional chemotherapy agents".) ●(See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Dermatologic and mucosal toxicity'.) ●(See "Infusion reactions to systemic chemotherapy".) ●(See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".)

EGFR INHIBITORS

The array of drugs that inhibit the epidermal

growth factor receptor (EGFR) include: ●Monoclonal antibodies: •Cetuximab •Panitumumab •Necitumumab •Pertuzumab ●Oral small molecules: •Erlotinib •Gefitinib •Afatinib •Lapatinib •Dacomitinib •Osimertinib •Neratinib As a group, these drugs are associated with prominent dermatologic adverse events, the most common of which is a papulopustular acneiform eruption (table 1) [2]. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

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Acneiform eruption — The most common cutaneous reaction pattern with the EGFR inhibitors is a diffuse papulopustular acneiform eruption, which is noted in more than twothirds of patients receiving any of these agents (severe in 10 to 20 percent) [3-6]. The eruption consists of erythematous, follicle-based papules and pustules, typically without comedones. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".) The acneiform eruption is often dose dependent and typically begins early, within one to two weeks of treatment initiation (picture 1A-C) [7,8]. The lesions typically occur on the face, scalp, chest, and back, sparing the extremities. Scaling of the interfollicular skin may also be present. Significant pruritus accompanies the cutaneous eruption in up to one-third of patients [9]. Studies note a consistent positive correlation between the severity of the acneiform rash and antitumor activity [10-13]. The presence of an acneiform eruption is not a contraindication to continued therapy. In fact, there is evidence that the development of moderate to severe acneiform eruption is associated with an improved survival [14-17]. However, for grade 3 (severe) dermatologic adverse events, dose interruptions are indicated (table 2). Dose reduction guidelines are available for most agents in their corresponding package inserts. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Monotherapy'.) The clinical course, complications, management, and prevention of the acneiform eruption associated with EGFR inhibitors are discussed in detail separately. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

Other reactions — Although the acneiform rash is the most prominent cutaneous adverse reaction, several other skin reactions are reported with anti-EGFR therapies (table 1), including: ●Paronychia – Paronychial inflammation (often with pyogenic granuloma-like lesions) is a frequent adverse event of anti-EGFR agents (picture 2), and secondary bacterial infection (often with Staphylococcus aureus) is frequent [18-20]. Onycholysis or onychodystrophy may occur secondary to nail bed inflammation. Treatment options include topical or oral antimicrobials, chemical cauterization, and partial nail avulsion [21]. (See "Paronychia", section on 'Drug-induced paronychia' and "Pyogenic granuloma (lobular capillary hemangioma)".) ●Hair abnormalities – Hair on the scalp and body may become brittle, finer, and curly. Hirsutism, trichomegaly (excessive growth of the eyelashes), and a marked increase in the length of the eyebrows have been described [22,23]. Reversible alopecia has also been reported with EGFR inhibitors. (See "Alopecia related to systemic cancer therapy", section on 'Molecularly targeted agents'.) ●Other – Other reactions include pruritus, xerosis, mucositis, and photosensitivity [2,24,25]. This constellation of symptoms, in addition to the acneiform eruption, has been labeled PRIDE syndrome (papulopustules and/or paronychia, regulatory abnormalities of hair growth, itching, and dryness due to epidermal growth factor receptor inhibitors) [26].

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Bullous and exfoliative eruptions, including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, have been rarely reported [27,28]. However, the risk appears to be quite low: •No increased frequency was observed by the international Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) [29]. •A systematic review of 117 clinical trials including approximately 9000 patients did not find any additional fatal reactions attributed to erlotinib, cetuximab, or panitumumab [30,31]. ●Radiation dermatitis – Increased risk of severe radiation dermatitis is reported in patients treated concomitantly with EGFR inhibitors [32,33]. (See "Radiation dermatitis".)

BCR/ABL TYROSINE KINASE INHIBITORS

Inhibitors of the BCR-ABL fusion protein are multitargeted tyrosine

kinase inhibitors (TKIs) that inhibit signal transduction through the BCR-ABL fusion protein, which functions as a tyrosine kinase. They include: ●Imatinib is a first-generation multitargeted TKI used for a variety of tumor types, most commonly Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML), which is characterized by the presence of a fusion protein (BCR-ABL, which functions as a tyrosine kinase), and gastrointestinal stromal tumors, which are characterized by KIT mutations. ●Dasatinib, nilotinib, and bosutinib are second-generation TKIs that are only used in patients with Ph+ CML. ●Ponatinib is a third-generation TKI used for the treatment of chronic myeloid leukemia with BCRABL1 T315I mutation. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy".) Skin adverse events associated with inhibitors of the BCR/ABL fusion protein have multiple presentations, including maculopapular rash, alopecia, pigmentation disorders, and keratosis pilaris (table 3). Severe skin reaction can also rarely occur.

Maculopapular eruption — The most common cutaneous adverse event of TKIs is an exanthematous, maculopapular eruption. In patients taking imatinib, the frequency of cutaneous eruptions is dose dependent, ranging from 33 percent at doses less than 400 mg daily to 93 percent with daily doses of 600 mg or more [34]. Although mild cases often spontaneously resolve over time despite drug continuation, more severe skin reactions require discontinuation of treatment for up to two weeks followed by reintroduction at a lower daily dose with or without a temporary course of an oral corticosteroid [35,36]. As with imatinib, cutaneous eruptions have been reported with dasatinib, nilotinib, ponatinib, and bosutinib:

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●In a total of 911 patients reported in phase I and II studies of dasatinib, cutaneous eruptions were reported in 35 percent [37]. Reactions included localized and generalized erythema, papular eruptions, "exfoliative rash," and pruritus. Two cases of dasatinib-induced panniculitis have been described [38]. ●In phase I and II studies, the most frequent nonhematologic side effects of nilotinib were "nonspecific rash" (20 to 28 percent of all patients), pruritus (15 to 24 percent), and dry skin (12 percent) [39,40]. ●Ponatinib, which is available only with limited access in the United States because of a high frequency of venous and arterial thromboembolic phenomena, has been associated with rash and dry skin in up to 40 percent of patients [41]. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'VEGFR tyrosine kinase inhibitors'.) ●In clinical trials of bosutinib, adverse skin reactions were reported in 20 to 44 percent of patients and included erythema, maculopapular eruption, pruritic rash, allergic dermatitis, acne, folliculitis, and skin exfoliation [42,43].

Severe cutaneous adverse reactions — Severe reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), have been linked to higher initial doses of imatinib therapy [35,44]. Severe skin rashes, especially SJS/TEN and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, usually prompt permanent drug discontinuation, although a causal association may have not been determined [45,46]. There is a single case report of one patient with exfoliative dermatitis who had complete resolution of skin reaction when the regimen was decreased to once weekly dosing [47]. Whether the once weekly dose regimen was sufficient for disease control was not reported. Acute generalized exanthematous pustulosis (AGEP) and Sweet syndrome (acute febrile neutrophilic dermatosis) have both been associated with imatinib therapy [48-51]. The skin lesions in AGEP generally resolve within two weeks [52]. In such cases, the decision as to whether to attempt retreatment with imatinib depends on the severity of the reaction and whether there are other therapeutic alternatives. In one case of Sweet syndrome, the eruption resolved with oral glucocorticoid therapy and did not recur with reinitiation of imatinib, while in another case, recurrent skin lesions were observed with subsequent imatinib treatments. (See "Acute generalized exanthematous pustulosis (AGEP)" and "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)

Photosensitivity — Photosensitization has been reported in patients treated with imatinib [34,53]. In a prospective study of 54 patients treated with imatinib for chronic myeloid leukemia, four (7 percent) developed photosensitivity [34]. Imatinib has also been associated with pseudoporphyria, a bullous photodermatosis with the clinical and histologic features of porphyria cutanea tarda [54,55]. (See "Pseudoporphyria".)

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Pigmentary changes — A number of patients have noted pigmentary changes of the skin and hair while undergoing treatment with imatinib, including both hypopigmentation (in black patients [56]) and hyperpigmentation [56-60]. In a systematic review and meta-analysis, the incidence of all-grade pigmentary changes of the skin with imatinib monotherapy was 23 percent [61]. As the KIT receptor is known to play a role in melanogenesis and in melanocyte homeostasis [62], the photosensitivity and pigmentary changes may represent direct physiologic responses by skin melanocytes.

Other — In early clinical trials, up to 60 percent of patients treated with imatinib had edema, typically in a periorbital distribution [63]. Induction of psoriasiform eruptions and exacerbations of psoriasis have occurred in patients treated with imatinib [34,64,65]. In a prospective study of 54 patients treated with imatinib for chronic myeloid leukemia, four developed a psoriasiform eruption; two had a known history of psoriasis [34]. However, improvement of psoriasis has also been reported in one patient receiving imatinib for a gastrointestinal stromal tumor [66]. Other miscellaneous reactions that have been reported in patients receiving imatinib include small vessel vasculitis, erythema nodosum, a graft-versus-host-like skin reaction [67], an exfoliative dermatitis with fever and nonfollicular pustules [34], lichenoid drug eruption [68], and a single report of hand-foot syndrome [69]. Keratosis pilaris and xerosis are also frequent with TKIs that inhibit signal transduction through the BCR-ABL fusion protein, likely related to concomitant plateletderived growth factor receptor (PDGFR)-alpha inhibition [70].

VEGFR/PDGFR INHIBITORS

Vascular endothelial

growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitors are a group of small molecule tyrosine kinase inhibitors (TKIs) that target a number of tyrosine receptors and tyrosine kinases involved in tumor growth and angiogenesis, including VEGFR, PDGFR, fibroblast growth factor receptor (FGFR), and RET. These include: ●Sorafenib ●Sunitinib ●Axitinib ●Pazopanib ●Regorafenib ●Cabozantinib ●Vandetanib ●Lenvatinib

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These agents, which are used for the treatment of a variety of tumors, including renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer, are associated with a variety of cutaneous effects that are summarized in the table (table 3).

Hand-foot skin reaction — Hand-foot skin reaction (HFSR) is the most common cutaneous adverse effect of multitargeted VEGFR-TKIs. Its frequency appears to be higher with sorafenib and regorafenib compared with other VEGFR inhibitors [71-76]. Overall, all-grade and high-grade HFSR occurs in approximately 35 and 10 percent of patients, respectively [77,78] and differs in its clinical presentation and histologic appearance from the acral erythema caused by other conventional chemotherapy drugs [79,80]. (See "Cutaneous side effects of conventional chemotherapy agents", section on 'Hand-foot syndrome (acral erythema)'.) HFSR typically presents with focal, hyperkeratotic, callus-like lesions on an erythematous base in areas of pressure or friction, such as the fingertips, heels and metatarsal areas, and over joints (picture 3A-C). The clinical and histologic appearance of HFSR differs from the classic form of acral erythema that is associated with conventional cytotoxic chemotherapy agents, which is most often characterized by a symmetric edema and erythema of the palms and soles that may progress to blistering and necrosis, with loss of the epidermis and crusting (picture 4 and picture 5) [60,71,72,81,82]. Although HFSR is not included in the National Cancer Institute's Common Terminology Criteria for Adverse Events as its own category, "palmoplantar erythrodysesthesia" can be used to grade HFSR (table 4). The management and prevention of HFSR are discussed in detail separately and summarized in the algorithm (algorithm 1). (See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors", section on 'Management' and "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors", section on 'Prevention'.)

Hair changes — Diffuse, reversible alopecia has been described in up to 50 percent of patients treated with sorafenib but less frequently in those treated with sunitinib (5 to 21 percent), pazopanib (8 to 10 percent), or axitinib (4 percent) [2,73,83,84]. (See "Alopecia related to systemic cancer therapy", section on 'Molecularly targeted agents'.) Reversible hair depigmentation can occur during treatment with sunitinib and pazopanib [2]. In a phase III trial in which 290 patients with renal cell carcinoma were treated with pazopanib, changes in hair color occurred in 38 percent of treated patients and skin hypopigmentation was noted in 3 percent [85]. In a meta-analysis of 11 trials, the relative risk of all-grade alopecia and hair color changes in cancer patients treated with pazopanib was 1.75 (95% CI 1.33-2.31) and 4.54 (95% CI 3.67-5.62), respectively [86]. It is postulated that pigmentary changes associated with pazopanib may result from alterations in melanocyte proliferation or function secondary to the inhibition of KIT [87].

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Squamoproliferative lesions — Sorafenib has been associated with cutaneous squamoproliferative lesions, including keratoacanthomas (KAs) and squamous cell carcinomas (SCCs) [88-93]. In a retrospective study of 131 patients receiving sorafenib for metastatic renal cell carcinoma, seven were diagnosed with SCC and two with KA [89]. Another report described the appearance of 22 squamoproliferative lesions in 13 patients within nine months of initiating sorafenib [88]. One was described as a classic invasive SCC, five as KA-like SCC, and 16 as classic KA. Prospective studies are necessary to clarify the risk and natural history of sorafenibinduced squamoproliferative lesions. Squamoproliferative lesions that develop during sorafenib therapy should be treated similarly to lesions that develop in patients not receiving the drug (usually with complete surgical excision). However, spontaneous regression of KAs has been reported after discontinuation of the drug and also in a few patients who continued therapy [88,94]. Definitive guidelines for continuing versus discontinuing sorafenib in patients who develop SCCs or KAs while on therapy have not been established. Close clinical follow-up during treatment is warranted. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma".)

Other cutaneous effects — A wide range of other cutaneous adverse effects have been described in patients treated with VEGFR inhibitors. Examples include the following: ●Sorafenib and sunitinib – Treatment with sorafenib and sunitinib has been associated with a variety of cutaneous adverse effects, including seborrheic dermatitis-like facial and scalp erythema, scalp dysesthesia, and subungual splinter hemorrhages [73,84]; eruptive, melanocytic lesions [95,96]; Stevens-Johnson syndrome (SJS); mucositis; geographic tongue [97]; erythema multiforme [98] and erythema multiforme-like eruptions [99,100]; periungual erythema [101]; acquired perforating dermatosis [102]; xerosis; and exanthematous rashes [103]. Sunitinib may induce facial edema and pyoderma gangrenosum, a rare noninfectious neutrophilic dermatosis [104-106]. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis".) ●Vandetanib – Seborrheic dermatitis, acneiform eruption, dry skin, pruritus, photosensitivity, or HFSR have been reported in 28 to 71 percent of patients treated with vandetanib; they were severe (grade 3 or worse) in 3 to 6 percent [107-112]. Paronychia, genital eruptions resembling intertrigo, photodistributed lichenoid drug eruption, and subacute cutaneous lupus erythematosus have also been reported [113]. Severe skin reactions, some leading to death, have been reported with this agent [114,115]. Patients should be counseled to wear sunscreen and protective clothing when exposed to the sun. ●Regorafenib – Regorafenib targets VEGFR-1, VEGFR-2, and VEGFR-3, in addition to RET, KIT, PDGFR-alpha and PDGFR-beta, FGFR1 and FGFR2, and several other membrane-bound and intracellular kinases that are involved in normal cellular function and in pathologic processes. It is approved in the United States for treatment of refractory metastatic colorectal cancer. In a phase III

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trial (the CORRECT trial), rash/desquamation was reported in 26 percent (versus 4 percent with placebo), and it was severe in 6 versus 0 percent [116]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Regorafenib'.) ●Cabozantinib – Hair depigmentation, alopecia, dry skin, scrotal erythema/ulceration, and subungual splinter hemorrhages have been reported with cabozantinib, which is approved in the United States for the treatment of medullary thyroid cancer but is also used for the treatment of metastatic castration-resistant prostate cancer [117,118]. (See "Medullary thyroid cancer: Chemotherapy and immunotherapy".)

BRAF INHIBITORS

The BRAF inhibitors are serine-threonine kinase

inhibitors that act as kinase inhibitors in mutant BRAF. They include vemurafenib, dabrafenib, and the second-generation BRAF inhibitor encorafenib, all of which are approved for the treatment of metastatic melanoma with a V600E BRAF mutation. Cutaneous toxicities are common with these agents and include a wide range of manifestations, including nonspecific rash (maculopapular eruption), phototoxicity, and squamoproliferative lesions [119]. (See "Molecularly targeted therapy for metastatic melanoma", section on 'BRAF inhibition'.)

Maculopapular rash — A maculopapular eruption is the most common skin reaction associated with BRAF inhibitors. In a meta-analysis of nine randomized trials of vemurafenib, the overall prevalences of all-grade rash and high-grade rash were 45 percent (95% CI 0.34-0.57) and 12 percent (95% CI 0.03-0.38), respectively [120]. A granulomatous dermatitis, presenting as a widespread eruption of grouped, papular lesions coalescing into plaques, has been reported in a few patients months after starting treatment with vemurafenib [121].

Phototoxic reaction — The phototoxic reaction associated with vemurafenib appears to be caused by ultraviolet A (UVA) radiation and may be prevented with the use of broadspectrum sunscreens (table 5) [122]. A meta-analysis of eight randomized trials (4095 patients) found an overall prevalence of all-grade phototoxic reaction of 30 percent (95% CI 0.23-0.38) among patients treated with vemurafenib.

Squamoproliferative lesions — Patients treated with BRAF inhibitors frequently develop keratinocytic, proliferative lesions, including cutaneous squamous cell carcinoma (cSCC), keratoacanthoma (KA), and verrucal keratotic lesions. A meta-analysis of seven randomized trials found a prevalence of cSCC and KA of 18 percent (95% CI 0.12-0.26) and 10 percent (95% CI 0.06-0.15), respectively, among patients taking vemurafenib [120]. In patients taking dabrafenib, verrucal keratotic lesions with low to moderate epidermal dysplasia have been reported in up to 66 percent and KAs or well-differentiated cSCCs in 6 to 26 percent [119,123-125].

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These squamoproliferative lesions, which are thought to be induced by a paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway, appear in weeks to a few months after initiating treatment, are fast growing, are widely distributed on the body, and may occur in sunprotected sites [126]. In a series of 134 patients with metastatic melanoma treated with dabrafenib or vemurafenib, 32 patients (24 percent) developed one or multiple cSCCs, most of which in the first three months of treatment [127]. The risk of developing cSCC increased with age, with cSCCs arising in 30 percent or more of patients older than 60 years [127]. Interestingly, skin papilloma and cSCC occur less frequently in patients treated with the combination of encorafenib plus binimetinib compared with encorafenib or vemurafenib as monotherapy. In a randomized phase III trial including 577 patients with BRAF-mutant melanoma, cSCC developed in 4 percent, 8 percent, and 17 percent of patients receiving encorafenib plus binimetinib, encorafenib alone, or vemurafenib alone, respectively [128]. The skin tumors that develop in patients treated with these agents are managed with surgical excision, and patients are usually able to continue treatment without dose adjustment [129].

Hair changes — Alopecia is one of the most common adverse reactions of BRAF inhibitors. It has been reported in over 50 percent of patients receiving encorafenib and nearly 40 percent of patients receiving vemurafenib [130,131]. Changes in hair structure and color have been reported in patients taking dabrafenib [125].

Palmoplantar keratoderma — In clinical trials, palmoplantar keratoderma has been reported in 15 to 25 percent of patients receiving BRAF inhibitors [125,130,132]. Grade 1 to 2 and grade 3 hand-foot skin reaction have been reported in 38 and 14 percent of patients treated with encorafenib, respectively [130].

Other — Other cutaneous adverse events associated with BRAF inhibitors include hyperkeratosis, palmoplantar erythrodysesthesia, acrochordon, keratosis pilaris, actinic keratosis, lichenoid keratosis, papilloma, seborrheic keratosis, and pyogenic granuloma [128,133-137]. Vemurafenib has also been associated with radiation enhancement when radiation therapy was administered concurrently [138,139]. (See "Radiation dermatitis".) Stevens-Johnson syndrome/toxic epidermal necrolysis has been reported in patients taking vemurafenib [140-142]. Grover disease (transient acantholytic dermatosis) has been reported in up to 27 percent of patients receiving dabrafenib [125]. (See "Grover's disease (transient and persistent acantholytic dermatosis)".)

BRAF PLUS MEK INHIBITORS

Trametinib,

cobimetinib, and binimetinib are orally bioavailable inhibitors of mitogen-activated protein kinase (MAPK) enzymes (MEK1 and MEK2) approved for the treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation in combination with the BRAF inhibitors

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vemurafenib, dabrafenib, and encorafenib [143,144]. (See "Molecularly targeted therapy for metastatic melanoma", section on 'MEK inhibition' and "Molecularly targeted therapy for metastatic melanoma", section on 'Combined MEK plus BRAF inhibition'.) Cutaneous adverse effects of MEK inhibitors are common and include acneiform eruption, pruritus, and xerosis [132,145,146]. Data from studies of combination therapy with dabrafenib plus trametinib for advanced melanoma indicate that the combination therapy is associated with a marked reduction of cutaneous toxicities compared with vemurafenib or dabrafenib alone [124,147,148]: ●In a phase III study including 350 patients treated with dabrafenib plus trametinib and 349 patients treated with vemurafenib alone, skin toxic effects were less frequent in the combination therapy group than in the vemurafenib group: rash (22 versus 43 percent), photosensitivity reaction (4 versus 22 percent), hand-foot syndrome (4 versus 25 percent), skin papillomas (2 versus 23 percent), cutaneous squamous cell carcinoma (cSCC) and keratoacanthoma (KA) (1 versus 18 percent), and hyperkeratosis (4 versus 25 percent) [147]. ●In another phase III randomized trial including 211 patients treated with dabrafenib plus trametinib and 212 with dabrafenib alone, cutaneous adverse events occurred less frequently in the combination therapy group than in the dabrafenib alone group: hyperkeratosis (7 versus 35 percent), alopecia (9 versus 28 percent), skin papilloma (2 versus 22 percent), and cSCC/KA (2 versus 7 percent) [148]. In a phase II randomized trial including 192 patients treated with encorafenib plus binimetinib, 194 with encorafenib alone, and 191 with vemurafenib alone, cutaneous adverse events occurred less frequently in the combination therapy group than in the encorafenib and vemurafenib groups: rash (22, 41, and 53 percent, respectively), palmoplantar keratoderma (9, 26, and 16 percent, respectively), palmoplantar erythrodysesthesia (7, 52, and 14 percent, respectively), skin papilloma (7, 10, and 19 percent, respectively), and cSCC/KA (3, 8, and 17 percent, respectively) [130].

BRUTON KINASE INHIBITORS

Ibrutinib is an oral

irreversible inhibitor of Bruton's tyrosine kinase (BTK), an integral component of the B cell receptor pathway; it is approved by the US Food and Drug Administration for the treatment of mantle cell lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia [149]. Cutaneous adverse effects of ibrutinib include petechial to purpuric skin eruptions and nail and hair changes. Petechiae and bruising are reported to occur in up to 54 percent of patients treated with ibrutinib [150]. One study described mild, petechial eruptions that did not require skin-directed therapy or ibrutinib dose adjustment as well as palpable, purpuric eruptions that improved with topical steroids, oral steroids, and/or temporary interruption of ibrutinib [151]. The ibrutinib-associated bleeding diathesis is thought to be due to the inhibition of the platelet BTK, which is involved in collagenmediated platelet activation [152,153].

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Nail changes, including onychoschizia (lamellar splitting of the nail) and onychorrhexis (longitudinal ridging), have been reported in approximately two-thirds of patients after 6 to 12 months of treatment with ibrutinib [154]. Hair changes include straightening and softening or increased curliness. These effects are postulated to be specific to ibrutinib, as ibrutinib covalently binds to the cysteine residue at the active site of BTK, and disulfide bonds in hair and nail keratins are known to be important for their integrity.

PI3K INHIBITORS

Phosphoinositide 3-kinase (PI3K) is a family of

highly conserved enzymes involved in the intracellular PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. There are three classes of PI3K kinases (class I, further divided into IA and IB, class II, and class III) and four isoforms (alfa, beta, gamma, delta). Hyperactivation of the PI3K pathway is involved in a variety of human cancers [155]. Class IA PI3K inhibitors include idelalisib, copanlisib, and duvelisib, which are approved in the United States for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and relapsed or refractory follicular lymphoma; dacomitinib, which is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer; and alpelisib, which is approved for the treatment of breast cancer in combination with aromatase inhibitors [156-159]. Mucocutaneous adverse reactions, including maculopapular rash and oral mucositis, have been reported in approximately 14 and 23 percent of patients treated with copanlisib, respectively, and in 20 to 40 percent and 16 percent, respectively, of patients treated with duvelisib [160-163]. A maculopapular rash has been reported in up to 30 percent of patients treated with alpelisib [159]. Serious cutaneous reaction, including drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN), have been reported in 5 percent of patients treated with duvelisib [158]. Maculopapular rash and exfoliative skin reactions have been reported in 78 and 7 percent of patients, respectively, treated with dacomitinib [164].

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of symptoms and toxicities of anticancer therapy".)

SUMMARY ●Epidermal growth factor receptor (EGFR) inhibitors (eg, cetuximab, panitumumab, erlotinib, gefitinib, lapatinib) are associated with prominent dermatologic adverse events, the most common of which is a papulopustular acneiform eruption (table 1). It typically begins early, within one to two weeks of treatment initiation and is often dose dependent (picture 1A-C) [7,8]. The lesions occur on the face, scalp, chest, and back, usually sparing the extremities. Other reactions associated with

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EGFR inhibitors include paronychia (picture 2), hair abnormalities, xerosis, mucositis, and photosensitivity. (See 'EGFR inhibitors' above and "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".) ●The most common cutaneous adverse event associated with inhibitors of the BCR-ABL fusion protein (eg, imatinib, dasatinib, ponatinib) is an exanthematous, maculopapular eruption. Severe skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and Sweet syndrome, have been reported with imatinib. Other reactions include photosensitivity, pigmentary changes of the skin and hair, edema, psoriasiform eruption, keratosis pilaris, and xerosis. (See 'BCR/ABL tyrosine kinase inhibitors' above.) ●Vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitors (eg, sorafenib, sunitinib, pazopanib, regorafenib) are most frequently associated with hand-foot skin reaction (HFSR). It typically presents with focal, hyperkeratotic, callus-like lesions on an erythematous base in areas of pressure or friction, such as the fingertips, heels and metatarsal areas, and over joints (picture 3A-C). HFSR is discussed in detail separately (see "Handfoot skin reaction induced by multitargeted tyrosine kinase inhibitors"). Other adverse events include a diffuse, reversible alopecia and changes in hair color, maculopapular rash, desquamation, and xerosis. Sorafenib has also been associated with cutaneous squamoproliferative lesions, including keratoacanthomas (KAs) and squamous cell carcinomas (SCCs). (See 'VEGFR/PDGFR inhibitors' above.) ●BRAF inhibitors (eg, vemurafenib, dabrafenib, encorafenib) are frequently associated with a maculopapular eruption. Vemurafenib may also cause an ultraviolet A (UVA)-induced phototoxic reaction. Patients treated with BRAF inhibitors frequently develop keratinocytic proliferative lesions, including cutaneous squamous cell carcinoma (cSCC), KA, and verrucal keratotic lesions, which appear in weeks to months after initiating treatment. Other reactions include alopecia, palmoplantar keratoderma, palmoplantar erythrodysesthesia, acrochordon, actinic keratosis, and pyogenic granuloma. (See 'BRAF inhibitors' above.) ●Cutaneous adverse effects of MEK inhibitors (trametinib, cobimetinib, and binimetinib) include acneiform eruption, pruritus, and xerosis. Of note, the cutaneous toxicity of the BRAF-MEK combination therapy is markedly reduced compared with BRAF therapy alone. (See 'BRAF plus MEK inhibitors' above.) ●The Bruton kinase inhibitor ibrutinib is associated with petechiae, bruising, and nail and hair changes. (See 'Bruton kinase inhibitors' above.) ●Phosphoinositide 3-kinase (PI3K) inhibitors (idelalisib, copanlisib, duvelisib, dacomitinib, and alpelisib) are associated with maculopapular rash and oral mucositis. Serious cutaneous reaction, including DRESS and TEN, have been reported in patients treated with duvelisib. (See 'PI3K inhibitors' above.)

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ACKNOWLEDGMENTS

The editorial staff at UpToDate would

like to acknowledge Diane MF Savarese, MD, and Aimee S Payne, MD, PhD, who contributed to an earlier version of this topic review.

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Epidemiology, natural history, and diagnosis of actinic keratosis uptodate.com/contents/epidemiology-natural-history-and-diagnosis-of-actinic-keratosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jul 29, 2019.

INTRODUCTION

Actinic keratosis (AK, also known as solar keratosis) is a

cutaneous lesion that results from the proliferation of atypical epidermal keratinocytes. AKs represent early lesions on a continuum with squamous cell carcinoma (SCC) and occasionally progress to SCC. AKs often present as erythematous and scaly macules or papules; lesions are most commonly detected in adults with fair skin. Chronic sun exposure is a major risk factor for the development of these lesions, which accounts for the usual detection of AKs in frequently sun-exposed areas (eg, balding scalp, face, lateral neck, and distal upper or lower extremities). The epidemiology, clinical features, natural history, and diagnosis of AK will be discussed here. The management of AK and SCC is reviewed elsewhere. (See "Treatment of actinic keratosis" and "Epidemiology and risk factors for cutaneous squamous cell carcinoma" and "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis" and "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma".)

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EPIDEMIOLOGY AND RISK FACTORS

In the United States, AKs are among the most common reasons for visits

to dermatologists [1-4]. It is estimated that between 1990 and 1999, 14 percent of dermatology visits in the United States were related to AKs [3]. Individuals with fair skin are most likely to develop AKs, and many of the data on the epidemiology and risk factors for AK are derived from studies in Australia, northern Europe, and the United States. Factors such as the extent of exposure to ultraviolet light and certain phenotypic features have been associated with risk for developing these lesions.

Ultraviolet radiation — Ultraviolet radiation is believed to contribute to the development of AK through the induction of mutations in epidermal keratinocytes that lead to increased survival and proliferation of atypical cells [5]. Mutations in the p53 tumor suppressor gene, a gene involved in cell cycle regulation, apoptosis, and DNA repair, have been detected in 30 to 50 percent of lesional skin samples from patients with AKs [6,7].

Extent of sun exposure — Individuals with extensive sun exposure, such as those with outdoor occupations, are at increased risk for AK [8-11]. In a population-based study of 20,637 people in the United States, AKs were present in 55 percent of white men and 37 percent of white women between the ages of 65 and 74 years and who were classified as having high cumulative sun exposure [12]. In contrast, among a similar demographic population composed of subjects with low cumulative exposure to the sun, AKs were present in only 19 percent of men and 12 percent of women.

History of sunburn — A history of sunburn increases the risk for AK [8-10]. In an Australian study of 2045 residents of Queensland, Australia (aged 20 to 69 years), six or more painful sunburns over the course of life were associated with an increased likelihood for AK (prevalence odds ratio [OR] 1.47, 95% CI 1.01-2.14) [9]. A separate cohort study of 197 residents of the same Australian state found that even a single episode of sunburn in childhood elevated the risk for AK [10]. (See "Sunburn".)

Impact of sun protection — The stimulatory role of sun exposure on the development of AKs is supported by evidence that use of sunscreens reduces the development of these lesions [13,14]. In a seven-month randomized trial, 588 residents (aged 40 or older) of Victoria, Australia who had between 1 and 30 AKs were instructed to apply either a broad-spectrum sunscreen with a sun protection factor (SPF) of 17 or a vehicle cream to the head, neck, and forearms daily. Patients in the sunscreen group developed significantly fewer new AKs (mean number of new lesions 1.6 versus 2.3) and had significantly more spontaneous remissions of AKs

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(mean percentage of resolved lesions 28 versus 20 percent) [13]. The 157 subjects who withdrew from the study prior to completion were not included in the study analysis. (See "Epidemiology and risk factors for cutaneous squamous cell carcinoma", section on 'Protection from sun exposure'.)

Phenotype — Skin color contributes to the risk for AK, as the majority of AKs are detected in individuals with fair skin [8-10,12,15,16]. Epidermal melanin absorbs ultraviolet radiation and shields keratinocytes against damage from ultraviolet light, resulting in a reduced risk for AK with darkening skin pigmentation. The importance of skin color is supported by a study of 197 residents of Queensland, Australia [10]. Compared with olive-skinned individuals, people with fair or medium-toned (between fair and olive) skin were significantly more likely to develop AKs (age and sex adjusted odds ratios [OR] of 14.1, 95% CI 2.9-69.6 and 6.5, 95% CI 1.2-34.7, respectively) [10]. In addition, AKs are uncommon in African-Americans [12]. Freckling, light hair color, a propensity to sunburn easily, and an inability to tan, which are more often seen in people with fair skin, are additional features that have been associated with increased risk for AK [1,12]. The balding scalp is a common site for AK in men and may represent a risk factor for lesion development. In a Dutch population-based cohort study of 2061 men and women over the age of 50, severe baldness was associated with increased risk for AK when compared with minimal or no baldness [17]. In particular, men with severe baldness were approximately seven times more likely to have 10 or more AKs than men with minimal or absent baldness (adjusted OR 7.0, 95% CI 3.8-13.1).

Gender, age, and geographic location — Sex and age influence the risk for AK. Men are more likely than women to develop these lesions, and the prevalence of AK rises with age [9,15,17-20]. The magnitude of these effects is illustrated by the following observations: ●In a study in Queensland, Australia that evaluated the prevalence of AK in 2045 adults between the ages of 20 and 69 years, AKs were detected in 40 percent [9]. Lesions were present in 79 percent of men and 68 percent of women between the ages of 60 and 69 compared with only 10 percent of men and 5 percent of women aged 20 to 29 years. ●A cohort study of 1040 people over the age of 40 in North Central Victoria, Australia also detected a high prevalence of AK that increased with age. Fifty-nine percent of study participants had at least one AK, and the mean age of individuals with AK was significantly higher than in those without AK (62 versus 54 years) [19]. Compared with Australia, AKs are less prevalent in the United States and northern Europe, where there is generally less sun exposure. Estimates of the proportion of adults with AKs in these locations range from 11 to 26 percent [1,18,20,21]. In a Dutch population-based study limited to individuals over the age of 50 years, physical examination revealed AK in 38 percent [17].

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The impact of geographic location was illustrated in a cohort study that compared the prevalence of AKs in Australian-born adults with that in British immigrants to Australia. All subjects were age 40 years or older. The prevalence of AKs in those who immigrated to Australia before the age of 20 became similar to native Australians in late adulthood, while those who immigrated after the age of 20 had fewer AKs than native Australians in all age groups [22]. These results suggest that living in a location associated with greater exposure to ultraviolet light early in life may increase the risk for AK.

Other Genetic disorders — Individuals with genetic disorders that interfere with effective DNA repair after exposure to ultraviolet radiation are at increased risk for AK. Examples include xeroderma pigmentosum, Bloom syndrome, and Rothmund-Thompson syndrome. (See "The genodermatoses: An overview", section on 'Xeroderma pigmentosum' and "Bloom syndrome".)

Human papillomavirus — Betapapillomavirus types of human papillomavirus (HPV) have been detected in AKs, squamous cell carcinomas (SCCs), and basal cell carcinomas (BCCs) [15,23-27]. However, HPV is also detected in normal skin [25], and an etiologic relationship between HPV and these lesions is uncertain. A cohort study of 291 adults (ages 36 to 86 years) in Queensland, Australia who were tested for the presence of betapapillomavirus in eyebrow hairs in 1996 did not identify an independent association of betapapillomavirus infection with the detection of AK in 2003 [15]. However, when combined with risk factors for AKs (eg, fair skin, male sex, age over 60), betapapillomavirus infection appeared to increase the likelihood for the development of AK. Additional studies are necessary to explore the role of HPV in this disorder.

Immunosuppression — Immunosuppression has been associated with an increased risk for SCC and may also increase the risk for AK [28-30]. In a study of 94 renal transplant recipients in England (mean age 38 years and mean duration from transplant 4.5 years) and their matched controls, AKs developed in seven of the transplant recipients (7.4 percent) and in none of the controls [29]. All patients with AKs had a history of high sun exposure, defined as more than three months in a tropical or subtropical climate or more than five years in an outdoor occupation. The risk for AK may rise as the time interval after transplant increases [28,30].

CLINICAL FEATURES

AKs typically develop as solitary or

multiple lesions on highly sun exposed areas, such as the balding scalp, neck, dorsal hands, and dorsal forearms. The lower extremities are an additional common site for AKs in women. Skin adjacent to AKs usually shows signs of solar damage, such as a yellow or pale color, spotty hyperpigmentation, scattered telangiectasias, or xerosis. AKs are generally asymptomatic, but some patients experience local tenderness or a stinging sensation. AKs present as several clinical variants, including:

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●Classic (common) – The classic form of AK presents as an erythematous, scaly macule, papule, or plaque (picture 1A-B). Lesions typically range from a few millimeters to 2 cm in diameter. Occasionally, lesions are larger. ●Hypertrophic – Hypertrophic AKs are characterized by the presence of thick, adherent scale on an erythematous base (picture 2A-B). ●Atrophic – Scale is absent in atrophic AKs. Lesions are smooth, red macules. ●AK with cutaneous horn – A cutaneous horn is a keratotic projection the height of which is at least one-half of the largest diameter (picture 3) [31]. The mound of compact keratin often resembles a spicule or cone. Several other skin lesions can present with cutaneous horns. (See 'Differential diagnosis' below.) ●Pigmented – Pigmented actinic keratoses usually present as scaly, hyperpigmented macules or patches. Lesions may be large, exceeding 1.5 cm in some cases [16]. Pigmented AKs can be difficult to distinguish from lentigo maligna. (See 'Differential diagnosis' below and 'Dermoscopy' below.) ●Actinic cheilitis – Actinic cheilitis (also known as solar cheilosis) is a term that is used to refer to lesions analogous to AKs that occur on the lip [32]. This disorder typically presents on the lower lip as a persistent rough or scaly area (picture 4A-C). Patients often complain of a constantly dry lip. Actinic cheilitis may involve only a small portion of the lip or the entire lower lip. Fissuring or ulceration may also occur. (See "Cheilitis", section on 'Actinic cheilitis'.)

CLINICAL COURSE

AKs are increasingly considered lesions that are

on a continuum with squamous cell carcinoma (SCC) rather than lesions that are distinct from SCC [33]. This viewpoint recognizes the potential for AKs to progress to invasive skin cancer.

Progression to skin cancer — The likelihood of progression of an individual AK to SCC is low. Estimates of annual rates of transformation have ranged from 0.03 to 20 percent [34-37]. The following data come from two of the largest studies: ●An Australian study that evaluated 1689 adults over the age of 40 who had more than 20,000 AKs found the risk for transformation of an individual AK to SCC within one year to be less than 0.1 percent [34]. ●Analysis of data from a cohort of patients in a United States trial designed to investigate the use of topical tretinoin for skin cancer prevention in patients with at least two prior keratinocyte carcinomas revealed a rate of transformation to invasive or in situ SCC of 0.6 percent in 6015 AKs followed for one year and a rate of 2.6 percent in 1480 lesions followed for four years [35]. Progression of AKs to basal cell carcinoma (BCC) occurred in 0.5 percent of AKs within one year and in 1.6 percent within four years. However, it is unclear whether this finding was related the misdiagnosis of early BCCs as AKs or was true disease progression.

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Although few AKs progress to SCC, data from these studies suggest that approximately 60 percent of cutaneous squamous cell carcinomas (cSCCs) arise from preexisting AKs [34,35]. However, in an Australian cohort of immunosuppressed renal transplant recipients, the presence of an AK >1 cm2 (AK patch) was predictive of invasive or in situ SCC development in sun-exposed sites within 18 months [38]. This observation supports a close relationship between these lesions. Molecular studies support the hypothesis that the coexpression of putative pathogenetic genes in AK and SCC underlie the progression of AK to cSCC [33,39-42].

Spontaneous resolution — Lesions that do not progress to SCC may regress or persist as AKs [19,35,43]. Reported rates of AK regression generally range between 20 to 30 percent per year, though a regression rate up to 63 percent per year has been reported [44]. Lesions that regress may subsequently reappear; studies with limited follow-up suggest that 15 to 53 percent of spontaneously regressed AKs recur within one year [44].

Risk for skin cancer in other sites — Although the majority of AKs do not progress to SCC, the presence of AKs serves as a marker of chronic sun damage and, therefore, of an increased risk for the development of both SCC and BCC [45-48]. Increasing age and the presence of AKs are correlated with an increased risk of developing SCC and BCC in addition to malignant melanoma [49,50].

DIAGNOSIS

AK is frequently diagnosed clinically through a combination of touch

and visual inspection. Some macular lesions lack erythema and are more easily identified through the detection of rough texture. Lesion biopsy is performed if the diagnosis is uncertain. A common indication for biopsy is the differentiation of AK from squamous cell carcinoma (SCC).

Differential diagnosis — Distinguishing AK from SCC can be challenging, as both disorders commonly present as erythematous, scaly papules on sun exposed areas. Lesions with underlying substance, or that are tender, ulcerated, or rapidly growing, are particularly suspicious for SCC. Such lesions should be biopsied for definitive diagnosis. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".) In addition to SCC, multiple other lesions may resemble AKs. Classic (common) AKs may resemble: ●SCC (picture 5) ●Benign lichenoid keratoses (picture 6) ●Superficial basal cell carcinoma (picture 7) ●Inflamed seborrheic keratosis (picture 8) ●Porokeratosis (picture 9A-B)

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●Inflammatory dermatoses (psoriasis, seborrheic dermatitis) (picture 10A-C) Hypertrophic AKs or AK with cutaneous horn may resemble: ●SCC (picture 11) ●Viral wart (picture 12) ●Seborrheic keratosis (picture 13) Pigmented AKs share clinical features with: ●Seborrheic keratosis (often distinguished by a "stuck on" appearance) (picture 14) ●Solar lentigo (picture 15) ●Lentigo maligna melanoma (picture 16)

Biopsy — The decision of whether to perform a biopsy is determined by certainty of diagnosis. In particular, biopsy to rule out SCC should be considered for: ●Lesions greater than 1 cm in diameter ●Lesions with underlying substance/induration ●Rapidly growing lesions ●Ulcerated lesions ●Tender lesions ●Lesions that fail to respond to appropriate therapy (eg, AK that persists 8 to 12 weeks after treatment with liquid nitrogen)

Technique — Biopsies of lesions suspicious for AK are most commonly performed with a shave or punch biopsy technique. If only a portion of the lesion can be removed due to size or concern for scarring, the thickest area of the lesion should be biopsied as SCC arising in an AK is most likely to be detected in this area. Shave biopsies should extend into the dermis, and preferably at least into the mid-reticular dermis for lesions that are suspicious for SCC. An insufficient biopsy depth will compromise the pathologist's ability to rule out an invasive SCC. Punch biopsies performed with the full length of the punch blade usually reach the subcutaneous fat. (See "Skin biopsy techniques", section on 'Biopsy techniques'.)

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Pathology — The histopathologic findings of AKs are dependent upon the clinical variant and specific lesion characteristics. Unlike invasive SCCs, atypical keratinocytes do not invade into the dermis. Common histopathologic features of AK include: ●A collection of atypical keratinocytes with hyperchromatic and pleomorphic nuclei that extends from the basal layer of the epidermis upward; the full thickness of the epidermis is spared (picture 17A-B). Mitoses are not uncommon, and acanthosis (epidermal thickening) may be present. ●A hyperkeratotic stratum corneum with alternating areas of orthokeratosis and parakeratosis ("flag sign"), particularly in hypertrophic AKs. ●A variable lymphocytic dermal infiltrate. ●Dermal changes consistent with solar elastosis. In addition to the above, pigmented AKs demonstrate increased melanin in the lower epidermis and dermal melanophages. Clinically atrophic lesions demonstrate a thin epidermis with atypia that predominantly involves the basal layer. Histologic variants of AK include bowenoid, lichenoid, and acantholytic subtypes. The existence of the histologic bowenoid variant of AK is controversial. Bowenoid AKs are characterized by fullthickness epidermal dysplasia that is indistinguishable from SCC in situ; notably, keratinocytes in the acrosyringium are spared. Lichenoid lesions feature vacuolization of the basal layer of the epidermis and a band-like chronic inflammatory infiltrate in the superficial dermis. Acantholytic AKs exhibit detachment of keratinocytes due to loss of intercellular bridges; this results in the formation of clefts or lacunae immediately above the basal layer. A histologic grading system analogous to that used for cervical intraepithelial neoplasia in gynecology has been proposed for AKs [51]. In this system, the term keratinocytic intraepidermal neoplasia, divided into grades of I, II, and III, is used to describe the progression of AK to in situ SCC. This grading system has not been widely adopted. Biopsy specimens should be sent to a dermatopathologist when feasible. If pathology results fail to correlate with the clinical findings, consultation with the dermatopathologist may be beneficial. Additional pathologic sections may aid in identifying an invasive SCC, particularly in cases in which clinical suspicion for SCC is high [52].

Dermoscopy — Dermoscopy is a noninvasive procedure that involves use of a handheld tool that combines magnification and a transilluminating light source to aid in the diagnosis of many cutaneous lesions. Dermoscopy is widely used for the evaluation of melanocytic nevi and lesions suspicious for melanoma. Common dermoscopic features of nonpigmented AKs include a strawberry pattern (picture 18 and picture 19) (background erythema or a red pseudonetwork that consists of unfocused large vessels between hair follicles and prominent follicular openings surrounded by white halos) or a vascular

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pattern with linear, wavy vessels [53]. Pigmented AKs commonly demonstrate slate-gray to brown dots and globules around follicular ostia and annular-granular and rhomboidal structures (picture 20) [48]. In clinical practice, distinguishing between pigmented AKs and lentigo maligna can be challenging. Dermoscopy may not be reliable for distinguishing between these lesions [48], but helpful clues suggestive of an AK are white and clearly defined follicles, scale, and red color (picture 20). Intense pigmentation, gray rhomboid lines, and loss of identifiable follicles are suggestive of lentigo maligna. However, histopathologic examination remains the gold standard for such cases. (See "Dermoscopic evaluation of skin lesions" and "Dermoscopy of facial lesions", section on 'Actinic keratosis'.)

INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topics (see "Patient education: Actinic keratosis (The Basics)")

SUMMARY AND RECOMMENDATIONS ●Actinic keratoses (AKs) are common cutaneous lesions that result from the proliferation of atypical epidermal keratinocytes. Major risk factors for the development of AKs include chronic sun exposure, fair skin, advancing age, and male sex. (See 'Introduction' above and 'Epidemiology and risk factors' above.) ●AKs most commonly present as scaly, erythematous macules or papules on sites of chronic sun exposure (picture 1A-B). Lesions may also be pigmented, nonerythematous, or free of scale. Typical locations for AKs include the scalp, face, lateral neck, dorsal forearms, and dorsal hands. Actinic cheilitis is a variant of AK that involves the lip (picture 4A-C). (See 'Clinical features' above.) ●AKs may progress to squamous cell carcinoma (SCC). The risk that an individual AK will progress is low, but approximately 60 percent of cutaneous squamous cell carcinomas (cSCCs) arise in sites of preexisting AKs. In addition, patients with AKs are at an increased risk for the development of

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SCCs or basal cell carcinomas (BCCs) in other sites. (See 'Clinical course' above.) ●The diagnosis of AK is often made based on visual and tactile clinical inspection. Biopsy is indicated if the diagnosis is uncertain; a common indication for biopsy is distinguishing AK from SCC. In particular, lesions that are greater than 1 cm in diameter, indurated, ulcerated, or rapidly growing and lesions that fail to respond to appropriate therapy should be considered for biopsy. (See 'Diagnosis' above.) ●Pigmented AKs are often difficult to distinguish from lentigo maligna on clinical exam. Histopathologic examination is the gold standard for diagnosis. Dermoscopy may not reliably distinguish between these lesions. (See 'Dermoscopy' above.)

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Treatment of actinic keratosis - UpToDate uptodate.com/contents/treatment-of-actinic-keratosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 21, 2019.

INTRODUCTION

Actinic keratoses (AKs or solar keratoses) are keratotic

macules, papules, or plaques resulting from the intraepidermal proliferation of atypical keratinocytes in response to prolonged exposure to ultraviolet radiation. Although most AKs do not progress to squamous cell carcinoma (SCC), AKs are a concern because the majority of cutaneous SCCs arise from pre-existing AKs, and AKs that will progress to SCC cannot be distinguished from AKs that will spontaneously resolve or persist [1,2]. Because of these factors, most clinicians routinely treat AKs [3]. Improvement in associated symptoms and cosmetic appearance can be additional benefits of treatment. The treatment of AKs will be reviewed here. The epidemiology, clinical manifestations, and diagnosis of AKs are discussed separately. (See "Epidemiology, natural history, and diagnosis of actinic keratosis".)

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OVERVIEW OF TREATMENT OPTIONS

Treatment options for actinic keratosis (AK) include destructive therapies

(eg, surgery, cryotherapy, dermabrasion, photodynamic therapy [PDT]), topical medications (eg, topical fluorouracil, imiquimod, ingenol mebutate, diclofenac), and field ablation treatments (eg, chemical peels, laser resurfacing). In general, lesion-directed treatments, such as cryotherapy and surgical procedures, are the primary approach for isolated lesions [3]. Field-directed therapies, such as topical fluorouracil, imiquimod, and PDT, are particularly useful for treating areas with multiple AKs. (See 'Choice of therapy' below.) Evidence for efficacy of these therapies is derived from multiple randomized trials and metaanalyses [4-8]: ●One systematic review and meta-analysis of 83 randomized trials evaluating 24 treatments in over 10,000 patients found sufficient evidence to conclude that topical fluorouracil, imiquimod, ingenol mebutate, and topical diclofenac are superior to placebo for complete clearance of lesions in the treated field in patients with AKs [4]. In addition, this meta-analysis found that PDT performed with aminolevulinic acid (ALA-PDT) with red light or blue light or with methyl aminolevulinate (MAL-PDT) with red light was superior to placebo for the treatment of individual AK lesions [4]. The metaanalysis also found that treatment with imiquimod or PDT generally resulted in better cosmetic outcomes than topical fluorouracil or cryotherapy [4]. ●A subsequent network meta-analysis of 26 individual or pooled randomized trials evaluated the relative efficacy in inducing complete lesion clearance for eight main interventions for AK [5]. This analysis suggests that topical fluorouracil is the most effective treatment followed by 5-ALA-PDT, topical imiquimod, ingenol mebutate, 5-MAL-PDT, cryotherapy, topical diclofenac with hyaluronic acid, and placebo. However, the ranking of relative efficacies should be interpreted with caution because of the variability in the parameters used to describe the AK severity in the included studies.

CHOICE OF THERAPY

Given the multiple effective treatment

options for actinic keratoses (AKs), the choice of therapy is influenced by factors such as the number and distribution of lesions, lesion characteristics, patient preference for the mode of treatment (eg, office based versus home administered, duration of therapy), patient tolerance for side effects (eg, pain, inflammation, hypopigmentation, scarring), and treatment availability and cost. Our approach is generally consistent with current international guidelines (algorithm 1) [9-11]. In general, lesion-directed treatments, such as cryotherapy and surgical interventions (eg, tangential excision or curettage followed by electrodesiccation or cryotherapy), are the primary approach for isolated lesions. Cryotherapy is most frequently used because it is rapid, inexpensive, and does not require local anesthesia.

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Field-directed therapies are indicated for the treatment of areas with multiple AKs, subclinical lesions that are not detected by visual inspection or palpation, and field cancerization (presence of genetically altered cells at risk of malignant transformation in clinically normal skin). They include topical agents (eg, topical fluorouracil, imiquimod, ingenol mebutate), photodynamic therapy (PDT), or field ablation with dermabrasion, chemical peels, and carbon dioxide laser resurfacing [3]. Topical therapies have many advantages (noninvasive, effective against subclinical lesions, selfadministered). However, patient adherence to these treatments is generally low, due to the high frequency of adverse events (eg, skin irritation, erosions, ulcerations) and the long duration of treatment.

PATIENTS WITH ONE OR FEW DISCRETE LESIONS

Lesion-directed treatments, such as

cryotherapy and surgical interventions (eg, tangential excision or curettage followed by electrodesiccation), are the primary approach for patients with one or few isolated lesions (algorithm 1).

Liquid nitrogen cryotherapy — We suggest liquid nitrogen cryotherapy as first-line therapy for patients with one or few (two to three or more, depending on the patient's tolerance of treatment) isolated AKs. The treatment is delivered by either spray or contact with a cryoprobe. The contact technique is particularly useful for treating small lesions in sensitive areas of the face (eg, periocular, perioral). The freezing time varies from 5 to 10 seconds or more, depending upon lesion size and thickness, with the "ice ball" extending 1 mm beyond the clinical margin of the lesion. A single freeze-thaw cycle is adequate for thin lesions, while a double freezethaw cycle is required for thicker lesions. Cryotherapy is the most widely utilized treatment for AK. It can be quickly performed in an officebased setting, does not require local anesthesia, is inexpensive, is well tolerated by patients, and in most cases, results in good or excellent cosmetic outcome [12]. (See "Minor dermatologic procedures", section on 'Cryotherapy (cryosurgery)'.) However, since this procedure does not produce a specimen for histologic confirmation, it should only be performed when the clinical diagnosis of AK is relatively certain. If there is doubt about the diagnosis, a biopsy for histologic confirmation is warranted. The efficacy of liquid nitrogen cryotherapy has been evaluated in a limited number of randomized trials. In a systematic review of eight randomized trials comparing cryotherapy combined with other topical treatments (ie, imiquimod, topical fluorouracil, ingenol mebutate, diclofenac) with cryotherapy alone, the response rate for cryotherapy alone ranged from 39 to 76 percent [13]. The included studies were heterogeneous and generally of low methodologic quality. Similar clearance rates, ranging from 40 to 88 percent, were reported in randomized trials comparing cryotherapy with other treatment modalities [14-21].

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The wide variability in the reported clearance rates may be related to differences across studies in cryotherapy administration, such as freeze time, number of freeze-thaw cycles, use of contact versus spray technique, and distance from the spray tip to the AK [22,23].

Other destructive therapies — Shave excision, curettage with or without electrodesiccation, and dermabrasion can be used for the treatment of isolated AK lesions. None of these therapies has been evaluated in clinical trials, and their use is based upon limited evidence from small observational studies and clinical experience [24]: ●Shave excision and curettage followed by electrodesiccation or cryotherapy are frequently used for AKs, particularly for hyperkeratotic lesions (see 'Patients with hypertrophic lesions' below). Although these techniques can provide tissue for histopathologic evaluation, the specimens are usually not adequate to determine whether a lesion is invasive or intraepidermal. ●Dermabrasion, or surgical skin planing, may be used for treating large areas (eg, a sun-damaged bald scalp or forehead) when lesions are too large to treat effectively with topical preparations. Dermabrasion is a procedure in which a specialized handheld instrument is used to "sand" the skin to improve skin contour. The surface of the epidermis of the skin (the stratum corneum) is removed, leaving the skin red and raw looking. The procedure can be very painful and usually requires procedural sedation and analgesia. A retrospective study of 23 patients treated with dermabrasion found that 96 percent remained free of new AKs at one year after treatment. However, the benefits of dermabrasion gradually diminished, with 83 percent clear at two years and 54 percent at five years [24].

PATIENTS WITH HYPERTROPHIC LESIONS Initial treatment — We suggest liquid nitrogen cryotherapy as the initial treatment for hyperkeratotic/hypertrophic lesions (picture 1 and algorithm 1). Because thick lesions are more resistant to liquid nitrogen, freezing times >10 seconds or repeat applications may be necessary. We typically use two freeze-thaw cycles, allowing time to thaw the lesion's peripheral rim. (See "Minor dermatologic procedures", section on 'Cryotherapy (cryosurgery)'.) Shave removal or curettage followed by electrodesiccation to ensure hemostasis may be used as alternative treatment modalities for thick lesions that do not respond to liquid nitrogen cryotherapy. Lesion specimens should be sent for histopathologic examination to exclude invasive squamous cell carcinoma (SCC). (See 'When to biopsy' below.)

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When to biopsy — A skin biopsy for histopathologic examination to exclude or confirm the presence of invasive SCC should be performed in the following circumstances [25]: ●Lesions that appear indurated (a finding that suggests the possibility of SCC) ●Painful, ulcerated, or bleeding lesions ●Hyperkeratotic/hypertrophic actinic keratoses (AKs) that failed to resolve after standard therapies or recurred rapidly (10 seconds or repeat applications may be necessary. We typically use two freeze-thaw cycles. Shave removal or curettage may be used as alternative treatment modalities, particularly for suspicious lesions requiring histopathologic examination (eg, indurated lesions, painful or ulcerated lesions, lesions recurring in 25 years, age ≥60 years, light skin phototype, and personal history of nonmelanoma skin cancer [12]. Actinic cheilitis may occur at an early age in patients with genetic conditions associated with increased susceptibility to solar damage (eg, xeroderma pigmentosum, oculocutaneous albinism) [4,13-15].

CLINICAL FEATURES

Actinic cheilitis initially presents as a

persistent area of dryness and desquamation typically located on the lower lip (picture 1) [16]. On palpation, these lesions have a characteristic "sandpapery" feel to the touch. It is more common on the lower lip, which protrudes beyond the upper lip and receives more UV radiation exposure. Atrophic changes, blurred demarcation of the vermilion border, erythema, edema, hyperkeratotic (leukoplakia-like) plaques, ulceration, and crusting may be seen in more advanced lesions (picture 2A-C). Lesions are usually solitary, but multiple or diffuse lesions can occur.

DIAGNOSIS

The diagnosis of actinic cheilitis is usually clinical. However, the

presence of ulceration or erosion raises the suspicion of squamous cell carcinoma (SCC) and warrants a biopsy for histopathologic examination.

Histopathology — Histopathologic changes of actinic cheilitis include acanthosis, hyperkeratosis, focal areas of atrophy, and a variable degree of keratinocyte atypia (picture 3) [17]. A dermal inflammatory infiltrate composed predominantly of lymphocytes with occasional plasma cells and eosinophils can also be seen. Solar elastosis is a frequent and important secondary finding.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis

of actinic cheilitis includes:

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●Squamous cell carcinoma – Actinic cheilitis with severe cytologic atypia and an intense inflammatory infiltrate may be difficult to differentiate from squamous cell carcinoma (SCC). Since microscopic changes suggestive of SCC may not occur homogeneously in the involved area, a single punch biopsy may not be an accurate method for precise diagnosis [18]. Rather, an elliptical incision biopsy in the thickest part of the lesion is preferred. If vermilionectomy is performed as treatment, serial sections of the entire specimen should be examined. Keratinocytic dysplasia involving the full thickness of the epidermis with atypical, pleomorphic cells indicates SCC in situ. Invasive SCC typically shows dysplastic keratinocytes involving the full thickness of the epidermis and dermal invasion. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis", section on 'Diagnosis'.) ●Lupus erythematosus – Atrophic actinic cheilitis may resemble discoid lupus erythematosus clinically and histologically (picture 4). However, the presence of vacuolization of the basal layer, follicular plugging, and patchy periappendageal infiltrate differentiates lupus erythematosus from actinic cheilitis. (See "Overview of cutaneous lupus erythematosus", section on 'Discoid lupus erythematosus'.) ●Lichen planus – Lip involvement of lichen planus typically shows a reticular, white pattern (picture 5) and is usually associated with oral buccal mucosal lesions. On histologic examination, lichen planus shows damage of basal keratinocytes with multiple apoptotic cells (Civatte bodies) and a band-like lymphocytic infiltrate in the upper dermis. (See "Oral lichen planus: Pathogenesis, clinical features, and diagnosis".) ●Other primary lip diseases – Several inflammatory lip diseases, such as plasma cell cheilitis, cheilitis glandularis, and cheilitis granulomatosa, may share clinical features with actinic cheilitis (picture 6A-C). Histologic examination of a lip biopsy clarifies the diagnosis. (See "Cheilitis".)

TREATMENT

A variety of treatments are used for the management of actinic

cheilitis. These include topical medications (eg, topical fluorouracil, imiquimod), destructive therapies (eg, liquid nitrogen, electrodessication, chemical peels, laser therapy, photodynamic therapy [PDT]), and surgery (vermilionectomy) [1,19-29]. Reinforcing the use of sunscreens on the lips as well is also important in the ongoing management of these patients. In addition, smoking cessation should be encouraged. Evidence for efficacy of these treatments is limited to a few small randomized trials and several uncontrolled clinical studies [25,30]. The choice of treatment is made in the individual patient, based upon the extent and severity of the disease, clinical experience, and patient preference. Our approach is described below.

Focal mild to moderate actinic cheilitis — Observation is a reasonable choice for the motivated patient with mild actinic cheilitis (focal erythema, desquamation, and/or atrophy of the vermilion border) who is willing to commit to regular follow-up visits to monitor for possible progression and adhere to daily sunscreen application to the lips.

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If a decision is made to treat, we suggest cryosurgery with liquid nitrogen for focal lesions of mild to moderate cheilitis. Cryotherapy is widely available, rapid, and inexpensive and can be performed without local anesthesia. Adverse effects of cryotherapy include pain, edema, and scarring. In cases of incomplete clearance, retreatment with additional cryosurgery after six to eight weeks followed by a topical therapy as noted below may be undertaken (see 'Multifocal or diffuse mild to moderate actinic cheilitis' below). Persistent lesions should be biopsied to rule out squamous cell carcinoma (SCC). In one study, 37 patients with 53 histologically confirmed actinic cheilitis lesions of the lower lip were treated with liquid nitrogen using the paintbrush technique [31]. Recurrence was noted after two and three years of follow-up in two patients, of whom one developed SCC.

Multifocal or diffuse mild to moderate actinic cheilitis — For patients with multifocal or diffuse mild to moderate actinic cheilitis, we suggest field therapy with topical fluorouracil or imiquimod as first-line therapy. Fluorouracil 5% cream is applied twice a day for two to four weeks. Adverse effects of treatment include pain, erythema and edema of the lips, erosions, and ulcerations [20]. Although topical fluorouracil has the potential to treat subclinical disease in adjacent areas ("field therapy"), the discomfort associated with treatment may cause poor adherence to treatment in many patients. Recurrence after treatment with topical fluorouracil has been reported. Imiquimod is an alternative to topical fluorouracil for the treatment of multifocal or diffuse mild to moderate actinic cheilitis. Imiquimod 5% cream is applied to the involved area three times per week for four to six weeks. Imiquimod 2.5% or 3.75% cream is used on a schedule of daily application for two weeks, rest period for two weeks, and then another two weeks of daily application. Adverse effects included erythema, induration, erosions, and ulcerations. There is very limited evidence from small observational studies supporting the efficacy of topical fluorouracil and imiquimod for actinic cheilitis. Indirect evidence for their efficacy is derived from studies in patients with actinic keratosis of the skin [30]. In a small study comparing different treatment modalities (ie, topical fluorouracil, chemical peel, lip shave, laser therapy) in patients with actinic cheilitis involving >50 percent of the lower lip, recurrence was observed in 7 of 10 patients treated with topical fluorouracil after a median follow-up time of 50 months [29]. In a series of 15 patients with actinic cheilitis treated with topical imiquimod, all patients showed clinical clearing four weeks after discontinuing treatment [32]. Additional treatments that have been used for multifocal actinic cheilitis include ingenol mebutate and PDT. Ingenol mebutate, a topical medication approved for the treatment of actinic keratosis, has been used off-label for the treatment of actinic cheilitis in a few patients with good results [27,28]. However, the United States and European prescribing information for ingenol mebutate recommend to avoid applying ingenol mebutate on or around the lips. (See "Treatment of actinic keratosis", section on 'Ingenol mebutate'.)

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PDT, including daylight PDT, has also been used for the treatment of actinic cheilitis, although its efficacy appears to be relatively low [33,34]. In a review of 15 case series including 242 patients with actinic cheilitis treated with PDT, 139 of 223 patients (62 percent) evaluated for complete clinical clearing had complete response at 3 to 30 months, and 57 of 121 (47 percent) evaluated for histologic clearance demonstrated histologic cure 1.5 to 18 months after treatment [33]. However, in a subsequent report of 16 patients treated with two sessions of methyl aminolevulinatephotodynamic therapy (MAL-PDT) with a similar rate of clinical clearing, none achieved histologic cure [35]. (See "Photodynamic therapy".) Ablative laser-assisted PDT may be more effective than standard PDT for the treatment of actinic cheilitis. In a small comparative study, 33 patients with actinic cheilitis were treated with a single session of ablative fractional laser (AFL) therapy immediately followed by MAL-PDT or with two sessions of MAL-PDT one week apart [36]. At 12 months, the complete clinical and histologic response rates were 85 and 29 percent in the AFL plus MAL-PDT and MAL-PDT only groups, respectively.

Severe actinic cheilitis — Patients with severe actinic cheilitis presenting with hyperkeratotic (leukoplakia-like) areas with or without ulceration or fissuring should undergo a lip biopsy prior to treatment to determine the presence and grade of dysplasia and whether invasive SCC is present. ●For patients with severe actinic cheilitis without evidence of high-grade dysplasia or cancer on biopsy, we suggest laser ablation with carbon dioxide (CO2) laser or erbium:yttrium aluminum-garnet (Er:YAG) laser rather than surgical excision or topical therapies. Adverse effects of laser ablation include a prolonged healing time and post-treatment hypo- or hyperpigmentation. ●For patients with severe actinic cheilitis with evidence of high-grade dysplasia, surgical excision (vermilionectomy) followed by defect repair by primary closure or mucosal advancement flap is the treatment of choice [37,38]. In contrast with laser ablation, vermilionectomy allows the histopathologic examination of the entire vermilion and margins as well as the detection of occult SCC not identified by a previous biopsy [18]. The procedure may be associated with significant postoperative complications including bruising, wound dehiscence, partial flap necrosis, scarring, and loss of normal lip contour [25]. (See "Treatment of stage I and II (early) head and neck cancer: The oral cavity", section on 'Lip'.) In a systematic review and meta-analysis of nine observational studies and one randomized trial (283 patients) comparing surgical (vermilionectomy or laser therapy) and nonsurgical (imiquimod, topical diclofenac, PDT) treatments for actinic cheilitis, the weighted remission rate among 122 patients treated with surgical excision or laser therapy was 93 percent (95% CI 85.5-96.5 percent), with a weighted recurrence rate of 8.4 percent (95% CI 4.5-15.1 percent) [39]. For nonsurgical therapies, the weighted remission and recurrence rates were 66 and 19 percent, respectively. However, these results must be interpreted with caution because the included studies were small and none of them directly compared surgical versus nonsurgical therapies.

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PROGNOSIS AND FOLLOW-UP

The risk of

malignant transformation of actinic cheilitis into squamous cell carcinoma (SCC) is unknown [40]. However, as patients with actinic cheilitis have an increased risk of developing lip cancer, regular clinical surveillance and repeated biopsies of suspicious areas are recommended.

PREVENTION

Strict sun protection is an important aspect of preventing the

progression of actinic cheilitis to squamous cell carcinoma (SCC) and the development of further disease. Sun protection measures include sun avoidance, wearing hats, and daily use of lip products with sunscreens [3]. Smoking and chewing tobacco cessation is recommended. (See "Selection of sunscreen and sun-protective measures".)

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Actinic keratosis".)

SUMMARY AND RECOMMENDATIONS ●Actinic cheilitis, also called solar cheilitis or solar cheilosis, is a premalignant disorder of the lip caused by chronic exposure to ultraviolet radiation. It occurs most frequently in light-skinned individuals with high levels of occupational sun exposure (eg, fishermen, farmers) and is more common in males than in females. (See 'Introduction' above and 'Epidemiology and risk factors' above.) ●Actinic cheilitis initially presents as a persistent area of dryness and scaling typically located on the lower lip (picture 1). More advanced lesions show atrophy, blurred demarcation of the vermilion border, erythema, edema, ulceration, and crusting (picture 2A-C). (See 'Clinical features' above.) ●The diagnosis of actinic cheilitis is usually clinical. However, a biopsy may be necessary for ulcerated or crusted lesions that are suspicious for squamous cell carcinoma (SCC). (See 'Diagnosis' above and 'Differential diagnosis' above.) ●Topical, destructive, or surgical therapies are used for the treatment of actinic cheilitis. The choice of treatment is made in the individual patient, based upon the extent and severity of the disease, clinical experience, and patient preference. Our approach is as follows: •We suggest cryotherapy with liquid nitrogen for patients with limited mild to moderate actinic cheilitis. (Grade 2C). However, observation is a reasonable choice for the motivated patient with mild actinic cheilitis (focal erythema, desquamation, and/or atrophy of the vermilion border) who is

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willing to commit to regular follow-up visits to monitor for possible progression and adhere to daily sunscreen application to the lips. (See 'Focal mild to moderate actinic cheilitis' above.) •For patients with multifocal or diffuse mild to moderate actinic cheilitis, we suggest field therapy with topical fluorouracil or imiquimod rather than photodynamic therapy or laser therapy (Grade 2C). (See 'Multifocal or diffuse mild to moderate actinic cheilitis' above.) •Patients with severe actinic cheilitis presenting with hyperkeratotic (leukoplakia-like) areas with or without ulceration should undergo a lip biopsy prior to treatment to determine the presence and grade of dysplasia and whether invasive SCC is present. •For patients with severe diffuse actinic cheilitis without evidence of high-grade dysplasia or cancer on biopsy, we suggest laser ablation with carbon dioxide (CO2) laser or erbium:yttrium aluminumgarnet (Er:YAG) laser rather than surgical excision or topical therapies (Grade 2C). Surgical excision (vermilionectomy), which allows for the histopathologic examination of the entire vermilion, is the treatment of choice for actinic cheilitis with high-grade dysplasia on biopsy. (See 'Severe actinic cheilitis' above and "Treatment of stage I and II (early) head and neck cancer: The oral cavity", section on 'Lip'.) ●As patients with actinic cheilitis have an increased risk of developing lip cancer, regular clinical surveillance and repeated biopsies of suspicious areas are recommended. Sun protection measures and tobacco smoking or chewing cessation are important aspects of lip cancer prevention. (See 'Prognosis and follow-up' above and 'Prevention' above.)

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Epidemiology, pathogenesis, and clinical features of basal cell carcinoma uptodate.com/contents/epidemiology-pathogenesis-and-clinical-features-of-basal-cell-carcinoma/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Aug 26, 2019.

INTRODUCTION

Basal cell carcinoma (BCC) is a common skin cancer

arising from the basal layer of epidermis and its appendages. These tumors have been referred to as "epitheliomas" because of their low metastatic potential. However, the term carcinoma is appropriate since they are locally invasive, aggressive, and destructive of skin and the surrounding structures, including bone (picture 1A-B). The epidemiology, pathogenesis, clinical presentation, and differential diagnosis of BCC will be reviewed here. The treatment and prognosis of BCC are discussed separately. Gorlin syndrome is also discussed separately. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence" and "Treatment of basal cell carcinomas at high risk for recurrence" and "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)

EPIDEMIOLOGY

Estimates of the incidence of BCC are imprecise since in

most countries there is no cancer registry that collects data on BCC [1]. The American Cancer society estimates that in 2012, 5.4 million cases of nonmelanoma skin cancers (NMSCs) were diagnosed in 3.3 million people, of which approximately 8 in 10 cases would have been BCC [2]. A population-based study with several methodologic limitations estimated that 3.5 million NMSCs

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were treated in the United States in 2006 [3]. One study using data from a commercially insured population in the United States estimated an age-adjusted incidence and prevalence of BCC of 226 and 343 per 100,000 persons per year, respectively [4]. These rates were similar to those from Olmsted County, Minnesota, where the age- and sex-adjusted incidence of BCC was 222 per 100,000 person-years (95% CI 204.5-239.5) from the years 1976 to 1984 and increased to 321.2 per 100,000 person-years (95% CI 310.3-332.2) from 2000 to 2010 [5]. An analysis of data on over 140,000 participants from the Nurses' Health Study (1986 to 2006) and the Health Professionals' Follow-up Study (1988 to 2006) found that age-adjusted BCC incidence rates increased from 519 cases per 100,000 person-years to 1019 cases per 100,000 person-years for women and from 606 cases per 100,000 person-years to 1488 cases per 100,000 person-years for men during the 20-year follow-up period [6]. Multiple epidemiologic observations provide insights into the etiology of BCC: ●BCC is particularly common in white populations; it is very uncommon in darker-skinned populations. In white populations in the United States, the incidence of BCC has increased by more than 10 percent per year, and the lifetime risk of developing a BCC is 30 percent [7]. An increasing incidence over time has also been noted in other countries, including Canada, Finland, and Australia [8-10]. Of greater concern, there may be an increasing incidence of aggressive-growth histologic subtypes, which are more difficult to treat [11]. ●The incidence in men is 30 percent higher than in women, particularly with the superficial type [8,12,13]. ●Within the United States, there is striking geographic variation in incidence. States closer to the equator, such as Hawaii and California, have an incidence of BCC at least twice that of the Midwestern United States [13,14]. ●There are also prominent global variations in incidence. Northern European countries, such as Finland, have an incidence one-fourth that of the Midwestern United States. This contrasts with Australia where rates are 40 times that of Finland [8,9,12]. ●The incidence of BCC increases with age; persons aged 55 to 75 have about a 100-fold higher incidence of BCC than those younger than 20 [15]. Although increasing longevity may underlie some of the increasing incidence of BCC, the incidence of BCC among Americans younger than 40 also appears to be increasing, particularly among women [16].

RISK FACTORS

Environmental, phenotypic, and genetic factors contribute

to the development of BCC. Although exposure to ultraviolet (UV) radiation in sunlight is the most important risk factor for BCC, other established risk factors include chronic arsenic exposure, radiation therapy, long-term immunosuppressive therapy, and the nevoid basal cell carcinoma syndrome (Gorlin syndrome).

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Environmental UV radiation Sun exposure — Exposure to UV radiation from sunlight is the most important environmental cause of BCC, and most risk factors relate directly to a person's sun exposure habits or susceptibility to solar radiation. These risk factors include having fair skin, light-colored eyes, red hair, northern European ancestry, older age, childhood freckling, and an increased number of past sunburns [17-19]. The type, quantity, and timing of sun exposure associated with an increased risk of BCC are not clearly defined. Childhood sun exposure appears to be more important than exposure during adult life [17,20]. Evidence supporting this hypothesis comes from case control studies and clinical trials [18-21]. In a Canadian case control study that included 226 men with BCC and 406 age-matched controls, the development of BCC was strongly correlated with childhood and adolescent sun exposure but not cumulative or recent sun exposure [20]. In other studies, however, adult sun exposure was a risk factor for BCC [18]. The frequency and intensity of sun exposure may also be important. Solar exposure in intermittent, intense increments increases the risk of BCC more than a similar dose delivered more continuously over the same period of time [22]. A French case-control study including more than 1000 women with BCC and more than 3600 controls found that a history of severe sunburn before the age of 25 years and after the age of 25 were both independently associated with a twofold increased risk of BCC, after adjusting for skin sensitivity to sunlight and hair, eye, and skin color [23].

Tanning beds — The use of tanning beds may increase the risk for early development of BCC [24-26]. A cohort study of approximately 73,000 female nurses found that women who used tanning beds more than six times per year during high school or college were more likely to develop BCC than women who did not use tanning booths during these time periods (adjusted hazard ratio 1.73, 95% CI 1.52-1.98) [27]. A contribution of ultraviolet light exposure from indoor tanning to BCC is also suggested by the results of a 2012 meta-analysis of observational studies [28]. Subjects with a history of any tanning bed use were more likely to develop BCC than those who had never used tanning beds (relative risk 1.29, 95% CI 1.08-1.53). The relative risk for BCC for individuals who began tanning prior to age 25 was 1.40 (95% CI 1.29-1.52). A subsequent population-based case-control study, including approximately 650 cases of BCCs and 450 controls, found that tanning bed users had a 60 percent increased risk of developing a BCC at or before the age of 50 years (odds ratio 1.6; 95% CI 1.3-2.1) [25]. The risk was doubled for those reporting a first use of tanning devices before the age of 20.

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A Canadian study estimated that 5 percent of BCCs were attributable to ever use of indoor tanning devices [29]. This was a meta-analysis of previously published literature, and the possibility that the association between tanning bed use and BCC in fair-skinned individuals is overestimated due to confounding cannot be excluded. Tanning bed use may be a marker of populations more exposed to the sun. Studies have shown that tanning bed users are more likely to be regular sunbathers and to have poorer sun-protection behavior than nonusers [30,31]. In these epidemiologic studies, the amount of UVA versus UVB and other wavelengths of nonionizing radiation to which participants were exposed in tanning beds is not known.

Phototherapy — Therapeutic exposure to psoralen plus ultraviolet A light (PUVA) for cutaneous disorders such as psoriasis increases the risk of nonmelanoma skin cancer (NMSC), particularly squamous cell carcinoma (SCC) [32]. The risk of BCC in patients treated with PUVA is lower than the risk for cutaneous SCC. In a 30-year prospective cohort study documenting the incidence of NMSC in patients given PUVA for psoriasis, the increase in risk for BCC was modest compared with cutaneous SCC [33]. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Skin cancer'.) Broadband (280 to 320 nm) ultraviolet B (UVB) and narrowband (311 to 313 nm) UVB phototherapy appear to be less likely to promote the development of NMSC than PUVA [34], but further research is necessary to determine the true carcinogenic potential of these therapies. Most studies examining the role of UVB have examined narrowband UVB alone or broadband UVB in combination with NBUVB [34-40]. Although some observational studies have reported a small increased risk for BCC after UVB therapy [35,36], others have reported no increased risk [37-40]. As an example, in a retrospective study of 3867 phototherapy patients (of which 352 received ≥100 narrowband UVB treatments), narrowband UVB was not associated with an increased risk of BCC, except in cases where patients were treated with both narrowband UVB and PUVA [37]. (See "UVB therapy (broadband and narrowband)".)

Photosensitizing agents — The association of BCC with ultraviolet light exposure has led to questions about the impact of photosensitizing drugs on development of BCC. An association between prior use of photosensitizing tetracyclines or thiazide diuretics and increased risk for BCC has been documented in several observational studies [41-43]. In addition, an American populationbased case-control study of 1567 adults with BCC and 1906 controls found a minor increase in risk for multiple BCC (odds ratio [OR] 1.4; 95% CI 1.0-2.1) and BCC before the age of 51 (OR 1.5; 95% CI 1.1-2.1) among participants who recalled use of a photosensitizing medication [41]. A meta-analysis of eight observational studies with nearly 400,000 participants found a weak association between the use of thiazide diuretics and the risk of BCC (OR 1.19; 95% CI 1.02-1.38) [44]. Beyond drugs, dietary factors may contribute to risk of developing BCC. A study using participants in the Health Professionals Follow-up Study and the Nurses' Health Study examined the effect of dietary intake of photocarcinogenic agents, such as furocoumarins in the form of citrus products, on NMSC [45]. Compared with those who consumed citrus products less than twice per week, the pooled multivariable-adjusted hazard ratios for BCC increased from 1.03 (95% CI 0.99-1.08) for those

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who consumed citrus two to four times per week, up to 1.16 (95% CI 1.09-1.23) for citrus consumption 1.5 times per day or more, supporting an association between high citrus consumption and slightly increased risk of BCC in those cohorts. Additional studies are necessary to clarify the relationship between photosensitizing agents and BCC. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photosensitivity due to exogenous agents' and "Epidemiology and risk factors for cutaneous squamous cell carcinoma", section on 'Thiazide diuretics and other photosensitizing drugs'.)

Chronic arsenic exposure — Superficial multicentric BCC may occur due to chronic exposure to arsenic from ingestion of contaminated drinking water, seafood, or medications [46-50]. (See "Arsenic exposure and poisoning", section on 'Chronic and latent toxicity'.) In a nationwide population-based study using registry data from the National Taiwan Cancer Registry Center between 1979 and 2007, the risk of BCC was three- to fourfold higher in the blackfoot disease, a form of peripheral vascular disease associated with arsenic exposure, endemic areas compared with other areas of Taiwan [49].   The risk of BCC associated with arsenic exposure may be influenced by genetic factors, such as variants of the AS3MT gene, encoding the arsenite methyltransferase enzyme, and telomer length [50,51]. In a study including 528 arsenic-exposed cases with BCC and 533 healthy controls, within each tertile of arsenic exposure, individuals with shorter telomeres were at increased risk of BCC, with the highest risk in the highest exposure group [51].

Ionizing radiation — Superficial therapeutic ionizing radiation, as for facial acne, psoriasis, or tinea capitis, increases the risk of NMSC, including BCC [52-54]. The latency period for development of BCCs is about 20 years, and lesions are limited to sites within the radiation field. Due to the advent of other effective therapies, the use of ionizing radiation for the treatment of inflammatory skin conditions has declined. Ionizing radiation used to treat childhood cancers also increases the risk for the subsequent development of BCC. This was illustrated in a study of 776 subjects, five of whom developed BCCs, approximately 10-fold more than was expected in this population [55]. All of the BCCs were located within the radiation field. In addition, a case-control study of 199 patients with a history of both childhood cancer and BCC and 597 controls with a history of childhood cancer without BCC found a linear dose-response relationship between the radiation dose and risk for BCC [56]. An increase in risk was detected among patients who received at least 1 Gy of radiation to the skin, and patients who received 35 Gy or more were 40 times more likely to develop BCC than those who were not treated with radiation (odds ratio 39.8, 95% CI 8.6-185). The treatment of other noncutaneous disorders with radiation therapy, such as thymic enlargement in infancy and ankylosing spondylitis, as well as the use of radiation therapy for conditioning prior to hematopoietic stem cell transplantation, have also been associated with the appearance of BCC

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[53,57,58]. Studies of survivors of the atomic bomb explosions in Japan support the role of exposure to ionizing radiation in the development of BCC [59-62]. In a retrospective study of bomb survivors, the incidence of subsequent BCC increased with proximity to the hypocenter of the explosion [59]. BCC development is strikingly absent in black survivors of irradiated childhood cancer [63] and substantially lower in black versus white patients who received radiation for tinea capitis [64] for reasons that are not understood or completely explained by darker skin pigmentation alone [63].

Phenotypic traits — Light skin pigmentation, light hair and eye color, and poor tanning ability, which reflect the skin sensitivity to sunlight, are well-known risk factors for BCC. A meta-analysis of 29 observational studies found that red hair, fair complexion, and skin that burns but never tans were associated with a twofold risk of developing a BCC [65].

Personal history of basal cell carcinoma — Individuals with a history of BCC are at increased risk for subsequent lesions. Approximately 40 to 50 percent of patients who have had one BCC will develop another lesion within five years [66,67]. However, the probability of developing a subsequent BCC is significantly less after a first BCC than after a nonfirst BCC (13 versus 34 percent at one year, 20 versus 52 percent at two years, and 35 versus 75 percent at five years) [68]. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence", section on 'Prognosis'.)

Predisposing genetic variants — In addition to specific mutational drivers of BCC (see 'Pathogenesis' below), germline polymorphisms in genes that determine pigmentary traits, such as melanocortin-1 receptor (MC1R), human homolog of agouti signaling protein (ASIP), and tyrosinase (TYR), are associated with increased risk of BCC [69-71]. However, independent of melanocortin 1 receptor (MCR1) phenotype, a family history of skin cancer is associated with increased risk of BCC under age 40 (odds ratio 2.49, 95% CI 1.80-3.45) [72]. Specific gene polymorphisms have been associated with the truncal phenotype and clustering of BCCs. Patients are often younger, male, and have more clusters of BCCs compared with those with BCCs arising in sun-exposed sites. The associated genes include those encoding the detoxifying enzyme genes cytochrome P-450 CYP2D6 and glutathione S-transferase, the vitamin D receptor, and tumor necrosis factor [73-77]. The link between these genetic polymorphisms, tumorigenesis, and the clinical phenotype is not clear. Genome-wide association studies have identified genetic variants that may influence BCC risk through other pathways, such as an effect on the growth or differentiation of basal layers of the epidermis or an effect on the TP53 tumor suppressor gene [78-81]. A genome-wide association meta-analysis found that single nucleotide polymorphisms in genes involved in DNA excision repair may be involved in the pathogenesis of BCC [82].

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Genes that affect the immune response may also impact susceptibility to BCC. Cytotoxic lymphocyte-associated antigen-4 (CTLA-4) is expressed on regulatory T cells and is involved in UVinduced immune tolerance. In a case-control study, genetic variation at the CTLA4 locus influenced the risk of BCC, particularly among patients with a higher number of severe sunburns [83].

Inherited disorders — Inherited disorders that are associated with a greatly increased risk of developing BCCs at an early age include:   ●Nevoid basal cell carcinoma syndrome – Nevoid basal cell carcinoma syndrome (NBCCS), also known as basal cell nevus syndrome or Gorlin syndrome, is a rare multisystem disorder of autosomal dominant inheritance caused in most cases by germline mutations of the human patched gene (PTCH1) [84]. Affected patients have both developmental anomalies and postnatal tumors, including multiple BCCs, at an average age of 20 to 21 years, odontogenic keratocysts, and medulloblastoma [85]. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)" and 'PTCH1 mutations' below.) ●Xeroderma pigmentosum – Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder due to mutations in any of eight genes involved in repair of ultraviolet (UV)-induced DNA damage [86]. Clinical findings include early-onset pigmentary skin changes and early development of skin cancers. Squamous cell carcinomas and BCCs develop at an average age of nine years. (See "Xeroderma pigmentosum".) ●Bazex-Dupré-Christol syndrome – Bazex-Dupré-Christol syndrome (also called Bazex syndrome or follicular atrophoderma and basal cell carcinomas [BCCs]) is an X-linked dominant disorder characterized by congenital hypotrichosis, follicular atrophoderma, milia, and multiple BCCs [87]. ●Oculocutaneous albinism – Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders of melanin biosynthesis presenting with a spectrum of visual disturbances and hypopigmentation of the skin and hair. Individuals with OCA have an increased risk of early-onset skin cancer, possibly by their teenage years. Squamous cell carcinoma is the most common type of cancer occurring in OCA patients, but basal cell carcinoma and melanoma also occur [88]. (See "Oculocutaneous albinism".)

Immunosuppression — Chronic immunosuppression (as occurs with solid organ transplantation and with human immunodeficiency virus [HIV] infection) may increase risk for the development of BCC, although the increase in risk is less than that observed for SCC [89,90]. The risk for BCC after solid organ transplantation appears to increase linearly over time, whereas the risk for SCC rises exponentially [89]. As in other populations, sun exposure, phenotype, and other factors influence the likelihood that an organ transplant recipient will develop BCC [91]. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients", section on 'Squamous cell and basal cell carcinoma'.)

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The increased risk for skin cancer in organ transplant recipients is attributed to chronic exposure to immunosuppressive agents [92,93]. The specific impact of systemic glucocorticoid therapy on BCC risk is uncertain; studies performed in patients without a history of organ transplantation conflict on whether systemic glucocorticoid therapy significantly increases risk for BCC [94-97]. There is increased risk of skin cancer in the allogeneic stem cell transplant population as well. A Danish study of 1007 patients who received allogeneic stem cell transplants found a hazard ratio for BCC of 3.1 (95% CI 1.9-5.2), compared with the background population. This rate was on par with the renal transplant recipients [98]. Another study of adult allogeneic stem cell transplant recipients at two Boston hospitals reported an incidence rate ratio of 2.5 for BCC development (95% CI 1.9-3.2) [99]. The reasons for the increase are not clear and have been attributed in part to the conditioning regimen (including total body irradiation), disease prior to transplant (ie, chronic lymphocytic leukemia), and presence of graft-versus-host disease [98-100]. Less is known about the risk for skin cancer in nontransplanted patients treated with immunosuppressants other than glucocorticoids. In a retrospective cohort study of 405 patients with rheumatoid arthritis (n = 349, 86 percent) or psoriatic arthritis (n = 56, 14 percent), the use of methotrexate and methotrexate with cyclosporine A or D-penicillamine was associated with an increased risk of NMSC [101]. Among patients treated with methotrexate, a dose-response relationship was noted only for BCC, with a standardized incidence ratio of 5.77 (95% CI 4.19-7.74) for those treated with a cumulative dose >8 grams versus 2.21 (95% CI 1.35-3.41) for those treated with a cumulative dose T at dipyrimidine sites and CC>TT tandem base substitutions, although the latter occur less frequently [111]. This is true for BCCs that arise sporadically, and even more so for BCC arising in patients with xeroderma pigmentosum, suggesting that repair of UV-induced DNA damage can reduce BCC carcinogenesis. Beyond UV-induced changes, other factors, such as oxidative stress, are also associated with the mutagenesis of BCCs [110,112]. (See "Xeroderma pigmentosum".)

PTCH1 mutations — Our understanding of the pathogenesis of BCC was greatly enhanced with the discovery of mutations in the PTCH1 gene on chromosome 9q22.3 in patients with the inherited nevoid basal cell carcinoma syndrome [113] (see "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)"). Subsequently, somatic mutations of PTCH1 were identified in over 70 percent of sporadic BCCs and BCCs associated with xeroderma pigmentosum, indicating that an aberrant HH signaling activation is a prerequisite for the development of both BCC associated with the Gorlin syndrome and sporadic BCCs [110,112,114-118]. In a manner similar to the retinoblastoma gene, two somatic "hits" in the same cell are required for sporadic cases, while one somatic "hit" plus the inheritance of one defective allele is responsible for the familial cases.

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PTCH1 encodes a protein acting as a transmembrane receptor for the HH protein family, an important component of the HH signaling pathway, which directs embryonic development of a variety of organs in vertebrates (figure 1) [119]. Three HH ligands are present in mammals: sonic hedgehog (SHH), Indian hedgehog (IHH) and desert hedgehog (DHH). SHH is the most studied HH ligand; it binds a cell membrane receptor complex that is formed by PTCH and a second protein, smoothened (SMO), relieving the inhibition of the pathway induced by unbound PTC1 and thus activating the HH pathway [114,120]. However, the mechanism by which HH signal overexpression leads to tumorigenesis is unclear. It may involve the activation of the transcription factors Gli1 (glioma-associated oncogene homolog) and/or Gli2.

TP53 mutations — The second most important gene in BCC carcinogenesis is TP53, encoding the P53 protein involved in maintaining genomic stability by regulating the cell cycle, inducing apoptosis, and activating DNA repair. TP53 mutations have been detected in 20 to over 60 percent of sporadic BCCs [110].

Other genes — In addition to PTCH1 and TP53, other tumor-related genes have been implicated in BCC pathogenesis [110-112,121]. In a series of 293 BCCs, 85 percent harbored mutations in genes involved in the HH pathway (PTCH1 73 percent, SMO, 20 percent, and SUFU 8 percent), and TP53 (61 percent) and also in multiple other cancer-related genes, such as MYCN, PPP6C, PTPN14, STK19, and LATS1 [112]. In a whole-exome sequencing study of 12 sporadic BCCs and normal skin, mutations were found in a number of known or putative cancer genes, including CSMD1, DPP10, NOTCH1, and PREX2; mutational hotspots were detected in STAT5B, CRNKL1, and NEBL [111]. However, the relevance of these mutations in the BCC pathogenesis is unclear.

PATHOLOGY

On histopathologic examination, common findings of BCC are

nodules and/or strands of atypical basaloid cells that show nuclear palisading, cellular apoptosis, and scattered mitotic activity in the dermis (picture 2A-B). Artifactual cleft formation may be seen between the tumor lobules and the surrounding stroma, which may be mucinous. Solar elastosis is usually present in the dermis. The histologic patterns of BCC (nodular, superficial, morpheaform/infiltrative, basosquamous, micronodular, and pigmented) are often reflected in the clinical appearance. ●Hematoxylin-eosin staining of nodular BCC, the most common subtype, reveals discrete nests of basaloid cells in the dermis. There is peripheral palisading of the malignant keratinocytes and a mucinous-surrounding tumor stroma. Between the tumor and the dermis, a separation or "cleft," is often apparent due to retraction artifact in tissue processing. ●Superficial BCC is characterized histologically by foci of malignant, basaloid, palisading tumors "budding" off the epidermis. ●In morpheaform/infiltrative BCCs, there are thin cords of basaloid tumor cells penetrating the surrounding collagen, which may appear sclerotic.

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●Micronodular BCCs appear as numerous small collections of malignant basaloid cells within the dermis and exhibit more subtle findings of peripheral palisading and retraction compared with nodular BCCs. ●Pigmented BCCs represent approximately 6 percent of BCCs and are so named due to melanin and melanophages found within the tumor nodules. ●Basosquamous BCCs have a component of nodular or superficial BCC overlying an invasive portion that has features of BCC and SCC [122,123]. ●A less common and indolent subtype, fibroepithelial BCCs (fibroepitheliomas of Pinkus), exhibit thin strands of basaloid keratinocytes in a reticular pattern and a spindle celled stroma. Morpheaform/infiltrative, micronodular, and basosquamous are considered more "aggressive growth" subtypes of BCC [11]. Some lesions have a mixed histology, and up to 40 percent have features of more than one histologic subtype [123,124].

CLINICAL PRESENTATION

Approximately 70 percent of

BCCs occur on the face, consistent with the etiologic role of solar radiation, and 15 percent present on the trunk. Only rarely is BCC diagnosed on areas like the penis, vulva, or perianal skin [125]. The clinical presentation of BCC can be divided into three groups, based upon lesion histopathology: nodular, superficial, and morpheaform.

Nodular — Nodular BCCs, which represent approximately 80 percent of cases, typically present on the face as a pink or flesh-colored papule (picture 3G) [126]. The lesion usually has a pearly or translucent quality, and a telangiectatic vessel is frequently seen within the papule. The papule may often be described as having a "rolled" border, where the periphery is more raised than the middle. Ulceration is frequent (picture 3J), and the term "rodent ulcer" refers to these ulcerated nodular BCCs (picture 1A-C).

Superficial — Approximately 15 percent of BCCs are superficial BCCs [126]. For unclear reasons, men have a higher incidence of superficial BCC than do women. Superficial BCCs most commonly occur on the trunk and typically present as slightly scaly, non-firm macules, patches, or thin plaques light red to pink in color (picture 3A-F). The center of the lesion sometimes exhibits an atrophic appearance and the periphery may be rimmed with fine translucent papules. A shiny quality may be evident when a superficial BCC is illuminated. Occasionally, spotty brown or black pigment is present, which may contribute to confusion with melanoma (picture 3D). Superficial BCCs tend to grow slowly, and can vary in size from macules measuring just a few millimeters in diameter to lesions several centimeters in diameter or more if left untreated. Superficial BCCs are usually asymptomatic.

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Morpheaform/infiltrative — Morpheaform or sclerosing BCCs constitute 5 to 10 percent of BCCs. These lesions are typically smooth, flesh-colored, or very light pink papules or plaques that are frequently atrophic; they usually have a firm or indurated quality with ill-defined borders (picture 4A-B). Infiltrative and micronodular subtypes are less common than the morpheaform BCC.

Other subtypes — Several other BCC subtypes have been described. Basosquamous cell carcinoma is a rare tumor that behaves aggressively. Both nodular and superficial BCCs can produce pigment. These lesions are referred to as pigmented BCCs (picture 3H). (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma".)

Multiple basal cell carcinoma syndromes — Several rare syndromes have been described that present with multiple BCCs. The most common is the nevoid basal cell carcinoma syndrome. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".) Bazex syndrome is another rare disorder characterized by multiple BCCs and follicular atrophoderma [127]. Rombo syndrome presents with BCCs, atrophoderma vermiculatum, and vellus hair cysts with milia-like appearance [128]. Patients with xeroderma pigmentosum (XP) and Muir-Torre syndrome are at increased risk for BCC as well as other skin cancers. The incidence of BCCs, squamous cell carcinomas, and melanomas for individuals with XP under the age of 20 is approximately 2000 times that seen in the general population. (See "Xeroderma pigmentosum" and "Muir-Torre syndrome".)

Natural history — Most BCCs remain localized, and the growth rate is variable. However, a few become locally aggressive or metastatic, and the acquisition of cytogenetic aberrations may be associated with aggressive biologic behavior. In one series, for example, trisomy 6 was identified in none of 22 nonaggressive, two of four locally aggressive, and all four metastatic BCCs [129].

DIAGNOSIS Clinical and dermoscopic examination — Clinicians who are familiar with the clinical manifestations of BCC are often able to make the diagnosis based upon clinical examination (picture 3A-B, 3D, 3G-J). Examination of the lesion with a dermatoscope may assist in the clinical diagnosis of BCC [130-132].

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Dermoscopic features of BCC include the lack of a pigmented network (which is typically associated with melanocytic lesions) and the presence of one or more findings that are characteristic of BCC, such as arborizing vessels, blue-gray ovoid nests, and ulceration (figure 2 and picture 5). A metaanalysis of 13 studies found that the pooled sensitivity and specificity of dermoscopy for the diagnosis of BCC were 91 and 95 percent, respectively; in a subgroup of five studies comparing the accuracy of naked eye examination followed by dermoscopy with naked eye examination alone, the sensitivity and specificity were 85 percent and 98 percent, respectively [133]. (See "Dermoscopic evaluation of skin lesions", section on 'Criteria for basal cell carcinoma'.) However, a skin biopsy is usually performed to provide pathologic confirmation of the diagnosis and determine the histologic subtype.

Biopsy — In cases for which the clinical diagnosis of BCC appears certain and the tumor lacks clinical features associated with a high risk for tumor recurrence, clinicians experienced in the diagnosis of BCC sometimes elect to perform the biopsy at the same time as definitive treatment (eg, immediately prior to electrodesiccation and curettage). In addition, some clinicians choose to treat lesions without a biopsy when high-risk clinical features are absent and the patient has a history of multiple similar low-risk BCCs. (See "Treatment of basal cell carcinomas at high risk for recurrence", section on 'Features associated with high risk for recurrence' and "Treatment and prognosis of basal cell carcinoma at low risk of recurrence".) However, the decision not to perform a biopsy prior to definitive treatment is not without risk. Because the histologic features of a tumor provide additional information on the risk for tumor recurrence following treatment, not performing a biopsy prior to definitive treatment may result in a failure to detect a tumor with aggressive histologic features that might be best managed with a different approach to therapy. The misdiagnosis of a different tumor as BCC (eg, amelanotic melanoma) is an additional risk of deferring a biopsy (picture 6A-B). To reduce the risk for patient mismanagement, we suggest always performing a biopsy in the following situations: ●The lesion exhibits features atypical for BCC ●The patient lacks a prior history of BCC ●The lesion exhibits clinical features suggestive of a BCC with a high-risk for recurrence Shave biopsies, punch biopsies, and excisional biopsies can be used for the diagnosis of BCC. Although shave and punch biopsies are frequently performed for diagnosis due to the simplicity of these procedures, clinicians should be aware that biopsies that remove only a portion of the lesion do not always provide an accurate assessment of the histologic subtype of a tumor [134-138]. With punch biopsies, an aggressive histologic subtype may be missed in up to 20 percent of cases [134136]. A retrospective study in which the majority of biopsy procedures were shave biopsies (230 shave biopsies and 27 punch biopsies) found that an aggressive histologic subtype was missed in 7 percent of cases [137]. (See "Skin biopsy techniques", section on 'Biopsy techniques'.)

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DIFFERENTIAL DIAGNOSIS

The differential diagnosis

varies with the subtype of BCC (ie, nodular, superficial, or morpheaform): ●Early nodular variants with little ulceration clinically may be identical to benign growths such as dermal nevi (picture 7), small epidermal inclusion cysts, or even sebaceous hyperplasia (picture 8). A single lesion of molluscum contagiosum has a similar appearance, as does amelanotic melanoma. ●Larger lesions with central ulceration can appear cup-shaped. These can resemble squamous cell carcinoma, keratoacanthomas, or dermal metastases from internal organs such as the colon [139]. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis" and "Keratoacanthoma: Epidemiology, risk factors, and diagnosis".) ●Superficial BCCs may be confused with inflammatory disorders of the skin such as nummular eczema (also known as nummular dermatitis (picture 9)) or psoriasis (picture 10), especially when a peripheral rim of small, pearly papules is absent. In particular, the possibility of superficial BCC should be considered when a lesion presumed to be inflammatory fails to respond to topical corticosteroids. (See "Nummular eczema" and "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".) ●Benign lichenoid keratoses (picture 11), actinic keratoses (picture 12), and rarely amelanotic melanoma (picture 6A-B) presenting as scaly erythematous macules may also be mistaken for superficial BCC. (See "Epidemiology, natural history, and diagnosis of actinic keratosis" and "Melanoma: Clinical features and diagnosis".) ●Morpheaform BCCs frequently appear similar to a scar or other site of trauma. The induration of the lesion simulates localized scleroderma. ●Pigmented nodular or superficial BCCs may resemble melanoma or, less likely, a benign nevus. (See "Melanoma: Clinical features and diagnosis".)

PREVENTION Sun protection — The primary approach to the prevention of BCCs is protection from sun exposure. The various techniques to minimize solar exposure are discussed elsewhere. (See "Selection of sunscreen and sun-protective measures".) It has been estimated that aggressive sun protection before the age of 18 years could reduce the number of nonmelanoma skin cancers (NMSCs) by almost 80 percent [140]. Several trials provide evidence that sunscreen use decreases the incidence of squamous cell carcinomas (SCCs) and that there are no adverse effects from sunscreen use [141-143]. However, a randomized trial evaluating

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the effects of sunscreen and the antioxidant beta-carotene over a four-year period found that participants using topical sunscreen had a 40 percent reduction in SCCs but no decrease in BCCs [141].

Chemoprevention Nonsteroidal anti-inflammatory drugs — Data conflict on the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on the risk for BCC [144-147]: ●The results of an 11-month randomized trial suggested that celecoxib (a cyclooxygenase-2 inhibitor) may be beneficial for chemoprevention. In this trial of 240 patients with actinically damaged skin, patients treated with celecoxib (200 mg twice daily for nine months) developed fewer BCCs than patients who were given placebo (adjusted rate ratio 0.40, 95% CI 0.18-0.93) [148]. ●In contrast, a Danish population-based case-control study failed to find an association between the use of celecoxib or other prescription NSAIDs and overall risk for BCC [149]. ●Another population-based case-control study including over 65,000 cases with incident, first-time diagnosis of BCC and the same number of matched controls selected from the United Kingdom Clinical Practice Research Datalink did not find an association between the use of any NSAIDs and the overall risk of BCC [150]. In subgroup analyses, a modest risk reduction was observed among long-term users of ibuprofen (odds ratio [OR] 0.85, 95% CI 0.77-0.94), and risk was further reduced among mono-users (OR 0.61, 95% CI 0.48-0.78). However, these results must be interpreted with caution because of the lack of information on potential confounders or effect-modifying factors such as sun exposure and skin phototype. Although not explicitly mentioned in those studies, adverse effects of NSAID therapy on multiple organ systems (eg, cardiovascular, gastrointestinal, renal) warrant additional consideration when recommending long-term use as chemoprevention. (See "Nonselective NSAIDs: Overview of adverse effects".)

Oral nicotinamide — The efficacy of oral nicotinamide (vitamin B3), a dietary supplement available over-the-counter, for the prevention of nonmelanoma skin cancer (NMSC) has been evaluated in a phase III randomized trial [151]. In this study, 386 immunocompetent participants (mean age 66 years) with ≥2 histologically confirmed NMSCs in the past five years were treated with 500 mg of nicotinamide twice daily or placebo for 12 months. The primary endpoint was the number of new NMSCs at 12 months. At the end of the study, patients in the nicotinamide group had a lower number of BCC and SCC (NMSC) than patients in the placebo group (1.8 versus 2.4), corresponding to a rate reduction of 23 percent (95% CI 4-38 percent) after adjustment for center and five-year nonmelanoma skin-cancer history and 27 percent (95% CI 5-44 percent) without adjustment. For BCC, the rate reduction was 20 percent (95% CI -6 to 0.39). There was no significant difference in adverse events between the placebo and nicotinamide groups. No effect on NMSC rates was observed in the six months after discontinuation of treatment.

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An underpowered phase II randomized trial of nicotinamide in 22 renal transplant patients found a statistically nonsignificant 35 and 15 percent reduction in the rate of NMSCs and actinic keratoses, respectively [152]. Further, a published response to the original Phase III study suggested that with Bayesian reinterpretation, the 23 percent estimated reduction in NMSC would not be reproducible [153]. Additional studies are needed to evaluate the effects of long-term treatment and establish the optimal patient population and dose of medication.

Topical fluorouracil — A single course of topical fluorouracil has been shown to reduce the development of new actinic keratoses, a marker for increased risk of keratinocyte cancers (ie, BCC and squamous cell carcinoma [SCC]) in older male patients with multiple previous keratinocyte cancers [154,155]. However, topical fluorouracil seems not to be effective in preventing the development of BCC in high-risk patients. In a randomized trial, 932 participants with a history of at least two keratinocyte cancers in the previous five years were instructed to apply topical fluorouracil 5% cream or vehicle cream twice daily to the face and ears for four weeks (a total of 56 doses) [156]. The primary study endpoints were surgically treated BCC or SCC on the face or ears. After a median follow-up time of 2.8 years, the proportions of patients who underwent surgical excision for one or more BCC or SCC were 32 and 11 percent, respectively, in the fluorouracil group and 32 and 12 percent, respectively, in the control group.

INFORMATION FOR PATIENTS

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two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topics (see "Patient education: Skin cancer (non-melanoma) (The Basics)" and "Patient education: Sunburn (The Basics)") ●Beyond the Basics topics (see "Patient education: Sunburn (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS 4189

●Basal cell carcinoma (BCC) is a common skin cancer arising from the basal layer of epidermis and its appendages. Although these tumors have a low metastatic potential, they are locally invasive and can be destructive of skin and the surrounding structures (picture 1A-B). ●BCC is the most common malignancy in white populations and its incidence is increasing worldwide. BCC has been linked to exposure to ultraviolet (UV) light, especially during childhood. Most other risk factors act through an interaction with UV exposure. (See 'Epidemiology' above and 'Risk factors' above.) ●Approximately 80 percent of BCCs present on the face and head. The most common presentations for BCC are the nodular (picture 3G) and superficial forms (picture 3A-F), which together account for over 90 percent of cases. (See 'Clinical presentation' above.) ●Biopsies are useful for confirming a diagnosis of BCC and determining the histologic subtype of a tumor. A biopsy is particularly indicated in cases in which the diagnosis is uncertain, the patient lacks a history of BCC, the lesion exhibits features suggestive of an increased risk for tumor recurrence after treatment, or when the tumor exhibits atypical clinical features. (See 'Diagnosis' above.) ●Once the diagnosis is established, appropriate treatment offers a high probability of cure, although the patient remains at increased risk for additional skin malignancies. (See 'Diagnosis' above and "Treatment and prognosis of basal cell carcinoma at low risk of recurrence" and "Treatment of basal cell carcinomas at high risk for recurrence".)

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Treatment and prognosis of basal cell carcinoma at low risk of recurrence uptodate.com/contents/treatment-and-prognosis-of-basal-cell-carcinoma-at-low-risk-of-recurrence/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Aug 13, 2019.

INTRODUCTION

Basal cell carcinoma (BCC) is a common skin cancer

that arises from the basal layer of epidermis and its appendages (picture 1A-B). Treatment of BCC is indicated due to the locally invasive, aggressive, and destructive effects of this tumor on skin and surrounding tissues (picture 2A-B). Treatment options for BCC include surgical excision, Mohs micrographic surgery, curettage and electrodesiccation (C&E), topical agents, photodynamic therapy, cryotherapy, and radiation therapy (table 1). Tumor characteristics such as size, location, and pathology, as well as treatment tolerability, cost, and patient preference, influence the selection of treatment. This topic will review the treatment of BCCs without aggressive clinical or pathologic features and the prognosis of BCC. The treatment of BCCs with high risk for recurrence, the epidemiology and diagnosis of BCC, the options for systemic therapy in locally advanced or metastatic BCC, and the management of BCC in patients with Gorlin syndrome are discussed separately. ●(See "Treatment of basal cell carcinomas at high risk for recurrence".) ●(See "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma".)

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●(See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".) ●(See "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas".) ●(See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)

PRETREATMENT EVALUATION History and physical examination — The evaluation of the patient with a suspect BCC involves a detailed history (lesion history, personal or family history of nonmelanoma skin cancer, use of immunosuppressive medications, presence of comorbidities), a physical examination, and a biopsy of the suspicious lesion.

Lesion biopsy and risk assessment — Although the diagnosis of BCC can often be made by the experienced clinician based upon the clinical and dermoscopic examination, a skin biopsy is essential to confirm the diagnosis and provide additional information on the risk for tumor recurrence following treatment. Obtaining a lesion biopsy for diagnostic confirmation is especially important for patients who are not surgical candidates before proceeding to destructive or nonsurgical treatment. The assessment of risk for lesion recurrence is the most important step in the choice of treatment for BCC. Tumors that lack aggressive clinical or pathologic features are less likely to recur than lesions with more aggressive features. (See 'Features associated with low risk of recurrence' below.) Overly aggressive management of BCCs at low risk for recurrence may result in unnecessary inconveniences to the patient and increased costs. Conversely, inadequate treatment of lesions with aggressive features can lead to subsequent tumor recurrence with potentially devastating consequences (picture 2A-B).

Features associated with low risk of recurrence — The following characteristics have been proposed as features that identify BCCs with a low likelihood for recurrence after treatment in the National Comprehensive Cancer Network clinical practice guidelines on cutaneous BCC [1]: ●Location and size •80 percent of trichilemmomas in patients with Cowden syndrome and in only 3 percent of sporadic trichilemmomas [9]. ●Adipophilin – Marker of sebocytic lineage. ●CD117 (c-kit) and MYB – Positive markers for adenoid cystic carcinoma. Also expressed in cylindroma and spiradenoma.

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●Phosphohistone H3 and Ki-67 (MIB-1) – Immunostains to assess the mitotic and proliferative rate of tumors, respectively. ●Cytokeratin 7 or CAM 5.2 – Positive in many sweat gland tumors, including extramammary Paget disease. ●MSH2, MLH1, MSH6, and PMS2 – Screening stains for loss of protein expression in sebaceous tumors associated with Muir-Torre syndrome.

Differentiation of primary cutaneous adnexal carcinoma from metastatic adenocarcinoma — Significant histopathologic overlap exists between primary cutaneous adenocarcinomas of apocrine or eccrine derivation and various internal adenocarcinomas that metastasize to the skin. Clinical history of prior cancer is the most useful information when confronted with this differential diagnosis. Immunostaining can also be helpful in distinguishing primary cutaneous tumors from cutaneous metastases. Since no single stain is fully sensitive or specific, a combination of these stains provides the best results. Positive staining for p63, D2-40 (podoplanin), cytokeratin 5/6, and cytokeratin 15 is supportive of primary cutaneous origin [10,11]. Additional staining with cytokeratin 7, cytokeratin 20, estrogen receptor, progesterone receptor, thyroid transcription factor 1, prostate specific antigen, renal cell carcinoma antigen, and various other stains can be used in appropriate settings to exclude various forms of metastatic carcinomas. (See "Adenocarcinoma of unknown primary site", section on 'Immunohistochemistry'.) In cases of cutaneous metastases of unknown origin, molecular assays that assess gene expression profiles can also be used to identify potential candidates for the primary site of the tumor. (See "Adenocarcinoma of unknown primary site", section on 'Molecular cancer classifier assays'.)

ECCRINE AND APOCRINE TUMORS Benign Syringoma — Syringomas are small tumors of eccrine or apocrine origin that present as multiple discrete, skin-colored papules 2 to 4 mm in diameter [12,13]. They occur most frequently in the periorbital area (picture 2) but they may involve any body site. Eruptive syringomas appear during childhood or early adulthood on the anterior neck (picture 3A-B), chest, shoulders (picture 4), abdomen, and genital areas (picture 5).

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Multiple or eruptive syringomas may be associated with Down's syndrome [14], anti-epileptic medications [15], and hyperthyroidism [16]. Reports of eruptive syringomas at the sites of prior inflammatory lesions [17] or hair waxing [18] have led to discussion of a reactive rather than neoplastic etiology in some cases. Multiple clear cell syringomas have been reported in patients with diabetes mellitus [19]. Histologically, syringomas are characterized by multiple small epithelial collections with central ducts surrounded by a bilayer of cuboidal cells in the superficial dermis (picture 6). Frequently, a tapering, comma-shaped edge is present at one edge of the epithelial collections with an encompassing fibrotic stroma [14-19].

Poroma — Poroid tumors, including hidroacanthoma simplex, classic poroma, dermal duct tumor, and poroid hidradenoma, are benign adnexal tumors characterized by small round, monomorphous cells with small amounts of cytoplasm (poroid cells) that exhibit ductal differentiation. Originally regarded as a purely eccrine tumor, it is now clear that both eccrine and apocrine poromas occur. HRAS mutations have been reported in a small percentage of poromas [20]. RNA sequencing has identified recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in approximately 90 percent of poromas and approximately 65 percent of porocarcinomas [21]. The classic variant of poroma presents as a skin-colored or erythematous papule with a predilection for the palms and soles (picture 7A-B). The other variants are found on the trunk and limbs (picture 1A). The average age at diagnosis for poroid tumors is the fifth and sixth decade of life with no sex predilection [22,23]. Multiple poromas (poromatosis) can occur sporadically but have also been associated with pregnancy, hidrotic ectodermal dysplasia, bone marrow transplant, radiation exposure, chemotherapy, or radiation therapy [24-28]. Histologically, the intraepidermal variant of poroma (hidroacanthoma simplex) resembles a seborrheic keratosis, but is distinguished by duct formation (picture 8). Classic poroma consists of a superficial dermal proliferation of poroid cells with multiple epidermal connections and a highly vascular stroma (picture 9). A purely dermal variant of poroma (dermal duct tumor) is composed of multiple small nodular aggregations (picture 10). Poroid hidradenoma consists of one or a few large aggregations of poroid cells in the dermis, often extending into the subcutaneous fat (picture 11). Cytologic atypia is typically minimal. Tumor necrosis and mitotic activity are often present in benign poroid neoplasms and should not be mistaken for an indication of malignancy. Porocarcinoma is distinguished by nuclear atypia, infiltrative growth pattern, and rapid growth. (See 'Porocarcinoma' below.)

Cylindroma and spiradenoma — Cylindromas and spiradenomas are sweat duct tumors centered in the dermis that often show overlapping features in the same tumor (spiradenocylindroma). They occur sporadically in the older adult population, typically as a solitary papule or nodule on the head or neck or, less commonly, on the trunk and extremities (picture 1B,

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1D). Detection of multiple cylindromas (picture 12) or spiradenomas should raise the suspicion of Brooke-Spiegler syndrome or familial cylindromatosis caused by mutation of CYLD. (See 'Syndromes associated with cutaneous adnexal tumors' below.) Sporadic cylindromas and spiradenomas also have frequent CYLD mutations. In addition to CYLD mutations, some cylindromas harbor t(6;9) MYB-NFIB gene fusions and mutations in DNMT3A [29,30]. Spiradenomas frequently have ALPK1 mutations, which appear to be mutually exclusive from CYLD mutations [30]. Histologically, cylindroma consists of small, irregularly shaped aggregations of basaloid keratinocytes closely opposed to one another in a pattern resembling interconnecting pieces of a jigsaw puzzle (picture 13). Scattered lymphocytes and small ducts are present within the neoplastic clusters of cells. Hyalinized basement membrane material surrounds the individual clusters and forms small circular collections between cells within the clusters. Spiradenomas have a similar appearance, with basaloid keratinocytes, interspersed lymphocytes, ductal differentiation, and hyalinized basement membrane material, but form one or a few large nodules in the dermis with a trabecular pattern (picture 14), as opposed to the many small clusters in cylindroma.

Cutaneous mixed tumor — Mixed tumors of the skin, also called chondroid syringoma, are rare apocrine or eccrine tumors with mixed epithelial and stromal components. They usually present in older adults as asymptomatic, slow-growing firm nodules, most frequently located in the head and neck region (picture 15) [5]. Cutaneous mixed tumors and myoepitheliomas frequently have PLAG1 or EWSR1 gene rearrangements similar to pleomorphic adenomas of the salivary gland [31,32]. PHF1-TFE3 fusion has been reported in a malignant mixed tumor [33]. Histologically, mixed tumors of the skin resemble mixed tumors of the salivary gland (pleomorphic adenoma). Follicular and sebaceous elements may also be observed. Mixed tumors form large, wellcircumscribed, nodular aggregations of epithelial cells with focal ductal differentiation in the dermis and upper subcutis. A prominent myxoid, chondroid, or fibrous stroma surrounds the epithelial cells and distinguishes this variant of sweat gland tumor (picture 16). Prominent myoepithelial differentiation is frequently present and can be demonstrated with myoepithelial markers such as smooth muscle actin or calponin. When myoepithelial differentiation is the dominant pattern, a diagnosis of myoepithelioma is rendered. The presence of decapitation secretion or concurrent folliculosebaceous differentiation confirms apocrine lineage.

Syringofibroadenoma — Typically regarded as an eccrine tumor, syringofibroadenoma is a superficial dermal tumor presenting as a hyperkeratotic or verrucous plaque usually found on the extremities and, less commonly, on the eyelid [34] or in a nevus sebaceus [35]. An association with ectodermal dysplasia syndromes has also been reported [36].

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Histologically, syringofibroadenoma is composed of thin, interconnecting strands of keratinocytes in a lattice pattern that connects with the undersurface of the epidermis (picture 17). Small ducts are present in variable numbers in the thin strands [34-36]. Syringofibroadenomatosis is a reactive hyperplasia of eccrine ducts seen in areas of trauma or inflammation that histopathologically resembles syringofibroadenoma [37].

Syringocystadenoma papilliferum — Syringocystadenoma papilliferum (SCAP) is an adnexal tumor affecting a much younger patient population than most adnexal tumors, with an average age of 15 at diagnosis [6]. SCAP presents as a warty plaque most often located on the scalp. Less commonly, lesions can be found on the face, chest, arms, or thighs. SCAP may occur sporadically, but approximately one-third of cases are associated with a nevus sebaceus [38]. (See "Nevus sebaceus and nevus sebaceus syndrome".) Histologically, SCAP is a tumor of apocrine derivation characterized by cuboidal and columnar epithelial cells lining ducts that invaginate from the epidermis into the superficial dermis. Dilated, cystic ducts are frequently present, some of which have papillary projections into their lumens. An inflammatory infiltrate with many plasma cells surrounds the tumor (picture 18). Frequently, apocrine (decapitation) secretion is visible in some parts of the tumor. Most SCAPs harbor RAS or BRAF mutations [39].

Hidradenoma papilliferum — Hidradenoma papilliferum usually occurs on the vulvar region of middle-aged women (picture 19) [40]. It displays some histopathologic overlap with syringocystadenoma papilliferum, but resides in the deeper dermis and subcutis with a more nodular configuration, lacks a plasmacytic infiltrate, and is found almost exclusively in the anogenital region. It has been suggested that hidradenoma papilliferum may derive from anogenital mammary-like glands [41-43]. Mutations in PIK3CA and AKT1 have been detected [44,45]. Rare cases occurring outside the anogenital region have been reported [46-48]. (See "Vulvar lesions: Differential diagnosis based on morphology".)

Hidradenoma — Hidradenoma is a benign adnexal tumor related to poroma that presents as a solitary nodule, typically ranging from 1 to 3 cm in size. It occurs in all areas of the body, usually in adults. Hidradenoma can be either apocrine or eccrine, with variants including solidcystic, clear (pale) cell, nodular, and poroid types. The term "acrospiroma" has also been used for the spectrum of hidradenoma and poroma. Approximately 50 percent of hidradenomas harbor a t(11;19) translocation causing a MECT1-MAML2 gene fusion [49]. Histopathologic examination shows a circumscribed dermal tumor with variable extension into the subcutis, composed of one or more large nodules of epithelial cells with areas of ductal differentiation (picture 20). Epidermal connection is present in 25 percent of cases.

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Tubular/papillary adenoma, including papillary cystadenoma — Numerous reports have described benign apocrine or eccrine tumors with a papillary, tubular, and/or cystic pattern under various names, including papillary eccrine adenoma, tubular apocrine adenoma, and papillary apocrine fibroadenoma. These tumors have no sex predilection and are most frequently seen on the head and extremities [6]. BRAF V600E mutations have been identified in >50 percent of these tumors, and KRAS mutations occur in a small percent [50]. Histologically, tubular/papillary adenomas are well-circumscribed proliferations of small epithelial aggregations exhibiting ductal differentiation. They form round, cystic, or tubular structures in the dermis (picture 21). Papillary projections into cystically-dilated ducts are sometimes prominent.

Malignant — Malignant adnexal tumors are rare and typically affect older adults or individuals with familial tumor syndromes. For nearly all of the benign apocrine and eccrine tumors listed above, there is a malignant counterpart (eg, poroma and porocarcinoma) which is differentiated from the benign form by clinicopathologic features including larger size, infiltrative growth pattern (poor circumscription), nuclear enlargement and pleomorphism, increased mitotic activity, necrosis, and ulceration.

Porocarcinoma — Eccrine porocarcinoma or malignant eccrine poroma is a rare tumor that occurs most often on the head and neck or lower extremities of older individuals (mean age 68) and sometimes arises in a pre-existent poroma [51,52]. A meta-analysis of 453 cases showed equal gender distribution and progression to metastasis in 31 percent of cases, with lymph node being the most common site of metastasis [52]. Histologically, porocarcinoma is characterized by infiltrative growth pattern, nuclear atypia, increased mitotic activity, and necrosis (picture 22). The presence of an adjacent benign poroid component is helpful in establishing the diagnosis. DNA sequencing data have shown mutations in EGFR, HRAS, TP53, RB1, ATM, ARID1A, PIK3CA,and CDKN2A [20]. RNA sequencing has identified recurrent YAP1 gene fusions in approximately 65 percent of porocarcinomas [21]. Retrospective analysis of the National Cancer Database found 5and 10-year survival rates of 69 and 54 percent, respectively, for porocarcinoma [53]. Large tumor size (particularly >4 cm) is associated with a poor prognosis. Wide local excision is the mainstay of treatment. Data are lacking to support sentinel lymph node biopsy, though lymph node dissection is typically utilized when lymph node involvement is detected [52]. Chemotherapy and/or radiation have been reported for treatment of advanced stages of porocarcinoma.

Adenoid cystic carcinoma — Adenoid cystic carcinoma (ACC) is a variant of adenocarcinoma that can arise in multiple organ types. Salivary gland ACC is the most frequent type, but primary ACC has been reported in skin, breast, lung, prostate, lacrimal gland, female genital tract, and gastrointestinal tract. (See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging".)

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A characteristic t(6;9) MYB-NFIB gene fusion is present in cutaneous as well as noncutaneous ACC [54]. MYBL1 rearrangements occur in a small minority of cases [55]. Primary cutaneous ACC has a more favorable prognosis than its salivary counterpart [56]. The average age of onset for primary cutaneous ACC is approximately 60 years [56]. The tumor can occur on the scalp, trunk, and extremities, and typically presents as a slow-growing, nondescript nodule on the skin. Diagnosis of ACC on the lower half of the face should prompt evaluation for local spread of salivary gland ACC. ACC exhibits three primary histopathologic growth patterns (ie, cribriform, solid, tubular). The cribriform pattern is the most unique of the three, with clusters of epithelial cells with both true ducts and duct-like collections of mucin interspersed in a sieve-like pattern (picture 23). Solid and tubular patterns are also observed, with multiple patterns frequently present in the same tumor. Perineural invasion is frequently present.

Mucinous carcinoma and endocrine mucinproducing sweat gland carcinoma — Mucinous carcinoma is a type of adenocarcinoma that occurs in multiple organ systems including breast, skin, ovary, lung, and gastrointestinal tract. Cutaneous mucinous carcinoma presents as a slow-growing blue or reddish nodule ranging from 0.5 to 8 cm with a predilection for the scalp, eyelids, and axilla. The mean age of onset is approximately 60 years [57]. Endocrine mucin-producing sweat gland carcinoma (EMPSGC) represents a low-grade adnexal carcinoma that can be a precursor to mucinous carcinoma and typically occurs on or near the eyelid [58]. Histologically, mucinous carcinoma consists of islands of epithelial cells seemingly floating within large pools of mucin in the dermis and/or subcutis. Sometimes apocrine decapitation secretion and ductal differentiation is apparent. Biopsy findings in EMPSGC include rounded aggregations of epithelial cells with mild to moderate cytologic atypia in the dermis that express neuroendocrine markers and estrogen and progesterone hormone receptors. Mucin deposition is present but to a lesser degree than mucinous carcinoma.

Microcystic adnexal carcinoma — Microcystic adnexal carcinoma (MAC), also known as sclerosing sweat duct carcinoma, is a locally aggressive malignancy that typically occurs on the central face, although extra-facial cases have been reported [59,60]. MAC presents as a slowly expanding scar-like plaque or firm nodule (picture 24A-D) [60]. Recurrent TP53 and JAK1 mutations have been identified with next-generation sequencing [61]. Histologically, MAC shows divergent differentiation, with follicular elements of keratin cysts in the upper dermis and infiltrating strands of epithelial cells with sweat ductal differentiation that often extends into the subcutis, and an associated fibrotic stroma (picture 25). The clinical presentation, diagnosis, and treatment of MAC are discussed in detail separately. (See "Microcystic adnexal carcinoma".)

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(Aggressive) digital papillary adenocarcinoma — Digital papillary adenocarcinoma (DPA), also called aggressive digital papillary adnexal carcinoma or aggressive digital papillary tumor, is a malignant adnexal tumor presenting as a nodule on the volar surface of the digits of the hands and, less often, of the feet [62,63]. DPA is a rare tumor, with an estimated incidence of 0.08 per million person-years [64]. It usually occurs in adult individuals, with a male predominance [63]. Rarely, patients present with metastatic disease to the lymph nodes and lungs. Sequencing analysis from one study showed BRAF V600E mutations in one out of nine tumors [65]. Gene expression profiling of eight cases showed overexpression of FGFR2, indicating that pathway as a potentially treatment-targetable genetic alteration [66]. Histopathologically, the tumor displays a multinodular, sometimes infiltrative configuration of epithelial cells with glandular and ductal differentiation. Frequently, papillary projections within cystic ductal spaces are present (picture 26). Cytologic atypia is variable, ranging from mild to severe, and does not appear to correlate with prognosis [63]. Wide local excision or digital amputation is the treatment of choice for digital papillary adenocarcinoma [62,63]. Local recurrence rates range from 16 to 50 percent. In one study, local recurrence was reported in 1 of 21 patients treated with re-excision or amputation after the initial excision and in 11 of 22 patients who did not undergo additional procedures after the initial excision, after an average follow-up time of six years [62]. Metastasis occurs in approximately 15 to 30 percent of cases [62-64].

Extramammary Paget disease — Extramammary Paget disease (EMPD) can be either a primary cutaneous adenocarcinoma or a tumor with secondary cutaneous involvement via extension from a lower gastrointestinal or urinary tract carcinoma. The cell of origin for primary cutaneous EMPD is controversial. While some cases of EMPD represent epidermal extension of an adenocarcinoma arising from underlying apocrine or eccrine glands, EMPD may also arise from pluripotent stem cells or Toker cells [67,68]. PIK3CA, AKT1, ERBB2, and RAS/RAFpathway mutations have been reported in EMPD [45,69]. EMPD usually presents with well-demarcated, eczematous plaques predominantly located in the anogenital region and, less commonly, in the axillae. Multifocal and bilateral tumors have been reported. Histopathologically, EMPD mimics Paget disease of the breast with a poorly circumscribed proliferation of large epithelial cells distributed singly and in small clusters between normal keratinocytes in the epidermis (ie, pagetoid scatter) with variable ductal differentiation (picture 27). HER2 overexpression in some cases may indicate potential therapeutic response to trastuzumab [70]. The diagnosis, differential diagnosis, and treatment of extramammary Paget disease are discussed separately. (See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment", section on 'Paget disease of the vulva'.)

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Cutaneous cribriform carcinoma — Cutaneous cribriform carcinoma (cutaneous apocrine cribriform carcinoma) is a rare, low-grade sweat gland carcinoma with frequent apocrine differentiation that occurs in adults of all ages and has a predilection for the upper and lower extremities [71]. It presents as a solitary, slow-growing, skin-colored nodule ranging from 1 to 3 cm in size. Surgical excision is the primary treatment, and no metastases have been reported. Biopsy findings for cutaneous cribriform carcinoma include a relatively well-circumscribed, nodular growth pattern centered in the dermis with peripheral lymphoid aggregates (picture 28). Subcutaneous extension can be seen. The tumor is composed of interconnecting aggregations of epithelial cells with irregular, dilated ductal spaces forming a cribriform pattern (picture 29). The thin, thread-like strands seen in cribriform areas are characteristic. Mitotic figures are frequently present but typically low in number.

Cutaneous secretory carcinoma — Cutaneous secretory carcinoma, also known as cutaneous mammary analogue secretory carcinoma, is a low-grade sweat duct carcinoma caused by a t(12;15) translocation resulting in ETV6-NTRK3 fusion [72]. These are rare tumors analogous by histopathology and molecular origins to secretory carcinoma of the breast and salivary glands. Twelve cases have been reported with no metastatic cases [73]. Histopathologically, they have a nodular, relatively well-circumscribed pattern with characteristic eosinophilic secretions in ducts.

FOLLICULAR TUMORS Benign Trichoblastoma and trichoepithelioma — Trichoblastoma and trichoepithelioma are benign epithelial tumors composed of follicular germinative cells resembling those seen in the embryologic buds of primitive folliculosebaceous units. They present as smooth, nonulcerated, skin-colored papules, sometimes with associated telangiectasias usually located on the head and neck (picture 1C, 1E). The majority of cases occur in adults after the age of 40. The presence of multiple trichoepitheliomas should raise the suspicion of Brooke-Spiegler syndrome or multiple familial trichoepithelioma. (See 'Brooke-Spiegler syndrome' below.) Histologically, trichoblastoma shows large and small aggregations of basaloid keratinocytes surrounded by a fibrous stroma rich in fibroblasts and mesenchymal cells that often form densely cellular aggregations (papillary mesenchymal bodies) closely opposed to the epithelial cells in a pattern recapitulating embryologic hair follicle development (picture 30). Trichoepithelioma represents a subset of trichoblastoma composed of smaller islands of basaloid cells, sometimes only one to two cells thick, with marked fibrosis (desmoplastic trichoepithelioma). Numerous histopathologic variants of trichoblastoma have been described, including nodular, retiform, cribriform, racemiform, columnar, and adamantinoid (lymphadenoma) [6].

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Trichoadenoma — Trichoadenoma presents as a slow-growing, skin-colored papule on the face. Histologically, trichoadenoma is composed of multiple cystic collections of keratinocytes with differentiation toward the follicular infundibulum (picture 31).

Trichofolliculoma — Trichofolliculoma is a rare hamartomatous lesion with follicular differentiation that typically occurs on the face (picture 32A-C). Histologically, trichofolliculoma is composed of a large central follicle from which multiple small (vellus) hair follicles emanate (picture 33). The vellus follicles sometimes produce fully developed hair, resulting in a clinical appearance of multiple hairs growing centrally from a small papule. A sebaceous variant without fully developed hair shafts has also been described [74].

Trichilemmoma — Trichilemmoma (also known as tricholemmoma) is a benign follicular tumor with differentiation toward the outer root sheath of the hair follicle. It has been hypothesized that human papillomavirus (HPV) may have a pathogenetic role. However, polymerase chain reaction studies for HPV detection in trichilemmomas provided conflicting results [75-78]. The discovery of frequent HRAS mutations supports a neoplastic etiology [79]. Solitary trichilemmomas usually occur in older adults without sex predilection [1]. They present as a small skin-colored papule or verrucous lesion, most often located on the central face (picture 34). Trichilemmoma is a frequent secondary tumor found in nevus sebaceous, and multiple facial trichilemmomas are seen in patients with Cowden syndrome (picture 35). (See 'Cowden syndrome (multiple hamartoma syndrome)' below.) Histopathologically, trichilemmoma exhibits a papillated, well-circumscribed, exo-endophytic growth pattern (picture 36). Lobules of keratinocytes with pale cytoplasm predominate centrally, with smaller basaloid keratinocytes with peripheral palisading forming a peripheral rim around the tumor. Focal hypergranulosis resembling koilocytic changes of HPV is frequently present at the periphery.

Trichodiscoma and fibrofolliculoma — Although originally described as distinct entities, evidence suggests that trichodiscomas and fibrofolliculomas represent a spectrum of the same neoplastic process [80]. There is also overlap with perifollicular fibroma (angiofibroma). Both fibrofolliculoma and trichodiscoma present as small, 2 to 4 mm, dome-shaped, skin-colored papules on the face, scalp, ears, or upper trunk. They occur sporadically in adults and are seen in multiplicity in patients with Birt-Hogg-Dubé syndrome (picture 37). (See 'Birt-Hogg-Dubé syndrome' below.) Histologically, trichodiscomas and fibrofolliculomas are tumors of the follicular mantle with both stromal and epithelial components. In trichodiscoma, a central zone of fibromucinous stroma predominates, with surrounding sebaceous glands in a "mitt-like" configuration (picture 38). In fibrofolliculoma, thin interconnecting strands of keratinocytes punctuated by small collections of mature sebocytes radiate from a dilated follicular infundibulum and are accompanied by a variably fibrotic and mucinous stroma (picture 39).

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Tumor of the follicular infundibulum — Tumors of the follicular infundibulum (TFI) are rare adnexal tumors that usually present as solitary keratotic papules resembling basal cell carcinoma or actinic keratosis. They usually occur in older adults and are located on the head and neck in the majority of cases [81]. Multiple or eruptive TFIs may present as hypopigmented, scar-like macules or flat papules [82,83]. Microscopic TFIs are often discovered as incidental findings in skin biopsies and excisions. Despite its name, TFI is a follicular tumor with predominantly follicular isthmic differentiation and a superficial, plate-like growth pattern running parallel to the overlying epidermis. Keratinocytes with bright pink cytoplasm that contrast sharply with the darker pink epidermal keratinocytes descend from and reconnect with the undersurface of the epidermis (picture 40). Peripheral palisading, small keratin cysts, and ducts are sometimes present.

Panfolliculoma — Panfolliculoma is a very rare adnexal neoplasm that occurs predominantly on the head and neck of older individuals with a male predilection [84]. Panfolliculoma exhibits follicular upper and lower segment (infundibular, isthmic, germinative, and matrical) differentiation within the same tumor (picture 41). Intraepidermal and cystic variants have been described.

Pilomatricoma — Pilomatricoma, also called pilomatrixoma or calcifying epithelioma of Malherbe exhibits differentiation toward the hair matrix portion of the lower segment (stem) of hair follicles. Activating mutations in beta-catenin in the WNT-signaling pathway appear to be involved in the pathogenesis of these tumors [85,86]. Pilomatricomas occur at any age without gender predilection and exhibit a bimodal distribution with the highest incidence in children and adults over 50. Fifty percent occur on the head and neck [87]. They present as firm, skin-colored to bluish papules or nodules (picture 42A-B). Transepidermal elimination (perforation) sometimes occurs with extrusion of calcified/ossified portions of the neoplasm. Most lesions are 6 mm (as

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p y ( measured from the granular layer of adjacent normal epidermis to the base of the tumor); perineural invasion for T3 classification is defined as tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring 0.1 mm or larger in caliber, or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression. Regional lymph nodes (N) Clinical N (cN) N category

N criteria

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(–)

N2

Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–); or Metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–); or In bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–)

N2a

Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–)

N2b

Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(–)

N2c

Metastases in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–)

N3

Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(–); or Metastasis in any node(s) and clinically overt ENE [ENE(+)]

N3a

Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(–)

N3b

Metastasis in any node(s) and ENE(+)

NOTE: A designation of "U" or "L" may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(–) or ENE(+). Pathological N (pN)

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N category

N criteria

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(–)

N2

Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(+); or Larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–); or Metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–); or In bilateral or contralateral lymph node(s), none larger than 6 cm in greatest dimension, ENE(–)

N2a

Metastasis in a single ipsilateral lymph node 3 cm or smaller in greatest dimension and ENE(+); or A single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–)

N2b

Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(–)

N2c

Metastases in bilateral or contralateral lymph node(s), none larger than 6 cm in greatest dimension and ENE(–)

N3

Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(–); or In a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); or Multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+); or A single contralateral node of any size and ENE(+)

N3a

Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(–)

N3b

Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); or Multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+); or A single contralateral node of any size and ENE(+)

NOTE: A designation of "U" or "L" may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(–) or ENE(+). Di t

t

t

t

i (M)

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Distant metastasis (M) M category

M criteria

M0

No distant metastasis

M1

Distant metastasis

Prognostic stage groups When T is...

And N is...

And M is...

Then the stage group is...

Tis

N0

M0

0

T1

N0

M0

I

T2

N0

M0

II

T3

N0

M0

III

T1

N1

M0

III

T2

N1

M0

III

T3

N1

M0

III

T1

N2

M0

IV

T2

N2

M0

IV

T3

N2

M0

IV

Any T

N3

M0

IV

T4

Any N

M0

IV

Any T

Any N

M1

IV

TNM: tumor, node, metastasis; AJCC: American Joint Committee on Cancer; UICC: Union for International Cancer Control; ENE: extranodal extension. Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. Corrected at 4th printing, 2018. Graphic 110946 Version 6.0

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Brooke-Spiegler syndrome

(A) Adolescent patient with Brooke-Spiegler syndrome. This patient already has >50 papules on the temple and cheek ranging from 1 to 6 mm in size. (B) As patients with Brooke-Spiegler syndrome age, their adnexal tumors may increase in size to over 1 cm and develop prominent telangiectasias. Courtesy of Jeffrey P North, MD. Graphic 98305 Version 2.0

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Multiple cylindromas (turban tumor)

Large, confluent tumors in this patient with Brooke-Spiegler syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 98402 Version 3.0

Contributor Disclosures

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Jeffrey P North, MDNothing to discloseTimothy H McCalmont, MDNothing to discloseBeth S Ruben, MDNothing to discloseJune K Robinson, MDNothing to discloseRosamaria Corona, MD, DScNothing to disclose Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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Microcystic adnexal carcinoma - UpToDate uptodate.com/contents/microcystic-adnexal-carcinoma/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Oct 31, 2018.

INTRODUCTION

Microcystic adnexal carcinoma (MAC) is an infiltrative

cutaneous tumor that most often presents as a scar-like papule or plaque on sun-exposed skin [1]. Historical terms that have been used to refer to this tumor include sclerosing sweat duct carcinoma, malignant syringoma, and syringoid carcinoma. Tissue invasion by MAC frequently extends far beyond the clinical margins of the tumor. In addition, perineural involvement is common. Although metastasis and death from MAC are rare events, significant morbidity can occur as a result of deep local tissue invasion, and treatment of MAC is recommended. Surgery that results in complete removal of the tumor is the treatment of choice for MAC. The epidemiology, diagnosis, and management of MAC will be discussed in this topic review.

EPIDEMIOLOGY

Microcystic adnexal carcinoma (MAC) is a rare tumor

that was first described in 1982 [2]. In retrospect, earlier reports documented this tumor prior to its recognition as a distinct entity [3].

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The vast majority of reported cases of MAC have been in white individuals; however, MAC can also occur in other populations [4-9]. An analysis of data from the Surveillance, Epidemiology, and End Results (SEER) database collected between 1973 and 2004 found an incidence rate of 6.5 per 10 million white individuals [10]. The incidence rates for black subjects and Asian/Pacific Islanders were significantly lower, at 1.9 and 1.6 per 10 million individuals, respectively. The sex distribution in studies of patients with MAC has varied from fairly equivalent proportions to a slight female predominance [7,9-12]. In the SEER database analysis, which represents the largest reported series of patients with MAC (n = 223), 57 percent of patients were female and 43 percent were male [10]. MAC most commonly affects middle-aged and older adults [7,10]. The median age for the development of MAC in the SEER database analysis was 68 years [10]. Rarely, the tumor occurs in children [13,14]. Congenital MAC has been described in a few neonates [15,16].

RISK FACTORS

The rarity of microcystic adnexal carcinoma (MAC) makes

it difficult to draw definitive conclusions on risk factors for the disease. Ultraviolet radiation, ionizing radiation, and immunosuppression have been proposed as potential contributory factors: ●Ultraviolet radiation – The common localization of tumors to the head and neck and the elevated frequency in white individuals suggest that exposure to ultraviolet radiation may contribute to the development of MAC [10]. Also in support of a role for ultraviolet radiation, a series of 48 patients with MAC in the United States (where drivers sit in the left side of the vehicle) found a predominance of left-sided lesions (52 percent on left, 25 percent on right, and 23 percent in midline or unspecified) [11], whereas a series of 14 patients in Australia (where drivers sit in the right side of the vehicle) found that more lesions occurred on the right side (56 versus 38 percent) [17]. However, ultraviolet light-induced p53 mutations, which have been associated with the development of other cutaneous carcinomas, lack a strong association with MAC [18]. ●Ionizing radiation – The development of tumors in sites of previous radiation therapy has been reported in multiple patients [7,19-24]. These case reports raise the question of whether ionizing radiation increases risk for MAC. ●Immunosuppression – Although immunosuppression increases risk for cutaneous squamous cell carcinoma and basal cell carcinoma, the effect of immunosuppression on the risk for development of MAC is unclear (see "Epidemiology and risk factors for skin cancer in solid organ transplant recipients"). Aggressive tumor behavior has been reported in a few immunosuppressed patients [25,26]. ●Other – MAC has appeared to arise within a nevus sebaceous in at least three patients [27-29] and in association with multiple benign syringomas in at least two patients [30]. (See "Nevus sebaceus and nevus sebaceus syndrome".)

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HISTOGENESIS

Histologic studies strongly suggest that microcystic

adnexal carcinoma (MAC) derives from pluripotent cells that exhibit differentiation towards both eccrine structures and hair follicles [2,31-35]. Immunohistochemical stains that demonstrate hard keratins in the superficial cystic component of MAC support the presence of follicular differentiation [31,32,36], and the often positive stains for carcinoembryonic antigen in MAC tumors indicate the presence of eccrine differentiation (table 1) [28,32,34,37]. Of note, sebaceous differentiation has also been detected in at least two cases of MAC, a finding that lends additional support to the status of pluripotent cells as the cells of tumor origin [38]. Few data are available on the cytogenetic analysis of MAC [39,40]. One study found a clonal chromosome 6q deletion similar to that seen in salivary tumors, suggesting a histogenetic relationship between these tumors [39].

CLINICAL FEATURES

Microcystic adnexal carcinoma (MAC)

most frequently manifests as a fairly unremarkable, white or yellowish papule or plaque with or without overlying telangiectasias (picture 1A-D). Individuals with dark skin may present with only an ill-defined papule or nodule that lacks surface or pigmentary changes. The tumor margins are often indistinct, a feature consistent with the common discrepancy between the clinical size of the tumor and the more extensive tumor invasion regularly detected on histologic examination. MAC usually presents as a solitary tumor. However, multiple primary tumors have occurred in at least one patient [4]. Tumor development is usually characterized by slow, gradual growth; periods of stability and more rapid growth may be observed [41]. Early tumors are often only slightly elevated; a more nodular quality tends to develop over time. Tumors that seem fixed to underlying tissues may have invaded underlying structures, such as muscle, cartilage, and bone. Ulceration and necrosis are rare findings. The vast majority of tumors occur on the head and neck, many of which can be found on the central face [41]. In an analysis of Surveillance, Epidemiology, and End Results (SEER) data on 223 patients with MAC, tumors were located on the head and neck in 74 percent of patients [10]. However, tumors may develop in any cutaneous site. Examples of additional reported sites of MAC include the trunk and extremities, breast, vulva, auditory canal, axilla, perineum, hands, feet, and scalp [4,5,7,9,36,4244]. Rarely, MAC develops in extracutaneous locations. MAC involving the tongue, oral cavity, or maxillary sinus has been documented in a few patients [10,45]. Most patients with MAC do not experience associated symptoms. Occasionally, symptoms related to perineural invasion, such as burning, pain, hyperesthesia, or paraesthesias, are present [46].

DIAGNOSIS

The assessment of skin biopsy findings is usually sufficient for the

diagnosis of microcystic adnexal carcinoma (MAC). The use of dermoscopy may also provide clues to diagnosis, particularly the absence of scar-like, white, structureless areas [47]. Confocal

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microscopy and optical coherence tomography have been used in single case reports to assist in the clinical diagnosis [48,49]. Despite the relative ease of skin biopsy procedures, the undramatic clinical appearance and insidious growth of MAC can lead to a delay in biopsy and diagnosis for several years [19,28,46].

Biopsy — Superficial shave biopsies are not recommended for the diagnosis of MAC, since the recognition of the architecture of this deeply infiltrative tumor and the detection of perineural invasion are useful for diagnosis. The depth of the biopsy should extend into the deep dermis and subcutis. Thus, punch biopsies, incisional or excisional biopsies, or deep (saucerization) shave biopsies are preferred. (See "Skin biopsy techniques", section on 'Biopsy techniques'.) The use of fine-needle aspiration for the diagnosis of MAC has been reported [50]. However, in such cases, a subsequent, larger tissue specimen is necessary to confirm the diagnosis.

Pathology — The pathology findings of MAC consist of a deeply infiltrative tumor composed of small nests and cords of bland-appearing cells. The common histologic features of MAC are listed below [51]: ●Small, keratin-filled cysts in the upper dermis (picture 2). ●Nests and cords of epithelial cells within a hyalinized stroma that seem to form ductal structures; these structures decrease in size at greater depths (picture 3A-B). ●Little, if any, cytologic atypia and few mitoses. ●Perineural invasion (picture 4). ●Deep infiltration within the dermis (infiltration into the subcutaneous tissue, muscle, or deeper structures may also be present) (picture 5). When MAC encounters bone or cartilage, the tumor may grow laterally along the periosteal or perichondrial plane or may directly invade these structures [46]. Although not typically seen, amyloid deposition [35] and an inflammatory infiltrate with eosinophils [31,52] have been detected in specimens of MAC. Findings of necrosis and ulceration are uncommon.

Histologic differential diagnosis — Several other cutaneous tumors share pathologic features with MAC. Careful assessment of the histologic features is essential for obtaining the correct diagnosis (table 2) [11,31,53]. The histologic differential diagnosis for MAC primarily consists of benign or malignant cutaneous tumors. The recognition of ductal features in MAC distinguishes it from desmoplastic trichoepithelioma and trichoadenoma [54], which are adnexal tumors of follicular origin. The asymmetrical architecture, single-cell strands, and the perineural and deep invasion of MAC

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differentiate MAC from syringoma, a benign eccrine tumor [54]. Other disorders to consider in the histologic differential diagnosis include morpheaform basal cell carcinoma, desmoplastic squamous cell carcinoma, and metastatic breast carcinoma.

Immunohistochemistry — Tests beyond routine hematoxylin and eosin staining of pathology specimens are not typically needed for the diagnosis of MAC [41]. However, immunohistochemical studies are occasionally utilized to support the diagnosis and rule out other disorders when the diagnosis is uncertain [18,32,55-60]. In particular, the carcinoembryonic antigen stain, which is positive in half of specimens from MAC, is useful for distinguishing MAC from basal cell carcinoma and squamous cell carcinoma (picture 6) [41]. The addition of androgen receptor stain will help distinguish MAC from infiltrating basal cell carcinoma and desmoplastic trichoepithelioma [61]. The immunohistochemical characteristics of MAC and several disorders that may be mistaken for MAC are provided in a table (table 1).

DIFFERENTIAL DIAGNOSIS

The indurated papules,

plaques, or nodules of microcystic adnexal carcinoma (MAC) may clinically resemble scars, morpheaform basal cell carcinoma (picture 7), squamous cell carcinoma, syringomas (picture 8), and cysts (table 3). Histopathologic examination distinguishes MAC from these disorders. (See 'Pathology' above and 'Histologic differential diagnosis' above.)

EVALUATION AND STAGING

Patients diagnosed

with microcystic adnexal carcinoma (MAC) should receive a full skin examination that includes careful inspection of the tumor site to assess the clinical extent of the tumor. While nodal spread is rare, palpation of the regional lymph nodes should also be performed to assess for enlarged lymph nodes that may indicate regional metastasis. If enlarged lymph nodes are detected, lymph node biopsy via fine-needle aspiration or surgical removal of the enlarged lymph node is indicated [62]. Radiologic studies are not necessary in most patients diagnosed with MAC. However, if the physical examination suggests that the tumor may be fixed to underlying structures or there is a large tumor (eg, ≥2 cm) in the periorbital area, computerized tomography (CT) or magnetic resonance imaging (MRI) is useful for evaluating for invasion of bone, other deep structures, or the orbit [51,63-66]. Radiologic imaging of other body sites is not indicated in the absence of signs or symptoms suggestive of distant disease. The staging of MAC correlates with the staging system for cutaneous squamous cell carcinoma outlined by the American Joint Committee on Cancer Staging (table 4) [67].

TREATMENT

Surgery is the primary treatment modality utilized for the

management of microcystic adnexal carcinoma (MAC). Radiation therapy has been employed in select cases; however, the indications for radiation therapy remain uncertain.

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Local disease Approach to treatment — Surgery that results in complete removal of the tumor is the treatment of choice for locally invasive MAC [10]. The surgical techniques most commonly utilized for MAC include Mohs micrographic surgery (MMS), a procedure that involves histologic assessment of the complete tissue margin, and conventional surgical excision with postoperative margin assessment. (See "Mohs surgery".) We suggest Mohs surgery, rather than conventional surgical excision with postoperative margin assessment, for the treatment of MAC [1,48,68]. This is because the infiltrative quality and often extensive subclinical extension of this tumor can make complete removal by other surgical procedures challenging [11,12]. No high-quality trials have evaluated Mohs surgery or conventional surgical excision for the treatment of MAC, and the relative efficacy of these procedures for improving patient outcomes remains uncertain. A systematic review of small case series and single case reports suggests that tumors treated with Mohs surgery are less likely to have positive margin and recur compared with those treated with wide local excision [69]. A 10-year review of periocular tumors highlights the high incidence of perineural tumor, concluding that MMS is the treatment of choice in this location [70]. Mohs surgery may result in defect sizes that may be up to six times larger than the size of the clinically apparent tumor, due to the subclinical extent of the tumor [12]. When Mohs surgery is not an option (eg, tumor size or patient comorbidities prohibit treatment in an outpatient setting, or the procedure is unavailable), conventional surgical excision with postoperative pathologic margin assessment can be utilized for treatment. Intraoperative frozen sections are useful for guiding the extent of excision in these cases.

Mohs surgery — Mohs surgery is an outpatient procedure that allows for intraoperative assessment of 100 percent of the excised tumor margin. This enables the surgeon to confirm complete removal of the tumor on the day of surgery prior to wound closure and allows for the sparing of the maximum amount of healthy tissue. (See "Mohs surgery", section on 'Surgical technique' and "Mohs surgery", section on 'Advantages'.) In comparison with conventional surgical excision, Mohs surgery may reduce the need for subsequent surgical procedures. A retrospective study of 48 patients with MAC found that 7 of 23 patients (30 percent) treated with conventional surgical excision did not achieve clear margins after the procedure and had to return for additional surgery. In contrast, clear margins were achieved within a single treatment session in all 22 patients who were treated with Mohs surgery [11]. In another retrospective study of 67 patients treated with Mohs surgery, the mean number of stages was two for primary MAC and increased to four for recurrent tumors [68].

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MAC has recurred after Mohs surgery, a finding that reflects the difficulty in achieving complete removal of the tumor [54]. A prospective study found that MAC recurred in 1 of 20 patients who were followed for at least five years after Mohs surgery for primary or recurrent tumors [53]. Retrospective studies with more than 10 patients have found recurrence rates after Mohs surgery between 0 and 12 percent [11,12,25,53,68,71]. Disadvantages of Mohs surgery include its status as a potentially lengthy procedure and as a specialized surgical technique that is not available in all clinical settings. (See "Mohs surgery", section on 'Advantages and disadvantages'.) Several authors have suggested alterations to the standard Mohs surgery procedure in attempts to improve surgical outcomes. One example is the use of a toluidine blue stain, which may facilitate the identification of isolated tumor nests and perineural invasion [72]. In addition, because the histologic detection of small islands or strands of tumor cells may be easier in permanent sections than in the frozen sections typically utilized in Mohs surgery, techniques utilizing permanent sections have been proposed as methods that may reduce the risk for treatment failure. These include the obtainment of an additional layer of tissue for permanent sections after apparent tumor clearance via Mohs surgery and the performance of a staged Mohs surgery-like procedure utilizing permanent rather than frozen sections ("slow Mohs") [46,73,74]. The effects of these procedures on patient outcomes have not been evaluated in formal studies.

Conventional surgical excision — Conventional surgical excision has been successfully used for the treatment of MAC. A major challenge with conventional surgical excision is the often extensive subclinical extension of MAC, a feature that makes it difficult to identify the true clinical margin that is likely to result in complete removal of the tumor. Surgical margins are determined on an individual basis, with reported margins ranging from a few millimeters to 5 cm [41]. Re-excision is performed if postoperative histologic examination reveals that a tumor is not completely removed [11]. Although the impact of the addition of intraoperative frozen sections to traditional surgical excision in MAC has not been specifically studied, our experience suggests that this intervention may help surgeons to more closely approximate the amount of tissue removal necessary for complete tumor excision during surgery. Frozen sections may be particularly useful in sites on the head and neck where tissue sparing is a significant concern. We suggest the use of intraoperative frozen sections to guide the extent of excision when feasible. Another challenge of conventional surgical excision is the fact that less than 1 percent of the tissue margin is typically evaluated during histologic examination of the excised tissue. Due to the infiltrative and often asymmetric architecture of MAC, this could lead to a failure to detect residual tumor. Data are limited on the frequency with which tumor recurrence develops following conventional surgical excision. The likelihood of recurrence was high in a retrospective study in which 15 patients were followed for 3 to 25 years; tumors recurred in seven patients (47 percent) [75].

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Radiation therapy — The role radiation therapy should play in the treatment of MAC is uncertain. Case reports suggest that radiation therapy alone is capable of achieving clinical clearance of tumors [76,77]; however, tumors may recur [76,78] or fail to respond to therapy [45]. Of note, the recurrence of MAC in a histologically more aggressive form after radiation therapy has been reported in one patient [79]. This finding has not been documented elsewhere. The use of radiation therapy as an adjuvant to surgical intervention was evaluated in a retrospective study of 14 patients with MAC (11 of whom had positive surgical margins) who were followed for a median of five years [17]. In the study, 13 of 14 patients achieved local control, prompting the authors to suggest that conventional surgical excision plus radiation therapy could yield success rates similar to those observed with Mohs surgery. Data are insufficient to support a routine recommendation for the use of radiation therapy in patients with MAC. Complete surgical excision remains our treatment of choice for MAC; we reserve radiation therapy for the infrequent cases in which complete surgical removal is not possible and for adjuvant treatment following the complete excision of recurrent tumors in critical locations, such as the periorbital area. Additional studies are necessary to determine the efficacy, safety, indications, and optimal treatment regimen.

Metastatic disease — Locoregional or distant metastasis of MAC is a rare event, and standards for the approach to such patients are lacking. Data on the management of metastatic disease are limited to case reports. A patient with a 4 cm tumor in the axilla, for whom excision of the tumor and axillary lymph nodes revealed two positive lymph nodes, exhibited no signs of tumor recurrence for 31 months after surgery [44]. A separate patient with MAC on the scalp and biopsy-confirmed cervical lymph node involvement who was treated with a modified radical neck dissection and radiation therapy had no signs of recurrence at one year [62]. Other case reports document failures to respond to treatments directed at metastatic disease. An immunocompromised patient with intransit metastases failed to achieve a lasting response with radiation therapy [26]. In addition, a single course of cisplatinum and 5-fluororuracil resulted in no improvement or minimal improvement in two patients with MAC and distant metastases [63,78].

PROGNOSIS

Microcystic adnexal carcinoma (MAC) is primarily a locally

aggressive tumor. Metastasis to the lymph nodes or other sites is uncommon. As of 2011, fewer than 10 cases of regional lymph node or distant metastasis had been reported in the literature [76]. The rarity of metastasis is supported by Surveillance, Epidemiology, and End Results (SEER) data; among 223 patients with MAC, regional lymph node involvement was present in three patients (1 percent), and distant metastases occurred in one patient [10]. Deep local invasion occurred more frequently; extension into the subcutaneous tissue was noted in 7 percent of patients, and invasion of the underlying soft tissue, muscle, or bone was documented in 9 percent of patients.

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Tumor recurrence is the major prognostic concern in MAC (picture 9). The time to tumor recurrence varies widely. Most cases recur within two to three years [41]. However, recurrence up to 29 years after surgery has been reported [7]. Risk factors for tumor recurrence have not been definitively established. In one series of 67 patients with MAC, the risk of recurrence increased by 11 percent for every 1 cm2 increase in tumor size, and tumors >5 cm2 had a 13-fold higher recurrence rate [68]. Some authors propose that tumors that demonstrate perineural invasion may be more likely to recur after Mohs surgery [74]. This may be due to tumor "skip" areas along involved nerves that lead to failures to detect residual perineural tumor. There are multiple reports of MAC extending into the orbit, leading to tumor invasion into the brain through the optic nerve or the nerves superior to the orbit [51,65,74,78,80].This suggests that this location is associated with increased risk for morbidity and that treatment should be followed with close long-term monitoring. A few cases of death related to local tumor extension into vital areas (eg, intracranial invasion) have been reported [64,74,81]. Only one death directly attributable to metastatic MAC has been documented [81].

FOLLOW-UP

Guidelines for the follow-up of patients with microcystic adnexal

carcinoma (MAC) have not been established. The potential for delayed recurrence after years indicates that long-term follow-up is necessary. We typically follow patients every 6 to 12 months and perform a full skin examination and lymph node palpation at each visit. Patients with histories of tumors that invade into deep, vital, or conduit structures (such as the orbit) likely need to be followed more closely. The optimal frequency of follow-up of these patients depends on the individual clinical scenario. We usually perform radiologic imaging only if signs or symptoms suggestive of extracutaneous involvement are present. Occasionally radiologic studies (computed tomography [CT] or magnetic resonance imaging [MRI]) are used to follow patients with deeply invasive tumors in which physical examination is not adequate for assessing signs of tumor recurrence.

SUMMARY AND RECOMMENDATIONS ●Microcystic adnexal carcinoma (MAC) is a rare, infiltrative cutaneous tumor that is often found on the head and neck. White, middle-aged and older adults are most commonly affected. (See 'Epidemiology' above.) ●The risk factors for MAC are poorly defined. Exposure to ultraviolet radiation may play a role in the development of some tumors. (See 'Risk factors' above.)

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●MAC most commonly presents as a nonulcerated, white or yellow papule, plaque, or nodule on the skin. The head and neck are frequent sites for involvement. Tumors usually grow slowly over the course of years. (See 'Clinical features' above.) ●The diagnosis of MAC is based upon the detection of consistent pathologic findings. Characteristic features include small, keratin-filled cysts; nest and cords of cells that resemble ductal structures; and an infiltrative growth pattern. Perineural invasion is common. Immunohistochemical studies are occasionally used to distinguish MAC from other disorders (table 1). (See 'Diagnosis' above.) ●The evaluation of the patient with MAC should include a complete skin examination with careful attention to the tumor site and lymph node palpation. Most patients do not require radiologic studies. (See 'Evaluation and staging' above.) ●For patients with MAC, we suggest treatment with Mohs surgery (Grade 2C). If Mohs surgery cannot be performed, patients may be treated with conventional surgical excision with pathologic margin assessment. Intraoperative frozen sections are useful for guiding the extent of conventional surgical excision. ●Data are limited on the efficacy of radiation therapy for the treatment of MAC. We typically reserve radiation therapy for tumors for which complete excision is not possible and for use as an adjuvant to complete excision of recurrent tumors in critical locations (eg, periorbital area). The optimal treatment regimen for radiation therapy has not been determined. Further study is necessary prior to a recommendation for the routine use of this modality. (See 'Radiation therapy' above.) ●Recurrence of MAC may occur after many years. Patients should be routinely followed for signs of disease recurrence. (See 'Prognosis' above and 'Follow-up' above.)

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Epidemiology and risk factors for cutaneous squamous cell carcinoma uptodate.com/contents/epidemiology-and-risk-factors-for-cutaneous-squamous-cell-carcinoma/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Mar 30, 2020.

INTRODUCTION

Cutaneous squamous cell carcinoma (cSCC) is a

common cancer arising from malignant proliferation of epidermal keratinocytes [1]. The likelihood of developing cSCC is dependent upon exposure to risk factors (most importantly ultraviolet light) and patient-specific characteristics, such as age, skin type, and ethnicity. The epidemiology and risk factors of cSCC will be reviewed here. The clinical features, diagnosis, treatment, and prognosis of cSCC are discussed elsewhere. Skin cancer in solid organ transplant recipients is discussed separately. ●(See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".) ●(See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".) ●(See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma".) ●(See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients".) ●(See "Prevention and management of skin cancer in solid organ transplant recipients".)

EPIDEMIOLOGY Incidence — Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer in the United States, behind basal cell carcinoma (BCC), and accounts for approximately 20 to 50 percent of nonmelanoma skin cancers [2-6]. Because cSCCs are not typically reported to cancer registries, the exact incidence of this malignancy is unknown. Moreover, as epidemiologic studies often combine data on cSCC, BCC, and other nonmelanocytic skin tumors, incidence estimates are widely variable [3,7,8]. In an analysis of data from cancer registries in Australia (2011 to 2014) and Germany (2007 to 2015) and from medical claim data in the United States (2013 to 2015), the incidence of cSCC per 100,000 persons per year in men and women were 341 and 209, 54 and 26, and 497 and 296, respectively, for the three countries [9].

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The incidence of cSCC has increased over the past 20 years in the United States and other countries. In the United Kingdom, the age-standardized incidence of primary cSCC in the period 2013 to 2015 was 77 per 100,000, with a mean annual percentage increase of 5 percent [10]. This increase may be related to higher levels of sun exposure, tanning bed use, an increase in the aging population [11], and improved skin cancer detection [12,13]. Epidemiologic factors such as geographic location, skin pigmentation, and ancestry also appear to influence the risk for cSCC.

Geographic variation — The age-adjusted annual incidence of cSCC in the United States varies according to latitude. For example, the incidence of cSCC is higher in Arizona than in New Hampshire (270 versus 97 per 100,000 in men and 110 versus 32 per 100,000 in women) [14-17]. A similar pattern of geographic variability exists globally with a higher incidence of cSCC closer to the equator. In Australia, for example, there are approximately 1035 and 472 cases per 100,000 for men and women, respectively [18]. In contrast, the age-adjusted incidences for men and women in Finland are only about 6 and 4 per 100,000 [19].

Age — The incidence of cSCC increases dramatically with age. It is infrequent in those under 45 years of age, although the incidence of cSCC is increasing significantly in young individuals [20]. For those over 75, the incidence is approximately 5 to 10 times higher than the incidence in younger age groups and 50 to 300 times higher than for those under 45 [14,15].

Skin pigmentation and ancestry — Individuals with darker skin types have low reported rates of cSCC, whereas non-Hispanic white populations have the highest reported rates [21-23]. While the incidence of cSCC in non-Hispanic white women and men in the United States has been estimated to be as high as 150 and 360 per 100,000 individuals, respectively, the incidence in black individuals is estimated to be 3 per 100,000 [24]. In individuals with highly pigmented skin, cSCC tends to arise on non-sun-exposed areas and is frequently associated with chronic inflammation, chronic wounds, or scarring. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis", section on 'Location'.)

RISK FACTORS

Environmental and genetic factors and

immunosuppression contribute to the development of cutaneous squamous cell carcinoma (cSCC) [1]. Among light-skinned individuals, the most important risk factors are cumulative sun (ultraviolet [UV] light) exposure and age. Furthermore, sun exposure increases the likelihood of cSCC in the presence of other risk factors (see below).

Ultraviolet light exposure — UV radiation is absorbed by DNA and can result in DNA damage. If the damage is not repaired, a series of changes can result in malignant transformation. In particular, the p53 tumor suppressor gene often has point mutations specifically

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associated with damage caused by ultraviolet B (UVB) radiation [25]. An estimated 45 to 60 percent of cSCCs have p53 mutations [26,27].

Ultraviolet B radiation — Epidemiologic studies indicate that cumulative sun exposure (principally UVB radiation) is the most important environmental cause of cSCC. In contrast, intense intermittent sun exposure (eg, sunburn, childhood exposure) is the most important risk factor for basal cell carcinoma (BCC) and melanoma [21,28-30]. (See "Risk factors for the development of melanoma", section on 'Ultraviolet radiation' and "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma", section on 'Risk factors'.) High occupational sun exposure is a major risk factor for cSCC [31-34]. In a case-control study including 632 patients with a first diagnosis of invasive or in situ cSCC in the previous two years and 632 sex- and age-matched controls without a history of cSCC, patients with high occupational UV exposure (≥90th percentile) had a nearly twofold increased risk for cSCC compared with participants with no or low (3cm) may be treated with photodynamic therapy, if available, or topical fluorouracil. (See 'Bowen's disease (squamous cell carcinoma in situ)' above.)

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●Careful follow-up is required to evaluate for evidence of local recurrence, regional or distant metastasis, and treatment-related complications. We generally reassess patients every three to six months for two years and then annually after the initial diagnosis and treatment of SCC. (See 'Follow-up' above.)

ACKNOWLEDGMENT

We are saddened by the death of Timothy

K Chartier, MD, who passed away in May 2017. UpToDate wishes to acknowledge Dr. Chartier's past work as an author for this topic.

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Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma uptodate.com/contents/recognition-and-management-of-high-risk-aggressive-cutaneous-squamous-cellcarcinoma/print

Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Sep 20, 2019.

INTRODUCTION

Cutaneous squamous cell carcinoma (cSCC) is a

relatively common malignancy derived from epidermal keratinocytes. Although most patients with cSCC present with localized disease that is cured with local treatment, tumor recurrence, metastasis, and death related to this disease occasionally occur. "High-risk" cSCCs are tumors that exhibit clinical or histologic features that have been associated with increased risk for aggressive tumor behavior. The best approach to the management of high-risk cSCC is not definitively known. Mohs micrographic surgery, surgical excision with complete circumferential and peripheral margin assessment (CCPDMA), radiation therapy, and cemiplimab are used in the management of these lesions. The clinical and pathologic features of high-risk cSCC and the management of patients with these tumors will be reviewed here. The risk factors and diagnosis of cSCC, the treatment of low-risk cSCC, and systemic therapy for advanced cSCC are reviewed separately. ●(See "Epidemiology and risk factors for cutaneous squamous cell carcinoma".) ●(See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".) ●(See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".) ●(See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma".) ●(See "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas".)

BACKGROUND

Cutaneous squamous cell carcinoma (cSCC) is the second

most common human cancer, with more than one million tumors undergoing treatment in Medicare patients alone in the United States [1]. It may occur in individuals of all races and ethnicities but most frequently occurs in people with light skin who sunburn easily. Highly curable, localized cSCC occurs most frequently; locoregional or distant metastases develop in 6 mm or beyond the subcutaneous fat, poor differentiation, perineural invasion (PNI), location on the ear, and immunosuppression [2,12-14]. These may be the most significant drivers of poor outcomes in SCC. However, all major characteristics that have been associated with aggressive tumor behavior are reviewed below (table 1).

Clinical features — Clinical findings that have been used to identify high-risk cSCC include tumor location, tumor size, tumor status as primary or recurrent, and the presence of neurologic symptoms.

Anatomic location — Certain tumor locations have been linked to increased risk for aggressive tumor behavior [5,6]. Local recurrence of cSCC is estimated to occur in 2 to 22 percent of lip tumors and 5 to 19 percent of ear tumors, and metastasis develops in 3 to 20 percent and 9 to 12 percent of these lesions, respectively [15]. The relatively thin nature of auricular skin and the low depth of invasion required for the tumor to invade the perichondrium (approximately 2 mm) may contribute to the increased risk for local recurrence observed with tumors on the ear. In addition, the proximity of the ear to the lymph nodes of the parotid gland and neck may be an important factor for

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metastasis. A retrospective cohort study of 353 patients with cSCC of the ear found that 10.5 percent developed nodal metastasis, and the five-year, disease-specific survival in patients with nodal metastasis was significantly lower as compared with those without nodal metastasis (59 versus 99 percent) [16]. Tumors on the cheek also may portend an increased risk for metastasis compared with tumors in some other sites; a retrospective study of approximately 9000 cases of primary cSCC found that tumors on the auricular area, lip, and cheek were more likely to metastasize than tumors on the lower leg [6,17]. While anatomic location of the lip or ear was included initially in cSCC staging systems, with improved data and refinement of these systems it is no longer considered a factor that warrants upstaging of a tumor.

Tumor diameter — Data from multiple studies suggest that tumors 2 cm or larger in diameter are more likely to behave aggressively than smaller tumors [4-6,18-23]. A 1992 review found local recurrence rates for tumors ≥2 cm and 2 mm and a Clark level of IV or higher were classified as high-risk features based on AJCC 7. In 2017, AJCC released the 8th edition, which included a staging system of cSCC for head and neck tumors only (table 2B). The AJCC 8th edition defines "deep invasion" as invasion beyond the subcutaneous fat or >6 mm (as measured from the granular layer of adjacent normal epidermis to the base of the tumor) [24]. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma", section on 'Primary tumor (T)'.) The importance of tumor thickness was demonstrated by a 2016 meta-analysis of 36 observational studies including over 17,000 patents with cSCC [40]. This study found that Breslow tumor thickness >2 mm, invasion beyond subcutaneous fat, and thickness >6 mm were associated with a high risk of recurrence (odds ratio [OR] 9.64, 95% CI 1.30-71.52; OR 7.61, 95% CI 4.17-13.88; and OR 7.13, 95% CI 3.04-16.72, respectively) and metastasis (OR 10.76, 95% CI 2.55-45.31; OR 11.21, 95% CI 3.59-34.97; and OR 6.93, 95% CI 4.02-11.94, respectively). Invasion beyond the subcutaneous fat was also associated with an increased risk of disease-specific death (OR 4.49, 95% CI 2.05-9.82)

Perineural invasion — Perineural invasion (PNI) is associated with an increased incidence of tumor recurrence, metastasis, and death [20,33,40-42]. The local recurrence rate for tumors that exhibit this feature is estimated to be 16 to 47 percent, and metastasis is estimated to occur in 10 to 50 percent of cases [15,33].   The caliber of the involved nerves in patients with PNI may provide additional prognostic information. Tumors with PNI of large nerves may portend a worse prognosis than tumors with smaller nerve involvement. The findings of a retrospective cohort study of 48 patients with cSCC and PNI (mean follow-up time = three years) support this concept; 8 of 25 patients (32 percent) with PNI involving nerves that were at least 0.1 mm in diameter died from cSCC versus 0 of 23 patients with

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PNI limited to smaller nerves [20]. Although a separate retrospective study that included 62 patients with cSCC and PNI who had the involved nerve diameter assessed failed to find a statistically significant impact of nerve diameter on prognosis, the study was limited to patients who were treated with both surgery and radiation, many of whom had positive surgical margins prior to radiation therapy [43]. Thus, patients in this study may have had an increased likelihood for poor prognosis compared with the general population of patients with PNI. Tumors with PNI often have other high-risk features that may impact prognosis. This was illustrated in a retrospective study of 114 cases of cSCC with PNI [33]. Although the study found worse prognoses in patients with cSCC with PNI of large nerves (≥0.1 mm diameter) than in patients with PNI of smaller nerves (50 percent in tumor cells) PD-L1 expression correlated with lymph node metastasis in a study of 46 cSCC patients [66]. In a study of cSCC on the head and neck, PD-L1 expression was a significant risk factor for nodal metastasis with a HR of 3.39 [67]. A retrospective analysis of 83 patients found that high-grade staining of tumor cells for PD-L1 was significantly associated with regional recurrence [68]. PD-L1 is a commercially available biomarker that may be especially useful in risk stratification and treatment planning in cSCC, with compelling evidence of an association with increased risk of nodal metastasis.

INPP5A — Inositol polyphosphate 5-phosphatase (INPP5A) appears to be a useful tumor marker in cSCC. In a study of 174 patients with actinic keratosis and cSCC, low expression of INPP5A was associated with a nearly fivefold higher risk of local metastasis and a nearly threefold higher risk of death [69].

p300 — The transcriptional coactivator p300 was found to be associated with advanced clinical stage and shown to be an independent prognostic factor of poor overall survival in a study of 165 cSCC tumors [70].

TERT promoter — A study of 152 cSCC lesions corroborated prior findings that patients with telomerase reverse transcriptase (TERT) gene promoter-mutated cSCC are at increased risk for local recurrence and lymph node metastases [71].

CD133 — The expression of cancer stem cell marker CD133 in cSCC samples from 165 patients was deemed to be an independent predictor of poor overall survival [72].  

Nuclear morphometry — A retrospective case series of 40 patients evaluated the utility of nuclear morphometry (karyometry) for differentiating between aggressive and nonaggressive SCCs [73]. Investigators found that karyometric classification scores correlated with tumor behavior; the score accurately categorized tumors in 80 percent of patients. Further studies are necessary to determine the role of such testing in the stratification and management of cSCC.

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Epidermal growth factor receptors — Although overexpression of the epidermal growth factor receptor (EGFR) has been associated with aggressive clinical behavior in head and neck cancer [74-76], the prognostic value of EGFR expression levels in lesions of cSCC is uncertain. Evidence in support of a relevant role of EGFR expression includes a retrospective study that found that primary cSCCs that subsequently metastasized were significantly more likely to overexpress EGFR than tumors that did not metastasize (11 of 14 versus 9 of 25 tumors) [77], as well as documentation of improvement of advanced or unresectable cSCC after treatment with cetuximab, an EGFR inhibitor [78,79] (see "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas", section on 'Treatment targeting the EGFR pathway'). However, a retrospective study of 56 patients with advanced cSCC on the head or neck found no association between EGFR overexpression and aggressive disease or patient survival [80].

STAGING

The regional lymph nodes are the most common initial site of metastasis

in cutaneous squamous cell carcinoma (cSCC) [4]. A beneficial role of early detection of metastatic disease on patient outcomes is supported by the observation that patients with locally limited, operable tumors or limited nodal involvement are more likely to be cured (five-year survival of 73 percent) than patients with extensive nodal disease (five-year survival of 26 to 34 percent) [2,5]. In a prospective cohort study of 1434 patients who underwent surgery for invasive cSCC, 40 patients died of SCC; of those, 28 died because of tumor growth by local infiltration in the head region or infiltration into regional lymph nodes and 12 from visceral metastases [37]. However, definitive guidelines for staging patients with high-risk cSCC have not been established. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".)

Staging systems — In 2017, the American Joint Committee on Cancer (AJCC) released an updated staging system for cSCC based upon expert review of the available evidence [24]. The system classifies cases by tumor burden (T), nodal involvement (N), and metastatic disease (M). A major change of the AJCC 8th edition compared with the former AJCC 7th edition [4] is that the cSCC staging system is limited to head and neck tumors since the system was developed within the AJCC's head and neck committee. Moreover, the AJCC 8th edition cSCC staging system expanded the criteria for upstaging to T3 and also included extranodal extension as a risk factor for upstaging of the N classification. A table that demonstrates the updated AJCC staging criteria for head and neck SCC is provided (table 2B). The Union for International Cancer Control, which is the AJCC's European counterpart, also updated its staging system in 2017, which parallels the AJCC staging system.   Further alterations to the staging system were proposed based upon studies suggesting that the AJCC 7 staging system may not optimally stratify the prognostic groups for cSCC [12,81-83]. As an example, a retrospective study of 1818 cSCC tumors found that less than 1 percent of the cohort (six tumors) met AJCC 7 stage T3 or T4 criteria owing to the rarity of bone invasion that is required for these stages, and most poor outcomes were clustered in stage T2 (72 percent local recurrence, 82 percent nodal metastases, and 67 percent of deaths from cSCC) [83]. The results of these studies were incorporated into AJCC 8 tumor classification with a marked expansion of criteria for T3. A

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study of 680 cutaneous head and neck SCC comparing AJCC 7 and AJCC 8 T classifications found that 17.8 percent of tumors were classified as AJCC 8 T3/T4, and this small subset accounted for 70.4 percent of the cohort's poor outcomes (local recurrence, metastasis, and death from SCC). In comparison, few tumors (0.7 percent) and poor outcomes (16.9 percent) were classified as AJCC 7 T3/T4. AJCC 8 therefore demonstrates an improved ability to stratify tumors with a significant risk of poor outcomes as compared with AJCC 7 [84]. The authors of this topic contributed to the development of an alternative T staging system (the Brigham and Women's Hospital [BWH] Tumor Staging for cSCC) with the aim of prognostically stratifying AJCC stage T2 (table 3) [12,83]. The BWH system has performed superiorly to AJCC 7 in its ability to stratify low-risk versus high-risk tumors [84]. Another clear advantage of BWH staging is that it can be applied to tumors across all body sites, whereas AJCC 8 can only be applied to tumors on the head and neck. The BWH system has also been compared with AJCC 8 in a cohort of 459 cases with 680 cSCC of the head and neck and found to be better able to identify patients at risk for metastasis [85]. In this study, there was a similar risk of metastasis in high T-classes (71 and 70 percent for AJCC 8 T3/T4 and BWH T2b/T3, respectively), with a similar risk of death from disease in both systems (85 and 92 percent, respectively). AJCC 7, AJCC 8, and BWH classification systems have been directly compared with one another in an external data set. In a nested case-control study, the BWH system appeared to perform slightly better than AJCC 8, with both of these systems performing significantly better than AJCC 7 as evidenced by concordance (C) statistics of 0.81 (95% CI 0.75-0.88), 0.75 (95% CI 0.68-0.82), and 0.63 (95% CI 0.58-0.68) for BWH, AJCC 8, and AJCC 7, respectively [86]. An accompanying editorial review suggested that all three systems were suboptimal and not ready for implementation in clinical practice given low C statistics [87]. However, the numbers for BWH and AJCC 8 are similar to C statistics reported in validation studies for other well-defined staging systems (0.78 for AJCC 8 lung cancer, 0.84 for AJCC 8 breast cancer) [88,89]. Incorporation of biomarkers into staging will further improve the accuracy of cSCC staging in the future. (See 'Biomarkers for risk stratification in cutaneous squamous cell carcinoma' above.) Likewise, a retrospective study of 603 patients found that stages N2a, N2c, and N3 of the AJCC staging system contained less than 10 percent of patients and that this division of stages lacked prognostic relevance [81]. This study also compared the AJCC nodal classification with an alternative three-stage system (N1S3) developed for head and neck cancer in 2010 (I, single nodal metastasis ≤3 cm; II, multiple nodes ≤3 cm or a single node >3 cm; and III, multiple nodes with ≥1 node >3 cm) [90]. Although the N1S3 and AJCC overall performances were similar, N1S3 resulted in a better risk stratification, with a linear increase in death hazard ratios across the three stages. Additional research on patient outcomes from cSCC will be useful for confirming which adjustments to the AJCC staging system are indicated.

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Tools for staging — Radiologic imaging is the diagnostic modality of choice for assessment for bone invasion (needed for T3 or T4a/T4b staging) and determination of nodal and distant metastatic involvement in patients with high-risk cSCC. Computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasound have been utilized for disease staging. In general, CT is most appropriate in the detection of bone invasion, cartilage invasion, and nodal necrosis, while MRI is best suited to evaluate for tumor extension into soft tissue and large nerves [91]. A retrospective cohort study of 108 high-stage cSCC found that patients who did not receive imaging had a higher risk of developing nodal metastasis (30 versus 13 percent) [92]. Additionally, imaging was independently associated with a reduced risk of disease-related outcomes (including local recurrence, nodal metastasis, and death from disease) after adjusting for tumor stage, sex, and anatomic location (subhazard ratio 0.5, 95% CI 0.2-0.9) [92]. The more favorable disease-related outcomes in radiology groups were attributed to earlier aggressive treatment. Clinically detectable enlarged lymph nodes can be evaluated via biopsy (ie, fine needle aspiration or core biopsy) or surgical excision. The evaluation for regional and distant metastases in patients with cSCC is discussed in detail separately. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".)

Sentinel lymph node biopsy — Sentinel lymph node (SLN) biopsy is a surgical procedure utilized to detect subclinical nodal metastases in melanoma and multiple other malignancies. However, as high-quality studies evaluating the use of SLN biopsy in high-risk cSCC are lacking and the impact of this procedure followed by completion lymph node dissection on patient survival is unclear, SLN biopsy is not routinely recommended [10,93-96]. In a 2018 systematic review of 23 observational studies including 566 patients with cSCC who underwent SLN biopsy, the pooled estimate of the prevalence of nodal metastasis was 7.9 percent (95% CI 5.2-10.6 percent) [94]. Most of the studies included patients classified as high risk, but the definition of this risk varied from one study to another. Among 361 patients for whom follow-up data were available, 32 (8.9 percent) had positive SLN biopsy, 22 experienced regional recurrence (9 SLNpositive and 13 SLN-negative), 11 developed distance metastasis (5 SLN-positive and 6 SLNnegative), and 12 died of SCC (4 SLN-positive and 8 SLN-negative). The false-negative rate was 3.9 percent. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma", section on 'Sentinel lymph node biopsy'.)

MANAGEMENT

Early and aggressive surgical excision is the primary

modality utilized for the management of patients with localized cutaneous squamous cell carcinoma (cSCC) with clinical and/or pathologic high-risk features. (See 'High-risk features' above.)

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Treatment modalities that do not provide opportunities to assess the tissue margins, such as cryosurgery, electrodesiccation and curettage, topical therapies, and photodynamic therapy, are not recommended. Radiation therapy is sometimes used as adjunctive therapy in an attempt to reduce the risk for disease recurrence. However, there is no high level of evidence to determine which patients will benefit from adjuvant radiation therapy (ART). Radiation therapy may also be employed as salvage or palliative therapy when complete surgical removal is not possible. Patients with locally advanced or metastatic disease that cannot be effectively managed with surgery and/or radiation are candidates for systemic chemotherapy or immune checkpoint inhibitor therapy [97]. (See "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas".) Patients with locally advanced or metastatic disease often benefit from management by a multidisciplinary team (eg, a dermatologic surgeon, otolaryngologist, surgical oncologist, radiation oncologist, and/or medical oncologist). Organ transplant recipients may also benefit from collaboration with transplant clinicians to assess for the need for modification of their immunosuppressive regimens.

Surgery — Surgical excision is the primary treatment modality utilized for the management of high-risk cSCC. Options include Mohs micrographic surgery (MMS), surgical excision with complete circumferential peripheral and deep margin assessment (CCPDMA) using permanent or frozen section analysis, and standard excision with wide margins. The National Comprehensive Cancer Network (NCCN) recommends CCPDMA (via MMS or en face sectioning) for high-risk SCCs since these procedures assess complete tumor removal via the examination of 100 percent of the tissue margin [10].  

Mohs surgery — MMS is performed under local anesthesia by a surgeon (usually a dermatologic surgeon) specifically trained in the technique. During the procedure, frozen sections encompassing 100 percent of the tissue margin are examined by the surgeon, allowing for confirmation of the removal of the tumor prior to wound closure. The MMS technique is discussed in greater detail separately. (See "Mohs surgery".) Although randomized trials comparing MMS with conventional surgical excision have not been performed, reports of high cure rates support the efficacy of MMS for cSCC: ●A 2013 systematic review of 10 observational studies that assessed outcomes from MMS in a total of 1572 patients with cSCC (not all high-risk, inconsistent definition of "high-risk" tumor across studies) found a pooled average local recurrence rate of 3 percent (95% CI 2.2-3.9 percent) after this procedure [98]. Similar average recurrence rates were found in seven studies with mean follow-up time of two to five years (2.8 percent, 95% CI 2.0-3.9 percent) and in two studies with mean follow-up >5 years (3.1 percent, 95% CI 1.4-5.4 percent). ●In a retrospective study in which 215 patients with 260 high-risk tumors (defined as a site on the ear or lip, or temple in elderly men; size greater than 2 cm; rapid growth larger than 1 cm; perineural involvement; or occurring in the setting of immunosuppression) were treated with MMS, the recurrence rate after almost four years was only 1 percent [99].

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●A case series that included 381 patients with primary (n = 229) or recurrent (n = 152) cSCC followed for five years after MMS found recurrence rates of 3 and 6 percent, respectively [100]. In this series, 96 percent of tumors were located on the head or neck (including 18 percent in the auricular region), 32 percent of tumors were ≥2 cm in size, and 13 percent of tumors were poorly differentiated [101].

Excision with complete margin assessment — Surgical excision with complete circumferential peripheral and deep margin assessment (CCPDMA) is an alternative to Mohs surgery. The procedure involves the examination of the entire margin of the tissue specimen by a pathologist. Histopathologic examination may be performed intraoperatively with frozen sections or with permanent sections and delayed wound closure. Surgical excision with CCPDMA is typically performed for advanced tumors that are best approached under general anesthesia due to large tumor size or great depth. CCPDMA is also useful when the continuous layers of tissue removed during Mohs surgery are not ideal, such as when surgical preservation of important deep anatomic structures (eg, major vessels or nerves) is required.

Standard excision — In accordance with the guidelines proposed by the NCCN, standard surgical excision is not the preferred method for surgical removal of high-risk SCCs [10]. However, if this method is used, the consensus-based guidelines of the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization for Research and Treatment of Cancer (EORTC) suggest a margin of 10 mm for highrisk tumors [102]. The NCCN guidelines do not specifically recommend a margin size for high-risk tumors removed with standard excision but state that it should be greater than 4 to 6 mm In addition, when performing standard excision, it is prudent to utilize a primary or delayed closure to allow for further excision with CCPDMA if margins are positive.

Extensive cases — The complete removal of the tumor can be challenging in patients with perineural invasion (PNI) involving large nerves or deep invasion into underlying tissues or bone. Aggressive surgical resections of named nerves and/or the skull base to achieve clear margins have been beneficial in some patients with head or neck tumors [103,104]. In cases characterized by deep or extensive local tumor involvement, MMS may be used as a preliminary step prior to deeper dissection to establish the peripheral margin and clarify the locations where deeper dissection is necessary [105]. This approach may minimize the time required for general anesthesia. Preoperative imaging to evaluate the extent of disease is also advised [106].

Radiation therapy

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General considerations — In high-risk cSCC, radiation therapy is not routinely utilized as monotherapy given the higher rate of local recurrence (15 to 20 percent or greater) compared with surgery with or without postoperative radiation therapy [107,108]. The use of radiation therapy as primary therapy is typically reserved for older patients not suitable for surgery because of comorbidities and for those who refuse surgery. The techniques, doses, and fractionation of radiation therapy for the primary treatment of cSCC are discussed elsewhere. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma", section on 'Radiation therapy'.) In high-risk cSCC, radiation therapy is most commonly combined with surgery. Patients may receive radiation to the sites of high-risk tumors as an adjuvant therapeutic measure aimed at reducing the likelihood for local recurrence following a surgical excision with clear margins [27]. Alternatively, radiation therapy may be used for control of symptoms (eg, bleeding, pain) or as a salvage therapy for patients with incompletely resected tumors [10].

Adjuvant radiation therapy — Data on the role of adjuvant radiation therapy (ART) for high-risk primary cSCC excised with clear surgical margins are limited, and there are no definitive recommendations on the indications for ART. ●A 2009 systematic review that identified 91 patients treated with surgery and ART and 2358 patients treated with surgery alone found high cure rates among cases in which documentation specified the attainment of clear margins but failed to find sufficient data to indicate which patients benefit from ART [109]. Differences in local recurrence and disease-specific death rates were not detected between the two groups. Moreover, among patients with PNI, statistically significant differences in patient outcomes were not detected. ●In a single-institution retrospective study, 32 patients with primary high-risk or recurrent cSCC (23 with perineural involvement) excised with clear margins underwent ART with a total of 2700 to 6000 Gy in 3 to 30 fractions [110]. Fifteen patients died, of whom 12 from causes unrelated to cSCC; three patients developed recurrent cSCC 0.9 to 2.6 years after completion of ART, and two of them died of cSCC-related causes. ●In a phase 3 randomized trial of ART with or without concurrent chemotherapy in patients with high-risk cSCC of the head and neck, high two- and five-year rates of freedom from locoregional relapse (88 and 83 percent, respectively) were achieved in the radiation therapy alone arm [111]. Guidelines from the NCCN and the American College of Radiology (ACR) recommend the use of ART for tumors that exhibit extensive perineural or large nerve involvement [10,112], and there is general agreement among clinicians that patients with PNI of large named nerves, lymph node involvement, massive local extension, uncertain surgical margins, or intracranial invasion are appropriate candidates for postsurgical ART [109,113].

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ART can be considered for one positive lymph node ≤3 cm with no extracapsular extension. This indication is based on the results of two retrospective studies where disease-free survival was improved in patients with a single involved lymph node (hazard ratio [HR] 2.2, 95% CI 1.05-4.9) and no extracapsular extension (HR 5.12, 95% CI 1.50-17.47) [114,115]. The NCCN recommends ART for two or more positive lymph nodes, one node >3 cm with no extracapsular extension, any node with extracapsular extension, or incompletely excised nodal disease [10]. We also consider the use of ART in patients with multiple high-risk features, PNI of unnamed nerves >0.1 mm in diameter, two or more nerves demonstrating PNI in the pathology specimen, multifocal tumor spread, presence of microsatellitosis, or multiple tumor recurrences [20,105].

Salvage radiation therapy — In general, patients who have clear surgical margins prior to ART have better outcomes than patients given radiation therapy following incomplete surgical clearance (salvage radiation therapy) [103,108,109]. Thus, complete surgical excision is the preferred initial therapy whenever feasible [103,109,116]. However, complete tumor resection is not always possible without introducing an unacceptable level of morbidity, such as some cases of widespread skull base invasion or advanced intracranial extension. In such cases, radiation therapy is administered in an attempt to destroy surgically inaccessible tumor remnants [10]. The efficacy of radiation therapy in this setting has not been prospectively evaluated. A dose of 60 to 66 Gy given in six to seven weeks is required for positive surgical margin [10].

Chemotherapy and chemoradiotherapy — Chemotherapeutic agents, such as cisplatin, topical fluorouracil (FU), capecitabine, methotrexate, cetuximab, bleomycin, and doxorubicin, have been utilized in patients with locally advanced cSCC that cannot be adequately managed with surgical excision or radiation therapy or metastatic cSCC. (See "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas", section on 'Squamous cell carcinoma'.) Cisplatin and carboplatin have been used as chemosensitizing agents in conjunction with radiation therapy for patients with SCC arising in noncutaneous sites. However, an additional benefit with these agents has not been demonstrated in patients with high-risk cSCC. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".) A phase 3 randomized trial compared ART versus adjuvant chemoradiotherapy in high-risk head and neck cSCC, defined as primary lesion >5 cm, involvement of muscle/cartilage/bone, the presence of in transit disease, or high-risk nodal disease (>3 cm in size, two or more involved nodes or extranodal spread) [111]. In this trial, 321 patients were randomized to postoperative radiation therapy (60 to 66 Gy in 30 to 33 fractions) or postoperative radiation therapy plus six cycles of weekly carboplatin. After a median follow-up of 60 months, no significant benefit with the addition of

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carboplatin was noted. The two- and five-year freedom from locoregional relapse rates were 88 and 83 percent, respectively, in the radiation therapy alone group and 89 and 87 percent, respectively, in the chemoradiation group. Severe late toxicities (grade 3 or 4) were infrequent [111].   The anti-programmed cell death 1 protein (PD-1) antibody cemiplimab is a US Food and Drug Administration (FDA)-approved systemic therapy for locally advanced and unresectable and metastatic cSCC cases. In a multicenter phase I/II study of cemiplimab, 41 out of 85 patients (48 percent, 95% CI 30-70) had a complete response (n = 4) or partial response (n = 37) to the medication [97]. A further 15 patients (18 percent) demonstrated stable disease during the follow-up period. While 100 percent of patients enrolled demonstrated some type of adverse effect, only 25 (42 percent) developed a grade 3 or higher toxicity, and four patients (7 percent) discontinued the medication due to the side effect. Other anti-PD-1 and PD-L1 antagonists, such as pembrolizumab, have also been utilized in cases of locally advanced or unresectable cSCC unresponsive to other treatments [117-119]. (See "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas", section on 'Checkpoint inhibitor immunotherapy (cemiplimab)'.)

Oral retinoids — Although oral retinoids may reduce the development of new primary cSCCs, they have not been shown to impact the recurrence of aggressive SCCs [120,121]. A sixmonth randomized trial in which patients were given a combination of oral 13-cis-retinoic acid (isotretinoin) 1 mg/kg per day and interferon alfa 3 million units three times per week or no adjuvant therapy failed to find a reduction in the risk for tumor recurrence in patients treated with this regimen [122]. Because of the lack of evidence to support the efficacy of oral retinoids for the prevention of tumor recurrence or metastasis in patients with high-risk cSCC, we cannot recommend the routine use of oral retinoids for this indication. However, patients with a history of SCCs are at risk for developing subsequent SCCs. Therefore, oral retinoids can be considered in patients with high-risk SCCs and in those who develop three to five SCCs annually. (See "Epidemiology and risk factors for cutaneous squamous cell carcinoma", section on 'Chemoprevention' and "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Chemoprevention for SCC'.)

Immunosuppressed patients — Immunosuppressed patients, such as solid organ transplant recipients and chronic lymphocytic leukemia (CLL) patients, are at high risk of developing multiple and aggressive cSCCs. The prevention and management of cSCC in organ transplant recipients is reviewed separately. (See "Prevention and management of skin cancer in solid organ transplant recipients".) In patients with CLL, particularly those with Rai stage III or IV, treatment of the underlying CLL should be considered for high-risk SCCs to improve the immune status of the patient and decrease the risk of recurrence.

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MANAGEMENT OF NODAL DISEASE

Aggressive surgical resection of the nodal basins is the primary treatment

modality for histologically confirmed lymph node involvement. The administration of adjuvant radiation therapy (ART) following resection has improved locoregional disease control in patients with involvement of parotid and cervical nodes [123]. In a prospective study of 87 patients with highrisk cutaneous squamous cell carcinoma (cSCC) metastatic to the parotid gland followed for a minimum of two years, multivariate analysis demonstrated that failure to have postoperative radiation was an independent predictor of reduced disease control in the parotid region [124]. In addition, a retrospective review of 167 immunocompetent patients with cSCC metastatic to the lymph nodes found a lower rate of recurrence in patients who received lymphadenectomy and ART compared with patients treated with lymphadenectomy alone (20 versus 43 percent) [114]. (See "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas".)

FOLLOW-UP

Approximately 70 to 80 percent of recurrences or metastases of

cutaneous squamous cell carcinoma (cSCC) occur within two years after therapy, and approximately 95 percent occur within five years [5]. Thus, close follow-up is indicated. Specific guidelines for frequency and duration of follow-up for patients with a history of high-risk cSCC have not been established. We agree with the general guidelines proposed by the National Comprehensive Cancer Network (NCCN) for patients with cSCC, which recommend performing a full skin examination and a regional lymph node examination according to the following schedule [10]: ●Patients with local disease – every three to six months for two years, then every 6 to 12 months for three years, then annually for life ●Patients with regional disease – every one to three months for one year, then every two to four months for one year, then every four to six months for three years, then every 6 to 12 months for life The optimal frequency of follow-up may vary from the above, based upon the clinician's assessment of the risk for recurrence. At follow-up appointments, patients should be questioned about symptoms of pain, focal weakness, and numbness in the region of the tumor, and patients with head and neck tumors should receive a basic cranial nerve examination. (See "The detailed neurologic examination in adults".) The presence of neurologic symptoms may be indicative of tumor recurrence involving the nerves. Some patients experience postsurgical sensory defects that may or may not slowly improve over time. Worsening signs or symptoms of neurologic dysfunction should raise concern for a recurrent tumor. Any palpable lymphadenopathy at follow-up warrants tissue evaluation via fine needle aspiration or excisional biopsy.

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Imaging surveillance — Clear guidelines regarding indications for baseline and follow-up imaging as surveillance for perineural and nodal metastases in the absence of clinical signs of advanced disease have not been defined. Additionally, recommendations for specific imaging modality vary widely and include ultrasound, computed tomography (CT) with contrast, positron emission tomography (PET) CT, and magnetic resonance imaging (MRI).  Some authors have recommended the routine use of ultrasonography for the detection of nonpalpable lymph node involvement, but the value of routinely performing this procedure requires further study [2]. A small study evaluated the utility of PET CT in detecting nodal metastases at the time of diagnosis in 30 lymph nodes from 26 patients with primary cSCC [125]. The definition of a standardized uptake value (SUV) max >2.5 as malignant on imaging yielded a sensitivity of 100 percent and specificity of 81 percent. A large study of over 1800 patients with primary cSCC reported that those with Brigham and Women's Hospital (BWH) Stage T2b/T3 disease accounted for 70 percent of nodal metastases and 83 percent of disease-specific death, revealing that this group is at especially high risk for poor outcomes [83]. Based on the results of this study, many providers agree that baseline CT with contrast and MRI is indicated for patients with BWH stage T2b/T3 and that surveillance imaging via biannual CT with contrast in this population is judicious [126].

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nonmelanoma skin cancer" and "Society guideline links: Mohs surgery".)

SUMMARY AND RECOMMENDATIONS ●Cutaneous squamous cell carcinoma (cSCC) is a relatively common form of skin cancer that is curable in a high percentage of patients. A small proportion of patients develop aggressive disease characterized by local recurrence or regional or distant metastases. (See 'Background' above.) ●Multiple clinical and pathologic features have been labeled as indicators of increased risk for aggressive tumor behavior. Tumor location, tumor size, tumor status as primary or recurrent, and associated symptoms should be assessed during the clinical evaluation. Pathologic features that portend an increased likelihood for aggressive tumor behavior include tumors that are not well differentiated, tumors with desmoplastic growth patterns, thick tumors, and tumors with perineural invasion (particularly with nerve invasion ≥0.1 mm diameter). (See 'Clinical features' above and 'Histologic features' above.)

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●The management of patients with high-risk cSCC begins with an assessment of the extent of disease based upon clinical, pathologic, and radiologic features (table 2B). As high-quality studies evaluating the use of sentinel lymph node (SLN) biopsy in the staging and management of high-risk cSCC are lacking and the impact of SLN biopsy followed by completion lymph node dissection on patient survival is unclear, SLN biopsy is not routinely performed in these patients. (See 'Staging' above and "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".) ●Surgical therapy is the primary treatment for patients with high-risk cSCC. For patients with surgically resectable tumors, we suggest treatment with Mohs micrographic surgery or surgical excision with complete circumferential peripheral and deep margin assessment rather than standard excision (Grade 2C). If standard excision is used, margins of 6 to 10 mm are considered acceptable in most cases. (See 'Surgery' above.) ●The indications for adjuvant radiation therapy (ART) following the attainment of clear surgical margins are unclear. We suggest the use of ART in patients with tumors that exhibit extensive perineural or large nerve involvement (Grade 2C). We also consider ART for patients with cSCC with multiple risk factors, particularly those with highly infiltrative growth and/or poor differentiation in which surgical margins are uncertain. (See 'Radiation therapy' above.) ●Cemiplimab, an anti-programmed cell death 1 protein (PD-1) antibody, has shown high efficacy in the treatment of locally advanced and metastatic SCC in a phase I/II trial. However, further studies are needed to confirm the role of cemiplimab and other checkpoint inhibitors in the management of SCC. (See "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas", section on 'Checkpoint inhibitor immunotherapy (cemiplimab)'.) ●Patients with aggressive cSCC require frequent clinical follow-up to evaluate for signs of disease recurrence and the development of new cSCCs. The frequency of follow-up is dependent upon the extent of disease. A full skin examination, palpation of regional lymph nodes, and evaluation for neurologic symptoms should be performed at every follow-up visit. (See 'Follow-up' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like

to acknowledge Chrysalyne D Schmults, MD, MSCE, who contributed to an earlier version of this topic review.

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Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma uptodate.com/contents/evaluation-for-locoregional-and-distant-metastases-in-cutaneous-squamous-cell-and-basalcell-carcinoma/print

Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 30, 2019.

INTRODUCTION

In the majority of patients with cutaneous squamous

cell carcinoma (SCC) or basal cell carcinoma (BCC), disease remains limited to the skin and is successfully managed with local therapy, such as excision, lesion destruction, or irradiation of the primary lesion. However, in 3 to 7 percent of patients with cutaneous SCC and in rare individuals with BCC, locoregional or distant metastases occur, resulting in an increased risk for mortality and the need for alternative approaches to therapy [1-3].

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The evaluation for regional and distant metastases in patients with cutaneous SCC or BCC will be reviewed here. The clinical features and treatment of SCC and BCC are discussed elsewhere. ●(See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".) ●(See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma".) ●(See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".) ●(See "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma".) ●(See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence".) ●(See "Treatment of basal cell carcinomas at high risk for recurrence".)

SQUAMOUS CELL CARCINOMA

The

identification of patients at increased risk for metastasis and, concordantly, the most appropriate work-up for metastatic disease are important components of the management of patients with cutaneous squamous cell carcinoma (SCC) [4]. Clinical and pathologic features associated with an elevated risk of recurrence include tumor diameter >2 cm, Breslow thickness >2 mm, poor differentiation, anatomic location (lip, ear, and temple), perineural invasion, and invasion beyond the subcutaneous fat (table 1) [4-7]. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".) However, data on the approach to the evaluation for metastatic disease are limited, contributing to the absence of definitive recommendations on the indications for investigative tests and the selection of appropriate studies. In general, clinical assessment by physical examination is considered sufficient for the evaluation of most patients with cutaneous SCC, whereas those with tumors who exhibit clinical and/or pathologic high-risk features may need further evaluation with imaging studies [8]. The impact of sentinel lymph node (SLN) biopsy, which has been used to evaluate lymph node status in select patients with high-risk SCC, remains uncertain. (See 'Patients without palpable lymph nodes' below and 'Evaluation for distant metastases' below and 'Sentinel lymph node biopsy' below.)

Locoregional evaluation — Lymph nodes are the most common sites for metastasis of cutaneous SCC, and, regardless of the presence or absence of high-risk features, all patients diagnosed with invasive cutaneous SCC should undergo regional lymph node palpation at the time of diagnosis and during post-treatment follow-up. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma", section on 'Follow-up'.)

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The selection of sites for palpation is based upon knowledge of the pathways for lymphatic drainage (figure 1A-B). Lymphatic drainage on the head is complex, and lesions in close proximity to one another may drain to different lymph node basins. Common initial sites for metastasis from lesions on the face and scalp include [9]: ●Nose and cheek lesions – submandibular nodes ●Lip and anterior mouth lesions – submental nodes ●Auricular lesions – posterior auricular nodes ●Posterior scalp lesions – occipital nodes ●Anterior scalp, forehead, temple lesions – parotid nodes The cervical lymph nodes are additional potential sites of metastasis and also should be palpated in all patients with head or neck lesions. In addition to palpation for enlarged regional lymph nodes, all patients should receive a complete skin examination that includes palpation of the skin and soft tissue near the tumor. Papules or nodules in the tumor vicinity or between the tumor and a regional lymph node basin may represent in transit metastases (picture 1) [9,10].

Patients with palpable lymph nodes — When an enlarged lymph node is detected on palpation, we typically refer the patient for lymph node biopsy via fine needle aspiration (FNA) [11]. Alternatively, the lymph node may be surgically removed for pathologic examination. If the FNA or surgical pathology results are positive for metastatic disease, further evaluation with radiologic imaging is indicated. Radiologic imaging provides information on the size, number, and location of involved lymph nodes, which are necessary for disease staging (table 2) [11]. (See 'Choice of imaging study' below.) If the cytology of a head or neck nodule that is clinically suggestive of an enlarged lymph node is negative for metastatic disease, re-evaluation of the site via radiologic imaging, repeat FNA, or open surgical biopsy to confirm the benign or malignant nature of the nodule is appropriate [12]. Enlarged lymph nodes on the trunk or extremities that are negative for metastatic disease are typically reevaluated via open surgical biopsy [12].

Patients without palpable lymph nodes — Definitive guidelines for the investigation for metastatic disease beyond lymph node palpation in patients with cutaneous SCC have not been established. In studies of patients with head and neck cancer, palpation has been shown to have a false-negative rate for the detection of lymph node metastases of 15 to 30 percent

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when compared with radiologic imaging or nodal dissection [13-18]. Hence, it is conceivable that a similar scenario may occur in some patients with cutaneous SCC. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'Imaging studies'.) Factors that often lead us to proceed with imaging studies for subclinical nodal disease in patients with cutaneous SCC who do not have palpable lymph nodes include [19,20]: ●Tumors larger than 2 cm ●Tumors located near major nerves in the head or neck ●In transit metastases ●Tumors invading deep structures (muscle, bone, cartilage) ●Systemic signs or symptoms suggestive of extracutaneous involvement ●Histopathologic or clinical findings suggestive of perineural invasion of a large nerve trunk (ie, a nerve with an anatomic name), such as neurologic signs or symptoms ●Multiple high-risk features (table 1) Perineural invasion, which can be detected on histopathologic examination, suspected due to the presence of sensory or motor neurologic symptoms or seen on radiologic studies in advanced cases, portends an increased risk for metastasis [7,21]. In a survey of Mohs surgeons, perineural invasion was the most commonly reported reason for considering radiologic imaging in patients with high-risk SCC [22]. Adenosquamous, spindle cell, or poorly differentiated SCCs are most likely to exhibit perineural invasion [11,23-25]; the facial and trigeminal nerves are most frequently affected [26]. In a single institution study, patients receiving radiologic imaging had a 50 percent lower risk of developing nodal metastases (13 versus 30 percent) and any disease-related outcome (20 versus 42 percent) compared with patients who did not undergo imaging studies [27].

Choice of imaging study — Computed tomography (CT) is often used for the evaluation of regional lymph node status in patients with cutaneous SCC [22]. Other radiologic studies utilized include magnetic resonance imaging (MRI), positron emission tomography (PET), ultrasound (US), and ultrasound-guided fine needle aspiration cytology (USG-FNAC). Comparative studies on the use of these modalities for the evaluation for locoregional metastases in patients with cutaneous SCC are lacking. Thus, much of the information used to guide study selection is based upon information from studies in head and neck cancer and other malignancies. In a 2007 meta-analysis of 17 studies comparing US, USG-FNAC, CT, and MRI in the detection of lymph node metastases among patients with head and neck SCC, the pooled sensitivity and specificity were 87 percent (95% CI 76-93) and 86 percent (95% CI 74-93), respectively, for US; 80 percent (95% CI 57-92) and 98 percent (95% CI 93-100), respectively, for USG-FNAC; 81 percent (95%

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CI 68-90) and 76 percent (95% CI 62-87), respectively, for CT; and 81 percent (95% CI 65-91) and 63 percent (95% CI 43-80), respectively, for MRI [28]. These results suggest that the diagnostic accuracy in the detection of metastatic lymph nodes in patients with head and neck cancer is similar for all imaging modalities, with US and USG-FNAC having a higher specificity. Consultation with a radiologist may assist with the selection of the most appropriate study to evaluate specific targeted features. Patient tolerance for specific radiologic modalities and test availability also influence test selection. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'Diagnosis and staging evaluation'.)

Computed tomography and magnetic resonance imaging — We suggest the use of CT or MRI for the evaluation for nodal disease. CT and MRI are the most common initial radiologic tests used in the assessment of patients with cutaneous SCC [22]. Both CT and MRI can detect lymph node metastases. In a 2012 meta-analysis of 16 studies evaluating the diagnostic accuracy of MRI in the detection of cervical lymph node metastases in patients with head and neck SCC, the pooled sensitivity and specificity of MRI were 76 percent (95% CI 70-82 percent) and 86 percent (95% CI 73-93 percent) [29]. Radiologic imaging with CT or MRI is also useful for evaluating tumor extent for preoperative planning and staging in patients with large or deeply invasive lesions. CT is superior to MRI for the evaluation of skull base invasion, involvement of cartilage, and bone erosion or destruction, while MRI is more useful for detecting perineural invasion, providing soft tissue contrast, defining tissue planes, and identifying bone marrow infiltration in the absence of significant osseous destruction [30]. CT is less expensive than MRI, and, in many clinical settings, CT is more easily attained. The properties of MRI prohibit use in patients with certain implanted devices. The contraindications for MRI are reviewed separately. (See "Patient evaluation for metallic or electrical implants, devices, or foreign bodies before magnetic resonance imaging", section on 'Assessing implants, devices, or foreign bodies for MRI'.)

Positron emission tomography — The use of PET in the setting of malignancy has risen with increasing test availability and decreasing test cost. PET functions through the detection of the accelerated uptake of intravenously administered fluorodeoxyglucose that occurs in tumor cells. A beneficial feature of PET is its ability to detect metastases in sites of fibrosis, necrosis, and dense scarring related to radiotherapy, areas that may be difficult to assess with other studies [31]. However, false-positive results are common with PET due to the incidental detection of metabolically active inflammatory, infectious, or other lesions. Another, less favorable feature of PET is the poor spatial resolution attained with this study. The integration of PET and CT (PET/CT) has addressed this issue through providing improved anatomic correlation.

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Study data on the use of PET for the evaluation of lymph nodes specifically in patients with cutaneous SCC are limited to a retrospective study of 12 patients with cutaneous SCC in which PET detected lymph node metastases in three out of nine patients with high-risk SCC [32]. In head and neck cancer, the value of PET for the detection of occult metastases is uncertain; PET/CT may be more beneficial. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'PET and integrated PET/CT'.)

Ultrasound and ultrasound-guided fine needle aspiration cytology — The results of studies that suggest that USG-FNAC may be useful for the evaluation of lymph nodes in patients with vulvar SCC and head and neck cancer raise the question of whether the procedure may be of value for lymph node surveillance in patients with cutaneous SCC [33,34] (see "Overview of the diagnosis and staging of head and neck cancer", section on 'Fine needle aspiration biopsy'): ●In a series of 44 patients with primary SCC of the vulva, USG-FNAC was more sensitive (80 versus 58 percent) and specific (100 versus 75 percent) than CT for the diagnosis of lymph node metastases [33]. ●In a subsequent meta-analysis of three studies examining the performance of USG-FNAC in the detection of nodal metastases in patients with head and neck cancer, the pooled sensitivity and specificity of USG-FNAC were 80 percent (95% CI 57-92) and 98 percent (95% CI 93-100), respectively [28]. US spares the radiation exposure associated with CT, but the utility of this procedure may be compromised by operator-dependent accuracy, difficulty in following specific lesions over time, and reduced ability to detect metastases to deep lymph nodes. The last item may be less of a concern in cutaneous SCC, which typically metastasizes to superficial lymph nodes; however, additional studies are necessary to determine the role of USG-FNAC for surveillance in this population.

Evaluation for distant metastases — The lungs, liver, brain, and bone are the most frequent sites for distant metastases of cutaneous SCC. We typically evaluate for distant metastases in patients with lesions that have a very high risk for metastasis, known locoregional metastases, or signs or symptoms suggestive of distant disease. CT, PET, and PET/CT have been used for whole-body imaging for the evaluation for distant metastases. The comparative efficacy of these studies for the detection of distant metastases has not been evaluated in cutaneous SCC. Data on the utility of these studies in head and neck cancer are available separately. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'Evaluation for distant metastases'.) Systemic therapy for metastatic SCC is discussed separately. (See "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas".)

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Sentinel lymph node biopsy — Early metastatic disease involving lymph nodes may be microscopic and nonapparent on clinical examination and radiologic imaging. SLN biopsy is a minimally invasive procedure that identifies the lymph node or lymph nodes most likely to harbor micrometastases through the use of lymphoscintigraphy to detect uptake of radiolabeled colloid and blue dye injected at the site of the tumor. (See "Imaging studies in melanoma", section on 'Lymph node evaluation'.) The role of SLN biopsy in the management and outcome of patients with high-risk cutaneous SCC has not been evaluated in randomized trials. Data from observational studies are insufficient to determine whether early detection of microscopic metastatic disease has a beneficial effect on patient survival [35]: ●A 2014 meta-analysis of 19 observational studies including 130 patients who underwent SLN biopsy for high-risk cutaneous SCC evaluated which stages in the American Joint Committee on Cancer (AJCC) 7 criteria and the Brigham and Women's Hospital (BWH) staging system were most closely associated with positive SLN biopsy [36]. A positive SLN was found in 16 of 130 patients (12 percent) included in the analysis. Based on AJCC 7 staging, the majority of positive SLN occurred in T2 (13 out of 116), whereas, based on the BWH staging system, there was a positive SLN in 7 percent of T2a (6 out of 85) and 30 percent of T2b (5 out of 17). The positive SLN rate for AJCC 7 T4 and BWH T3 were 60 and 50 percent, respectively [36]. This analysis suggests that SLN biopsy may provide additional prognostic information for patients with high-stage cutaneous SCC tumors. However, comparative data on management and outcome of patients with and without a positive SLN were not provided in this study. ●In a 2018 systematic review of 23 observational studies including 566 patients with cutaneous SCC who underwent SLN biopsy, the pooled estimate of the prevalence of nodal metastasis was 7.9 percent (95% CI 5.2-10.6 percent) [37]. Most of the studies included patients classified as high risk, but the definition of this risk varied from one study to another. Among 361 patients for whom followup data were available, 32 had positive SLN biopsy, 22 experienced regional recurrence (9 SLNpositive and 13 SLN-negative), 11 developed distant metastasis (5 SLN-positive and 6 SLN-negative), and 12 died of SCC (4 SLN-positive and 8 SLN-negative). The false-negative rate was 3.9 percent. ●In another review including 327 patients with cutaneous SCC who underwent SLN biopsy, 12 percent had a positive SLN result [38]. Among 98 patients for whom follow-up information was available, recurrence-free survival was 95 percent (95% CI 90-99) at one year and 73 percent (95% CI 62-86) at four years. Among the 18 patients who experienced recurrence, 3 had a positive SNL biopsy and 15 had a negative SLN biopsy. Sixteen patients died, of whom 2 had a positive SLN biopsy and 14 had a negative SLN biopsy. These results suggest that in patients with cutaneous SCC, recurrence and survival are not affected by the SLN status. Based upon the available evidence, SLN biopsy cannot be routinely recommended. Randomized trials evaluating the impact of SLN biopsy followed by completion lymph node dissection on survival of patients with high-risk cutaneous SCC are awaited.

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BASAL CELL CARCINOMA

Compared with cutaneous

squamous cell carcinoma (SCC), there is an even greater lack of data on the evaluation for metastatic disease in patients with basal cell carcinoma (BCC). This is likely related to the rarity of systemic involvement; the risk of metastasis for BCC is estimated to be between 0.05 to 0.1 percent [39,40]. (See "Treatment of basal cell carcinomas at high risk for recurrence", section on 'Metastatic disease'.) Metastatic BCC most frequently involves the regional lymph nodes, lungs, bone, skin, and liver [41]. Large lesions (particularly those over 10 cm2) and tumors that invade deep structures, such as cartilage, skeletal muscle, or bone, are most likely to metastasize [39]. Perineural invasion, aggressive histologic growth patterns, and longstanding lesions are additional risk factors for metastasis [41]. As in cutaneous SCC, computed tomography (CT) and magnetic resonance imaging (MRI) may be used for the evaluation for metastases and local tissue invasion. The value of positron emission tomography (PET) and sentinel lymph node (SLN) biopsy in BCC is uncertain. PET detected lymph node metastases in a patient with BCC [42] but was unable to detect primary BCCs in three out of six patients in one series, raising questions about the sensitivity of the test for BCC [43]. In a study of 22 patients with metastatic BCC treated with vismodegib, PET/CT images tended to demonstrate more disease in bone and soft tissue compared with contrast-enhanced CT images; contrast-enhanced CT images tended to demonstrate more disease in the lung [44]. PET/CT was also used to demonstrate response to vismodegib; a decrease in maximum standardized uptake value (SUVmax) was associated with improved progression-free survival and overall survival [45]. Detection of lymph node metastasis via SLN biopsy in a patient with pathologic evidence for lymphatic invasion in a primary excision specimen of a BCC has been reported [46]. Systemic therapy for advanced BCC is discussed separately. (See "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas".)

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nonmelanoma skin cancer".)

SUMMARY AND RECOMMENDATIONS ●The majority of patients with squamous cell carcinoma (SCC) can be evaluated for locoregional metastatic disease through skin examination and regional lymph node palpation. If features associated with an elevated risk for metastasis are present (high-risk SCC (table 1)), further evaluation with radiologic imaging may be indicated. (See 'Locoregional evaluation' above.)

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●Enlarged regional lymph nodes detected on physical examination should be sampled via fine needle aspiration (FNA) or surgical excision in patients with cutaneous SCC. If disease is identified in lymph nodes, radiologic imaging to determine the size, number, and location of involved lymph nodes should be performed. (See 'Patients with palpable lymph nodes' above.) ●The indications for further evaluation of lymph node status when lymph nodes appear normal on physical examination are less certain. We typically proceed with radiologic imaging in patients with clinical or histopathologic features that suggest an elevated risk for metastasis. We suggest the use of computed tomography (CT) or magnetic resonance imaging (MRI) for the initial evaluation for nodal disease. (See 'Patients without palpable lymph nodes' above.) ●The value of sentinel lymph node (SLN) biopsy in high-risk cutaneous SCC is unknown. It has not been evaluated in randomized trials and data from observational studies are insufficient to determine whether early detection of microscopic metastatic disease improves patient survival. Additional studies are thus necessary to determine the role of SLN biopsy in cutaneous SCC. (See 'Sentinel lymph node biopsy' above.) ●There are few data to guide the use of imaging studies for patients with basal cell carcinoma (BCC) at high risk of recurrence. CT or MRI studies may be used for the evaluation for metastases and deep local tumor invasion. The value of positron emission tomography (PET) and SLN biopsy in BCC is uncertain. (See 'Basal cell carcinoma' above and "Treatment of basal cell carcinomas at high risk for recurrence".)

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Systemic treatment of advanced cutaneous squamous and basal cell carcinomas uptodate.com/contents/systemic-treatment-of-advanced-cutaneous-squamous-and-basal-cell-carcinomas/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Mar 06, 2020.

INTRODUCTION

Basal cell carcinoma and squamous cell carcinoma of

the skin, together referred to as non-melanoma skin cancer (NMSC), are the most commonly diagnosed malignant neoplasms in the Caucasian population of the United States. Because many patients are treated as outpatients in an office setting, reliable statistics are difficult to obtain. Nonetheless, the National Cancer Institute estimates that approximately two million new cases occurred in 2012 [1]. The vast majority of patients can be successfully managed with a variety of simple procedures, such as cryotherapy, curettage and electrodesiccation, topical treatments (fluorouracil, imiquimod), or simple surgical excision. When lesions are more advanced, Mohs micrographic surgery, more extensive surgical resection, or radiation therapy are generally sufficient to control locoregional disease. Despite their high prevalence, these NMSCs are rarely fatal. It is estimated that in 2012 [1], approximately 1000 patients died of the disease. Squamous cell carcinomas are biologically more aggressive, and neglected lesions can be life-threatening due to local extension or metastasis. By contrast, basal cell carcinoma is only very rarely life-threatening. The use of systemic therapy is limited to patients with distant metastases or locally advanced disease that cannot be adequately managed with surgical or radiotherapeutic techniques.

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Systemic chemotherapy for basal cell and squamous cancers of the skin is discussed here. The treatment of localized basal cell and squamous cell carcinomas is discussed elsewhere. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence" and "Treatment of basal cell carcinomas at high risk for recurrence" and "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma".)

TNM STAGING SYSTEM

A Tumor, Node, Metastasis (TNM)

staging system has been developed for classification of patients with advanced cutaneous squamous cell carcinoma and other non-melanoma cutaneous carcinomas (except Merkel cell carcinoma) arising in the head and neck (table 1). This TNM system is supported by both the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) [2]. Advanced skin cancers arising at other sites are not staged using this system.

BASAL CELL CARCINOMA Preferred option: Hedgehog inhibitors — The hedgehog signaling pathway can cause basal cell proliferation and tumor growth [3]. Signaling in this pathway is initiated by the cell surface receptor smoothened homolog (SMO). In adults, this pathway normally is inhibited by another cell surface receptor, the patched homolog 1 (PTCH1). Binding of the hedgehog ligand to PTCH1 prevents this inhibition. Two mechanisms have been identified by which the hedgehog pathway may be involved in the pathogenesis of basal cell carcinoma. Mutations of PTCH1 may prevent inhibition of SMO activation of the hedgehog pathway [4,5], or mutations of SMO may result in constitutive activation of the pathway [6]. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)", section on 'PTCH protein function'.) Two SMO inhibitors, vismodegib and sonidegib, have clinically useful activity in patients with locally advanced or metastatic basal cell carcinoma. Itraconazole, an antifungal, also inhibits this pathway, but data are much more limited for this agent.

Vismodegib — Vismodegib (150 mg as a single oral daily dose) is an oral small-molecule inhibitor of SMO, which blocks activation of the hedgehog pathway [7,8]. Clinical trials have demonstrated the efficacy of vismodegib in patients with locally advanced and metastatic basal cell carcinoma, including a phase II trial (the SafeTy Events in VIsmodEgib [STEVIE] study) [9-12]. Treatment-related toxicity led to discontinuation in approximately one-third of patients receiving vismodegib [13-15]. Therefore, although vismodegib is typically administered on a continuous dosing schedule, appropriate alternatives exist for those who are unable to tolerate continuous dosing. There is no standard approach to intermittent therapy; options include administering vismodegib at 150 mg daily in three-month intervals alternating with two-month treatment breaks, or

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at 150 mg every other day. Additionally, for patients who achieve a complete response on vismodegib and are intolerant of therapy, an alternative approach includes discontinuing treatment, with the option of reinitiating therapy at the time of relapse. Retreatment schedules may also depend on toxicity resolution, as well as patient willingness to restart therapy. Data demonstrating the activity and toxicity of vismodegib in those with basal cell carcinoma are as follows: In an open-label phase II trial (STEVIE), 1215 patients (1119 with locally advanced disease and 96 with metastatic basal cell carcinoma) were treated continuously with vismodegib until progression [9]. At a median follow-up of 18 months, results were as follows: ●The objective response rate in those with locally advanced disease was 69 percent (33 percent complete, 35 percent partial). In those with metastatic disease, the objective response rate was 37 percent (5 percent complete, 32 percent partial). The median progression-free survival for the entire study population was 22 months (23 months in those with locally advanced disease and 13 months in those with metastatic disease). ●The relationship between vismodegib treatment and the subsequent development of cutaneous squamous cell carcinoma is unclear. A possible link between treatment with vismodegib and squamous cell carcinoma was suggested by a case control study that included 55 patients treated with vismodegib and 125 controls, in which there was an approximately eightfold increase in new cases of squamous cell carcinoma [16]. However, in a case-control series that included 556 patients treated with vismodegib and 1119 controls with basal cell carcinoma, there was no increase in the risk of squamous cell carcinoma at one year compared with that in patients not treated with vismodegib [17]. Whether or not there is an increased risk of subsequent squamous cell carcinoma after vismodegib treatment, careful surveillance of the skin for new lesions is indicated in this patient population. ●Acquired resistance in which the tumor responds to treatment but then regrows was observed in 21 percent of patients with a mean time of 56.4 weeks at the time of detection [18]. Primary resistance in patients with basal cell carcinoma treated with vismodegib has also been noted [19,20]. ●Serious adverse events were reported in 24 percent of patients. Treatment-associated adverse events leading to discontinuation of therapy occurred in 31 percent of cases; the most common of these included muscle spasms, dysgeusia, weight loss, alopecia, decreased appetite, and asthenia (in 7, 5, 4, 3, 3, and 3 percent of cases, respectively). Despite these promising results, concerns regarding the high rates of treatment discontinuation due to toxicity have led to interest in intermittent courses of vismodegib. This approach is based on a randomized study investigating the use of two different schedules of administration, which were both associated with high response rates, although the criteria for response were different than those used in the STEVIE trial [15]. In this placebo-controlled phase II trial (MIKIE), 229 patients with multiple advanced basal cell carcinomas were randomly assigned to one of two intermittent dosing

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schedules of vismodegib for a total of 72 weeks (18 months). The first group received vismodegib at 150 mg daily in three-month intervals, alternating with placebo at two-month intervals, whereas the second group received vismodegib at 150 mg daily for an initial six-month interval, followed by alternating two-month intervals of placebo and vismodegib. Both schedules demonstrated a similar reduction in the mean total number of basal cell carcinomas at the end of treatment relative to baseline (63 versus 54 percent, respectively) and comparable toxicity profiles. Other strategies to address the toxicities of continuous treatment have also been explored. For example, in patients with a complete response to vismodegib, treatment discontinuation can still result in sustained responses, with a high response rate upon vismodegib re-exposure for relapsed disease [13]. In one observational study, 116 patients with locally advanced basal cell carcinoma who experienced a complete response to vismodegib stopped therapy at a median of approximately eight months and were placed on clinical observation [13]. In these patients, three-year relapse-free survival was 36 percent. Among the 27 patients who relapsed and were rechallenged with vismodegib, 23 patients had an objective response (85 percent), 10 of whom had a complete response (37 percent). Additionally, other studies using a similar approach have suggested lower rates of grade ≥3 adverse events (29 to 36 percent) compared with continuous administration (43 percent) [13-15]. Vismodegib may also have a role in patients with nevoid basal cell carcinoma syndrome (ie, Gorlin syndrome), an inherited condition in which patients develop multiple basal cell carcinomas that are histologically identical to sporadic lesions. Since patients with nevoid basal cell carcinoma syndrome develop multiple basal cell carcinomas in their 20s and 30s, the potential teratogenic effects of vismodegib are very important in this group. Vismodegib should only be given to women of childbearing age using adequate methods of birth control for at least one month prior to initiation of and during treatment with vismodegib. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)

Sonidegib — Sonidegib, a second SMO inhibitor, demonstrated antitumor activity in a phase I study [21]. Based upon this, it was evaluated more extensively in a randomized phase II trial, and this provided the basis for its approval at a dose of 200 mg as a single daily oral dose. In a randomized phase II trial, patients were assigned to sonidegib at either 200 or 800 mg orally once a day, with treatment continued until progressive disease or toxicity [22-24]. Overall, 230 patients were enrolled; this included 193 patients with locally advanced basal cell carcinoma and 37 with metastatic disease. Results based upon the analysis 30 months after the final patient enrollment included the following [24]: ●The objective response rates based upon central review for the 200 and 800 mg/day cohorts with locally advanced disease were 56 and 45 percent, respectively. The disease control rates, including those with stable disease, were 91 and 83 percent, respectively, for patients with locally advanced disease.

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●For those with metastatic disease, the objective response rates were 8 and 17 percent, respectively, in the low- and high-dose groups. The disease control rates, including those with stable disease, were 92 and 91 percent, respectively. •The median duration of response based upon independent review was 24.0 months for patients treated at 200 mg per day and was not reached for those treated at 800 mg per day. ●The most common toxicities included muscle spasms, alopecia, dysgeusia, and nausea (54, 49, 44, and 39 percent of patients at 200 mg/day and 69, 58, 60, and 47 percent at 800 mg/day, respectively). Grade 3 or 4 toxicities occurred in 20 percent of patients treated with 200 mg/day and 39 percent of those treated with 800 mg/day. In a meta-analysis of studies evaluating vismodegib and sonidegib, the overall objective response rate was similar for vismodegib (62 percent) and sonidegib (55 percent), while in the metastatic setting they were 39 and 15 percent, respectively [25]. Patients receiving sonidegib experienced more nausea, but other adverse events were similar between the two agents. However, head-to headcomparisons between vismodegib and sonidegib are lacking, and, in the setting of limited data, either agent is appropriate.

Less preferred alternatives Itraconazole — Itraconazole, an antifungal agent, has been identified as a potent inhibitor of the hedgehog signaling pathway [26]. In a proof of concept study, itraconazole was studied in 19 patients, with an average of 4.8 cutaneous basal cell carcinomas per patient [27]. In one cohort, 15 patients were treated with 200 mg twice daily for four weeks prior to surgery; in the other cohort, four patients received 100 mg twice daily for one to four months (mean, 2.3 months). Eight patients had tumor reduction and re-epithelialization. Of note, none of the three patients previously treated with vismodegib responded. Additional clinical studies will be required to determine whether itraconazole has a role in the management of patients with basal cell carcinoma.

Chemotherapy — Because of the rarity of metastatic basal cell carcinoma, the approach to systemic treatment is based primarily upon isolated case reports, with only a few small case series. A case report of one patient with basal cell carcinoma metastatic to the lungs observed a complete response with a combination of carboplatin and paclitaxel [28]. The authors also reviewed the literature and found 12 other patients with metastatic basal cell carcinoma who were treated with platinum-containing regimens. Among these 12, five had a complete response and four had a partial response. (See 'Systemic chemotherapy' below.)

SQUAMOUS CELL CARCINOMA

Evidence of

activity for systemic therapy is derived from studies that include patients being treated in both the neoadjuvant and metastatic setting.

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Treatment targeting the EGFR pathway — Monoclonal antibodies (cetuximab, panitumumab) and oral agents (gefitinib, erlotinib) that target the epidermal growth factor receptor (EGFR) have antitumor activity in patients with advanced squamous cell carcinoma (SCC) of the skin, as initially suggested by case reports and small studies (picture 1). ●Cetuximab – The potential role of cetuximab in treating advanced SCC of the skin was studied prospectively in a phase II study that included 36 patients [29]. The majority of patients had localregional disease and only 8 percent had systemic metastases. Cetuximab was administered on its conventional weekly schedule (400 mg/m2 on week 1 and then 250 mg/m2 weekly). Eight partial and two complete responses were observed (objective response rate 28 percent in the intention-to-treat population), and 15 had stable disease for an overall disease control rate of 69 percent. Three patients were able to undergo complete resection of their tumor following treatment with cetuximab. The most common grade 3 and 4 toxicities included infection and tumor bleeding (eight and four cases, respectively). In line with what is observed in other malignancies, patients developing acneiform rash had a longer progression-free survival and a tendency for a longer survival (8.9 versus 4 months; p = 0.054). Cetuximab was also evaluated in the neoadjuvant setting. French investigators treated 34 patients with initially unresectable, locally advanced tumors with cetuximab in combination with platinum and fluorouracil, or cetuximab alone if chemotherapy was considered contraindicated [30]. Among the nine patients (median age 86 years) treated with cetuximab alone, five had a response which allowed for surgical resection, and three of these had a complete pathological response. Twenty-five patients with a median age of 70 years were treated with cetuximab and chemotherapy. Twentythree patients were able to have surgery, and a complete pathological response was achieved in 15 tumors. ●Panitumumab – In a small phase II study, 16 patients with cutaneous SCC not suitable for local therapy were treated with panitumumab (6 mg/kg every two weeks) [31]. Objective responses were observed in five patients, including three partial and two complete responses. Grade 3 and 4 toxicity was observed in five cases (four with rash, one with fatigue). ●Gefitinib and erlotinib – Both gefitinib and erlotinib, oral inhibitors of EGFR, have demonstrated only limited activity in patients with advanced SCC. In a phase II study with gefitinib, 40 patients were treated; six partial responses were observed in 40 patients (16 percent), which did not meet the predetermined level of activity for further evaluation [32]. In a phase II study with erlotinib, three partial responses were observed in 29 evaluable patients (10 percent), and the authors concluded that further investigation of EGFR tyrosine kinases in this disease was not warranted [33].

Systemic chemotherapy — There are only limited data on the role of systemic chemotherapy in the treatment of advanced cutaneous SCC. Cisplatin-based combinations appear to be the most active regimens [34,35] and have been adapted from those used for SCC arising in other noncutaneous sites.

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As an example, a combination of bolus cisplatin, plus a five-day infusion of bleomycin and fluorouracil, was used to treat 14 patients with advanced SCC of the skin or lip [34]. Objective tumor responses (four complete and seven partial) were observed in 11 patients. In seven patients, tumor regression with systemic chemotherapy permitted subsequent definitive local treatment with either surgery or radiation therapy (RT). Although cutaneous non-melanoma skin carcinomas are sensitive to platinum-based chemotherapy, the administration of cisplatin requires adequate kidney function. In addition, cytotoxic chemotherapy can be associated with significant bone marrow toxicity. Patients with these skin cancers often are older adults and have significant comorbidities, which make them unable to tolerate the toxicities associated with these regimens. (See "Systemic chemotherapy for cancer in older adults".)

Chemotherapy plus cetuximab — Platinum-based chemotherapy has also been combined with cetuximab in patients with unresectable, advanced, nonmetastatic cutaneous SCC, and this approach may be more effective than chemotherapy alone. (See 'Treatment targeting the EGFR pathway' above.)

Postoperative chemotherapy plus radiation — RT may be an alternative to surgery in selected patients with SCC of the skin. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma", section on 'Radiation therapy'.) In a randomized trial, carboplatin chemotherapy was studied in combination with RT for the treatment of high-risk cutaneous SCC of the head and neck in immunocompetent patients to prevent locoregional recurrence following surgery [36]. Surgery plus RT was effective in preventing locoregional recurrence, but there was no benefit from the addition of carboplatin. Both cisplatin and cetuximab prolong survival for SCC of the mucosa, and the potential benefits of these agents for cutaneous SCC remain unknown.

Checkpoint inhibitor immunotherapy (cemiplimab) — For most patients with metastatic or locally advanced SCC who are not eligible for curative treatment with surgery or RT, we suggest the anti-programmed cell death 1 protein (PD-1) inhibitor cemiplimab rather than chemotherapy, cetuximab, or their combination. We do not offer cemiplimab to patients with SCC secondary to immunosuppression related to organ transplantation. These patients were excluded from trials evaluating cemiplimab due to concerns regarding organ rejection and graft-versus-host disease (in the case of hematopoietic cell transplantation). Cemiplimab has activity in patients with locally advanced and metastatic cutaneous SCC. Data are as follows:

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●Locoregionally advanced or metastatic disease –The most extensive data on the efficacy of cemiplimab come from a phase I expansion cohort and an open-label phase II trial of patients with unresectable, locally advanced disease or distant metastases who had been previously treated with systemic therapy or RT [37]. The trials excluded patients who had undergone transplantation, those with autoimmune disease treated with immunosuppressive therapy any time in the previous five years, and those with hematologic malignancies (such as chronic lymphocytic leukemia). In the phase I study, objective responses were seen in 13 of 26 patients (50 percent). In the phase II study, objective responses were observed in 35 of 75 patients with metastatic disease (47 percent) and in 6 of 10 patients with unresectable, locally advanced disease (60 percent). With a median follow-up of eight months in the phase II cohort, approximately one-half of the responding patients with metastatic disease continued to have durable disease control at the time of data cutoff. Treatment was well tolerated, with no single grade ≥3 toxicity present in more than 5 percent of patients, including pneumonitis (3 percent) and diarrhea (2 percent). (See "Toxicities associated with checkpoint inhibitor immunotherapy".) ●Locally advanced disease without nodal or distant metastases – In further follow-up of a separate cohort in the phase II study reported above, 78 patients with locally advanced cutaneous SCC without nodal disease or distant metastases who were not eligible for RT or surgery were treated with cemiplimab for up to eight months [38]. At a median follow-up of approximately nine months, objective responses were seen in 34 patients (44 percent), including 10 complete responses (13 percent) and 24 partial responses (31 percent). There were no new unexpected toxicities. Based on these data, cemiplimab is approved by the US Food and Drug Administration (FDA) for treatment of patients with advanced cutaneous SCC who are not candidates for curative surgery or RT. The use of immunotherapy in patients with autoimmune disease is discussed separately. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Pre-existing autoimmune disorder'.)

ALLOGENIC ORGAN TRANSPLANTATION

The immunosuppression required after

allogenic organ transplantation increases the risk of various skin cancers. In this setting, squamous cell carcinoma is more common than basal cell cancer, in contrast to the distribution of skin cancers in the nontransplant population. The squamous cell and basal cell carcinomas that arise in this setting are more aggressive and are more likely to recur after resection. The development of skin cancer in patients with chronic immunosuppression following organ transplantation is discussed separately. (See "Development of malignancy following solid organ transplantation", section on 'Skin cancers'.) No specific recommendations for treatment of advanced skin cancer can be made for patients on chronic immunosuppression. For these patients, the choice of cetuximab, chemotherapy, or their combination (extrapolating from data in squamous cell carcinomas of head and neck) should

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consider patients' preferences, end-organ function, and performance status. For example, in the rare case of the patient with aggressive disease with visceral involvement, combination chemotherapy with cetuximab may be offered, as an attempt at controlling the disease. However, there are increased toxicities associated with this approach, and some chemotherapy agents may not be appropriate if nephrotoxic agents to prevent rejection are being administered. (See "Treatment of metastatic and recurrent head and neck cancer", section on 'Active agents' and "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents".) At least one report has suggested that a decrease in the level of immunosuppression may slow the development and progression of skin cancers in these patients [39], and some evidence suggests that use of a mechanistic target of rapamycin (mTOR) inhibitor as part of the immune-suppressive regimen reduces the rates of non-melanoma skin cancer (NMSC) in the post-transplant setting [40,41]. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'mTOR inhibitors'.)

SUMMARY AND RECOMMENDATIONS ●Cutaneous squamous and basal cell carcinomas are the most common malignancy in the white population in the United States. In the overwhelming majority of cases, locoregional therapy is curative and systemic therapy is not indicated. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence" and "Treatment of basal cell carcinomas at high risk for recurrence" and "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma".) ●For patients with metastatic or locally advanced basal cell carcinoma that is not amenable to treatment with surgery or radiation therapy, we suggest treatment with an inhibitor of sonic hedgehog pathway (vismodegib, sonidegib) (Grade 2B). (See 'Preferred option: Hedgehog inhibitors' above.) •For patients who are unable to tolerate the toxicities of continuous dosing of vismodegib, we administer treatment using an intermittent dosing schedule. For those who achieve a complete response to therapy and are intolerant of therapy, we discontinue vismodegib, with the option of reinitiating therapy at relapse. Retreatment schedules may also depend on toxicity resolution, as well as patient willingness to restart therapy. (See 'Vismodegib' above.) ●For most patients with metastatic or locally advanced squamous cell carcinoma that is not amenable to treatment with surgery or radiation therapy, we suggest the anti-programmed cell death 1 protein (PD-1) antibody cemiplimab (Grade 2C), rather than chemotherapy, cetuximab, or their combination.

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•However, this does not apply to patients who developed advanced squamous cell carcinoma of the skin as a consequence of immunosuppression from organ transplantation, as the efficacy and safety of cemiplimab in such patients are unknown. For these patients, the choice of cetuximab, chemotherapy, or their combination (extrapolating from data in squamous cell carcinomas of head and neck) should consider patients' preferences, end-organ function, and performance status. (See 'Allogenic organ transplantation' above.)

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Keratoacanthoma: Epidemiology, risk factors, and diagnosis uptodate.com/contents/keratoacanthoma-epidemiology-risk-factors-and-diagnosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Feb 06, 2020.

INTRODUCTION

Keratoacanthoma (KA) is a cutaneous tumor that most

commonly presents as a dome-shaped nodule with a central keratin-filled crater (picture 1A-E) [1]. KA most frequently develops on hair-bearing, sun-exposed skin. Middle-aged and elderly adults with fair complexions are most frequently affected [2]. A distinguishing feature of KA is a clinical course characterized by rapid initial growth followed by a variable period of lesion stability and subsequent spontaneous resolution [2]. The recognition of this unique characteristic in a tumor with clinical and histopathologic features that closely resemble cutaneous squamous cell carcinoma has led to significant debate over the classification of this lesion. The epidemiology, risk factors, and diagnosis of KA will be discussed here. The management and prognosis of KA is reviewed separately. (See "Keratoacanthoma: Management and prognosis".)

EPIDEMIOLOGY

Although KA is a common tumor, the potential for

spontaneous resolution, the variability in documentation of lesions as KA or squamous cell carcinoma, and the relative paucity of epidemiological studies performed on this disease hinder definitive conclusions on tumor incidence. The vast majority of reported cases of KA have occurred in fair-skinned individuals [3]. (See 'Risk factors' below.)

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KA can occur at any age, and may present as a solitary lesion (the most common presentation) or infrequently in the context of specific disorders associated with multiple KAs [4-7] (see 'Multiple keratoacanthomas' below). Solitary KA has a peak incidence between the ages of 50 and 69 [2]; rarely, lesions develop in individuals under the age of 20 [4]. Data on the distribution of KA among the sexes vary. Estimates of the sex ratio range from a similar incidence in both sexes to a three times greater risk for KA among males [3,8,9]. It is unclear whether the incidence of KA is subject to seasonal variation in temperate climates. A retrospective study at a medical center in Rhode Island that analyzed patient data obtained between 1990 and 1992 found that more lesions were diagnosed in the summer months than in the winter (incidence ratio 1.38:1) [10]. However, retrospective studies in Minnesota and Texas have failed to confirm these findings [3].

PATHOGENESIS

The pathogenesis of KA is poorly understood. It is

generally accepted that KA is most likely derived from the follicular infundibulum [11]. However, the mechanisms behind the characteristic phenomenon of rapid lesion growth followed by spontaneous resolution are not well defined. Based upon the available data, changes in the expression of genes and proteins involved in epidermal cell proliferation, cell adhesion, and cell survival may play significant roles in lesion development. Proposed contributors to lesion regression include the upregulation of factors that promote apoptosis, events related to normal cycling of the hair follicle, and activation of an immunologic response against the tumor [12].   Examples of specific factors identified as potentially relevant in the life cycle of KA include the homeodomain interacting protein kinase 2 (HIPK2) gene (a regulator of cell cycling and apoptosis) [13], the p53 tumor suppressor protein [14], the H-ras proto-oncogene [15,16], the adhesion molecules beta-catenin and CD44 [17], and levels of the bcl-2 apoptosis regulatory protein and Bak proapoptotic protein [14,18-20]. Additional potential contributors include granzyme B, a serine protease expressed by cytotoxic T cells and natural killer cells that promotes apoptosis [21], and p27 (kip), an inhibitor of cyclin dependent kinases that may promote lesion regression [22]. Further study is necessary to clarify the mechanisms involved in the development and involution of KA.

RELATIONSHIP WITH SQUAMOUS CELL CARCINOMA

The relationship between KA and squamous cell

carcinoma is controversial [2,23]. While some authors perceive KA as a distinct follicular-based squamous proliferation that usually follows a benign clinical course [24-28], others counter that KA is actually a clinical variant of cutaneous squamous cell carcinoma prone to spontaneous regression and occasional aggressive behavior and metastasis [5,29-31]. Dissolution of this controversy is hampered by the lack of histopathologic criteria that definitively differentiate KA and squamous cell carcinoma [32]. Reports documenting transformation of KA to squamous cell

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carcinoma also raise questions about whether these lesions represent a continuum of a single disease rather than distinct entities [27,33,34]. (See 'Differentiation from squamous cell carcinoma' below and "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)

RISK FACTORS

A variety of factors may influence the likelihood that an

individual will develop KA [1]. Examples include skin pigmentation; exposure to ultraviolet radiation trauma, chemical carcinogens, or certain medications; and genetic abnormalities. These factors are discussed in greater detail below. ●Skin color – The risk for KA decreases with increasing skin pigmentation [2,9,35]. Among 22,000 patients seen at a specialized surgical skin cancer practice in Houston, Texas between 1998 and 2006, all 234 patients with KA were Caucasian with Fitzpatrick skin phototypes I, II, or III (table 1) [3]. In addition, the differences in disease incidence reported in the late 20th century in the predominantly fair-skinned population of Australia (150 per 100,000 individuals), JapaneseHawaiians (22 per 100,000 individuals), and Filipinos in Hawaii (7 per 100,000 individuals) also lend support to an important role for skin type [36-38]. KA is rare among individuals with deeply pigmented skin [35]. ●Ultraviolet radiation –Although human studies that definitively link exposure to ultraviolet radiation to the development of KA are lacking, the observation that KA most frequently occurs on sunexposed skin and in fair-skinned individuals supports a role for ultraviolet radiation as a contributing factor [9]. Moreover, high numbers of treatments with psoralen plus ultraviolet A (PUVA) phototherapy have been linked to an increased risk for KA. In a retrospective study of approximately 500 patients with psoriasis who were treated with PUVA, patients who received high cumulative doses of PUVA were significantly more likely to develop KA than those who received lesser amounts of PUVA therapy [39]. ●Trauma – Infrequently, KA develops in sites of iatrogenic (eg, surgery, laser therapy, cryotherapy) or accidental trauma [40-48]. Although most reported cases of trauma-induced KA have occurred in adults, this phenomenon has also been documented in an adolescent [41]. Post-surgical KA usually appears one to three months after surgery [42-44]. Treatment with ionizing radiation has also been linked with the development of multiple KAs in a patient with multiple self-healing squamous epithelioma (MSSE, also known as Ferguson-Smith disease) [49]. (See 'Multiple keratoacanthomas' below.) The explanation for the development of KA at sites of trauma is unknown. Some authors have speculated that in skin previously exposed to carcinogens such as ultraviolet radiation, factors associated with the wound-healing response may promote the development of these tumors [23]. ●Genetics – Several genetic syndromes are associated with KA, including the variant of Lynch syndrome known as Muir-Torre syndrome, xeroderma pigmentosum, and MSSE. Muir-Torre syndrome may present with KA, sebaceous tumors, and visceral malignancy. In this syndrome, tumor formation occurs as a result of germline mutations in DNA mismatch repair genes.

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KAs may develop early in life in both xeroderma pigmentosum and MSSE. Xeroderma pigmentosum is an autosomal recessive syndrome associated with defects in DNA repair [50-52]. In contrast, MSSE is an autosomal dominant disorder associated with loss-of-function mutations in the transforming growth factor beta receptor 1 gene (TGFBR1 or ALK5) [53]. (See "The genodermatoses: An overview", section on 'Xeroderma pigmentosum' and "Muir-Torre syndrome" and 'Multiple keratoacanthomas' below.) ●Drug exposure –BRAF inhibitors (eg, vemurafenib, dabrafenib) are molecularly targeted agents used in the treatment of multiple malignancies. The development of KA or cutaneous squamous cell carcinoma is a potential adverse effect of these therapies [54,55]. A paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway resulting the proliferation and survival of abnormal cells may contribute to the occurrence of these lesions [56]. Additional agents that have been associated with the development of KA include sorafenib, a tyrosine kinase inhibitor used in the treatment of cancer [57,58], and immunosuppressive therapy [59-64]. (See "Molecularly targeted therapy for metastatic melanoma", section on 'BRAF inhibition' and "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Squamoproliferative lesions'.) ●Chemical carcinogens –Exposure to chemical carcinogens, such as tar, pitch, polyaromatic hydrocarbons in mineral oils, and cigarette smoking may increase risk for KA [8,23,65]. Smoking was associated with increased risk for solitary KA in a case-control study of 78 patients with KA and 199 controls; 69 versus 22 percent of subjects were smokers [8]. A contributory effect of acid refined mineral oils is supported by a Swedish study that found higher than expected rates of KA on the hands or forearms of workers exposed to these substances [65]. Concordant with an inciting effect of these particular oils, KAs were no longer detected after a switch to solvent-refined mineral oils, which contain much lower concentrations of polyaromatic hydrocarbons. ●Human papillomavirus infection –Similar to cutaneous squamous cell carcinoma, the role of human papilloma virus (HPV) in KA is uncertain. Although multiple serotypes of HPV have been detected in lesions from immunocompetent and immunocompromised patients with KA, data are insufficient to confirm a causative association between KA and this ubiquitous virus [23,66-68]. (See "Epidemiology and risk factors for cutaneous squamous cell carcinoma", section on 'Human papillomavirus infection'.)

CLINICAL MANIFESTATIONS

Multiple clinical

presentations of KA are described in the literature including solitary KA (the most common manifestation) and several less common variants characterized by isolated or multiple lesions (table 2).

Solitary keratoacanthoma — Solitary KA usually, but not always, develops on sun-exposed areas of the skin [34]. The face (especially the eyelids, nose, cheek, and lower lip), neck, hands, and arms are common sites for involvement [12]. Findings of consistent sun

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damage (eg, dyspigmentation, telangiectasias, and atrophy) are often present in the surrounding skin. Although solitary KA is classically described as a dome-shaped, bud-shaped, or berry-shaped 1 to 2 cm papule with a central keratinous plug, the appearance of lesions varies with the stage of lesion development (picture 1A-E) [9]. Three phases characterize the evolution of KA: proliferation, maturation, and involution. ●Proliferation – Proliferation, the first stage of KA development, is defined by rapid growth that may persist for up to six to eight weeks. The initial lesion is usually a small pink macule that subsequently takes on a papular quality and eventually forms a circumscribed nodule. The periphery of the nodule tends to be skin-colored or mildly erythematous and may have accompanying telangiectasias [9]. The center of the nodule typically demonstrates a prominent keratinous core. Removal of this core results in a crateriform appearance. Solitary KA typically grows to a diameter of 1 to 2 cm [29,69]. Lesions that exceed 2 cm in size are classified as giant KAs (picture 2) [12]. (See 'Clinical variants' below.) ●Maturation – In the maturation phase, growth ceases. The KA maintains the nodular or crateriform appearance but may begin to demonstrate signs of fragmentation [9,34,70]. This phase often lasts for several weeks to several months. ●Involution – The involution stage is characterized by spontaneous lesion regression. This process often takes four to six weeks, but may take longer. During involution, the remaining central keratin plug is expelled. The tumor eventually completely resolves leaving an atrophic, often hypopigmented scar [71,72]. The time course for lesions to proceed through the three phases is usually around four to nine months [2,9,73]. However, some KAs persist for greater than one year, complicating the clinical distinction of these lesions from cutaneous squamous cell carcinoma. (See "Keratoacanthoma: Management and prognosis", section on 'Deferring therapy'.)

Clinical variants — The major clinical variants of solitary KA include giant KA, subungual KA, mucosal KA, and keratoacanthoma centrifugum marginatum (KCM). ●Giant KA –KAs can develop into large lesions, with diameters ranging from greater than 2 cm to up to 15 cm (picture 2) [74-79]. Such lesions are referred to as giant KAs. Giant KA has a predilection for the nose and eyelids [78]. Although spontaneous resolution usually eventually occurs, these lesions can cause considerable cosmetic disfigurement via the destruction of underlying structures [76,80]. ●Subungual KA –Subungual KA develops on the nail beds and may present with pain, swelling, and inflammation [81,82]. As with classic KA, lesions develop quickly. The thumbs, index fingers, and middle fingers are the most frequently affected digits [12]. In addition, erosion of underlying bone is frequently evident on radiologic examination. Compared with classic KAs, spontaneous resolution is less likely to occur in this variant [82].  

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●Mucosal KA – Rarely, KAs develop on mucosal surfaces. The oral mucosa, conjunctiva, genitalia, or nasal mucosa may be affected [7,9,83,84]. Mucosal lesions may also be seen in patients with generalized eruptive keratoacanthomas of Grzybowski. (See 'Multiple keratoacanthomas' below.) Spontaneous resolution of mucosal lesions usually does not occur. ●Keratoacanthoma centrifugum marginatum (KCM) –KCM is distinguished from giant KA by its prominent horizontal growth pattern. The lesion exhibits progressive peripheral growth accompanied by central involution. Lesions of KCM may reach diameters of 20 or more centimeters and may occur on the face, trunk, or extremities (picture 3) [9]. Spontaneous resolution is unlikely [85]. In addition to these four major subtypes of solitary KA, other uncommon presentations have been described, including vulvar KA in women [86-90] and KA within nevus sebaceous, a presentation primarily reported in children and young adults [91,92].

Multiple keratoacanthomas — Several named disorders may present with multiple KAs (picture 4 and table 2). The major disorders characterized by this presentation are multiple self-healing squamous epithelioma (MSSE), generalized eruptive keratoacanthomas of Grzybowski, and eruptive squamous atypia (eruptive keratoacanthoma): ●Multiple self-healing squamous epithelioma –Multiple self-healing squamous epithelioma(MSSE, Ferguson-Smith disease, OMIM #132800) is an autosomal dominant disorder attributed to loss-offunction mutations in the transforming growth factor beta receptor 1 (TGFBR1 or ALK5) gene [53]. TGFBR1 mutations may lead to defects in TGF-beta function that result in the deregulation of cell proliferation and migration. Most affected families are of Scottish origin. (See 'Risk factors' above.) Features of MSSE most frequently appear during adolescence or early adulthood, but may also first occur earlier or later in life [9,93]. Affected patients develop several KAs to hundreds of KAs that spontaneously resolve, often leaving deep, destructive scars [23]. Sun-exposed areas are most frequently affected, but may not be the only sites of involvement. Exacerbation of this disorder has been reported following radiation therapy [49,94]. ●Generalized eruptive keratoacanthomas of Grzybowski –Generalized eruptive keratoacanthomas of Grzybowski is a rare, sporadic disorder characterized by the abrupt appearance of numerous KAs [9,95,96]. The disorder usually occurs between the fifth and seventh decades of life [97]. Patients with generalized eruptive keratoacanthomas of Grzybowski abruptly develop hundreds to thousands of follicular-based 1 to 5 mm papules with central keratotic cores on the trunk and extremities [12]. Palm, sole, genital, and mucosal involvement may also be present [9]. Affected individuals may experience pruritus, ectropion due to eyelid involvement, and sclerodermoid changes of the face due to extensive involvement in this area [2,9,23,98]. ●Eruptive squamous atypia (eruptive keratoacanthoma) – Eruptive squamous atypia (eruptive keratoacanthoma) is an idiopathic proliferation of well-differentiated squamous cell carcinoma with atypia. This process is sometimes prone to koebnerization, and thus, surgical excision may result in further development of eruptive squamous atypia at the sites of surgery [99]. Some of these lesions

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may not meet the histologic criteria for keratoacanthomas and may represent other entities, such as pseudoepitheliomatous hyperplasia or infundibulocystic hyperplasia. The use of intralesional 5fluourouracil has been described as a successful treatment of eruptive squamous atypia with a 67 percent rate of resolution and 90 percent of patients needing less surgery/fewer surgical excisions 12 months after the initiation of intralesional 5-fluourouracil [99]. A rare presentation of multiple KAs characterized by features of both MSSE and generalized eruptive keratoacanthomas of Grzybowski has been reported, and is referred to as multiple familial keratoacanthoma of Witten and Zak [95,100]. Patients with the variant of Lynch syndrome known as Muir-Torre syndrome, a genetic autosomal dominant condition characterized by KA, sebaceous tumors, and visceral malignancies, may also present with several KAs [98,101-106]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Muir-Torre and Turcot variants'.) In addition, a clinical presentation characterized by the coexistence of prurigo nodules and multiple KAs on pruritic, actinically damaged skin has been described in several patients [107].

DIAGNOSIS

Although observation of lesions with clinical features consistent

with KA from the proliferative phase through spontaneous resolution has been used by some clinicians to diagnose and manage KA [72], this process typically takes at least several months, and the diagnosis remains in question until lesion regression. A major concern related to this approach is the misdiagnosis of cutaneous squamous cell carcinoma, a lesion with a relatively greater risk for metastasis and death. Due to the difficulty in clinically distinguishing KA from cutaneous squamous cell carcinoma, we biopsy and treat all lesions suspicious for KA. In the case of eruptive squamous atypia, it would also be reasonable to consider intralesional 5-fluourouracil as a treatment choice [99]. The recognition of both clinical and histopathologic features consistent with KA is used to make the diagnosis.

Clinical assessment — The clinical assessment of patients with lesions suspicious for KA should always involve obtaining a clear account of the lesion time course since a history of rapid growth within weeks favors this diagnosis. Patients should also be questioned regarding a history of prior similar lesions, sebaceous tumors, and visceral malignancies. These questions may help to identify the presence of a syndromic disorder. (See 'Multiple keratoacanthomas' above.) Since extensive sun-exposure is likely a precipitating factor for KA as well as multiple other cutaneous tumors, careful examination of the entire skin surface should be performed. In addition, the incidental detection of multiple lesions suspicious for sebaceous tumors during the skin examination may suggest the possibility of the Muir-Torre variant of Lynch syndrome. (See "MuirTorre syndrome".)

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Dermoscopy may aid in clinically distinguishing KA from other lesions but cannot reliably distinguish KA from squamous cell carcinoma [108]. White circles, keratin, blood spots, and white structureless zones are common dermoscopic findings in both KA and squamous cell carcinoma. (See "Overview of dermoscopy" and "Dermoscopic evaluation of skin lesions".)

Biopsy — The recognition of the classic pathological architecture of KA is a key component of diagnosis, and thus, performing the appropriate biopsy procedure is crucial for accurate assessment. Whenever feasible, biopsies should involve removal of the entire lesion. The preferred method for obtaining a biopsy specimen is an excisional biopsy extending into the subcutaneous fat. At least a 4 mm margin is usually taken when feasible to concurrently suffice for treatment. (See "Keratoacanthoma: Management and prognosis", section on 'First-line therapy'.) An alternative method for obtaining the tissue specimen is the performance of a deep shave biopsy (also known as a saucerization procedure) that removes the entire lesion and extends into the subcutaneous fat. Since improperly performed shave biopsies are often inadequate for diagnosis, shave biopsies of KA should only be performed by clinicians with extensive experience with the shave procedure [2]. Punch biopsies do not allow for the examination of the lesion architecture, and therefore, are not recommended. (See "Skin biopsy techniques", section on 'Biopsy techniques'.) Removal of the entire lesion for diagnosis may be impossible in patients with giant lesions or keratoacanthoma centrifugum marginatum (KCM). In such cases, a fusiform incisional biopsy through the center of the lesion that includes a cross-section of the lesion (periphery and center) and extends into the underlying fat can be performed [9,109]. This provides a specimen that represents the lesion architecture without total removal of the lesion.

Histopathology — Although no single histopathologic finding reliably confirms a diagnosis of KA, an overall picture of consistent histopathologic and clinical findings is used to support the diagnosis. The histopathological features that typically characterize KA include [32,110]: ●Epidermal hyperplasia with large eosinophilic keratinocytes ●Central invagination with a keratotic core (this may be less evident in early stage lesions) ●"Lipping" or "buttressing" of the epidermis over the peripheral rim of the central keratotic plug ●Sharp demarcation between the tumor and the surrounding stroma ●Mixed inflammatory infiltrate in the dermis The majority of keratinocytes in KA do not exhibit signs of atypia, and mitoses are not a prominent feature, though they may be observed in the deepest components of some lesions [32]. Islands of tumor cells may be present underlying the main portion of the tumor. The tumor islands usually do not extend beyond the depth of the eccrine glands.

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Aggressive features such as perineural invasion and intravascular involvement may be seen in a minority of specimens from lesions of KA, and have been used by some authors to support the classification of KA as a variant of cutaneous squamous cell carcinoma [29,111]. The significance of perineural invasion, a negative prognostic factor in cutaneous squamous cell carcinoma, is unclear in KA. (See "Keratoacanthoma: Management and prognosis", section on 'Metastasis'.)

Differentiation from squamous cell carcinoma — Differentiating KA from cutaneous squamous cell carcinoma based upon histopathologic examination is challenging [30,32]. An analysis of approximately 300 KAs and squamous cell carcinomas found that no histopathologic criterion was sufficiently sensitive or specific to reliably distinguish between these lesions [32]. However, among the pathologic features typically ascribed to KA, the presence of an epithelial lip and a sharp outline between the tumor and stroma appeared to be the most useful factors for the diagnosis of KA. In contrast, the presence of ulceration, mitoses, and pleomorphism or anaplasia favored a diagnosis of squamous cell carcinoma. Due to the lack of histopathologic features that definitively distinguish KA from squamous cell carcinoma, studies of specific biomarkers and genetic analyses have attempted to identify additional methods for differentiating these lesions [25,28,112-127]. Promising examples include recognition of the labelling pattern of the cytolytic calcium channel receptor p2X7, a marker of apoptosis [25], and the detection of specific chromosomal aberrations within these lesions [28]. Further studies are necessary to determine whether these tests and other studies will be useful for diagnosis in the clinical setting.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis

of KA is broad and includes other nodular tumors and growths of the skin. The combination of a history of rapid growth, central keratotic crater formation, and consistent histopathologic findings are often helpful for distinguishing KA from other disorders. As noted above, squamous cell carcinoma is the most difficult disorder to distinguish from KA due to the multiple clinical and histopathologic similarities between these lesions. Examples of additional lesions to consider in the differential diagnosis of solitary KA include the following: ●Nodular basal cell carcinoma (picture 5) (see "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma", section on 'Nodular') ●Merkel cell carcinoma (picture 6) (see "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Clinical features') ●Prurigo nodule (picture 7) (see "Prurigo nodularis", section on 'Clinical manifestations') ●Giant molluscum contagiosum (picture 8) (see "Molluscum contagiosum", section on 'Clinical features')

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●Deep fungal infection (eg, sporotrichosis) (picture 9) ●Nodular Kaposi's sarcoma (picture 10) (see "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment", section on 'Clinical features') ●Cutaneous metastases [128,129] The combination of clinical assessment and biopsies are also useful for narrowing the differential diagnosis for other presentations of KA. The possibility of paronychia, periungual squamous cell carcinoma, viral warts, and subungual tumors associated with incontinentia pigmenti should be considered in patients with lesions suspicious for subungual KA [130]. (See "Incontinentia pigmenti", section on 'Extracutaneous findings'.) In addition, the clinical appearance of KCM may resemble giant porokeratosis of Mibelli or halogenoderma [131]. (See "Porokeratosis", section on 'Porokeratosis of Mibelli'.) In patients with suspected multiple KA syndromes, the possibility of other disorders that may present with widespread nodular lesions, including prurigo nodularis and perforating disorders (eg, Kyrle's disease), should be considered. (See "Perforating dermatoses".)

SUMMARY AND RECOMMENDATIONS ●Keratoacanthoma (KA) is a cutaneous tumor that most commonly occurs in middle-aged and elderly individuals with fair skin. Controversy exists over whether KA represents a distinct disease entity or a variant of cutaneous squamous cell carcinoma. (See 'Epidemiology' above and 'Relationship with squamous cell carcinoma' above.) ●The pathogenesis of KA is poorly understood. Factors that influence epidermal cell proliferation, cell adhesion, cell survival, and apoptosis have been identified as potential contributors to these lesions. (See 'Pathogenesis' above.) ●Risk factors associated with KA include fair skin, exposure to ultraviolet radiation or chemical carcinogens, genetic abnormalities, and certain medications. The role of human papillomavirus in KA remains uncertain. (See 'Risk factors' above.) ●Solitary KA is the most common manifestation of KA. Lesions are usually 1 to 2 cm in diameter and are most commonly found on sun-exposed skin (picture 1A-E). Solitary KAs undergo three phases of evolution: a proliferative period of several weeks, a maturation phase that may persist for several months, and eventual lesion regression. (See 'Solitary keratoacanthoma' above.) ●A variety of additional variants of KA have been described, including giant KA (picture 2), subungual KA, mucosal KA, and keratoacanthoma centrifugum marginatum. KAs may also present as a feature of multiple KA syndromes, such as multiple self-healing squamous epithelioma

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(Ferguson-Smith disease), generalized eruptive keratoacanthomas of Grzybowski, and eruptive squamous atypia (eruptive keratoacanthoma). In addition, the Muir-Torre variant of Lynch syndrome may present with KA, sebaceous tumors, and visceral cancer. (See 'Clinical variants' above and 'Multiple keratoacanthomas' above.) ●The diagnosis of KA is based upon the combination of clinical and histopathologic findings, as the differentiation of KA from cutaneous squamous cell carcinoma based upon histopathologic examination is challenging. (See 'Diagnosis' above and 'Histopathology' above.)   ●Complete removal of the lesion via surgical excision extending into the subcutaneous fat is the preferred procedure for lesions suspicious for KA. Alternatively, a deep shave biopsy (also known as a saucerization procedure) that removes the entire lesion and extends into the subcutaneous fat can be performed by clinicians experienced in this procedure. Alternatively, intralesional injections with 5-fluourouracil for the classic eruptive squamous atypia variant has been shown to be very effective. (See 'Biopsy' above.)

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Keratoacanthoma: Management and prognosis - UpToDate uptodate.com/contents/keratoacanthoma-management-and-prognosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Mar 11, 2019.

INTRODUCTION

Keratoacanthoma (KA) is a cutaneous

squamoproliferative tumor that usually presents as a 1 to 2 cm dome-shaped or crateriform nodule with central hyperkeratosis (picture 1A-E). A common and distinctive feature of KA is a clinical course characterized by phases of rapid growth, lesion stability, and spontaneous involution. The approach to the management of KA is debatable since lesions can resolve without treatment. However, the well-accepted difficulty in distinguishing KA from cutaneous squamous cell carcinoma, a common tumor associated with a risk for metastasis, leads many clinicians (including ourselves) to recommend treatment of these lesions. The treatment and prognosis of KA will be discussed here. The epidemiology, risk factors, and diagnosis of KA are reviewed separately. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis".)

OVERVIEW

A longstanding debate over the classification of KA as a benign,

spontaneously resolving tumor versus a variant of cutaneous squamous cell carcinoma with a rare potential for metastasis has contributed to a lack of definitive guidelines on the treatment of these lesions. Although most authors, including ourselves, advocate for treatment of KA [1-7], observation

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until spontaneous resolution has also been used for management of these lesions [4,8]. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Relationship with squamous cell carcinoma'.) We opt to treat KA based upon the following considerations [2]: ●No clinical or pathologic features can reliably differentiate KA and cutaneous squamous cell carcinoma ●Treatment accelerates lesion resolution ●Treatment is usually straight forward and efficient, with relatively minor risk ●Early treatment may improve cosmetic outcomes by limiting damage to the skin and underlying structures, such as the nose, eyelids, or lips Surgical excision is the first-line treatment for patients with the most common clinical presentation of KA, a solitary lesion. Other therapeutic options for solitary KA include electrodesiccation and curettage (ED&C), intralesional injections, radiation, and topical therapy. We defer therapeutic intervention and proceed with observation only in patients who refuse to proceed with treatment. (See 'Deferring therapy' below.) The management of patients with numerous KAs or very large KAs is more challenging than the treatment of solitary KA since the methods typically used to treat individual lesions are often impractical in these settings. Systemic pharmacologic therapy is an additional treatment option for patients with large or numerous KAs. Oral retinoids, such as acitretin and isotretinoin, are the systemic agents most commonly prescribed for this indication. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Clinical variants' and "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Multiple keratoacanthomas'.)

SOLITARY KERATOACANTHOMA First-line therapy — Conventional surgical excision is the treatment of choice for solitary KA since it allows for both the assessment of histopathologic features to aid in diagnosis and pathologic confirmation of the removal of the tumor. Mohs surgery, a more complex and more expensive method of surgical excision, is usually reserved for patients in whom a tissue-sparing procedure is desired. In a single institution, retrospective study, both surgical excision and Mohs surgery were associated with a recurrence rate of 85 years, respectively. Due to aging of the "baby boomer" generation, the United States' MCC incidence is predicted to climb to 2835 cases in 2020 and 3284 cases in 2025 [3]. Increases in incidence rates have also been reported in European countries: from 0.18 to 0.33 per 100,000 persons per year from 1993 to 2012 in Sweden [4], from 0.17 to 0.35 per 100,000 persons per year from 1993 to 2007 in the Netherlands [5], and from 0.57 to 0.74 per 100,000 persons per year from 2006 to 2010 in France [6]. Higher incidence rates are reported in Australia and New Zealand [7-9]. Data from the Queensland Cancer Registry indicate an average annual incidence of 1.6 per 100,000 between 2006 and 2010, with a peak rate of 20.7 per 100,000 for individuals 80 years or older [7]. Data from Western Australia between 1993 and 2007 indicate an annual incidence of 0.82 per 100,000 and 15.5 per 100,000 for individuals ≥85 years [9]. An annual incidence of 0.88 per 100,000 has been reported in New Zealand between 2002 and 2011, with a peak rate of 17.6 per 100,000 among individuals ≥85 years [8].

Risk factors — MCC predominantly affects persons with light skin. A study analyzing SEER data from 1973 to 2006 found that 95 percent of cases diagnosed during this interval arose in the white population [10]. MCC is typically seen in older individuals, with a mean age at diagnosis of 76 years for women and 74 years for men [10]. However, MCC occurs at a younger age and higher incidence in immunosuppressed subjects, including organ transplant recipients, HIV-infected individuals, and those with B cell malignancies [11-17]. Data from the United States Scientific Registry of Transplant Recipients and 15 population-based cancer registries indicate that transplant recipients have a 24-fold higher risk of MCC than immunocompetent patients [11]. The highest incidence occurs 10 or more years after transplant. Maintenance treatment with mammalian (mechanistic) target of rapamycin (mTOR) inhibitors and azathioprine or cyclosporine confers a higher risk of MCC [11]. (See 'Immunosuppression' below.) The risk of MCC is significantly increased in patients with other malignancies [16,18]. In a SEER database study of over two million patients with cancer, the risk of MCC was significantly increased in those with multiple myeloma, chronic lymphocytic leukemia, and malignant melanoma (standardized incidence ratio [SIR] 3.7, 6.9, and 3.1, respectively) [16]. During the first year after

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diagnosis, patients with a primary diagnosis of MCC had a significantly increased incidence of second cancers of the salivary gland, biliary tract, and non-Hodgkin lymphoma (SIR 11.6, 7.2, and 2.6, respectively). A retrospective study of 4164 patients with chronic lymphocytic leukemia and 172 patients with MCC supported the association between these two disorders reported in the SEER database study [19]. Among patients with a diagnosis of chronic lymphocytic leukemia, the incidence of a subsequent diagnosis of MCC was greatly elevated (SIR 15.7, 95% CI 3.2-46). Patients with a preceding diagnosis of MCC also exhibited an increased risk for developing chronic lymphocytic leukemia (SIR 17.9, 95% CI 2.2-64.6).

HISTOGENESIS

Based upon early histologic and ultrastructural studies,

Merkel cell carcinoma (MCC) has been traditionally believed to arise from Merkel cells, which are located in the basal layer of the epidermis and hair follicles and are associated with sensory neurites in the dermal papillae, the skin mechanoreceptors [20]. However, this hypothesis is controversial. An alternative hypothesis is that these tumors originate from an immature totipotential stem cell that acquires neuroendocrine features during malignant transformation [21]. Based on cancer genomic studies and an understanding of the two different etiologies of MCC (Merkel cell polyomavirus [MCPyV]-positive or -negative MCCs), it is plausible that MCC tumors might not have a single cell of origin. MCPyV-positive MCCs might arise from dermal fibroblasts and MCPyV-negative MCCs from epidermal keratinocytes, but this is a highly controversial area [22]. (See 'Merkel cell polyomavirus' below.)

PATHOGENESIS

Several factors have been associated with the

development of Merkel cell carcinoma (MCC). These include infection with the Merkel cell polyomavirus (MCPyV), ultraviolet (UV) radiation exposure, and immunosuppression.

Merkel cell polyomavirus — Merkel cell polyomavirus (MCPyV) is a nonenveloped, double-stranded DNA virus that has been causally linked to the development of MCC (picture 1) [23-26]. Previous studies have consistently reported that MCPyV can be detected in approximately 80 and 60 percent of all MCCs by real-time polymerase chain reaction (PCR) and immunohistochemistry, respectively [27]. A 2015 meta-analysis of 23 studies found an overall MCPyV prevalence of 79 percent (95% CI 72-84 percent) in Merkel cell tumors versus 12 percent (95% CI 8-9 percent) in control skin samples [28]. In one study using monoclonal antibodies capable of detecting large T antigen by immunohistochemistry, 56 of 58 (97 percent) MCCs were found to be associated with MCPyV, whereas enhanced quantitative PCR primers detected viral DNA in all 60 MCC tumors tested [29]. MCPyV is a ubiquitous virus, with five specific geographically related genotypic variants [30]. MCPyV is thought to be part of the human skin microbiome and appears to be chronically shed from the skin in the form of assembled virions [31]. The seroprevalence of antibodies specific to the capsid viral

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protein 1 (VP1) appears to increase with age, from approximately 40 percent in children to up to over 80 percent in older individuals [26,32-34]. The observation that the integration of the virus into the tumor genome precedes the clonal expansion of tumor cells suggests that the virus is present at tumor initiation and that one or more viral proteins are oncogenic drivers [23,35]. MCPyV encodes two main oncoproteins, the large tumor (LT) antigen and small tumor (sT) antigen, which are both persistently expressed in MCC and have been implicated in oncogenesis through multiple mechanisms. Sequential events involved in the pathogenesis of MCPyV-positive tumors include clonal integration into the host genome, expression of sT, acquisition of mutations in the 3' end of LT, and evasion of a destructive immune response [1,36,37]. Mutations in LT result in a truncated molecule that lacks the DNA binding domain and the helicase domain, which renders the virus replication incompetent while preserving its retinoblastoma (RB1) gene binding property and the expression of the oncogenic viral proteins [38]. LT antigens with intact RB1 binding domain sequester and inactivate the tumor suppressor, resulting in sustained tumor growth. MCPyV has been detected in normal-appearing skin and in other tumors, including cutaneous squamous cell carcinoma, chronic lymphocytic leukemia, and folliculotropic mycosis fungoides [3945]. In one series of patients with MCC, skin samples taken from sites distant from the tumor were positive for the virus in 10 out of 14 cases (71 percent), a frequency higher than that was observed in six skin samples from normal individuals (17 percent) [39]. Importantly, outside of MCC, evidence of clonal integration of the virus and expression of viral proteins in tumor cells is almost invariably lacking in other cancers, suggesting that the occasional detection of the virus was likely coincidental rather than causal in non-MCC tumors [46].

UV radiation — Ultraviolet (UV) radiation exposure, especially to the sun, is thought to play an important role in the etiology of many cases of MCC. The following observations are consistent with an etiologic role for UV radiation exposure: ●MCC has a predilection for sun-exposed areas. In a study of the clinical manifestations in 195 cases of MCC, the tumor arose in a UV-exposed region in 81 percent of assessable cases [17]. Furthermore, 98 percent of cases occurred in fair-skinned individuals. ●Regional incidence rates correlate with increasing sun exposure, as measured by the ultraviolet B (UVB) solar index [8,9,47,48]. ●Presentation with other skin cancers, for which sun exposure is a major risk factor, is common [18,49]. (See "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma" and "Epidemiology and risk factors for cutaneous squamous cell carcinoma".) ●MCC has been described in patients treated with PUVA (psoralen plus ultraviolet A) photochemotherapy [50].

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●Multiple reports describe UVB signature mutations in MCC tumors [51-54]. UV radiation exposure may be especially relevant in the pathogenesis of the viral-negative subtype of MCC. This hypothesis is supported by the observation that in Australia the incidence of MCC is highest, but the prevalence of MCPyV-positive tumors is much lower than in other geographic areas. An Australian study of 95 MCC reported a 23 percent prevalence of MCPyV positivity; the prevalence was even lower in tumors occurring in skin areas with evidence of sun damage (ie, elastosis, squamous dysplasia) [55].

Immunosuppression — The incidence of MCC is increased in immunosuppressed patients, including organ transplant recipients [11-13,56-58], HIV-infected individuals [14,15], and those with B cell malignancies [11,16,17]. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients", section on 'Merkel cell carcinoma' and "HIV infection and malignancy: Management considerations", section on 'Merkel cell carcinoma and other neuroendocrine tumors'.) The mechanism by which immunosuppression interacts with MCPyV and UV radiation exposure in the pathogenesis of MCC is unknown. Immunosuppression may facilitate the replication of MCPyV and increase the chance of virus integration in the MCC progenitor cell. In addition, reduced immune surveillance may contribute to the survival and proliferation of atypical cells. Finally, immunosuppressive agents, such as azathioprine or calcineurin inhibitors, have been shown to act synergistically with UV radiation in inducing mutagenesis and promoting skin carcinogenesis in an immunosuppression-independent manner [59-63].

Viral-negative Merkel cell carcinoma — Some MCCs have low or negligible levels of MCPyV T antigen expression. The mechanisms of oncogenesis underlying MCPyV-negative MCC are incompletely understood, but they are thought to involve somatic mutations in tumor suppressor genes such as TP53 and retinoblastoma (RB1), as well as epigenetic alterations, such as DNA methylation and microRNAs, resulting in aberrant expression and activity of oncogenes [38,64-67]. Mutations in TP53 (encoding p53) occur infrequently in MCCs and have been found almost exclusively in tumors with low or complete lack of MCPyV LT antigen expression [53,68]. The expression of retinoblastoma protein (RB), a key cell cycle regulator, is low or absent in viral-negative tumors, whereas nearly all MCPyV-positive tumors are also RB-positive [68]. The frequency of TP53 mutations, either UV signature mutations or non-UV signature mutations, appears to be higher in MCPyV-negative MCCs than in MCPyV-positive tumors [69]. An analysis of MCPyV-positive and MCPyV-negative MCCs using next-generation sequencing found an overall high mutational burden in MCPyV-negative tumors compared with MCPyV-positive tumors [53]. In MCPyV-negative tumors, the majority of tandem substitutions were CC > TT substitutions, characteristic of UV mutational signature, whereas only one CC > TT tandem substitution was detected across all MCPyV-positive tumors. Activating oncogenic mutations in HRAS, PIK3CA, KNSTRN, PREX2, and RAC1 were found in six of eight MCPyV-negative tumors but only in two of eight MCPyV-positive tumors. Highly recurrent mutations in tumor suppressor genes, including TP53, RBI,

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NOTCH1, and PRUNE2, were also found in MCPyV-negative tumors. These findings suggest that genetic aberrations independent of MCPyV infection are involved in the pathogenesis of viralnegative MCCs.

CLINICAL FEATURES

Merkel cell carcinoma (MCC) typically

presents in older patients with light skin tones as a rapidly growing, painless, firm, nontender, shiny, flesh-colored or bluish-red, intracutaneous nodule (picture 2A-C). Ulceration and crusting are infrequent. MCCs range in size from less than 1 cm to over 2 cm and are most often located in sunexposed areas. In an analysis of 9387 MCC cases from the National Cancer Database between 1998 and 2012 [70], patients had a median age of 76 years, with 88 percent aged ≥60 years and 70 percent aged ≥70 years. The most frequent anatomic locations for the primary tumor were the following: ●Head and neck – 43 percent ●Upper limbs and shoulder – 24 percent ●Lower limbs and hip – 15 percent ●Trunk – 11 percent ●Other areas – 9 percent In this series, patients presented with local disease only in 65 percent of cases, while 26 percent had regional lymph node involvement at presentation, and 8 percent had distant metastases; 3.6 percent had lymph node involvement with an unknown primary tumor and without distant metastases. In these patients, the primary tumor may have spontaneously regressed [71-74]. (See "Staging and treatment of Merkel cell carcinoma", section on 'Unknown primary'.)

DERMOSCOPIC FEATURES

Data on the dermoscopic

findings of Merkel cell carcinoma (MCC) are limited, and features specific to a diagnosis of MCC have not been identified. Some of the dermoscopic findings reported in small retrospective series include milky red areas; linear, irregular vessels; and polymorphous vessels (picture 3) [75-78]. Additional studies are necessary to clarify the dermoscopic features of MCC and to determine whether dermoscopy will be useful for early diagnosis, but this approach is unlikely to be broadly useful due to lack of specific features, rarity of MCC, and the need for a highly expert dermoscopist to potentially recognize the features. (See "Overview of dermoscopy".)

DIAGNOSIS 4460

Clinical suspicion — Merkel cell carcinoma (MCC) is often clinically misdiagnosed as a benign lesion (eg, cyst, lipoma, pyogenic granuloma) [17]. A high index of suspicion is required if the diagnosis is to be made without delay. An analysis of data from the Surveillance, Epidemiology, and End Results (SEER) registry from 1973 to 2014 on over 3400 patients with MCC found that younger age (2 cm (T2 or T3) or a primary tumor with invasion into bone, muscle, fascia, or cartilage (T4), without evidence of lymph node involvement. Stage II is divided into two subgroups based upon the size and depth of invasion of the primary tumor. ●Stage III – Any primary tumor with regional lymph node disease. Pathologic stage III is divided into subgroups based upon the extent of regional lymph node involvement. ●Stage IV – Metastasis beyond the regional lymph nodes, regardless of the status of the primary tumor and regional nodes. The eighth edition TNM classification is based upon an analysis of 9387 patients with MCC from the National Cancer Database who were diagnosed between 1998 and 2012, which provides more detailed correlation with clinical outcomes (figure 1A-C) [2]: ●Local disease – Sixty-five percent of patients had local disease without clinical or pathologic evidence of regional lymph node involvement or metastatic disease. The five-year overall survival rate for these patients was 55.6 percent, and there was a progressive decrease in overall survival for those with a T1 (≤2 cm), T2 to T3 (>2 to 5 cm; >5 cm), and T4 (invasion of the fascia or deeper tissues) primary lesion, with five-year overall survival rates of 55.8, 41.1, and 31.8 percent, respectively.

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●Regional disease – At presentation, 26 percent of patients had regional lymph node involvement without disseminated metastatic disease; the five-year overall survival for this group was 35.4 percent. This group included those with occult disease (detected at sentinel lymph node biopsy or regional lymph node dissection) and those with clinically detected regional lymph node involvement or in transit metastases. The five-year overall survival for those with occult disease was 39.7 percent; for those with clinically detected nodal disease, the five-year overall survival was 26.8 percent, while for those with in transit disease, the five-year overall survival was 41.4 percent. Patients with lymph node metastasis and an unknown primary tumor constituted 3.6 percent of the total cohort. The five-year overall survival for these patients was 42.2 percent. ●Distant metastases – At initial presentation, 8.4 percent of patients had distant metastatic disease. The five-year overall survival for these patients was 13.5 percent.

APPROACH TO STAGING AND MANAGEMENT Initial staging procedures — Once a tumor biopsy has confirmed the diagnosis of MCC, the initial evaluation should include a complete examination of the skin and regional lymph nodes, with appropriate evaluation of any abnormalities that are detected. Imaging studies are important because of the metastatic potential of this cancer. In patients with stage II or III disease, positron emission tomography (PET) with fludeoxyglucose (FDG), combined with computed tomography (CT) and/or magnetic resonance imaging (MRI), may be particularly useful and influence subsequent management [3]. Baseline determination of Merkel virus oncoprotein antibody titer can assist with prognosis and subsequent detection of recurrent disease [4,5].

Initial management — Based upon the initial evaluation, subsequent management depends on the pathologic characteristics of the primary tumor and whether or not there is clinical evidence of lymph node or distant metastases (algorithm 1). ●For patients with biopsy-confirmed MCC but without clinical evidence of regional lymph node involvement, sentinel lymph node (SLN) biopsy is generally indicated prior to or in conjunction with definitive local therapy. However, the role of SLN biopsy is less clear for lesions arising in the head and neck region since the lymphatic drainage from primary tumors in this region is variable. (See 'Clinically negative nodes' below and 'Head and neck lesions' below.) •For patients with a negative SLN biopsy, wide local excision is indicated. For patients in whom surgery is not technically feasible and for those who are not surgical candidates, radiation therapy (RT) to the primary tumor is an alternative [6,7]. (See 'Primary tumor' below.)

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•For patients with a positive SLN biopsy, careful evaluation for occult metastatic disease is indicated. -If no distant metastatic disease is detected, definitive treatment of the regional lymph node basin is indicated by nodal dissection or definitive RT. Preliminary evidence shows that lymph node excision followed by nodal RT has good results [6]. (See 'Regional lymph nodes' below.) -If distant metastatic disease is identified, systemic therapy, preferably in a protocol setting, and best supportive care are indicated. Local treatment with surgery or RT of a symptomatic primary or regional node(s) should be given if the metastatic disease is not responsive to systemic therapy. In situations such as spinal cord compression or superior vena cava obstruction, RT should be started promptly. (See 'Metastatic disease' below and 'Clinically positive nodes' below.) •For patients not undergoing SLN mapping and biopsy, adjuvant RT to the regional lymph nodes is indicated. Without any elective regional lymph node treatment, at least 17 percent of patients with a primary tumor ≤1 cm will eventually develop nodal disease [8,9]. (See 'Radiation therapy' below.) •Adjuvant RT to the primary tumor bed and/or regional lymphatics is recommended for those at increased risk for recurrence. Risk factors include the presence of any of the following: a primary tumor ≥1 cm in maximum dimension, a head and neck primary, positive or limited surgical resection margins, lymphovascular invasion, multiple involved nodes, extracapsular extension in an involved lymph node, or an immunocompromised host. These patients may also be considered for inclusion in a clinical trial of immunotherapy. (See 'Radiation therapy' below and 'Adjuvant immunotherapy' below.) ●For patients with suspected clinical lymph node involvement, biopsy confirmation (fine needle aspirate, core needle biopsy, or excisional biopsy) is indicated. •If biopsy confirms the presence of nodal disease, patients should be carefully evaluated for the presence of metastatic disease. If there are no distant metastases detected, we recommend excision of the primary tumor and definitive therapy of the draining lymphatics (regional lymph node dissection or nodal excision, followed by regional RT covering the intervening lymphatics if the RT field size is not too large or morbid). For very frail patients who cannot tolerate even local nodal excision under local anesthetic, definitive regional RT may be used instead, although local control will only be around 75 to 85 percent [10-13]. (See 'Clinically positive nodes' below.) •If fine needle aspirate or core needle biopsy of the suspicious node is negative, excisional nodal biopsy may be indicated [5]. (See 'Clinically negative nodes' below.) •For patients who have undergone wide local excision and regional lymph node dissection, risk factors indicating the need for adjuvant RT to the tumor bed include the presence of a primary tumor ≥1 cm, positive or limited surgical resection margins, lymphovascular invasion, a head and neck primary, and an immunocompromised host. In addition, extracapsular extension of tumor outside the lymph node(s) or involvement of multiple nodes is associated with an increased risk of

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recurrence and is an indication for adjuvant regional RT. Participation in a clinical trial of adjuvant immunotherapy, if available, should be considered for patients at high risk following treatment of the lymph nodes. (See 'Adjuvant immunotherapy' below.) ●For patients who are thought to have disseminated disease after their initial evaluation, biopsy confirmation of the metastasis is indicated prior to systemic therapy. •If disseminated metastases are confirmed, consideration of patient-specific factors, including sites of disease involvement, age, comorbidity, and patient preferences, is necessary in choosing an optimal approach. We suggest treatment with a programmed cell death ligand 1 (PD-L1)-blocking agent (avelumab) or programmed cell death protein 1 (PD-1) inhibitor-based immunotherapy (pembrolizumab, nivolumab) as a first-line treatment option. A clinical trial of systemic therapy is preferred whenever possible. (See 'Metastatic disease' below.) •Local treatment with surgery or RT of a symptomatic primary or regional node(s) should be given if metastatic disease is nonresponsive to systemic therapy. In situations such as spinal cord compression or superior vena cava obstruction, RT should be started promptly. •If distant metastases are not confirmed, patient management should be based upon the clinical status of the primary tumor and regional lymph nodes. (See 'Clinically negative nodes' below and 'Clinically positive nodes' below.)

PRIMARY TUMOR

Surgery, rather than radiation therapy (RT), is

preferred as the initial therapy of the primary tumor whenever possible, although it is associated with more morbidity in terms of cosmesis and function.

Surgery — Wide excision of the primary MCC is the standard approach to initial management of the primary tumor whenever possible [14,15]. A margin of at least 1 to 2 cm of normal-appearing skin is recommended. If margins are close or involved with tumor, postoperative RT is indicated to increase the probability of achieving local disease control. (See 'Radiation therapy' below.) Achieving negative margins with the initial wide local excision is important for long-term disease control. In a review of 661 cases, complete excision was associated with a statistically significant improvement in overall survival and a trend toward better disease-free survival (p = 0.08) [16]. Contemporary studies suggest that adjuvant RT improves overall and disease-free survival for patients at risk of recurrence (overall survival 73 versus 66 percent and disease-free survival 57 versus 30 percent, respectively) [17,18]. (See 'Radiation therapy' below.) However, data are limited regarding the appropriate surgical margin size if postoperative RT will be carried out. Based upon the available data, we suggest that surgery should not be so aggressive as to introduce significant delay in initiating adjuvant RT. In particular, extensive tissue movement and grafting should be avoided if adjuvant RT is planned [5].

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Because MCC often has extensive vertical growth and sometimes extends into muscle, deep margins are a potential site of failure. Mohs micrographic surgery can be considered to improve local tumor control and cosmetic outcomes in areas such as the face. If sentinel lymph node biopsy is to be carried out, it should be performed prior to Mohs surgery as tumor site excision would interfere with a subsequent node biopsy [5]. With this approach, 100 percent of all major borders, including the deep margins, are evaluated histologically. However, adjuvant RT still has a role in preventing locoregional recurrence even when Mohs surgery is used, as MCC recurs beyond pathologically negative margins more often than other skin cancers [19-21].

Radiation therapy — For patients in whom surgical resection is not technically feasible or who are medically unfit for surgery, definitive RT provides an alternative [6,10,14,22]. Higher doses of radiation (60 to 66 Gy) are recommended if RT is used alone rather than as an adjuvant [14]. RT achieves an in-field disease control rate of only 75 to 85 percent, and systemic relapse is not rare [10,11]. The role of chemoradiotherapy versus RT alone is controversial, and there are no randomized trials comparing chemoradiotherapy with RT alone as primary therapy for nonsurgical candidates. (See 'Chemotherapy or chemoradiotherapy' below.)

REGIONAL LYMPH NODES

Pathologic staging of

lymph node status is important for both prognosis and treatment planning [23]. Optimal management of the regional lymphatics depends on whether there is clinical or pathologic evidence of involvement with MCC as well as the size and pathologic characteristics of the primary tumor. The approach to management of the regional lymph nodes is based upon retrospective series since there are no randomized trials that provide definitive guidance.

Clinically negative nodes — Most patients with a biopsy-proven MCC should have sentinel lymph node (SLN) mapping and biopsy, including immunohistochemistry [14,15]. ●However, some clinicians do not perform SLN mapping and biopsy when the primary tumor size is ≥2 cm since radiation therapy (RT) is indicated because of the high risk of lymph node metastasis. ●In addition, the role of SLN biopsy is less clear for patients with a lesion arising in the head and neck region since the lymphatic drainage from primary tumors in this region is variable. If SLN biopsy is not carried out, lymph nodes should usually be treated with prophylactic RT [14]. SLN mapping and biopsy should be performed prior to or in the same setting as wide local excision because surgery may disrupt the lymphatic drainage from the primary tumor. This technique, which is widely used in patients with melanoma, is discussed separately. (See "Evaluation and treatment of regional lymph nodes in melanoma", section on 'Sentinel lymph node biopsy'.)

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The results of the SLN biopsy provide important prognostic information and help to guide further treatment. The impact on prognosis is illustrated by an analysis of 474 patients from the Surveillance, Epidemiology, and End Results (SEER) database who underwent SLN biopsy [24]. Patients with a negative biopsy had improved five-year MCC-specific survival compared with those with a positive biopsy (84.5 versus 64.6 percent). Approximately one-third of patients with clinically negative lymph nodes will have microscopic tumor involvement on pathologic examination [25]. However, a negative SLN biopsy does not preclude a subsequent regional recurrence. In an analysis of 721 patients, the false negative rate for SLN biopsy (as defined by a subsequent regional recurrence) was 17 percent [26]. Thus, adjuvant treatment to regional lymph nodes may be indicated even after a negative SLN biopsy, depending upon the characteristics of the primary tumor. (See 'Adjuvant therapy' below.) ●For patients with a negative SLN biopsy, adjuvant regional lymph node RT is indicated if there is a high risk of recurrence due to anatomic, technical, or histologic factors (previous wide local excision or immunohistochemistry not performed). If none of these factors is present and the patient is compliant with follow-up and imaging, observation is appropriate after SLN biopsy. ●If the SLN contains tumor, regional lymph node dissection or definitive RT to the lymph node basin is indicated. For patients managed with regional lymph node dissection, postoperative RT may be indicated, particularly in those with more extensive lymph node disease or extracapsular extension.

Clinically positive nodes — Patients with suspected lymph node involvement based upon clinical or radiographic findings require histologic confirmation of disease [14]. This may require fine needle aspirate, core needle biopsy, or open biopsy. If pathologic involvement of the regional nodes is confirmed, regional nodal therapy is indicated with surgery with or without postoperative RT. Excision of the clinically abnormal node followed by RT is supported by preliminary evidence [6]. Node dissection is recommended in the 2018 National Comprehensive Cancer Network (NCCN) guideline. RT as the primary modality can be considered in selected fragile cases who cannot tolerate even nodal excision under local anesthetic [12,13]. The role of adjuvant RT following complete lymph node dissection has not been definitively established by randomized trials. However, multiple studies provide evidence that RT can decrease the rate of locoregional recurrence and improve overall survival [17,27-29]. Involvement of multiple lymph nodes or extracapsular extension of tumor outside the lymph node(s) is associated with an increased risk of recurrence and is an indication for adjuvant regional RT following lymph node dissection. The risks of node dissection plus RT include lymphoedema, fibrosis of the joints, and subsequent functional impairment. Therefore, despite retrospective studies of decreased recurrence with adjuvant RT, clinical judgment is required to decide which patients can be followed after nodal dissection without adjuvant RT. In general, patients with clinically positive nodes have a five-year disease-specific survival of approximately 50 percent [30].

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The role of adjuvant immunotherapy is the subject of ongoing clinical trials. (See 'Immunotherapy' below.) For patients with a clinically positive lymph node that cannot be confirmed by appropriate pathologic examination (eg, confirmatory nodal biopsy is not feasible), we generally suggest RT to the primary tumor and draining lymph node basin. (See 'Adjuvant therapy' below.)

ADJUVANT THERAPY

Radiation therapy (RT) has an important

role in patients with MCC primarily managed with surgery to treat occult lymph node disease or minimum residual tumor at the primary site. The role of treatment (chemotherapy, immunotherapy) as part of a combined modality approach is not well established yet.

Radiation therapy — MCC is a radiosensitive malignancy. RT has been used as an adjuvant treatment after surgery to prevent recurrence in the primary tumor bed and regional lymphatics. Although there are no randomized trials supporting the role of adjuvant RT, multiple studies provide evidence that RT can decrease the rate of locoregional recurrence and improve overall survival [17,27-29]. The most extensive evidence supporting a role for adjuvant RT comes from an analysis of 6908 patients with MCC in the National Cancer Database [29]. In the 4843 patients without evidence of lymph node involvement (stage I or II), adjuvant RT was associated with significantly improved overall survival (hazard ratio [HR] 0.71, 95% CI 0.64-0.80). In contrast, there was no improvement in overall survival observed in the 2065 patients with lymph node positive (stage III) MCC (HR 0.98, 95% CI 0.86-1.12). When RT is used either as an adjuvant or as definitive treatment, it is important to treat all regional lymphatics to avoid geographic miss since recurrence in untreated regions may occur. Some use a 5 cm margin to cover the surgical bed for definitive or adjuvant RT [31,32]. As an example, the Trans Tasman Radiation Oncology Group (TROG) 96:07 study used a 3 to 5 cm margin, and the draining lymph nodes were treated in the same field as the primary if the nodal region was within 20 cm of the primary to reduce the risk of in transit recurrence [33,34]. The dose of RT to treat either the primary tumor or regional lymph nodes is based upon the tumor burden [14]. Following a resection with negative margins, a total RT dose of 50 to 56 Gy is generally considered adequate for those at significant risk for residual subclinical disease. A dose of 56 to 60 Gy is recommended for those with microscopically positive resection margins, and a dose of 60 to 66 Gy is recommended for definitive treatment of those with grossly positive margins, an unresectable primary lesion, or unresectable regional lymph nodes.

Chemotherapy or chemoradiotherapy — Systemic chemotherapy has demonstrated high response rates in patients with metastatic disease, but the duration of response is short. (See 'Metastatic disease' below.)

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The role of chemotherapy, either alone or in combination with RT, as an adjuvant following surgery for locoregional therapy is uncertain and/or controversial. Furthermore, there is concern about the immunosuppressive effects of chemotherapy. The immune system plays an important role in defense against MCC, based upon the increased incidence in immunosuppressed patients, association with Merkel cell polyomavirus, and reports of spontaneous regression. There are no randomized trials evaluating the efficacy of adjuvant chemotherapy or chemoradiotherapy in patients with MCC. ●The most extensive data supporting chemoradiotherapy come from a retrospective study of 4815 patients with MCC of the head and neck region [27]. Approximately 65 percent of patients had a primary tumor 50, and thoracic transplantation. Although limited prognostic data are available on patients who develop melanoma following organ transplantation, the results of a few studies suggest that while organ transplant recipients with thin melanomas may have survival rates that are comparable to patients in the general population, those with thicker lesions may have worse prognoses [95,112,113]. The largest study is a retrospective review of records from 638 patients with 724 post-transplantation melanomas that compared threeyear survival rates in this population with survival data on melanoma patients from the Surveillance, Epidemiology, and End Results (SEER) Program [112]. Melanoma-specific survival rates were lower than expected among organ transplant recipients with melanomas with 1.5 to 3.0 mm Breslow thickness but not significantly different from SEER data for lesions 2 mm thick) [113]. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".) Data on the prognosis of patients with melanoma prior to organ transplantation also are limited [95,112,114]. An analysis of the data from two retrospective studies [113,115] with a total of 17 patients who had invasive melanoma prior to organ transplantation (median depth 1 mm, range 0.35 mm to 18 mm) found no disease recurrences or disease-related deaths after organ transplantation within a median follow-up period of 5.5 years [116]. Of note, the majority of patients were

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transplanted more than two years after treatment of their melanomas. In contrast, recurrences of pretransplant melanoma were reported in 6 out of 31 patients in another retrospective study [114]. The six patients died 6 to 30 months after transplantation. Merkel cell carcinoma in transplant recipients tends to have a more aggressive course than in immunocompetent patients; approximately 70 percent of patients develop lymph node involvement, and the mortality rate at two years is estimated to be 56 percent [107]. Therefore, patients should be followed closely for the development of metastatic disease. (See "Staging and treatment of Merkel cell carcinoma", section on 'Prognostic factors'.)

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nonmelanoma skin cancer".)

SUMMARY AND RECOMMENDATIONS ●Chronic immunosuppression in organ transplant recipients is associated with a high risk for cutaneous malignancies. Squamous cell carcinoma (SCC) is the most common skin cancer in this population and is often associated with aggressive biologic behavior. Early detection and treatment of cutaneous malignancies, modulation of immunosuppression, and preventive measures play an important role in the management of these patients. (See 'Introduction' above.) ●A dermatologic consultation is recommended before transplantation for the screening and treatment of skin cancer and precursor lesions. A careful history of previous skin cancer should be obtained to determine whether a wait time is needed before proceeding to transplantation. (See 'Pretransplantation screening' above and 'Wait time' above.) ●The preventive management of skin cancer in organ transplant recipients requires a close collaboration between dermatologists and transplant teams and involves patient education, choice and modulation of the immunosuppressive regimen, and post-transplantation surveillance. (See 'Prevention' above.) ●Transplant recipients should be counseled on sun avoidance, the use of sunscreens and sunprotective clothing, and the warning signs of cutaneous malignancy. Patients should be instructed to perform a skin self-examination on a monthly basis. (See 'Sun protection' above.) ●Because type, intensity, and duration of immunosuppression appear to promote the development of cutaneous malignancies in organ transplant recipients, modification or reduction of immunosuppression may be beneficial for patients who develop numerous lesions, recurrent disease, or metastatic disease (table 3). (See 'Choice and modulation of immunosuppressive regimen' above.)

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●Chemoprevention with acitretin may be of benefit in patients who develop multiple or aggressive SCCs. (See 'Chemoprevention for SCC' above.) ●After transplantation, patients should continue to have total body skin examinations on a regular basis. We typically perform full skin examinations at least once yearly on fair-skinned individuals. More frequent examinations are indicated in patients with a history of actinic keratoses or skin cancer. Daily sun protection should be strongly encouraged. (See 'Post-transplantation surveillance' above.) ●All lesions suspicious for SCC in organ transplant patients should be biopsied and sent for pathologic evaluation. Patients should be staged based on the American Joint Committee on Cancer 8th edition criteria (table 5) and the alternative Brigham and Women's Hospital staging scheme (table 6). The treatment of SCCs is based upon the presence or absence of high-risk features. (See 'Squamous cell carcinoma' above.) ●Because SCCs in organ transplant recipients are generally considered high-risk lesions, excisional therapies that provide evaluation of histologic margins are generally preferred. Some clinicians perform electrodesiccation and curettage at the time of biopsy on lesions that are clinically consistent with small, well-differentiated SCCs. If pathology results demonstrate aggressive histopathologic features, subsequent surgical excision should be performed to ensure adequate tumor removal. (See 'Invasive lesions without additional high-risk features' above.) ●For SCCs in organ transplant recipients that exhibit additional high-risk features, we suggest treatment with Mohs surgery due to the high cure rates and tissue-sparing effect of this treatment (Grade 2B). If Mohs surgery is not available, excision with intraoperative frozen sections can be utilized. If neither of these options is feasible, patients can be managed with conventional surgical excision with postoperative margin assessment. (See 'Invasive lesions with additional high-risk features' above.) ●Basal cell carcinoma (BCC), melanoma, and Merkel cell carcinoma are managed similarly in organ transplant recipients and immunocompetent patients. Modulation of immunosuppression is the primary treatment for Kaposi sarcoma in organ transplant recipients. There are no definitive guidelines regarding alteration in immunosuppressive regimens in patients with BCC, melanoma, or Merkel cell carcinoma. The risks and benefits of reduction in immunosuppression should be considered carefully. (See 'Basal cell carcinoma' above and 'Melanoma' above and 'Kaposi sarcoma' above and 'Merkel cell carcinoma' above.) ●Population-based data on skin cancer mortality among organ transplant recipients are limited. A cohort study including nearly 500,000 patients who received a solid organ transplantation in the Unites States estimated a mortality from all skin cancers, including SCC, melanoma, and Merkel cell carcinoma, of approximately 35 per 100,000 person-years, a rate nearly nine times higher than that reported for the general population. (See 'Prognosis' above.)

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Sebaceous carcinoma - UpToDate uptodate.com/contents/sebaceous-carcinoma/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Apr 23, 2019.

INTRODUCTION

Sebaceous carcinoma is a rare malignant tumor of the

sebaceous glands [1]. It can occur in any body site where sebaceous glands are present, but is most commonly found in the head and neck region, particularly in the periocular area [2]. Sebaceous carcinoma of the eyelid (picture 1) may be mistaken for inflammatory lesions, such as chalazion or blepharoconjunctivitis, resulting in a delayed diagnosis and poorer prognosis [3]. Sebaceous carcinomas can occur sporadically or may be associated with Muir-Torre syndrome (MTS), a subset of the hereditary nonpolyposis colorectal cancer syndrome (HNCCS, Lynch syndrome) characterized by single or multiple sebaceous neoplasms, keratoacanthomas, and internal malignancy [4]. This topic will review the pathogenesis, clinical presentation, diagnosis, and treatment of sebaceous carcinoma. MTS and Lynch syndrome are discussed separately. (See "Muir-Torre syndrome" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management".)

EPIDEMIOLOGY

Sebaceous carcinoma is a rare tumor, with an estimated

incidence rate of approximately 1 to 2 per 1,000,000 per year [2,4,5]. However, sebaceous carcinoma is the most common eyelid malignancy after basal cell carcinoma and squamous cell carcinoma [6,7].

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A review of the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2012 identified 2201 cases of sebaceous carcinoma [8]. More than 98 percent of cases were seen in patients older than 40 years, with a peak incidence between the ages of 60 to 79 years. The incidence rate among whites was almost three times higher than among nonwhites. The five-year observed survival was 78 percent (95% CI 76-80 percent). The risk of all-cause mortality was higher in males, in black patients, and in patients with extraocular tumors [8]. Sebaceous carcinoma is exceedingly rare in children, with only a few cases reported [9,10].

PATHOGENESIS

Ocular sebaceous carcinomas arise from the

meibomian (tarsal), Zeiss (eyelash), or sebaceous glands of the eyelid and caruncle. There are several reports of sebaceous carcinoma arising within a nevus sebaceous [11]. The origin of extraocular sebaceous carcinoma is less clear. The observation of sebaceous carcinoma in association with actinic keratosis or Bowen disease, suggests that extraocular sebaceous carcinoma may originate from a preexisting intraepidermal neoplasia [12-14]. The molecular pathogenesis of sebaceous carcinoma is incompletely understood. Tumors associated with Muir-Torre syndrome (MTS) show loss of mismatch repair (MMR) gene expression and microsatellite instability (MSI) [15]. Loss of MSH2, MSH6, or MLH1 gene expression is seen in sebaceous carcinomas associated with MTS, as well as in hereditary Lynch-syndrome-associated cancers. Lynch syndrome is an autosomal dominant disorder characterized by a predisposition to colorectal cancer and extracolonic malignancies. Lynch syndrome is caused by a germline mutation in one of the four DNA MMR genes (MLH1, MSH2, MSH6, and PMS2) or loss of expression of MSH2 due to deletion in the EPCAM gene. MTS is considered a variant of Lynch syndrome in which patients present with sebaceous neoplasms and/or keratoacanthomas. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".) Loss of expression of MSH2 and microsatellite instability have also been detected in sebaceous carcinomas in organ transplant recipients, suggesting that immunosuppression may unmask a MuirTorre phenotype [16,17]. (See "Muir-Torre syndrome".) Sporadic sebaceous carcinomas usually do not show microsatellite instability and loss of mismatch repair gene expression [15,18]. P53 mutations without a UV signature have been found in a high proportion of sporadic sebaceous carcinomas, suggesting that p53 may be involved in tumor initiation and progression [6,19,20]. Studies have suggested a role for the Wnt/beta-catenin (a 92kDa molecule involved in cell-cell adhesion in adherens junctions) pathway and the downstream target lymphoid enhancer binding factor 1 (LEF-1) in the pathogenesis of sebaceous carcinoma, irrespective of the microsatellite status [15,21]. Hypermethylation of the CDKN2A promoter region has also been found with high frequency in periocular sebaceous carcinoma occurring at a younger age [22].

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CLINICAL PRESENTATION

Sebaceous carcinoma

typically presents as a firm, gradually enlarging subcutaneous nodule (picture 2). Approximately 80 percent of cases occur in the skin of the head or neck, and approximately 40 percent involve the eyelids [2].

Eyelid sebaceous carcinoma — Eyelid sebaceous carcinoma typically presents as a painless, rounded nodule, most often located on the upper eyelid. Occasionally, the lesion can be inflamed and painful (picture 1), and may be clinically mistaken for a chalazion (picture 6B), leading to a delay in diagnosis and appropriate treatment. The second most common presentation is a diffuse unilateral thickening of the eyelid accompanied by an inflammatory reaction that simulates blepharoconjunctivitis [23]. Eyelid sebaceous carcinoma may spread locally to involve the palpebral and bulbar conjunctiva and cornea. Unilateral signs of blepharoconjunctivitis with thickening of the eyelids, loss of cilia, diffuse erythema, and thickening of the conjunctiva and superficial vascularity of the cornea suggest epithelial involvement due to pagetoid spread of the tumor (picture 3) [24]. In advanced cases, the tumor can invade the orbital soft tissue, bone, and intracranial cavity.

Extra-ocular sebaceous carcinoma — Extra-ocular sebaceous carcinoma usually presents as a yellowish-tan nodule, often ulcerated, located in most cases on the head and neck or, less frequently, on the trunk or extremities. Rarely, sebaceous carcinomas may develop in extracutaneous sites such as the parotid gland, nasal cavity, breast, large bowel, ovary, and prostate [25,26].

Metastasis — Regional lymph nodes are the most common site of metastasis [27]. Tumors located on the upper eyelid tend to metastasize to preauricular and parotid nodes; tumors of the lower eyelid tend to metastasize to submandibular and cervical nodes [24]. Distant metastasis may involve the parotid gland, liver, lung, and bone [27,28].

Risk of visceral malignancies — Patients with sebaceous carcinoma have an increased risk of developing a subsequent visceral malignancy. In a series of 664 cases of sebaceous carcinoma, the overall risk of a subsequent cancer was 43 percent higher than in the general population (standardized incidence ratio [SIR] 1.43, 95% CI 1.15-1.76) [4]. The risk was much higher in patients diagnosed with sebaceous carcinoma before the age of 50 (SIR 4.58, 95% CI 2.44-7.84) than in older patients (SIR 1.28, 95% CI 1.02-1.60). (See "Muir-Torre syndrome".)

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ASSOCIATION WITH MUIR-TORRE SYNDROME

Although most sebaceous carcinomas occur sporadically, in a

small subgroup of patients, these tumors are a marker of Muir-Torre syndrome (MTS), an autosomal dominant disorder considered a subgroup of hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome). (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".) In an analysis of the National Cancer Institute Surveillance, Epidemiology, and End Results from 2000 to 2012, including 3299 cases of sebaceous carcinoma, 64 (1.9 percent) had MTS [29]. Sebaceous neoplasms in MTS are usually multiple, recurrent, show an early onset (before age 60), and precede visceral malignancies in approximately 60 percent of patients [30]. (See "Muir-Torre syndrome".)

DIAGNOSIS

The diagnosis of sebaceous carcinoma is suspected in older

patients with a history of recalcitrant chalazion or unilateral blepharoconjunctivitis that does not respond to standard treatment (picture 1). An excisional biopsy for histopathologic examination is required to establish the diagnosis. Immunohistochemistry may be performed to differentiate poorly differentiated sebaceous carcinoma from basal cell carcinoma and squamous cell carcinoma. (See 'Histology' below.)

Histology — Routine histologic examination with hematoxylin and eosin shows neoplastic cells (basaloid, basosquamous, and epidermoid) with various degrees of differentiation arranged in lobules or sheets of cells separated by a fibrovascular stroma (picture 4) [6]. Welldifferentiated tumors may contain sebocyte-like cells with vacuolated, foamy cytoplasm. In frozen specimens, an oil red-O stain can demonstrate intracytoplasmic lipid [31]. Differential diagnoses are multilineage adnexal tumors with partly sebaceous differentiation, sebaceous changes as a component of benign cystic lesions or epidermal tumors, nevus sebaceous, and the commonly encountered sebaceous hyperplasia [32,33]. Poorly differentiated lesions usually show both a sebaceous and squamous differentiation and may be confused with squamous cell carcinoma. Nuclear pleomorphism, prominent nucleoli, and mitotic figures are usually present. Upward migration and spreading to the surface epidermis or conjunctiva in a pagetoid pattern is often seen in eyelid lesions.

Immunohistochemistry — Immunostaining with epithelial membrane antigen (EMA), adipose differentiation-related protein (adipophilin, ADP), androgen receptor (AR), BerEP4, and cytokeratin 7 is useful to confirm sebaceous differentiation and to differentiate sebaceous carcinoma from basal cell carcinoma and squamous cell carcinoma [34-36]. Sebaceous carcinomas are in nearly 100 percent of cases EMA+, ADP+, and AR+.

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Screening for DNA mismatch repair defects — Sebaceous carcinoma is a rare tumor that in most cases occurs sporadically. However, it is found in a high proportion of patients with Muir-Torre syndrome, an autosomal dominant disorder caused by germline mutations in the DNA mismatch repair (MMR) genes and characterized by the development of sebaceous tumors in association with visceral neoplasms [37]. Based upon this observation, most experts recommend screening all sebaceous carcinomas for lack of expression of MMR proteins and/or microsatellite instability. (See "Muir-Torre syndrome".)

DIFFERENTIAL DIAGNOSIS

The differential diagnosis

of sebaceous carcinoma includes several benign and malignant conditions, including [23,31,38]: ●Benign sebaceous neoplasms – Benign sebaceous neoplasms (eg, sebaceous adenoma, sebaceoma) (picture 5) are not common in the periocular region. The finding of sebaceous differentiation in an eyelid lesion should raise the suspicion of malignancy. (See "Cutaneous adnexal tumors", section on 'Tumors with sebaceous differentiation'.) ●Inflammatory lesions – Sebaceous carcinoma may mimic chalazion (picture 6A-C), blepharoconjunctivitis, or keratoconjunctivitis. Inflammatory eye conditions that are unilateral and fail to respond to standard treatment should be biopsied and sent for histopathologic examination. (See "Eyelid lesions".) ●Basal cell carcinoma – Nodular basal cell carcinoma (BCC) is more common on the lower eyelid (picture 7) and tends to ulcerate at an early stage, whereas ulceration is uncommon in sebaceous carcinoma. The morpheaform variant of BCC may also simulate sebaceous carcinoma, but conjunctival involvement is uncommon. Immunohistochemical staining for epithelial membrane antigen (EMA) and adipophilin (ADP) are negative in BCC but positive in nearly all sebaceous carcinomas [34,35]. (See "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma".) ●Squamous cell carcinoma – Squamous cell carcinoma (SCC) may occur on the upper eyelid and mimic sebaceous carcinoma. Immunohistochemical staining for EMA may be positive in SCC, but ADP and androgen receptor (AR) are consistently negative [34,35]. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".) ●Merkel cell carcinoma – Merkel cell carcinoma may present as a red lesion on the eyelid. Histologic examination can clarify the diagnosis. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma".) Cutaneous clear cell tumors, including epidermoid carcinoma with sebaceous differentiation, clear cell acanthoma, trichilemmoma, and balloon cell melanoma may be confused histologically with sebaceous carcinoma.

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STAGING

Patients diagnosed with sebaceous carcinoma should receive a careful

examination of the tumor site to assess the clinical extent of the tumor. Palpation of the regional lymph nodes should be performed to assess for enlarged lymph nodes that may indicate regional metastasis. If enlarged lymph nodes are detected, lymph node biopsy via fine needle aspiration or surgical removal of the enlarged lymph node is indicated. Patients with sebaceous carcinoma of the eyelids should be referred to an ophthalmologist for the evaluation of conjunctival involvement. Slit-lamp biomicroscopy and conjunctival map biopsies are used to determine the presence and extent of intraepithelial disease [24]. In patients with large tumors located in the periorbital area, computerized tomography (CT) or magnetic resonance imaging (MRI) is useful for evaluating for invasion of orbital soft tissue, bone, or intracranial cavity. Positron emission tomography (PET) scan should be considered for patients with Muir-Torre syndrome [39]. The staging of periocular sebaceous carcinomas is performed according to the staging system for eyelid carcinoma, including basal cell carcinoma, squamous cell carcinoma, and Merkel cell carcinoma, outlined in the American Joint Committee on Cancer Staging Manual, seventh edition [40,41].

MANAGEMENT

Sebaceous carcinoma is a locally aggressive tumor that

can metastasize to locoregional lymph nodes and distant sites. The primary goal of management is the complete surgical removal of the tumor; for periocular lesions, additional goals include the identification and treatment of subclinical intraepithelial neoplasia, vision salvage, avoidance of exenteration, and acceptable cosmetic outcome [23,24].

Local disease Surgical treatment — Wide local excision with frozen section margin control or, if available, Mohs micrographic surgery is the first-line treatment for sebaceous carcinoma of the head and neck region, including eyelid tumors [2,23,42]. Because the interpretation of frozen sections may be problematic (eg, in differentiating vacuolating cytoplasm from freezing artifacts in conjunctival margins), some experts advocate the use of frozen and permanent paraffin-embedded sections for margin control [43]. (See "Mohs surgery".) The use of Mohs surgery for sebaceous carcinoma is supported by a limited number of observational studies with relatively short median follow-up demonstrating a low risk of recurrence with this procedure. ●In a review of 49 cases of orbital sebaceous carcinomas treated by Mohs surgery, six patients developed local recurrence, with an overall local cure rate of 88 percent after mean follow-up of three years [44]. 

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●In a series of 18 patients with sebaceous carcinoma of the eyelid treated with Mohs surgery, 17 were disease-free after an average follow-up of 37 months [45]. ●In a single-institution study of 52 patients (29 with Muir-Torre syndrome) with 73 sebaceous carcinomas, 35 tumors were treated with Mohs surgery, 26 with wide local excision, and 8 with biopsy only [42]. A local recurrence was documented in only one patient treated with Mohs surgery after a follow-up time of six years. ●In a single-institution review of 37 patients with 45 tumors treated with Mohs surgery, 27 patients were followed up for an average of 3.6 years [46]. None of the patients developed local recurrences or nodal or distant metastases. Six patients died for causes other than sebaceous carcinoma. ●In a series of 1265 patients with sebaceous carcinoma from the United States National Cancer Database, of whom 234 were treated with Mohs surgery and 1031 with wide local excision, Mohs surgery was associated with longer overall survival than surgical excision after adjusting for other prognostic factors, such as tumor size and clinical stage (hazard ratio [HR] 0.703, 95% CI 0.4960.995) [47]. Conjunctival epithelial involvement may be treated with surgical resection of the bulbar epithelium, cryotherapy, and/or topical mitomycin C [24]. For tumors with extensive intraorbital involvement, surgical management may include orbital exenteration.

Radiation therapy — The role of radiation therapy (RT) in the treatment of sebaceous carcinoma is uncertain. A few small studies have reported the use of radiation therapy as the primary treatment for eyelid sebaceous carcinoma [48-50]. ●In one study, eight patients with eyelid sebaceous carcinoma were treated with high dose rate interstitial brachytherapy (a total of 39 Gy in six fractions in six days) as initial treatment [48]. All patients showed a complete response, with a five-year disease-free survival rate of 57 percent. ●In another study, 16 patients with histologically confirmed sebaceous carcinoma were treated with a median dose of 60 Gy (range 50 to 66.6) delivered in 18 to 37 fractions [49]. The reported five-year overall and local progression-free rates were 80 and 93 percent, respectively. The general principle of RT to skin cancer also applies to sebaceous carcinoma, with the higher dose of up to 66.6 Gy applied to larger lesions. Radiation oncologists should use smaller fraction size to decrease long-term complications. An orthovoltage machine, if available, is preferred to electron treatment because the RT fields are smaller due to a narrow penumbra, shielding is easier (a 6 MeV electron beam produces bremsstrahlung radiation and the cornea receives a small RT dose behind the eye shield), it is less expensive since linear accelerator machines required to produce electrons are more costly, and it has a higher relative biologic effectiveness and local control is better. The electron dose should be higher by 10 percent to be as effective as orthovoltage.

4521

Eye drops with local anesthetic and steroid should be applied before inserting the eye shield. Electron eye shields are thicker. The patient should wear an eye patch one to two hours after RT each day. Common acute side effects of RT are conjunctivitis (from local anesthetic eye drops and RT), eyelid erythema and edema, and conjunctival congestion and chemosis. Long-term side effects of RT include loss of eyelashes, deformities of the eyelid including ectropion or entropion (eyelashes growing outside and inside, respectively), dry eye due to RT dose to lacrimal gland, keratitis of conjunctiva, epiphora or tearing due to fibrosis of lacrimal duct, and cataract. Cataract was reported in 3 out of 23 patients in the above series [49].

Adjuvant therapies — Cryotherapy is frequently used as an adjunctive treatment after surgical excision of sebaceous carcinoma of the eyelid, particularly for the management of pagetoid invasion of conjunctiva [51]. However, cryotherapy may be associated with serious adverse effects, including symblepharon and corneal erosions. Topical mitomycin C has been used in a small number of patients for the treatment of pagetoid spread to the conjunctiva and cornea with varying results [23,52-54]. Complications of topical mitomycin C treatment include persistent keratoconjunctivitis, epiphora secondary to punctal stenosis, allergic reaction, and limbal stem cell deficiency [55]. The use of radiation therapy as an adjuvant therapy after surgery has been evaluated in a small retrospective study of 13 patients with locally advanced tumors, 10 of whom had regional lymph node involvement [56]. A recurrence occurred in two of seven patients who had received adjuvant radiation therapy postoperatively and five of six patients who did not receive radiation therapy.

Nodal and distant metastatic disease — Sentinel lymph node biopsy and imaging to complete tumor staging may be indicated for larger or more aggressive tumors [57]. Data on the management of locoregional or distant metastasis of sebaceous carcinoma are limited to small case series and case reports [58,59]. Patients with regional nodal involvement are treated with lymph node dissection and/or RT [56,60,61]. There are isolated reports of successful use of topical fluorouracil, cisplatin, capecitabine, and RT for the management metastatic sebaceous carcinoma [58,62,63].

PROGNOSIS

Local recurrence due to incomplete removal of the primary tumor

is a major unfavorable determinant of prognosis. Local recurrence has been reported in 9 to 36 percent of patients, with distant metastasis occurring in 3 to 25 percent [44,64,65]. In a series of 60 patients with sebaceous carcinoma of the eyelids, local recurrence occurred in 18 percent of patients and metastasis in 8 percent [23]. In the Surveillance, Epidemiology, and End Results (SEER) database, the five- and ten-year overall survival rates were 71 and 46 percent, respectively [2]. Older age, poorly differentiated tumors, and distant, but not nodal, metastasis are unfavorable prognostic factors [66]. Patients with sebaceous

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carcinoma and Muir-Torre syndrome (MTS) have a worse prognosis. An analysis of SEER data on over 3000 patients with sebaceous carcinoma, of whom 64 had MTS, found that the five-year, causespecific survival rates among patients with and without MTS were 53 and 78 percent, respectively [29].

FOLLOW-UP

All patients with sebaceous carcinoma should undergo an

extended follow-up of several years after the initial treatment. Late relapses (pagetoid, nodal, or distant) have been reported 5 to 11 years after the excision of the primary sebaceous carcinoma [60,61,67,68].

SUMMARY AND RECOMMENDATIONS ●Sebaceous carcinoma is a rare malignant tumor of the sebaceous glands most commonly found in the head and neck region and particularly on the eyelids of older individuals. Sebaceous carcinomas can occur sporadically or may be associated with Muir-Torre syndrome, a subset of the hereditary nonpolyposis colorectal cancer syndrome (HNCCS, Lynch syndrome). (See 'Introduction' above and 'Epidemiology' above.) ●Eyelid sebaceous carcinoma typically presents as a painless, rounded nodule, most often located on the upper eyelid. Occasionally, the lesion can be inflamed and painful (picture 1), and may be mistaken clinically for a chalazion (picture 6B). (See 'Clinical presentation' above.) ●The diagnosis of sebaceous carcinoma is suspected in older patients with a history of recalcitrant chalazion or unilateral blepharoconjunctivitis that does not respond to standard treatment. A lesion biopsy for histopathologic examination is required to establish the diagnosis. (See 'Diagnosis' above.) ●The evaluation of patients with sebaceous carcinoma should include a careful examination of the tumor site and palpation of the regional lymph nodes. Enlarged lymph nodes should be biopsied. Patients with sebaceous carcinoma of the eyelids should be referred to an ophthalmologist for slitlamp biomicroscopy and conjunctival map biopsies to evaluate for intraepithelial disease. (See 'Staging' above.) ●We suggest wide local excision with frozen section margin control or Mohs micrographic surgery as the first-line treatment for sebaceous carcinoma of the head and neck region, including eyelid tumors (Grade 2C). Conjunctival epithelial involvement may be treated with surgical resection of the bulbar epithelium, cryotherapy, and/or topical mitomycin C. (See 'Management' above.)

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Atypical fibroxanthoma - UpToDate uptodate.com/contents/atypical-fibroxanthoma/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Nov 08, 2019.

INTRODUCTION

Atypical fibroxanthoma (AFX) is an uncommon,

pleomorphic, spindle cell cutaneous malignancy that most commonly presents as a solitary red or pink papule or nodule on the head or neck (picture 1A) [1]. Exposure to ultraviolet light most likely contributes to the development of AFX. The relationship between AFX, pleomorphic dermal sarcoma, and undifferentiated pleomorphic sarcoma (UPS), a soft tissue neoplasm that shares many histologic features with AFX, is unclear [2]. While some authors consider AFX a less aggressive, superficial variant of pleomorphic dermal sarcoma and UPS, many others view AFX as a distinct malignancy. The recommended treatment for AFX is surgical removal of the entire tumor with Mohs surgery or wide local excision. AFX generally has a good prognosis. Metastasis is a rare event. The clinical features, diagnosis, and management of AFX are discussed here. Undifferentiated pleomorphic sarcoma is reviewed separately. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma".)

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EPIDEMIOLOGY

Although it is accepted that atypical fibroxanthoma

(AFX) is an uncommon tumor, the incidence of AFX is unknown. The results of a retrospective study of surgical logs for Mohs surgery (a common treatment for AFX) from five practices in Texas offers support for the infrequent occurrence of this tumor. Out of 42,279 skin cancers treated with Mohs surgery, only 105 (0.2 percent) were AFX [3]. AFX most commonly occurs in older adults (usually seventh or eighth decade of life) and has a predilection for men [1,4]. Consistent with these assertions, a retrospective study of 91 patients with AFX found an average age of diagnosis of 72 years and 75 patients (82 percent) were men [5]. In a German study of 53 patients, the mean age was 80 years (range 52 to 99 years) and 45 (85 percent) were men [4]. Although AFX may occur in individuals of any racial background, most reported cases have occurred in non-Hispanic white individuals [4-6]. A personal history of prior basal cell or squamous cell carcinoma is common in patients with AFX [5,7].

RISK FACTORS

The mechanisms that lead to the development of atypical

fibroxanthoma (AFX) are not well-understood. Ultraviolet light exposure has been proposed as a major contributing factor based upon several observations: ●AFX most frequently occurs on sun-exposed skin of the head and neck [5,6,8,9] ●Similar to nonmelanoma skin cancers promoted by ultraviolet light exposure, AFX is most common in older individuals, men, and the non-Hispanic white population [5,6,8,9] ●P53 mutations and cyclobutane pyrimidine dimers (UV photoproducts involved in skin cancer development) have been detected in AFX [10,11] ●Children with xeroderma pigmentosum have developed AFX [12-14] Additional factors, including radiation therapy, immunosuppression, burns, and trauma have been proposed as contributors to AFX [6,15-17]. However, there are few data to support these theories, resulting in uncertainty about the role of these factors in tumor development. A potential role for radiation therapy was supported by a retrospective study of 140 patients with AFX in which at least six patients (4 percent) had a history of radiation treatment at the site of the tumor [6]. The detection of AFX in 1 of 642 renal transplant recipients followed during a two year period at a Swiss university hospital (equivalent to an estimated risk for AFX of 78/100,000 persons per year) suggested that the risk for AFX may be increased in immunosuppressed patients [16]. However, more data on the risk for AFX are necessary to confirm whether the risk exceeds the risk for the general population.

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HISTOGENESIS

The origin of tumor cells in atypical fibroxanthoma (AFX)

has been debated. Immunohistochemical analyses suggest that AFX most likely originates from myofibroblasts or fibroblast-like cells [1,18].

CLINICAL FEATURES

Atypical fibroxanthoma (AFX) usually

presents as a solitary, pink or red, firm, papule or nodule that grows over the course of several months and may ulcerate or bleed (picture 1A-B) [1,6,19]. Tumors are usually less than 2 cm in diameter, but occasionally reach several centimeters or more in diameter [6]. A rare pigmented variant of AFX has been reported [20,21]. The head and neck are the most common sites for AFX. Truncal and extremity tumors are less common and may present as larger tumors. Rarely sites such as the eyelid or cornea are affected [22,23]. Most AFX tumors are asymptomatic. Tenderness occurs in a minority. Pruritus is uncommon [6].

HISTOPATHOLOGY

Common histopathologic findings of atypical

fibroxanthoma (AFX) include (picture 2A-B) [24]: ●Well-circumscribed, nonencapsulated dermal tumor that is contiguous with the epidermis or separated from epidermis by narrow zone of collagen (Grenz zone) ●Cellular proliferation of plump spindle cells with prominent nuclei, epithelioid cells, and multinucleated giant cells ●Atypical mitoses and severe cellular pleomorphism ●Variable presence of thin or ulcerated epidermis, or peripheral epidermal collarette In addition to the classic features listed above, several histologic subtypes of AFX have been described in the literature. Examples include spindle cell predominant, pigmented, clear cell [25,26], osteoclastic, osteoid, chondroid, and granular cell variants [24]. The presence of extensive invasion of subcutaneous fat, a high-mitotic index, and the presence of perineural or lymphovascular invasion suggest the tumor falls into the higher-risk pleomorphic dermal sarcoma/undifferentiated pleomorphic sarcoma category [27].

DIAGNOSIS

Because of the rarity of atypical fibroxanthoma (AFX) and the

tumor's nonspecific clinical features, the correct diagnosis is rarely made solely with clinical examination. A skin biopsy and immunohistochemical studies are required to confirm the diagnosis. AFX is a diagnosis of exclusion.

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Biopsy — An excisional biopsy is the preferred biopsy procedure for AFX. This procedure provides a large tissue sample that allows for visualization of the tumor architecture, which can help to differentiate AFX from undifferentiated pleomorphic sarcoma (UPS), a tumor with a less favorable prognosis, but similar histologic features. However, because clinical suspicion for AFX is often low, a shave biopsy is sometimes the initial diagnostic procedure. The pathologic finding of a tumor composed of spindle cells and epithelioid cells that exhibits marked nuclear pleomorphism raises suspicion for a diagnosis of AFX. (See 'Histopathology' above and "Skin biopsy techniques", section on 'Excision' and 'Undifferentiated pleomorphic sarcoma' below.)

Immunohistochemistry — Immunohistochemistry is a valuable tool for differentiating AFX from other spindle cell tumors with similar clinical and histologic findings, including spindle cell squamous cell carcinoma and desmoplastic melanoma. The key immunohistochemical stains employed to distinguish AFX from these tumors include: ●Cytokeratin (negative in AFX, positive in spindle cell cutaneous squamous cell carcinoma) ●S100 (negative in AFX, positive in desmoplastic melanoma) Depending on the histologic differential, additional stains may aid with diagnosis [1,28-31]. CD10, actin, and vimentin are often positive in AFX, though these stains are not exclusive to this tumor [4,8,32,33]. Rarely, melanocyte stains, such as microphthalmia transcription factor (MITF), can be positive in AFX [34]. Spindle cell squamous cell carcinoma stains positively for the transcription factor p63; however, the p63 stain is negative in AFX [30]. P40 has been shown to be equally sensitive and more specific than p63 for the differentiation of spindle cell squamous cell carcinoma from AFX [35,36].

Dermoscopy — A report of the dermoscopic findings of three AFX tumors led to the identification of white areas and an atypical polymorphous vascular pattern characterized by linear, dotted, hairpin, arborescent, and highly tortuous vessels as dermoscopic features of AFX [37]. These findings are not specific to AFX. (See "Overview of dermoscopy".)

DIFFERENTIAL DIAGNOSIS

The differential diagnosis

for atypical fibroxanthoma (AFX) includes other benign and malignant cutaneous neoplasms.

Undifferentiated pleomorphic sarcoma — Undifferentiated pleomorphic sarcoma (UPS) (formerly known as malignant fibrous histiocytoma [MFH]) (picture 3A-B) is a tumor with a less favorable prognosis that can be difficult to distinguish histologically from AFX [38,39]. UPS is a soft tissue sarcoma that lacks an identifiable line of differentiation.

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The replacement of the term UPS for MFH arose after it was recognized that with more extensive testing, many tumors previously identified as MFH could be classified as other tumors [40]. Because of the pathologic similarities between AFX and UPS, some authors have questioned whether AFX represents a superficial, less aggressive variant of UPS, rather than a distinct tumor. Several histologic characteristics have been proposed as features that may help to differentiate AFX and UPS in the clinical setting. Features that may favor a diagnosis of UPS over a diagnosis of AFX include involvement of the deep subcutis, penetration of fascia or muscle, necrosis, and vascular invasion [18,41]. A few studies have identified additional findings that suggest a valid distinction between AFX and UPS. In a study of seven AFX tumors and four tumors identified as MFH, the score for cyclobutane pyrimidine dimers (UV photoproducts that appear to play an important role in skin cancer development) was significantly greater in AFX than in MFH [10]. In addition, p53 mutations were more commonly detected in AFX (4 of 6 versus 1 of 4). Small studies have also reported genetic differences between AFX and UPS/MFH [42,43].

Other disorders — Disorders that may clinically resemble AFX include basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, amelanotic melanoma, pyogenic granuloma, and adnexal tumors. The rare pigmented form of AFX may be clinically mistaken for pigmented melanoma or pigmented basal cell carcinoma [20,21]. The histologic differential diagnosis for AFX includes other dermal tumors that contain spindle cells. Examples include spindle cell squamous cell carcinoma, desmoplastic melanoma, and leiomyosarcoma. Immunohistochemical studies are useful for distinguishing AFX from these disorders. (See 'Immunohistochemistry' above.)

EVALUATION AND STAGING

Patients diagnosed

with atypical fibroxanthoma (AFX) should receive a full skin examination that includes inspection of the tumor site to estimate the clinical extent of the tumor and palpation of the regional lymph nodes. The skin examination also serves to detect the presence of other cutaneous malignancies. Radiologic imaging is not necessary for the evaluation of most patients with AFX. When the clinical examination suggests the possibility of extensive tissue invasion (large [eg, ≥2 cm diameter], infiltrative [bound-down], or poorly-defined tumors), radiologic imaging can be useful for estimating the extent and depth of tumor invasion. Radiologic imaging of distant body sites is not indicated in the absence of signs or symptoms that suggest distant disease. (See 'Prognosis' below.)

TREATMENT

Due to the potential for metastatic spread of atypical

fibroxanthoma (AFX), treatment of these tumors is recommended (see 'Prognosis' below). Complete surgical removal with Mohs surgery or wide local excision (WLE) is the recommended method of treatment.

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Mohs surgery is a staged, tissue-sparing surgical procedure in which cutaneous tumors are removed in a manner that allows the surgeon to evaluate 100 percent of the excisional margin intraoperatively through the use of frozen sections. The narrow surgical margins taken during each stage of the procedure allows the surgeon to take the minimal margin of healthy tissue necessary for tumor removal. In patients with AFX, the procedure is facilitated by the marked cellular pleomorphism characteristic of AFX. This feature makes the identification of tumor cells on frozen tissue sections relatively easy. No high quality trials have compared the efficacy of Mohs surgery and WLE, leading to uncertainty about the comparative efficacy of these procedures. (See "Mohs surgery".)

Our approach — Although we consider both Mohs surgery and WLE to be acceptable options for the treatment of AFX, we prefer Mohs surgery as our treatment of choice for AFX on the head and neck because of the tissue-sparing effects of the procedure. The 2 cm margin suggested for WLE of AFX is often difficult to achieve in these areas [44]. Tumors located in other sites in which securing a 2 cm margin is difficult (eg, lower leg) can also benefit from the Mohs surgery procedure. (See 'Mohs surgery' below and 'Wide local excision' below.)

Mohs surgery — The use of Mohs surgery for AFX is supported by several retrospective studies that have identified a low risk for tumor recurrence after this procedure [5,7,45-47]. In a systematic review and meta-analysis of 23 observational studies including 907 patients, of whom 175 were treated with Mohs micrographic surgery (MMS) and 732 with WLE, the local recurrence rate was 2 percent (95% CI 0-4.1) among patients treated with MMS versus 8.7 percent (95% CI 512.3) among those treated with WLE after a pooled mean follow-up period of 42 months (range 1 to 315 months) [48]. The metastatic rates were not significantly different in the MMS and WLE groups (1.9 percent [95% CI 0.1-3.8] and 1 percent [95% CI 0.2-1.9], respectively). Disadvantages of Mohs surgery compared with WLE include the longer duration of the procedure, higher cost, and the lower availability of the procedure. Mohs surgery requires a surgeon specifically trained in the procedure and specialized equipment for tissue examination. (See "Mohs surgery", section on 'Surgical technique'.) A modification to Mohs surgery, staged excision with circumferential margin assessment ("slow Mohs"), in which formalin-fixed, paraffin-embedded tangential sections are examined to determine circumferential tumor-free margins prior to wound closure has also been used [49]. The efficacy of this procedure for AFX has not been compared to standard Mohs surgery.

Wide local excision — Although wide local excision (WLE) can successfully treat AFX, only a small portion of the tumor margin is examined during pathologic examination. Tumors may recur if the margin used to excise the tumor is inadequate [5,46]. Data on the efficacy of WLE for the management of AFX are limited. Reported tumor recurrence rates following WLE typically have ranged between 0 and 20 percent [44]. However, in many reports of AFX treated with WLE, surgical margins have not been specified. Thus, the likelihood of successful treatment with any specific surgical excision marker is unclear.

4529

Surgical margins of 2 cm are suggested based upon a retrospective study that found that in 59 tumors treated with Mohs surgery, margins of 2 cm or less cleared 97 percent of tumors. Due to the frequent location of AFX on the head and neck, such margins are often not feasible. Postoperative margin assessment by a pathologist should be performed after all AFX excisions.

Radiation — Radiation therapy is an additional option for treatment of AFX that is typically reserved for adjuvant treatment of tumors that cannot be excised with clear surgical margins. Occasionally, radiation therapy is given as the primary mode of treatment for patients who are not candidates for surgery. (See 'Recurrent tumors' below.)

Immunosuppressed patients — Mohs surgery is our preferred method of treatment for AFX in immunosuppressed patients. In a retrospective study of 12 AFX tumors that occurred in solid organ transplant recipients, none of the six tumors initially treated with Mohs surgery recurred or metastasized [50]. In contrast, three of five tumors removed with surgical excision recurred, including one that also metastasized. Of note, the surgical margins for the WLEs were not specified. If WLE is performed, we suggest excising the tumor with 2 cm margins [50].

Recurrent tumors — Guidelines for the management of recurrent tumors are lacking. We typically manage recurrent AFX tumors with Mohs surgery. If WLE is performed, we excise these tumors with 2 cm margins whenever feasible. Adjuvant radiation therapy is administered if complete excision of the recurrent tumor is not possible.

PROGNOSIS

Overall, atypical fibroxanthoma (AFX) has a good prognosis.

Recurrences usually develop within three years after excision [50]. Metastasis is rare [51,52]. The lymph nodes are often the initial site of metastasis [51]. In a series of 53 patients with AFX treated with Mohs surgery, the relapse-free survival at 12 months was 91 percent; five patients had a relapse within two years and four developed metastases [4]. In a review of approximately 1500 published cases for which information on outcome was available, the overall recurrence rate was 7.6 percent; among 451 patients for whom complete follow-up data were available, the disease-specific survival was 98 percent at 5, 10, and 20 years [53]. Immunosuppressed patients with cutaneous squamous cell carcinoma have a less favorable prognosis for this tumor than immunocompetent patients. There is concern that immunosuppressed patients with AFX also may have an increased risk for aggressive tumor behavior based upon a small retrospective study of published and unpublished cases that documented three tumor recurrences and one metastasis in 12 solid organ transplant recipients with AFX [50]. Additional studies are necessary to confirm an increase in risk for aggressive tumor behavior in this population. Involvement of the subcutis portends a worse prognosis and should prompt concern for undifferentiated pleomorphic sarcoma. However, rare cases of metastases and death have been reported with little or no subcutaneous involvement [54]. Some authors have proposed labeling these more aggressive, superficial lesions as dermal pleomorphic sarcomas [55].

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FOLLOW-UP

There are no standard guidelines for the follow-up regimen for

patients with atypical fibroxanthoma (AFX). We perform a full skin examination every six months to check for tumor recurrence and additional cutaneous malignancies. We also palpate regional lymph nodes to evaluate for evidence of metastatic disease.

SUMMARY AND RECOMMENDATIONS ●Atypical fibroxanthoma (AFX) is an uncommon cutaneous tumor that is most likely to occur on sun-damaged skin in elderly men. Ultraviolet light exposure is theorized to be a major risk factor for the development of AFX. (See 'Epidemiology' above and 'Risk factors' above.) ●AFX usually presents as a solitary pink or red nodule. Tumors are often less than 2 cm in diameter, but may be larger. The head and neck are the most common sites for tumor development. (See 'Clinical features' above.) ●The classic pathologic findings of AFX are a dermal tumor composed of spindle cells, epithelioid cells, and multinucleated giant cells. Cellular pleomorphism is a prominent feature. (See 'Histopathology' above.) ●AFX is a diagnosis of exclusion. A skin biopsy and immunohistochemical studies are necessary to confirm the diagnosis. Immunohistochemistry is particularly useful for differentiating AFX from other spindle cell tumors that may present with similar clinical and pathologic features, such as spindle cell squamous cell carcinoma and desmoplastic melanoma. (See 'Diagnosis' above.) ●Complete surgical excision with Mohs surgery or wide local excision (WLE) with a 2 cm margin is the treatment of choice for AFX. Because Mohs surgery is a tissue-sparing technique, we suggest treatment with Mohs surgery over WLE for AFX on the head, neck, or other sites in which conservation of healthy tissue is a high priority (Grade 2C). ●The prognosis for AFX is usually good. Tumors may recur if surgical margins are inadequate. Metastasis is rare. (See 'Prognosis' above.)

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Porokeratosis - UpToDate uptodate.com/contents/porokeratosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Aug 02, 2019.

INTRODUCTION

Porokeratosis is a rare, acquired or inherited disorder of

keratinization characterized by one or more atrophic macules or patches, each surrounded by a distinctive hyperkeratotic, ridge-like border called "cornoid lamella" (picture 1D) [1,2]. Multiple clinical variants of porokeratosis exist. Malignant transformation occurs in a minority of cases. Although clinical surveillance for malignant transformation is sufficient for the management of most patients with porokeratosis, patients who are concerned about the appearance of lesions or who have associated symptoms, such as pruritus or pain, may desire therapeutic intervention. Formal studies of the therapeutic options for porokeratosis are lacking, but various topical, surgical, destructive, and systemic therapies appear to be effective in some patients. The pathogenesis, clinical manifestations, diagnosis, and management of porokeratosis will be reviewed here.

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EPIDEMIOLOGY

Porokeratosis is a rare disease. The exact incidence and

prevalence are not known. It typically occurs in adults or older adults with slight male predominance, but pediatric cases have been reported [3-7].  

CLASSIFICATION

The most commonly described variants of

porokeratosis include: ●Disseminated superficial actinic porokeratosis (DSAP1, MIM #175900, 616063, 614714, 616631) ●Disseminated superficial porokeratosis (DSP, MIM #175900, 616631) ●Porokeratosis of Mibelli (MIM #175800) ●Linear porokeratosis ●Porokeratosis palmaris et plantaris disseminata (PPPD, MIM #175850) ●Punctate porokeratosis (sometimes considered a variant of PPPD) ●Porokeratosis ptychotropica ●Genitogluteal porokeratosis Most clinical types of porokeratosis can manifest in localized or generalized forms; however, overlap between the forms as well as clinical variants are not uncommon.

PATHOGENESIS

The clonal proliferation of abnormal epidermal

keratinocytes is believed to account for the clinical manifestations of porokeratosis. However, the pathway that leads to this process remains unknown. A variety of factors have been proposed as potential contributors, including genetic susceptibility, ultraviolet radiation, and immune status.

Genetics — Inherited or sporadic genetic defects likely play an important role in porokeratosis. Studies in familial cases of disseminated superficial actinic porokeratosis (DSAP) support an autosomal dominant inheritance pattern with incomplete penetrance [8]. Four potential chromosomal loci for DSAP have been identified, including DSAP1 (12q23.2-24.1), DSAP2 (15q25.1-26.1), DSAP3 (1p31.3-p31.1), and DSAP4 (16q24.1-24.3) [9-12]. In Chinese studies, mutations in the phosphomevalonate kinase pathway genes, namely mevalonate decarboxylase (MVD), mevalonate kinase(MVK), phosphomevalonate kinase (PMVK), and farnesyl diphosphate synthase (FDPS), have been detected in some patients with porokeratosis [13,14]. There are over 200

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mutations identified so far [14-17]. At least one mutation in the mevalonate pathway genes was reported to be found in up to 98 percent of the familial and over 70 percent of sporadic porokeratosis cases [18]. The mevalonate pathway genes are involved in the biosynthesis of isoprenoids, which are precursors of multiple biologically important substances, such as cholesterol, and are indirectly involved in biologic events, such as cell growth of differentiation. It is thus hypothesized that mutations in mevalonate pathway result in accumulation of abnormal cell metabolites, retention of cell nuclei in the epidermis, and formation of the cornoid lamella [18,19]. Moreover, inhibition of enzymes within the mevalonate pathway leads to decreased expression of keratinocyte differentiation marker involucrin, p53 and Notch1, further supporting the causative relationship between mutations in mevalonate pathway and development of porokeratosis [20]. Familial cases of disseminated superficial porokeratosis (DSP) and porokeratosis plantaris palmaris et disseminata (PPPD) demonstrate autosomal dominant inheritance patterns. The loci linked to DSP and PPPD are on chromosome 18p11.3 and chromosome 12q24.1-24.2, respectively [21-23]. Focal forms of porokeratosis, such as porokeratosis of Mibelli and linear porokeratosis, may occur as a consequence of mosaicism. The occurrence of linear porokeratosis or porokeratosis of Mibelli in patients with DSAP has been attributed to this theory [8,24]. In such cases, focal loss of heterozygosity via somatic mutations may result in the prominent, localized clinical manifestations that characterize linear porokeratosis and porokeratosis of Mibelli, while the relatively milder manifestations of DSAP appear in a generalized distribution [8,24]. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Mosaicism'.)

Ultraviolet radiation — Exposure to ultraviolet radiation may contribute to the development of porokeratosis. This assertion is supported by the observation that DSAP preferentially occurs on areas of exposed skin and in individuals with histories of extensive sun exposure. In addition, the administration of artificial ultraviolet light in experimental and therapeutic settings has resulted in the induction of DSAP lesions [25-28]. Despite these findings, a definitive role for ultraviolet radiation in porokeratosis remains uncertain. Improvement in DSAP after treatment with psoralen plus ultraviolet A (PUVA) therapy has been documented in one patient [29]. The relative sparing of the face in DSAP also raises questions about the designation of ultraviolet radiation as a contributory factor. (See 'Disseminated superficial actinic porokeratosis' below.)

Immunosuppression — Drug-induced immunosuppression or immunodeficiency in the setting of nonmalignant diseases or hematologic malignancy may increase the risk for porokeratosis [30-36]. Estimates of the prevalence of porokeratosis in immunosuppressed organ transplant recipients range from less than 1 percent to as high as 11 percent [32,35].

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Porokeratosis has occurred 3 weeks to 14 years after the initiation of systemic immunosuppression [35,37]. DSP and porokeratosis of Mibelli are the most commonly associated variants [38]. A rapidly evolving form of porokeratosis, called eruptive disseminated porokeratosis, has been described in older patients, in association with solid cancers or immunosuppressive therapy [39]. New-onset DSP and porokeratosis of Mibelli have been reported in patients with known HIV infection and may indicate a worsening of the immunodeficiency [31,40]. A contributory role for immunosuppression is supported by reports of remission of porokeratosis after cessation of immunosuppressive therapy in two patients [41,42]. The development of porokeratosis in sites of long-term potent topical corticosteroid use in another patient also suggests a role for immunosuppression [43].

Other — Additional factors that have been associated with porokeratosis include radiation therapy [44,45], trauma [46], liver disease [47,48], solid organ cancer [49,50], and Crohn's disease [51].

CLINICAL PRESENTATION

The defining feature of

porokeratosis is the clinical and histopathologic presence of a cornoid lamella, which typically manifests as a thin, keratotic rim at the periphery of a slightly atrophic skin lesion (picture 1D). Lesions typically begin as small, keratotic papules that spread slowly and centrifugally [38]. Multiple clinical variants have been described. Disseminated superficial actinic porokeratosis (DSAP) is generally accepted to be the most common variant, followed by porokeratosis of Mibelli. In one series of 94 patients in Singapore, classic porokeratosis of Mibelli, DSAP, disseminated superficial porokeratosis (DSP), and linear porokeratosis accounted for 56, 18, 11, and 13 percent of cases of porokeratosis, respectively [5].

Disseminated superficial actinic porokeratosis — Disseminated superficial actinic porokeratosis (DSAP) is the most common type of porokeratosis. DSAP occurs more frequently in women than men, with an estimated female to male ratio of approximately 1.8:1 [38]. The onset of disease typically occurs in the third or fourth decade of life, and patients frequently report a history of extensive exposure to natural or artificial ultraviolet radiation. Worsening of disease during the summer months may occur [38]. DSAP is characterized by erythematous, skin-colored or hyperpigmented, well-defined macules that are typically less than 1 cm in diameter (picture 1A-C). The cornoid lamella is often subtle, manifesting as a fine, peripheral, keratotic ridge. The distribution of lesions typically involves the extensor surfaces of the arms, legs, shoulders, or back, with sparing of the palms and soles. Facial lesions, a less common finding, occur in approximately 15 percent of patients [52]. A less common variant (inflammatory DSAP) presents as erythematous lesions, accompanied by inflammation and severe pruritus [53].

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The number of skin lesions in DSAP is variable. Only a few or several hundred lesions may be present [29]. The cosmetic appearance of DSAP is a common concern for patients with this disorder and may be particularly bothersome for individuals who frequently wear skirts or shorts that expose the lower legs. Skin lesions are often asymptomatic, but pruritus or stinging sensations are estimated to occur in one-third to one-half of patients [29,38].

Disseminated superficial porokeratosis — Disseminated superficial porokeratosis (DSP) resembles DSAP but lacks photodistribution, appearing in both sun-exposed and non-sun-exposed sites. Like DSAP, the palms and soles are typically spared. In contrast to DSAP, DSP often develops in childhood, most commonly between the ages of 5 and 10 years [38]. As noted above, DSP also can occur in association with immunosuppression [54-56] (see 'Immunosuppression' above). In addition, DSP has been reported in a few patients with solid organ malignancies [49,50]. The term "eruptive disseminated porokeratosis" has been proposed for adult-onset, acute disseminated porokeratosis, which has a male preponderance and may show variable morphology [39]. Most patients with adult-onset DSP are immunosuppressed or have a coexisting internal malignancy.

Porokeratosis of Mibelli — Porokeratosis of Mibelli is the second most common type of porokeratosis [3]. The disorder often begins in childhood and affects males approximately twice as frequently as females [38]. Occasionally, lesions develop during adulthood, often in association with immunosuppression [31,33,35,57]. Porokeratosis of Mibelli typically begins as a small, asymptomatic or slightly pruritic papule that slowly expands over the course of years. Faster growth may occur in the setting of immunosuppression. Well-developed lesions are usually a few centimeters in diameter, and, rarely, lesions grow to 10 to 20 cm in size. The term "giant porokeratosis" has been used to describe these exceptionally large lesions [58,59]. The classic location for porokeratosis of Mibelli is on an extremity. However, lesions may occur in any site, including the palms, soles, genitalia, or mucous membranes [38,60,61]. Patients usually present with a solitary lesion or a few asymmetrically distributed lesions. Occasionally, widespread lesions occur [24,58,62]. Involvement of the distal portions of fingers and toes may result in dystrophy and/or complete loss of the nail [63]. The cornoid lamella is often prominent in lesions of porokeratosis of Mibelli. The lesion border is usually greater than 1 mm in height, and a thin furrow is typically seen in the center of the ridge, causing an appearance that resembles the Great Wall of China (picture 2A-C). The center of the

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lesion may be slightly hypopigmented or hyperpigmented, minimally scaly, slightly atrophic, and hairless. Uncommonly, lesions manifest as confluent, hyperkeratotic or verrucous, thick plaques [62,64].

Linear porokeratosis — Linear porokeratosis is a rare form of porokeratosis that may represent a segmental form of DSAP or DSP [8,24]. The skin lesions typically present during infancy or early childhood but occasionally develop in adults. Females are slightly more likely to be affected than males [35]. Based on the distribution of the lesions, linear porokeratosis can be subdivided into localized, zosteriform, systematized, or generalized variants (figure 1 and picture 3A-B). The localized variant of linear porokeratosis presents as single or multiple plaques with hyperkeratotic, peripheral rims on one extremity. As in porokeratosis of Mibelli, the hyperkeratotic border is often prominent, and a furrow is seen just inside of the hyperkeratotic ridge. In the zosteriform variant, the configuration of lesions usually follows the lines of Blaschko. Systematized linear porokeratosis presents as lesions distributed on the upper and lower extremities of one body side. In the generalized form of linear porokeratosis, lesions are found on more than one extremity or on the trunk. Linear porokeratosis is associated with increased risk of squamous cell carcinoma [65-68]. (See 'Malignant transformation' below.)

Porokeratosis plantaris palmaris et disseminata — Porokeratosis plantaris palmaris et disseminata (PPPD) is a rare variant of porokeratosis, inherited in an autosomal dominant pattern, that may develop at any age [3,69]. Lesions customarily first appear in adolescence or early adulthood. The initial manifestations of PPPD are multiple small, relatively uniform macules on the palms and soles that exhibit a slightly hyperpigmented and atrophic center and a minimally raised peripheral ridge [69-72]. A serpiginous configuration may evolve over time. Patients with PPPD can also develop lesions on the trunk and extremities that resemble lesions of DSAP and DSP. Involvement of the oral mucosa may also occur as multiple small, depressed, opalescent rings with hyperemic borders [73]. The lesions of PPPD may be asymptomatic, pruritic, or tender to palpation. Porokeratoses on the feet may cause discomfort with walking.

Punctate porokeratosis — Punctate porokeratosis (porokeratosis punctata palmaris et plantaris) is characterized by multiple small, seed-like, keratotic lesions on the palms and soles that have histopathologic findings consistent with a cornoid lamella [74,75]. Some authors consider punctate porokeratosis to be a forme fruste of PPPD rather than a separate entity.

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Porokeratosis ptychotropica — Porokeratosis ptychotropica is an unusual psoriasiform variant of the disease, also described as verrucous and hypertrophic porokeratosis [76-78]. This type of porokeratosis typically presents in male patients with inflammatory, keratotic, or verrucous plaques on the buttocks or genital skin. Pathology shows numerous histopathologic foci of cornoid lamellae [76,77,79]. Lesions of porokeratosis ptychotropica are often mistaken for psoriasis, lichen simplex chronicus, or chronic eczema not only due to clinical similarities (picture 4A-B) but also due to itching.

Genitogluteal porokeratosis — The genital area is uncommonly affected by porokeratosis, with approximately 50 cases reported in the literature [80]. The porokeratotic lesions in the genital area can either represent a separate entity or a localized form of other types of porokeratosis [81]. The genital involvement is more commonly reported in men; however, case reports of vulval porokeratosis have also been published. Over 10 cases of penoscrotal porokeratosis have been published [82,83]. The uncommon variant of the disease has been reported to only occur in young men in their third decade of life, with clinical manifestation on the penile shaft and anterior scrotum accompanied by severe burning and itching [81].

Other — Other subtypes of porokeratosis that have been described in the literature include follicular porokeratosis [84-87]; eruptive pruritic papular porokeratosis in the setting of DSP [88-90]; giant porokeratosis (see 'Porokeratosis of Mibelli' above); filiform porokeratosis [91]; and porokeratosis associated with craniosynostosis, delayed closure of the fontanel, cranial defects, clavicular hypoplasia, anal and genitourinary malformations, and skin eruption (CDAGS) syndrome [92,93].

MALIGNANT TRANSFORMATION

Malignant transformation may occur in

patients with all major variants of porokeratosis, with the exception of punctate porokeratosis [94]. It is estimated to occur in 7.5 to 11 percent of patients, with an average period to cancer onset of 36 years [38]. Squamous cell carcinoma is the most common associated malignancy [95]. Basal cell carcinoma and Bowen disease (squamous cell carcinoma in situ) may also occur. Linear porokeratosis and giant porokeratosis (a variant of porokeratosis of Mibelli) are the variants most susceptible to malignant transformation, while this occurrence in disseminated superficial actinic porokeratosis (DSAP) is less common [94,96,97]. One review of 281 patients with porokeratosis found risks for malignant transformation in patients with linear porokeratosis, porokeratosis plantaris palmaris et disseminata (PPPD), porokeratosis of Mibelli of any size, and DSAP of 19, 10, 8, and 3 percent, respectively [94]. However, as development of DSAP might be ultraviolet light dependent and ultraviolet irradiation causes development of cutaneous

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malignancies, concurrent presentation of DSAP, actinic keratoses, and other cutaneous malignancies is not infrequent. Large lesion size, location on the extremities, and long lesion duration are additional factors that have been identified as risk factors for malignant transformation [38,94,98,99].

DIAGNOSIS Clinical — The diagnosis of porokeratosis often can be made based solely on clinical examination. The clinical appearance of an atrophic macule or patch with a well-defined, raised, hyperkeratotic ridge suggests this disorder (picture 1D). Marker ink or iodine can be used to highlight the appearance of the cornoid lamella in subtle cases. Self-tanning lotions containing dihydroxyacetone also highlight the cornoid lamella. Skin biopsies usually are not necessary. Biopsies are typically performed when the appearance of the lesion is not classic or when there is concern for malignant transformation. (See 'Histopathology' below and 'Differential diagnosis' below.)

Histopathology — A shave biopsy deep enough to incorporate the mid-dermis is adequate for diagnosis, provided that it includes the edge of the lesion (site of the cornoid lamella). Small lesions may be removed entirely by shave excision. A punch biopsy of the lesion edge may also be performed. (See "Skin biopsy techniques", section on 'Biopsy techniques'.) The classic histopathologic feature of porokeratosis is the cornoid lamella, a thin column of tightly packed parakeratotic cells within a keratin-filled epidermal invagination (picture 5A-C). The apex of the column angles away from the center of the lesion, and the base of the column demonstrates interruption of the epidermal granular layer and dyskeratotic keratinocytes [35]. A moderate lymphocytic inflammatory infiltrate is typically present in the papillary dermis. Dermal amyloid deposits are occasionally seen [76,100,101]. Melanocytic hyperplasia, with or without clinical hyperpigmentation, was noted in approximately 25 percent of specimens in one study [102]. Although the vast majority of biopsy specimens that demonstrate a cornoid lamella are derived from true porokeratoses, the finding is not exclusive to these lesions. Rarely, cornoid lamellae may be seen in other disorders, such as actinic keratoses, seborrheic keratoses, viral warts, and basal cell or squamous cell carcinoma [103].

Dermoscopy — Dermoscopy is a noninvasive test that can be useful for diagnosis if the clinician has access to the equipment and is trained in its use. (See "Overview of dermoscopy".) On dermoscopic examination, the cornoid lamella appears as a thin, white, double-marginated rim that may have brown pigmentation [104-108]. The atrophic center of a lesion often demonstrates a white area with red dots, globules, and lines that represent capillary vessels [104].

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Additional evaluation — The possibility of associated immunosuppression or internal malignancy (especially hematologic malignancy) should be considered in adults who present with new-onset porokeratosis of Mibelli or porokeratosis plantaris palmaris et disseminata (PPPD), or sudden exacerbations of a longstanding porokeratotic disorder.

DIFFERENTIAL DIAGNOSIS

The detection of a

cornoid lamella on clinical examination in a lesion suspicious for porokeratosis is usually sufficient for diagnosis. However, when patients present with less classic findings, other disorders that share clinical features with porokeratosis must be considered. In such cases, a biopsy of the lesion for histopathologic evaluation is helpful for distinguishing between porokeratosis and other disorders. Lesions of disseminated superficial actinic porokeratosis (DSAP) or disseminated superficial porokeratosis (DSP) clinically may resemble: ●Multiple actinic keratoses (picture 6) (see "Epidemiology, natural history, and diagnosis of actinic keratosis") ●Macular seborrheic keratoses (picture 7) (see "Overview of benign lesions of the skin", section on 'Seborrheic keratosis') ●Inflammatory skin disorders, such as guttate psoriasis, pityriasis rosea, nummular dermatitis, tinea corporis, and lichen planus (picture 8A-E) (see "Guttate psoriasis" and "Pityriasis rosea" and "Nummular eczema" and "Dermatophyte (tinea) infections", section on 'Tinea corporis' and "Lichen planus") Lesions of porokeratosis of Mibelli clinically may resemble: ●Cutaneous squamous cell carcinoma in situ (picture 9) (see "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis") ●Tinea corporis (picture 8D) (see "Dermatophyte (tinea) infections") ●Granuloma annulare (picture 10) (see "Granuloma annulare") ●Lichen simplex chronicus ●Circumscribed palmar or plantar hypokeratosis [109] ●Sarcoidosis [110] (see "Cutaneous manifestations of sarcoidosis") Lesions of linear porokeratosis clinically may resemble: ●Linear warts (see "Cutaneous warts (common, plantar, and flat warts)") ●Lichen striatus (picture 11A-E) (see "Lichen striatus")

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●Linear verrucous epidermal nevus (picture 12) ●Linear Darier disease (see "Darier disease") ●Porokeratotic adnexal osteal nevus (a proposed term that incorporates porokeratotic eccrine ostial and dermal duct nevus [PEODDN] and porokeratotic eccrine and hair follicle nevus [PEHFN]) [111,112] In addition to porokeratosis plantaris palmaris et disseminata (PPPD) and punctate porokeratosis, other disorders may present with discrete, keratotic lesions on the palms and soles. Examples include: ●Arsenical keratoses (picture 13) ●Palmoplantar keratodermas (see "Hereditary palmoplantar keratodermas") ●Palmar pits in basal cell nevus syndrome (picture 14) (see "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)")

MANAGEMENT General approach — Education about sun protection and clinical surveillance for malignant transformation are sufficient for the management of most patients with porokeratosis. However, patients who are concerned about the appearance of lesions or those with symptomatic disease (eg, pruritic or painful lesions) may desire therapeutic intervention.   Options for the treatment of porokeratosis include topical pharmacologic therapy, destructive therapies, surgical excision, and oral retinoids. Since no randomized trials have evaluated therapies for porokeratosis and the available data are insufficient for definitive recommendations on treatment, the choice of therapy is primarily based on factors such as lesion size and number, lesion location, aesthetic considerations, treatment availability, and patient preference. Our approach is as follows: ●For patients who desire quick therapy for a few small lesions and who would not be disturbed by residual changes in skin pigmentation or scarring, destructive therapies, such as cryotherapy, curettage and electrodesiccation, photodynamic therapy, and laser therapy, or surgical excision can be offered. ●For patients with multiple or large lesions, topical pharmacologic therapy with topical fluorouracil or imiquimod can be offered. For older patients with widespread lesions, radiotherapy with Grenz rays may be a treatment option.

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The intense inflammatory response that typically accompanies treatment with topical fluorouracil or imiquimod limits the skin area that can be treated at one time. If treatment of a large area is required, topical retinoids, such as tretinoin or tazarotene, may be an alternative, although a longer treatment duration of several months is typically required. The response to treatment with topical agents is often unpredictable, and clinicians must remain cognizant that lesions that initially respond well to any treatment can recur. Additional options for the treatment of porokeratosis include emollients and topical keratolytics (eg, salicylic acid). (See 'Topical therapies' below.) Systemic retinoids are generally restricted to severe cases due to the possibility of systemic adverse effects and the high likelihood for lesion recurrence after the discontinuation of treatment. (See 'Surgical and destructive therapies' below and 'Systemic therapy' below.)

Sun protection — Due to the possibility for malignant transformation in porokeratosis, patients should be strongly encouraged to engage in protection from ultraviolet radiation, a known risk factor for squamous cell and basal cell carcinoma. (See 'Malignant transformation' above.) We recommend sun-protective clothing, shelter from the sun, and routine daily use of broadspectrum sunscreen with a sun protection factor (SPF) of at least 30 on areas of skin that cannot be protected physically. Of note, strict use of sun protection may increase the risk for vitamin D deficiency, especially in patients with phototypes IV to VI. (See "Selection of sunscreen and sunprotective measures".)

Topical therapies — There are no randomized clinical trials assessing topical therapies of porokeratosis, and their use is largely based on indirect evidence from studies on treatment of actinic keratosis (see "Treatment of actinic keratosis"). The optimal treatment regimen/duration has not been determined, and the response to treatment is often unpredictable. Combination therapy using several different topical agents or topical agents and destructive therapies may be beneficial. Topical therapeutic options for porokeratosis include: ●Topical fluorouracil – Topical fluorouracil has been used in patients with disseminated superficial actinic porokeratosis (DSAP), disseminated superficial porokeratosis (DSP), porokeratosis of Mibelli, and linear porokeratosis [47,113-116]. Patients are instructed to apply 5% topical fluorouracil cream daily until an intense inflammatory response is attained (typically several weeks). The intense inflammatory response with possible superficial ulceration and postinflammatory hyperpigmentation limits the use of fluorouracil to less esthetically important areas. ●Topical imiquimod – Topical imiquimod has been used in case reports and small case series of patients with porokeratosis of Mibelli, DSAP, linear porokeratosis, and porokeratosis plantaris palmaris et disseminata (PPPD) [117-127]. A systematic review found nine reports (11 patients) of

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partial to complete resolution of porokeratosis of Mibelli with imiquimod [113]. A reasonable initial course of therapy for imiquimod is application three to five times per week for a period of four to six weeks [118-120]. Longer or shorter periods of treatment may be needed depending on the treatment response and the occurrence of adverse effects [121,122]. Similar to topical fluorouracil, an intense local inflammatory response is expected during treatment with imiquimod. ●Topical retinoids – Tretinoin 0.05% cream and 0.1% gel have been beneficial for the treatment of linear porokeratosis [128-130]. Tazarotene and adapalene have also been used in some patients with porokeratosis [131]. Topical retinoids are less irritating and induce less inflammation than topical fluorouracil or imiquimod but require a longer course of treatment (10 to 16 weeks or longer) [128130]. ●Topical vitamin D analogs – Topical vitamin D analogs, such as calcipotriol and tacalcitol, have only been reported to be effective in DSAP, and several months or more of treatment may be required for improvement [4,132-134]. ●Topical diclofenac – The value of topical diclofenac 3% gel is unclear. In a series of eight patients with DSAP, only one patient had partial improvement after six months of treatment [135]. In a single case report, topical diclofenac was effective in inducing partial resolution of inflammatory DSAP lesions that persisted despite treatment with systemic retinoids [53]. A small case series suggests that the drug may be effective in reducing disease progression [136]. ●Topical ingenol mebutate – Ingenol mebutate, a topical agent approved for the treatment of actinic keratosis, may be a treatment option for isolated or limited porokeratosis lesions [137,138].

Combination therapy — In the authors' experience, pretreatment of affected skin with a topical retinoid, such as tretinoin or tazarotene, for two to three weeks prior to the use of topical fluorouracil or imiquimod seems to improve drug penetration and the response to therapy. The relative efficacy of this regimen to treatment with topical fluorouracil or imiquimod alone has not been formally studied in porokeratosis. Other combinations described in a few case reports include adapalene with calcipotriol [131], imiquimod with fluorouracil [139], and topical fluorouracil cream with photodynamic therapy (PDT) [140].

Adjunctive topical therapies — The application of keratolytic agents, such as salicylic acid, may also be beneficial [141]. Successful treatment with salicylic acid in combination with fluorouracil or imiquimod has been reported [126,142]. In two patients with porokeratosis of Mibelli, lesion clearance was achieved with topical cantharidin [143]. Topical corticosteroids may provide symptomatic relief but only partial or no improvement of lesions [117]. There is a single report of successful use of topical tacrolimus for linear porokeratosis [144]. Emollients, especially with keratolytic properties (eg, urea-containing emollients), may be useful in patients with porokeratosis, as they may reduce the rough, dry quality of lesions.

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Surgical and destructive therapies — Porokeratosis lesions can be removed or improved with procedures such as cryotherapy, curettage and electrodesiccation, surgical excision, and dermabrasion [145-149]. However, all of these treatments are associated with a high risk of scarring or postinflammatory hyperpigmentation. Alternative approaches include: ●Laser therapy – Light-based therapies may also be effective. Carbon dioxide laser has been successfully used to treat porokeratosis of Mibelli and linear porokeratosis [150-153]. Improvement in DSAP or DSP has been reported after treatment with a fractional laser, Q-switched ruby laser, frequency-doubled neodymium:yttrium aluminum garnet (Nd:YAG) laser, and erbium:yttrium aluminium garnet (Er:YAG) laser [154-158]. Combination of carbon dioxide laser and conventional methyl aminolevulinate-PDT showed improvement of the condition but no complete resolution of DSAP lesions [159]. (See "Photodynamic therapy".) ●Photodynamic therapy – Case reports of conventional PDT in DSAP and linear porokeratosis have yielded variable results [140,160-163]. Daylight photodynamic therapy (DLPDT) has led to favorable results in four patients with DSAP [164,165]. (See "Photodynamic therapy", section on 'Daylight photodynamic therapy'.) ●Radiation therapy – In a report of eight patients with DSAP, radiotherapy with Grenz and soft rays resulted in a good response in all patients, with only one recurrence suspected (picture 15) [166]. An inflammatory reaction and postinflammatory hyperpigmentation occurred in some cases and resolved spontaneously in several months.

Systemic therapy — Oral retinoids, including acitretin and isotretinoin, are infrequently used for the treatment of severe cases of porokeratosis. Retinoids have been reported to be effective in patients with DSAP, linear porokeratosis, porokeratosis of Mibelli, PPPD, and generalized linear lesions [69,167-170]. However, systemic retinoids need to be administered for many months. The degree of improvement is variable; recurrence after treatment discontinuation is likely. Systemic retinoids are teratogenic. Acitretin is contraindicated in female patients of childbearing potential; pregnancy must be avoided for three years after discontinuation. In a single case report, a patient with DSAP who received the keratinocyte differentiation factor palifermin for mucositis prophylaxis under chemotherapy for solid tumor treatment showed a marked improvement of DSAP with sustained clearance of the lesions at 12 months follow-up [171].

Skin cancer prevention and surveillance — Although removal of lesions via surgical or destructive methods is an option for the prevention of malignant transformation in lesions of porokeratosis, this is generally not needed or feasible, especially for patients with large or extensive lesions. Factors, such as the estimated risk for malignancy for specific lesion types and the risk for significant cosmetic or functional defects following removal, must be considered. The removal of the lesions with the greatest risk for malignancy (linear porokeratosis or large porokeratosis of Mibelli) often would result in an unacceptable amount of scarring and, possibly, functional impairment.

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Clinical surveillance with regular skin examinations and patient education about the warning signs of skin cancer and sun protection are thus key aspects of the management of all patients with porokeratosis. Although malignant transformation in DSAP and DSP is rare compared with porokeratosis of Mibelli and linear porokeratosis, the frequent presence of additional risk factors for cutaneous malignancy (eg, light skin type, history of high sun exposure, immunosuppression) makes close clinical follow-up of these patients worthwhile. ●Patient education – All patients should be educated about warning signs for malignancy. Patients should be instructed to return for follow-up if changes occur in a previously stable lesion, such as the development of induration, ulceration, nodularity, bleeding, crusting, or rapid growth. Similarly, patients should return for reevaluation if new symptoms develop in lesions (eg, prickling or tingling sensations or pain). ●Sun protection –The implementation of sun-protective practices is recommended to reduce actinic damage. (See 'Sun protection' above and "Selection of sunscreen and sun-protective measures".) ●Routine follow-up –Patients should be followed annually to monitor for signs and symptoms of malignancy, to screen for changes in health status that might suggest an underlying systemic disorder, and to reinforce sun protection education. In case of high number or large lesions, more frequent follow-up visits (eg, every six months) should be scheduled. Any lesion that exhibits clinical features suspicious for malignancy (eg, induration, ulceration, bleeding, crusting, rapid growth) should be excised or biopsied for histopathologic examination. If the decision is made to excise or destroy a lesion for prophylactic purposes, doing so in an urgent manner is not necessary, as the period between lesion development and malignancy often spans decades (see 'Malignant transformation' above). After removal, clinical follow-up still should be performed yearly to evaluate these patients for the development of new or recurrent lesions.

Immunocompromised patients — Although systemic immunosuppression has not been proven to increase the risk for malignant transformation in lesions of porokeratosis [35,97], immunosuppression is a known risk factor for cutaneous malignancy. Thus, skin examinations are often performed more than once yearly for skin cancer surveillance in this population regardless of the presence or absence of porokeratosis. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Followup'.)

Chemoprevention — Systemic retinoids are occasionally used for the management of patients with severe porokeratosis. Based on indirect evidence from studies on chemoprevention of cutaneous squamous cell carcinoma in solid organ transplant recipients, the risk for malignant transformation may be reduced during active treatment with systemic retinoids [172]. However, this has not been directly studied in porokeratosis, and the long-term impact of retinoid therapy on malignant transformation of these lesions is unknown.

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In a randomized trial, daily use of 1000 mg of nicotinamide for 12 months reduced the number of new basal cell carcinoma and squamous cell carcinoma by 20 and 30 percent, respectively, in patients at high risk of nonmelanoma skin cancer [173]. However, the value of nicotinamide supplementation in the prevention of skin cancer in patients with porokeratosis has not been specifically studied. (See "Epidemiology and risk factors for cutaneous squamous cell carcinoma", section on 'Chemoprevention' and "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Chemoprevention for SCC'.)

PROGNOSIS

Without treatment, lesions of porokeratosis usually persist

indefinitely [94]. Spontaneous regression is rare [35]. Malignant transformation is estimated to occur in 7 to 11 percent of patients with porokeratosis, most often in lesions of linear porokeratosis or giant porokeratosis (a form of porokeratosis of Mibelli). The vast majority of squamous cell carcinomas that develop in lesions of porokeratosis are successfully treated with local therapy. However, several cases of metastatic squamous cell carcinoma arising in the setting of porokeratosis have been reported [97,174-177]. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma" and "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)

SUMMARY AND RECOMMENDATIONS ●Porokeratosis is a rare, sporadic or inherited disorder of keratinization characterized by the presence of a characteristic ridge-like, keratotic border called "cornoid lamella" (picture 1D). Several clinical variants of porokeratosis have been described, all of which share this distinctive feature. (See 'Introduction' above and 'Classification' above.) ●The pathogenesis of porokeratosis is poorly understood. Factors such as genetic susceptibility, exposure to ultraviolet radiation, and immunosuppression may contribute to lesion development. (See 'Pathogenesis' above.) ●Disseminated superficial actinic porokeratosis (DSAP) is the most common form of porokeratosis. Patients are typically adults with a history of chronic sun exposure. Few or many small, porokeratotic macules are usually present on the extensor extremities (picture 1B, 1D). (See 'Disseminated superficial actinic porokeratosis' above.) ●Porokeratosis of Mibelli is the second most common type of porokeratosis. Lesions most commonly begin in childhood but may occur in adults, particularly in the setting of immunosuppression. An annular plaque a few centimeters in diameter with a prominent keratotic ridge is the typical clinical finding (picture 2A). (See 'Porokeratosis of Mibelli' above.)

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●Malignant transformation to squamous cell carcinoma is estimated to occur in 7 to 11 percent of patients with porokeratosis, most often in lesions of linear porokeratosis or giant porokeratosis (a form of porokeratosis of Mibelli). (See 'Malignant transformation' above.) ●Clinical examination is usually sufficient for the diagnosis of porokeratosis. Skin biopsy may be useful in the setting of atypical lesions or lesions that are suspicious for malignant transformation. Biopsy of the periphery of the lesion characteristically demonstrates a cornoid lamella, consisting of a narrow column of parakeratotic cells (picture 5A). (See 'Diagnosis' above and 'Histopathology' above.) ●Education about sun protection and clinical surveillance for malignant transformation are sufficient for the management of most patients with porokeratosis. However, patients with symptomatic or cosmetically distressing lesions may desire treatment. (See 'General approach' above.) ●For patients with a few small lesions who desire rapid treatment for symptom relief or cosmetic purposes, we suggest treatment with destructive therapies (eg, cryotherapy, curettage and electrodesiccation, laser therapy) or surgical excision (Grade 2C). Treatment-related pigmentation changes or scarring may occur. (See 'Surgical and destructive therapies' above.) ●For patients with large or multiple lesions that are not amenable to surgical or destructive therapy, we suggest treatment with topical therapies rather than systemic therapy (Grade 2C). Topical fluorouracil or imiquimod may be used for the treatment of localized areas. Topical retinoids are a less irritating therapeutic option and, thus, suitable for use on larger areas but may require a longer course of therapy. (See 'Topical therapies' above.) ●Sequential therapy with topical retinoids for two to three weeks followed by a course of topical fluorouracil or imiquimod may enhance drug penetration and response to treatment. (See 'Combination therapy' above.) ●Additional choices for lesion destruction include radiotherapy with Grenz rays, dermabrasion, laser therapy, and photodynamic therapy (PDT). (See 'Surgical and destructive therapies' above.) ●Treatment with systemic retinoids is usually reserved for severe cases. Relapse is likely after treatment cessation. (See 'Systemic therapy' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like

to acknowledge Linda V Spencer, MD, who contributed to an earlier version of this topic review.

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Overview of cutaneous lupus erythematosus Author: Joseph F Merola, MD, MMSc, FAAD, FACR Section Editors: David S Pisetsky, MD, PhD, Jeffrey Callen, MD, FACP, FAAD Deputy Editors: Abena O Ofori, MD, Monica Ramirez Curtis, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Sep 19, 2019.

INTRODUCTION Cutaneous lupus erythematosus (cutaneous LE) includes three subsets of LE-specific skin diseases: acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), and chronic cutaneous lupus erythematosus (CCLE) (table 1). CCLE encompasses discoid lupus erythematosus (DLE), lupus erythematosus tumidus (LE tumidus), lupus profundus (also known as lupus panniculitis), chilblain lupus erythematosus (chilblain LE), and lichenoid cutaneous lupus erythematosus-lichen planus overlap syndrome (LE-LP overlap syndrome). Cutaneous LE can occur as a manifestation of systemic lupus erythematosus (SLE) or independent of SLE. The varying strengths of association between SLE and the individual subtypes of cutaneous LE are best illustrated in a graphic (figure 1). Patients with SLE may also develop a variety of LE-nonspecific skin diseases, cutaneous disorders that lack histologic features of LE, but occur with increased frequency in patients with SLE. An overview of the various clinical manifestations of cutaneous LE and LE-nonspecific skin diseases is provided here. In-depth discussions of SLE and the treatment of DLE and SCLE are provided separately. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Initial management of discoid lupus and subacute cutaneous lupus" and "Management of refractory discoid lupus and subacute cutaneous lupus" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

CLASSIFICATION The modified Gilliam grouping system for cutaneous manifestations of LE provides a helpful organizational framework for the related but distinct clinical entities that comprise LE-specific and LE-nonspecific skin diseases. The three subcategories under LE-specific skin disease and their major clinical variants include: ●

Acute cutaneous lupus erythematosus (ACLE)

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• Localized ACLE (ie, malar rash, butterfly rash) • Generalized ACLE • Toxic epidermal necrolysis-like ACLE ●

Subacute cutaneous lupus erythematosus (SCLE)

• Annular SCLE • Papulosquamous SCLE • Drug-induced SCLE • Less common variants: erythrodermic, poikilodermatous, erythema multiforme-like (Rowell syndrome), and vesiculobullous annular SCLE ●

Chronic cutaneous lupus erythematosus (CCLE)

• Discoid lupus erythematosus (DLE)

- Localized DLE - Generalized DLE - Hypertrophic DLE • Lupus erythematosus tumidus (LE tumidus) • Lupus profundus (also known as lupus panniculitis) • Chilblain lupus erythematosus (chilblain LE) • Lichenoid cutaneous lupus erythematosus-lichen planus overlap syndrome (LE-LP overlap syndrome) The key characteristic that unites the LE-specific skin diseases is histopathology. Common shared histopathologic features include hyperkeratosis; epidermal atrophy; vacuolar interface dermatitis (liquefactive degeneration of the basal layer of the epidermis); a superficial, perivascular, and perifollicular mononuclear cell inflammatory infiltrate; thickening of the basement membrane; and pigment incontinence [1]. All of these features are not necessarily present in all variants. In particular, interface dermatitis is a consistent histopathologic feature of ACLE, SCLE, and discoid lupus erythematosus (the most common form of CCLE) but is not a typical feature of LE tumidus or lupus profundus. Interface dermatitis may also be seen in non-LE disorders, such as dermatomyositis.   In addition, most LE-specific skin diseases can occur in association with SLE, with the exception of LE tumidus, for which associated SLE is rare (figure 1). LE-specific diseases may also occur in conjunction with other LEspecific skin diseases and have a similar approach to treatment. (See 'Management' below.) The designations "acute," "chronic," and "subacute" do not necessarily or strictly reflect the duration of activity of the skin disease. The "acute" in ACLE reflects the often transient and recurrent course of ACLE and the tendency for exacerbations of ACLE to occur during acute flares of SLE; in addition, the terminology was

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originally coined in reference to a lack of residual long-term skin damage, dyspigmentation, or scarring. The "chronic" in CCLE reflects both the often prolonged course of CCLE and the resulting chronic skin changes of dyspigmentation and scarring that occur in DLE. SCLE may lead to longstanding skin dyspigmentation but typically does not cause scarring.   Although ACLE, SCLE, and the variants of CCLE are described as distinct entities, patients may develop more than one form of cutaneous LE. Many patients, up to 30 percent in some reports, may have overlap between subsets of cutaneous LE, particularly SCLE and DLE [2].

ASSOCIATION WITH SLE Cutaneous disease is common in systemic lupus erythematosus (SLE); approximately 80 percent of patients develop skin disease at some point in their disease course. However, cutaneous LE frequently exists independently of SLE and may be two to three times more prevalent than SLE [3-6]. The association with SLE varies among the subtypes of cutaneous LE and mainly has been estimated from cross-sectional studies and retrospective studies [6-8]. Studies evaluating cross-sectional percent prevalence of underlying SLE in patients with cutaneous LE have suggested the following levels of association with SLE (these data do not reflect incident cohort data): ●

ACLE – >90 percent [3]



SCLE – 48 to 50 percent [9]



Localized DLE – 5 to 10 percent [10]



Generalized DLE – 15 to 28 percent [10]



Lupus profundus/panniculitis – 5 to 10 percent [11]



Lupus erythematosus tumidus – Rarely associated with SLE [12]

It is important to again note that these data represent the cross-sectional co-prevalence between cutaneous LE and SLE, rather than a prospective incidence. A graphical representation of the associations between the subtypes of cutaneous LE and SLE is provided (figure 1). Patients who develop SLE after the onset of cutaneous LE often do so within the first few years after diagnosis [13]. In a Danish nationwide cohort study that included 2380 patients with cutaneous LE (62 percent with DLE, 20 percent with SCLE, and the remainder with other or unspecified forms of cutaneous LE), patients who did not have a diagnosis of SLE at the time of diagnosis had a 9 and 13 percent probability of a diagnosis of SLE 5 and 10 years after cutaneous LE, respectively [13]. The median time to diagnosis of SLE was two years. Women and patients with SCLE had the greatest probability for a diagnosis of SLE.

LUPUS ERYTHEMATOSUS-SPECIFIC SKIN DISEASE Acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), and chronic cutaneous lupus erythematosus (CCLE) comprise LE-specific skin disease.

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Acute cutaneous lupus erythematosus — ACLE is a manifestation of systemic lupus erythematosus (SLE) that may present as a characteristic localized facial eruption, less commonly as a generalized eruption, and rarely as a toxic epidermal necrolysis (TEN)-like presentation [14]. Localized ACLE appears in approximately one-half of patients with SLE. Almost all patients with ACLE have SLE. ●

Clinical manifestations – The facial eruption of localized ACLE (also known as "malar rash" or "butterfly rash") is characterized by erythema in a malar distribution (cheeks and bridge of the nose) (picture 1A-B). The nasolabial folds are spared. Localized ACLE may precede other symptoms of SLE by months or even years or may be accompanied by other symptoms and signs of acute SLE. The involved skin feels warm and appears slightly edematous. The erythema may last for hours, days, or weeks and often recurs, particularly with sun exposure. In darker skin types, postinflammatory hyperpigmentation or hypopigmentation may persist even after the acute inflammatory stage has resolved. Generalized ACLE presents as an erythematous maculopapular (morbilliform) eruption involving primarily sun-exposed skin. The extensor surfaces of the arms and hands are common sites. Notably, the skin overlying the knuckles often is spared, a feature that contrasts with dermatomyositis. Occasionally, the inflammatory infiltrate is severe enough to produce vesicles or bullae. Severe cases can resemble TEN-like ACLE [15-19]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults" and "StevensJohnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)



Histopathology – The classic histologic findings of localized and generalized ACLE are consistent with interface dermatitis and include apoptotic keratinocytes, vacuolization of the basal cell layer of the epidermis, a lymphohistiocytic infiltrate in the superficial dermis, and dermal mucin deposition [20]. The findings can be subtle.



Differential diagnosis – Localized ACLE should be distinguished from rosacea. Rosacea can present with malar erythema and may be exacerbated by sun exposure (picture 2). Features that favor a diagnosis of rosacea include involvement of the nasolabial fold, papules or pustules (papulopustular variant), and exacerbation of erythema with typical rosacea triggers (spicy foods, caffeine, heat, etc). Although rarely necessary, a skin biopsy can distinguish ACLE from rosacea [21]. (See 'Diagnosis' below and "Rosacea: Pathogenesis, clinical features, and diagnosis".) Other causes of facial erythema that may be confused with ACLE include sunburn, seborrheic dermatitis, contact dermatitis, erysipelas, flushing (idiopathic or associated with carcinoid syndrome, pheochromocytoma, or mastocytosis), and dermatomyositis. A skin biopsy can aid in distinguishing most of these disorders from ACLE. An exception is dermatomyositis, which exhibits similar pathologic findings. A helpful clinical feature of facial eruptions in dermatomyositis is the tendency to involve the nasolabial folds; in ACLE, the nasolabial folds are spared (picture 3). (See "Approach to the patient with facial erythema" and "Rosacea: Pathogenesis, clinical features, and diagnosis" and "Clinical manifestations of dermatomyositis and polymyositis in adults".)

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Subacute cutaneous lupus erythematosus — SCLE frequently is associated with SLE [22,23]. Approximately 50 percent of affected patients meet the 1997 American College of Rheumatology (ACR) classification criteria for SLE, but subsequent studies have revealed that approximately 10 to 15 percent of patients presenting with SCLE go on to develop severe clinical manifestations of SLE (eg, serious central nervous system or renal disease) (table 2) [9]. SCLE can also occur as a result of drug exposure. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and 'Drug-induced SCLE' below.)   The ACR classification criteria are known to have inherent limitations, which include classifying SLE too readily in patients with SCLE. Based upon SCLE features alone, at least 3 or 4 of 11 criteria are often met (ie, SCLE patients may have photosensitivity, positive antinuclear antibodies [SSA/Ro+], mild arthralgias, and/or oral ulcers, which could suggest the diagnosis of SLE). However, these patients may have no other systemic endorgan involvement or other SLE features. In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) proposed revised classification criteria that addressed some of these limitations regarding the cutaneous disease manifestations (table 2). It should be noted that the ACR and SLICC criteria were developed for study purposes and have limited use in clinical practice. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Classification criteria'.)     There is a strong association between SCLE, human leukocyte antigen (HLA)-DR3, antibodies to Ro/SSA, and polymorphisms in the tumor necrosis factor (TNF)-alpha promoter gene [24,25]. More than 80 percent of patients with SCLE are positive for anti-Ro/SSA antibodies [26,27]. SCLE has also been associated with homozygous deficiencies of the second component of complement [28,29]. (See "The anti-Ro/SSA and antiLa/SSB antigen-antibody systems".) ●

Clinical manifestations – SCLE begins as small, erythematous, slightly scaly papules that evolve into either psoriasiform plaques (papulosquamous SCLE) or annular plaques (annular SCLE) (picture 4A-B). The latter often coalesce to form polycyclic or figurative patterns. The plaques are typically erythematous with variable amounts of overlying scale. The most common sites of involvement are somewhat photodistributed and include the shoulders, forearms, neck, and upper torso. Despite a photoaggravated nature of the condition, the face is often spared [23]. Dyspigmentation at sites of resolved SCLE is common and may resemble vitiligo. Scarring usually does not occur. Less common variants include vesiculobullous annular, poikilodermatous, erythrodermic, and erythema multiforme-like (Rowell syndrome) SCLE. Drug-induced SCLE is reviewed separately. (See 'Drug-induced SCLE' below.) Most patients with SCLE exhibit photosensitivity, with exacerbations of disease stimulated by sun exposure. A case-control study of 76 patients with SCLE (including 48 who also fulfilled ACR criteria for SLE) and 24 patients with SLE without SCLE found photosensitivity nearly twice as prevalent in patients with SCLE than in patients with SLE without SCLE (86 versus 46 percent, respectively) [30]. Associated arthralgias and oral ulcers are reported; however, serious features such as cytopenias and serositis occur much less frequently.



Histopathology – Compared with discoid lupus erythematosus (DLE), the histopathology of SCLE shows less follicular plugging and hyperkeratosis, and the perivascular and appendageal lymphocytic infiltrates tend to be more superficial. There is vacuolization of the basement membrane and mucin deposition in the

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dermis. Basement membrane thickening is generally absent or minimal (picture 5A-B) [23,31]. (See 'Discoid lupus erythematosus' below.) ●

Differential diagnosis – The differential diagnosis of SCLE includes other disorders that may exhibit erythematous papules or plaques such as psoriasis, tinea corporis, nummular eczema, dermatomyositis, cutaneous T cell lymphoma, and drug eruptions [32]. If the diagnosis is uncertain, a biopsy can distinguish SCLE. (See 'Diagnosis' below.)

Drug-induced SCLE — Many classes of drugs have been implicated in SCLE, including antihypertensive drugs, lipid-lowering agents, proton pump inhibitors, antifungal agents, TNF-alpha inhibitors, and others (table 3) [10,33-36]. A case-control study that included 234 patients with incident SCLE found that more than one-third of cases appeared related to a drug exposure [33]. (See "Drug-induced lupus", section on 'Drug-induced cutaneous lupus'.) Drug-induced SCLE and idiopathic SCLE have similar clinical, histopathologic, and laboratory features and can be indistinguishable in the absence of a helpful medication history. However, certain features may be more likely to occur in each subtype. A retrospective study of 165 patients with idiopathic SCLE and 67 patients with drug-induced SCLE found that, compared with patients with idiopathic SCLE, patients with drug-induced SCLE were older (mean age 41 versus 53 years), reported more systemic symptoms (13 versus 48 percent), and were more likely to have leukocytoclastic vasculitis on histopathology (none versus 11 percent) [37]. Findings that were more common in idiopathic disease than in drug-induced disease included histopathology showing mucin deposition (70 versus 36 percent) and direct immunofluorescence findings of both immunoglobulin M (IgM) and C3c deposition at the dermoepidermal junction (52 versus 21 percent). Tissue eosinophilia does not help to distinguish idiopathic from drug-induced SCLE [38]. Drug withdrawal often leads to improvement in drug-induced SCLE. In the retrospective study of 11 patients with drug-induced SCLE and 79 patients with idiopathic SCLE, all cases of drug-induced disease resolved after drug withdrawal. The mean time to resolution was seven weeks and Ro/SSA antibodies eventually disappeared in 8 of the 10 patients who previously tested positive for these antibodies [27]. Similarly, most patients in a retrospective study of 15 patients with drug-induced SCLE experienced improvement in the clinical manifestations of SCLE within eight weeks of drug withdrawal and a decrease in anti-Ro/SSA antibodies within eight months following drug withdrawal [34]. Neonatal lupus — Neonatal lupus shares a variety of features with classic SCLE; therefore, some clinicians consider the cutaneous manifestations of this entity a subtype of SCLE. Similarities with classic SCLE include clinical features (arcuate erythematous plaques that resolve without scarring (picture 6)), histologic findings (interface dermatitis), and an association with anti-Ro/SSA antibodies. (See 'Neonatal lupus' below and "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".) Chronic cutaneous lupus erythematosus — CCLE includes: ●

Discoid lupus erythematosus (DLE)



Lupus erythematosus tumidus (LE tumidus)

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Lupus profundus (lupus panniculitis)



Chilblain lupus erythematosus (chilblain LE)



Lichenoid cutaneous lupus erythematosus-lichen planus overlap syndrome (LE-LP overlap syndrome)

The most common type of CCLE is DLE, accounting for 73 to 85 percent of CCLE [7,39]. Discoid lupus erythematosus — It is estimated that 15 to 30 percent of patients with SLE develop DLE [1,40,41]. Patients with localized or generalized DLE are estimated to have cross-sectional prevalences of concurrent SLE between 5 and 28 percent. (See 'Association with SLE' above.) The presence of DLE lesions among patients with SLE may modify the risk of specific SLE features. Compared with SLE patients without DLE, those with DLE have increased risk for photosensitivity and leukopenia but decreased risk for serositis and arthritis. There is no obvious change in risk of nephritis despite variable reports of a "renal-protective effect" of the presence of discoid lesions among SLE patients [42,43]. Data on the risk for progression of DLE to SLE are limited to retrospective cohort studies, studies lacking power to detect statistical significance of potential markers of progression, and studies that do not address DLE specifically as a CLE subset. In these studies, progression to SLE has occurred in 0 to 28 percent of patients initially presenting with DLE [7,13,41,44]. Progression to SLE often is delayed; in a Swedish-based population cohort study, 10 percent of patients with DLE who subsequently developed SLE did so within the first year and 17 percent developed SLE within the first three years [8]. Two retrospective studies have suggested SLE develops within five years in 50 percent of the DLE patients who indeed go on to develop SLE [10]. Risk factors for progression include an increasing number of clinical and serologic features of SLE: more widespread DLE lesions, arthralgias and arthritis, high antinuclear antibody (ANA) titers, leukopenia, and high erythrocyte sedimentation rates [10,45,46]. It is worth noting that patients with DLE and other mucocutaneous manifestations of LE may meet ACR classification criteria for SLE without having other end-organ disease [47]. Revised classification criteria (the SLICC criteria) have been proposed to address some limitations of the ACR criteria. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Classification criteria'.) ●

Clinical manifestations – The classic findings of DLE are discrete, erythematous, somewhat indurated plaques covered by a well-formed adherent scale that extends into dilated hair follicles (follicular plugging). The plaques tend to expand slowly with active inflammation at the periphery and then heal, leaving depressed central scars, atrophy, telangiectasias, and hyperpigmentation and/or hypopigmentation [45]. DLE most often involves the face, neck, and scalp but may also occur on the ears (particularly conchal bowls) and, less frequently, on the upper torso (picture 7A-D). Localized DLE is limited to sites above the neck. Generalized DLE refers to DLE occurring both above and below the neck. Hypertrophic DLE is an uncommon clinical variant of DLE characterized by the development of hyperkeratotic, verrucous plaques [48].

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Histopathology – Pathologic examination of DLE typically reveals hyperkeratosis, follicular plugging, basal layer vacuolar changes, and a mononuclear cell infiltrate (predominantly T cells) near the dermal-epidermal junction, dermal blood vessels, and appendages (picture 8) [31]. The basement membrane is usually thickened, a change that is best appreciated with a periodic acid-Schiff (PAS) stain, and there is dermal mucinosis. Although immunofluorescence microscopy may be positive in cutaneous LE, its use is limited by false-positive results on sun-exposed skin and by negative results in longstanding chronic LE lesions. (See 'Direct immunofluorescence (lupus band test)' below.)



Differential diagnosis – The cutaneous differential diagnosis of DLE includes:

• Tinea faciei • Granuloma faciale (picture 9A-B) • Sarcoidosis • Lupus vulgaris (cutaneous tuberculosis) • Lymphoproliferative disorders of skin (benign or malignant) • Cutaneous leishmaniasis (eg, lupoid leishmaniasis, leishmaniasis recidivans) • Tuberculoid leprosy Verrucous/hypertrophic discoid lupus may be confused with hypertrophic lichen planus, keratoacanthoma, squamous cell cancer, and prurigo nodularis. (See 'Diagnosis' below.) ●

Risk for squamous cell carcinoma – Infrequently, squamous cell carcinoma develops in sites of DLE. Squamous cell carcinoma in DLE is estimated to occur in 2 to 3 percent of DLE patients, is postulated to be related to the presence of chronic inflammation, and is associated with increased risk for a poor prognosis for squamous cell carcinoma [49].

Less common subtypes — LE tumidus, lupus profundus (lupus panniculitis), chilblain LE, and lupus erythematosus-lichen planus (LE-LP) overlap syndrome are additional manifestations of CCLE. Lupus erythematosus tumidus — Although often categorized as a form of LE-specific skin disease, the rarity of association with concurrent SLE and the lack of interface dermatitis on pathology have raised debate about where LE tumidus falls in the classification of cutaneous lupus disorders. In a series of 40 patients with LE tumidus, only 10 percent were ANA-positive [50]. An increased incidence among smokers has been noted [51]. ●

Clinical manifestations – LE tumidus is characterized by photodistributed, chronic, pink to violaceous, urticarial or edematous plaques or nodules [50,52,53]. Annular plaques may occur (picture 10A-B). Scale and scarring are absent.



Histopathology – There is a moderate to dense, superficial and deep, perivascular lymphocytic infiltrate, consisting of predominately CD3+/CD4+ lymphocytes. In addition, there is mucin deposition in the papillary

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and reticular dermis. Interface changes at the dermal-epidermal junction are absent in most cases. A minority of patients exhibit focal interface changes [52]. ●

Differential diagnosis – The differential diagnosis of LE tumidus includes causes of erythematous to violaceous plaques with absent surface change, such as benign lymphocytic infiltration of skin (Jessner's disease), polymorphous light eruption, pseudolymphoma, B cell lymphoma, plaque mucinosis, and solar urticaria. (See 'Diagnosis' below.) Lupus profundus (lupus panniculitis) — Lupus profundus (also known as lupus panniculitis) is an

uncommon form of CCLE. Coexistent DLE occurs in at least one-third of patients with lupus profundus; SLE is present in approximately 10 percent of patients [11,54]. ●

Clinical manifestations – Lupus profundus presents as indurated plaques or nodules with or without overlying cutaneous changes [55]. The plaques or nodules may appear on the scalp, face, upper arms, chest (particularly breasts), lower back, flank, upper thighs, or buttocks and are often tender or painful. Infrequently, patients develop ulceration or calcifications at sites of involvement. Upon resolution, lupus profundus may leave depressed areas of lipoatrophy (picture 11).



Histopathology – Histopathologic examination reveals perivascular infiltrates of mononuclear cells plus panniculitis, manifested as hyaline fat necrosis with mononuclear cell infiltration and lymphocytic vasculitis (picture 12A-B). The presence of immune deposits in the dermal-epidermal junction on direct immunofluorescence offers support for the diagnosis [56]. (See 'Diagnosis' below.)



Differential diagnosis – Nodules of lupus profundus on the breast may raise concern for a breast malignancy. The possibility of subcutaneous panniculitis-like T cell lymphoma, which often manifests with subcutaneous nodules or plaques on the trunk or extremities, also should be considered [57]. A biopsy will distinguish lupus profundus from these entities. (See 'Diagnosis' below.) Chilblain lupus erythematosus — Chilblain LE is diagnosed in patients with clinical findings of pernio

(also known as chilblains) in conjunction with clinical or laboratory features of cutaneous or systemic LE. Approximately 25 percent of patients who present with pernio meet classification criteria for SLE, and additional patients (5 to 6 percent in one study) may fulfill SLE criteria subsequently [58]. (See "Pernio (chilblains)".) Similar to idiopathic pernio, chilblain LE presents with tender, bright red to reddish-blue papules, nodules, or plaques on the toes, fingers, nose, or ears precipitated by cold exposure (picture 13) [59]. Nodules on acral areas may ulcerate. Chilblain LE is reviewed separately. (See "Pernio (chilblains)", section on 'Chilblain lupus erythematosus'.) Chilblain LE is distinct from lupus pernio, a subtype of sarcoidosis. (See "Cutaneous manifestations of sarcoidosis", section on 'Lupus pernio'.) Lupus erythematosus-lichen planus overlap syndrome — LE-LP overlap syndrome is a rare, chronic disorder that has clinical, histopathologic, and immunofluorescence findings of both LE and lichen planus [60,61].  

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Clinical manifestations – The cutaneous findings of LE-LP overlap syndrome are usually persistent atrophic blue-red to violaceous plaques or patches. The most common sites for involvement are the acral portions of the extremities, particularly the palms and soles. The nails are commonly involved, and there may be anonychia (absence of the nail). Photosensitivity and pruritus are generally absent.



Histopathology – Histopathologic examination may reveal features of lichen planus (hyperkeratosis, hypergranulosis, irregular acanthosis, pigment incontinence) and LE. Similarly, direct immunofluorescence (DIF) microscopy may reveal features of lichen planus (cytoid bodies staining for IgM and fibrin in a fibrillar pattern) and LE (immunoglobulin and complement deposition in a linear granular pattern along the dermalepidermal junction) [62]. (See "Lichen planus".)

Diagnosis — In general, cutaneous LE is largely a clinical diagnosis supported by contextual clinical features (such as the presence of known underlying SLE). Confirmatory histopathologic examination is indicated when diagnostic uncertainty remains (eg, atypical clinical presentation or clinical features that overlap with other cutaneous diseases). For example, localized ACLE often can be diagnosed by recognition of erythema in the classic malar distribution in a patient with known SLE, and clinical recognition of an eruption with the classic morphology and distribution of DLE is acceptable for the diagnosis of DLE. In contrast, the skin lesions of lupus profundus are often biopsied because of the nonspecific appearance of cutaneous nodules, and tumid lupus erythematosus is often biopsied because of the nonspecific clinical features and absence of an association with SLE. The overlap in the appearance of SCLE with other papulosquamous or annular skin disorders often warrants a biopsy; however, in a patient who also exhibits photosensitivity and positive SSA/Ro antibodies, diagnosis without a biopsy is reasonable. Performance of direct immunofluorescence is of variable utility if the diagnosis remains uncertain after clinical and histologic evaluation. (See 'Direct immunofluorescence (lupus band test)' below.) Other than the strong association between Ro/SSA antibodies for SCLE, there are no antibodies that are routinely predictive of variants of CLE. (See 'Subacute cutaneous lupus erythematosus' above.) Given the association of cutaneous LE with SLE, patients with cutaneous LE should be evaluated for SLE. While no clear guidelines exist for SLE screening or monitoring of the patient first presenting with cutaneous LE, obtaining a clinical history with a particular focus on a rheumatologic review of systems is recommended. A physical examination and select laboratory studies also should be performed. The evaluation for SLE is reviewed in detail separately. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis".) If systemic features of SLE or laboratory abnormalities are present, referral to a rheumatologist is appropriate for further evaluation and comanagement. Direct immunofluorescence (lupus band test) — Direct immunofluorescence (DIF) evaluation of lesional or nonlesional skin for deposition of a continuous band of immunoreactants along the dermal-epidermal junction as part of the evaluation for cutaneous lupus or SLE is historically referred to as the "lupus band test." Use of the terms "lesional lupus band test" and "nonlesional lupus band test" can help to clarify the source of the

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tissue used for the test. Overall, DIF is of unclear value for the diagnosis of cutaneous LE. Therefore, we do not routinely perform DIF. Occasionally, demonstration of a continuous band of immunoreactants at the dermal-epidermal junction in tissue taken from a site of cutaneous LE (ie, lesional lupus band test) is used to support a diagnosis of cutaneous LE when histologic findings are nondiagnostic (picture 14) [63,64]. Although these findings are detected in lesional skin from most patients with ACLE, the finding is not pathognomonic [65,66]. In particular, biopsies from sun-exposed skin from individuals without cutaneous LE or SLE have demonstrated similar features, as shown in a prospective study of 50 healthy young adults that found deposition of immunoglobulins at the dermal-epidermal junction in 10 of 50 biopsy specimens (20 percent) taken from sun-exposed skin [66]. A subsequent study that did not find immunoreactant deposition in sun-exposed skin from 41 healthy adults may have yielded different results because of differences in protocol or other factors [67]. Management — The approach to the treatment of LE-specific skin disease is influenced by the subtype of disease and the presence of underlying SLE. In all cases, photoprotection and use of appropriate broadspectrum sunscreens are recommended, given the known photoexacerbation of cutaneous LE. (See "Selection of sunscreen and sun-protective measures" and "Initial management of discoid lupus and subacute cutaneous lupus", section on 'Photoprotection'.) Topical and intralesional corticosteroids, oral glucocorticoids, oral antimalarial drugs, and glucocorticoidsparing immunomodulatory agents have all been utilized depending on extent of disease and response to firstand second-line therapies. The general approach to management of cutaneous LE is as follows: First-line therapy typically involves: ●

Photoprotection.



Use of topical or intralesional corticosteroids, topical calcineurin inhibitors, and/or systemic glucocorticoids depending on the extent of involvement and subset of disease.



Systemic antimalarial agents (treatment with either hydroxychloroquine or chloroquine, or with the addition of quinacrine to either of these agents) [68].

Second-line therapy typically involves glucocorticoid-sparing and immunomodulatory therapy and should take into account underlying SLE end-organ manifestations, if present: ●

Methotrexate (oral or subcutaneous): additional benefits may include treatment of SLE with inflammatory arthritis component.



Mycophenolate mofetil: may be of dual-benefit to patients with underlying lupus nephritis.

Other second- or third-line agents may include: ●

Thalidomide, lenalidomide, systemic retinoids, oral dapsone, belimumab, or azathioprine.

Case reports exist for the use of ustekinumab [69-71], apremilast [72], clofazimine, intravenous immunoglobulin (IVIG), cyclophosphamide, and other interventions. In addition, the findings of a prospective uncontrolled study

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and retrospective study suggest that rituximab may be useful for some patients with refractory cutaneous LE [73,74]. The treatment of DLE and SCLE is discussed in detail separately. (See "Initial management of discoid lupus and subacute cutaneous lupus", section on 'Photoprotection' and "Management of refractory discoid lupus and subacute cutaneous lupus".)

LUPUS NONSPECIFIC SKIN DISEASE Cutaneous disorders that occur with increased frequency among patients with systemic lupus erythematosus (SLE), but are not specific to SLE and lack histopathologic features of cutaneous LE comprise LE-nonspecific skin disease (table 4). Of note, many of these lupus nonspecific skin diseases are reported to occur with flares of underlying SLE. Vascular abnormalities — Examples of cutaneous manifestations of vascular involvement in SLE include periungual erythema, livedo reticularis, telangiectasia, Raynaud phenomenon, and vasculitis. Cutaneous vascular abnormalities occur in approximately 50 percent of patients with SLE [75]. ●

Periungual erythema – Periungual erythema is due to dilated tortuous loops of capillaries and a prominent subcapillary venous plexus along the base of the nail. Similar findings have been noted along the edges of the upper eyelid.



Livedo reticularis – Livedo reticularis refers to a reddish-cyanotic, reticular pattern on the skin of the arms, legs, and torso, particularly with cold exposure (picture 15A-B). In SLE, livedo reticularis is induced by vasospasm of the dermal ascending arterioles [76]. Vasospasm in these cutaneous vessels results in decreased blood supply to the superficial horizontal vascular plexus, with a secondary increase in circulation to the remaining patent vessels. Pathologic examination of involved blood vessels reveals thickening of the walls of the dermal vessels with subsequent narrowing of the lumens and, in some cases, intravascular thrombi.



Raynaud phenomenon – Raynaud phenomenon in SLE is a vasospastic process that occurs in approximately 15 to 30 percent of patients [77]. It is characterized by blanching of the nail beds, fingers, and toes (and occasionally ears, nose, tongue, and nipples) with accompanying pain. Involvement of the thumb or severe disease that leads to distal digital ulceration should raise suspicion for features of overlap with systemic sclerosis. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)



Vasculitis – Vasculitis develops in approximately 11 to 20 percent of patients with SLE [75,76,78]. The most common form, occurring in 10 to 15 percent of cases, is urticarial vasculitis. In contrast to urticaria, lesions of urticarial vasculitis may persist for more than 24 hours and frequently evolve into painful petechiae or purpura that may heal with hyperpigmentation. (See "Urticarial vasculitis".) Vasculitis may also affect small arteries, possibly resulting in microinfarcts of the tips of the fingers, the toes, the cuticles of the nail folds (splinter hemorrhages), and the extensor surface of the forearm and shin (picture 16). The palms of the hand, soles of the feet, and area around the ankle are less commonly

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involved [79]. Ankle involvement may develop into painful punched-out ulcers and may heal slowly. Periarteritis nodosa-like lesions may occur. Nonscarring alopecia — Nonscarring (reversible) hair loss in patients with SLE may reflect telogen effluvium or "lupus hair." Nonscarring hair loss usually responds well to treatment of SLE. Telogen effluvium is characterized by a shift in follicular cycling that leads to premature shedding of hair. Telogen effluvium can occur in the setting of serious illness or other significant physiologic stressors. (See "Telogen effluvium".) "Lupus hair" is generally seen during exacerbations of SLE. It is characterized by thin, unruly hair that easily fractures [80]. Lupus hair usually occurs along the frontal hairline. Other — Nail abnormalities, particularly pitting, ridging, and onycholysis, have been noted in 25 percent of patients with SLE [81]. Approximately 20 percent of patients have redness of the lunula, a finding nearly always associated with periungual erythema [82]. Papulonodular mucinosis is another LE-nonspecific skin disorder. This disorder typically presents as asymptomatic, skin-colored papules or nodules on the trunk or proximal extremities and abundant mucin in the papillary dermis and mid-dermis [83]. Multiple disseminated eruptive dermatofibromas have been reported in SLE, especially in immunosuppressed patients [84].   Additional disorders included among LE-nonspecific skin disorders include [1]: ●

Sclerodactyly



Rheumatoid nodules



Calcinosis cutis



Nonspecific bullous eruptions (resulting from damage to the basal layer of the epidermis)



Urticaria



Cutis laxa/anetoderma



Acanthosis nigricans



Erythema multiforme



Leg ulcers



Palisaded neutrophilic and granulomatous dermatitis

OTHER MANIFESTATIONS OF LUPUS

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Mucosal manifestations — Mucous membrane involvement can occur in the setting of cutaneous LE or systemic lupus erythematosus (SLE). Mucosal involvement occurs in 12 to 45 percent of patients with SLE [8587]. Oral involvement may manifest as white plaques, areas of erythema, or punched-out erosions or ulcers with surrounding erythema on the soft or hard palate or buccal mucosa (picture 17). The oral ulcers are usually painless. Oral ulcers may be the first sign of SLE. There is no apparent association between the presence of oral ulcers and systemic activity. The oral manifestations of LE may demonstrate the typical histopathology of discoid lupus erythematosus (DLE), including hyperkeratosis, atrophy of rete processes, and superficial and deep inflammatory infiltrates; edema in the lamina propria, continuous or patchy periodic acid-Schiff (PAS)-positive deposits in the basement membrane zone, deposition of intercellular mucin, and deposits of immunoglobulin and complement at the dermal-epidermal junction are also seen [87,88]. Oral LE should be distinguished from lichen planus, candidiasis, aphthous stomatitis, intraoral herpes, Behçet syndrome, bite marks, leukoplakia, and malignancy. Nasal ulcers occur in some patients with SLE [89]. They are usually in the lower nasal septum and tend to be bilateral. The appearance of nasal ulcers tends to parallel other features of active SLE. Nasal perforation, possibly secondary to vasculitis, is infrequent, occurring in 4.6 percent of 885 patients with SLE who were prospectively followed [90]. Involvement of the mucosa of the upper airway may also occur and may cause hoarseness [79]. Oral mucous membrane lesions may respond to topical corticosteroids, tacrolimus 0.1% ointment, intralesional corticosteroids, and systemic antimalarial drugs. The response to topical corticosteroids (usually Orabase mixed with either triamcinolone 0.1% or clobetasol 0.05%) takes a few days to weeks, while the response to hydroxychloroquine takes weeks to months. If the oral LE is refractory to these interventions and is causing significant symptoms, more aggressive systemic therapies used for cutaneous LE may be tried. (See "Management of refractory discoid lupus and subacute cutaneous lupus".) Bullous cutaneous lupus erythematosus — Bullous cutaneous lupus erythematosus (bullous CLE) is a rare and distinct complication of SLE characterized by the development of autoantibodies against type VII collagen and subepidermal blistering [91,92]. Affected patients develop a vesicular or bullous eruption that may affect any body site, including oral mucosa (picture 18A). There is a predilection for the upper trunk, upper extremities, and neck. Bullae may arise on normal or erythematous skin. Pruritus is usually absent. Dyspigmentation may occur in sites of resolved bullae. Scarring usually does not occur.   Typical biopsy findings in bullous CLE include subepidermal blistering and a neutrophil-predominant infiltrate in the upper dermis and dermal edema (picture 18A-B). Vasculitis may be present. Direct immunofluorescence studies demonstrate deposition of immunoglobulin (Ig)G, IgA, IgM, and/or complement at the basement membrane zone [91]. Oral dapsone is the mainstay of treatment. Responses to dapsone are often rapid. Neonatal lupus — Neonatal lupus is a rare syndrome that is associated with maternal antibodies to Ro/SSA, to La/SSB, and, much less frequently, to U1RNP. Infants develop eruptions characterized by erythematous arcuate

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patches or plaques with raised active margins shortly after birth (picture 6). Congenital heart block is the most concerning complication of neonatal lupus. Following the birth of an infant with neonatal lupus, the risk for congenital heart block is increased with subsequent pregnancies [93]. Of note, treatment with hydroxychloroquine may decrease the risk of neonatal lupus (congenital heart block) in at-risk pregnancies [94]. Neonatal lupus erythematosus is reviewed separately. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cutaneous lupus erythematosus".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topic (see "Patient education: Discoid lupus (The Basics)")

SUMMARY AND RECOMMENDATIONS ●

Cutaneous lupus erythematosus (cutaneous LE) may occur as an independent disorder or in association with systemic lupus erythematosus (SLE). Cutaneous LE includes three subsets of LE-specific skin disease: acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), and chronic cutaneous lupus erythematosus (CCLE). A variety of non-LE cutaneous disorders may also occur in patients with SLE (LE-nonspecific skin diseases). (See 'Classification' above.)



The subtypes of LE-specific skin disease have varying strengths of association with SLE (figure 1). Whereas ACLE almost always occurs in association with SLE, other types of lupus-specific skin disease are less strongly associated with SLE. (See 'Association with SLE' above.)



ACLE may occur as a localized, generalized, or toxic epidermal necrolysis-like eruption. The most common manifestation is the localized facial eruption (malar rash, butterfly rash), which is characterized by the

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development of erythema over the cheeks and bridge of the nose (picture 1A-B). ACLE may last for hours, days, or weeks and often recurs. (See 'Acute cutaneous lupus erythematosus' above.) ●

SCLE may occur as an idiopathic eruption, in association with SLE, or as a drug-induced disorder. SCLE classically presents as psoriasiform or annular erythematous plaques on the shoulders, forearms, neck, or upper torso (picture 4A-B). There is a strong association with Ro/SSA autoantibodies. The possibility of drug-induced SCLE should always be reviewed, particularly when skin involvement is widespread or severe. (See 'Subacute cutaneous lupus erythematosus' above.)



Discoid lupus erythematosus (DLE) is the most common form of CCLE. Patients with DLE develop erythematous, scaly plaques that may exhibit follicular plugging and heal with scarring (picture 7A-D). Associated hypopigmentation and hyperpigmentation are common. Frequent sites for DLE are the face, neck, scalp, and ears. Patients with the generalized variant of DLE also have involvement of the trunk or extremities. A hypertrophic variant of DLE is characterized by hyperkeratotic, verrucous plaques. LE tumidus, lupus profundus, chilblain LE, and lichenoid cutaneous lupus erythematosus-lichen planus overlap syndrome are additional subtypes of CCLE. (See 'Chronic cutaneous lupus erythematosus' above.)



Cutaneous LE is largely a clinical diagnosis supported by contextual clinical features (such as the presence of known underlying SLE). Confirmatory histopathologic examination is indicated when diagnostic uncertainty remains. Select patients with known SLE and/or classic clinical features of cutaneous LE may not require a biopsy. (See 'Diagnosis' above.)



The approach to the management of cutaneous LE is influenced by the extent of disease, subtype of cutaneous LE, response to initial therapy, and the presence of underlying SLE. Photoprotection, topical corticosteroids, topical calcineurin inhibitors, and oral antimalarials are common first-line treatments. (See 'Management' above.)



LE may affect mucous membranes. Oral involvement may manifest as white plaques, erythema, erosions, or ulcers. Oral LE should be distinguished from lichen planus, candidiasis, aphthous stomatitis, intraoral herpes, Behçet syndrome, bite marks, leukoplakia, and malignancy. (See 'Mucosal manifestations' above.)

ACKNOWLEDGMENT The editorial staff at UpToDate would like to acknowledge Samuel L Moschella, MD, FAAD, FACP, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Subscription and License Agreement. Topic 4666 Version 28.0

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GRAPHICS Major categories of cutaneous lupus erythematosus Acute cutaneous LE (ACLE) Localized ACLE (malar rash, butterfly rash) Generalized ACLE Toxic epidermal necrolysis-like eruption

Subacute cutaneous LE (SCLE) Annular SCLE Papulosquamous SCLE

Chronic cutaneous LE (CCLE) Localized DLE Generalized DLE Hypertrophic DLE/verrucous DLE Mucosal DLE Lupus panniculitis/lupus profundus Lupus tumidus/tumid lupus* Chilblains LE

Other clinical variants of cutaneous LE Lupus-lichen planus overlap syndrome Rowell syndrome (cutaneous lupus resembling erythema multiforme) LE: lupus erythematosus; DLE: discoid lupus erythematosus. * Some authors consider reticular erythematous mucinosis a form of tumid lupus. References: 1. Sontheimer RD. The lexicon of cutaneous lupus erythematosus - a review and personal perspective on the nomenclature and classification of the cutaneous manifestations of lupus erythematosus. Lupus 1997; 6:84. 2. Lee LA, Werth VP. Lupus erythematosus. In: Dermatology, 3rd ed, Bolognia JL, Jorizzo JL, Rapini RP, et al (Eds), Elsevier Limited, 2012. p.615. Graphic 93804 Version 2.0

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Coprevalent systemic lupus erythematosus by cutaneous lupus subtype

Circle size roughly reflects the relative prevalence of the subtypes of cutaneous lupus erythematosus. SCLE: subacute cutaneous lupus erythematosus; ACLE: acute cutaneous lupus erythematosus; LE: lupus erythematosus; DLE: discoid lupus erythematosus; SLE: systemic lupus erythematosus. Data from: 1. Watanabe T, Tsuchida T. Classification of lupus erythematosus based upon cutaneous manifestations. Dermatological, systemic and laboratory findings in 191 patients. Dermatology 1995; 190:277. 2. Sontheimer RD. Subacute cutaneous lupus erythematosus: 25-year evolution of a prototypic subset (subphenotype) of lupus erythematosus defined by characteristic cutaneous, pathological, immunological, and genetic findings. Autoimmun Rev 2005; 4:253. 3. Chong BF, Song J, Olsen NJ. Determining risk factors for developing systemic lupus erythematosus in patients with discoid lupus erythematosus. Br J Dermatol 2012; 166:29. 4. Watanabe T, Tsuchida T. Lupus erythematosus profundus: a cutaneous marker for a distinct clinical subset? Br J Dermatol 1996; 134:123. 5. Maize JC Jr, Costner M. Tumid lupus erythematosus: a form of lupus erythematosus. Arch Dermatol 2010; 146:451. Adapted from: Grönhagen CM, Nyberg F. Cutaneous lupus erythematosus: An update. Indian Dermatol Online J 2014; 5:7. Graphic 109668 Version 1.0

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Acute cutaneous lupus erythematosus

Malar erythema and subtle edema are present in this patient with systemic lupus erythematosus. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 75781 Version 5.0

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Acute cutaneous lupus erythematosus

An erythematous, edematous eruption is present on the malar area. Note the sparing of the nasolabial folds. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 55875 Version 4.0

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Rosacea

Centrofacial redness with telangiectasias in rosacea. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 77020 Version 6.0

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Heliotrope eruption in dermatomyositis

Violaceous erythema on the upper lids in a patient with dermatomyositis. Mid-facial erythema that does not spare the nasolabial folds is also present. Courtesy of Jeffrey Callen, MD, FACP, FAAD. Graphic 89101 Version 2.0

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Classification criteria for systemic lupus erythematosus ACR criteria [1,2]

SLICC criteria [3]

(4 of 11 criteria)*

(4 of 17 criteria, including at least 1 clinical criterion and 1 immunologic criterion; ¶ OR biopsy-proven lupus nephritis Δ)

Criterion

Definition

Criterion

 

Definition Clinical criteria

Malar rash

Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds

Acute cutaneous lupus

Lupus malar rash (do not count if malar discoid); bullous lupus; toxic epidermal necrolysis variant of SLE; maculopapular lupus rash; photosensitive lupus rash (in the absence of dermatomyositis); OR subacute cutaneous lupus (nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring, although occasionally with postinflammatory dyspigmentation or telangiectasias)

Photosensitivity

Skin rash as a result of unusual reaction to sunlight, by patient history or clinician observation

Discoid rash

Erythematosus raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions

Chronic cutaneous lupus

Classic discoid rash; localized (above the neck); generalized (above and below the neck); hypertrophic (verrucous) lupus; lupus panniculitis (profundus); mucosal lupus; lupus erythematosus tumidus; chilblains lupus; OR discoid lupus/lichen planus overlap

 

Nonscarring alopecia

Diffuse thinning or hair fragility with visible broken hairs (in the absence of other causes, such as alopecia areata, drugs, iron deficiency, and androgenic alopecia)

Oral ulcers

Oral or nasopharyngeal ulceration, usually painless, observed by a clinician

Oral or nasal ulcers

Palate, buccal, tongue, OR nasal ulcers (in the absence of other causes, such as vasculitis, Behçet syndrome, infection [herpesvirus], inflammatory bowel disease, reactive arthritis, and acidic foods)

Arthritis

Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion

Joint disease

Synovitis involving 2 or more joints, characterized by swelling or effusion OR

Pleuritis – Convincing history of pleuritic pain or rubbing heard by a clinician or evidence of pleural effusion OR

Serositis

 

Serositis

Tenderness in 2 or more joints and at least 30 minutes of morning stiffness

Pericarditis – Documented by ECG, rub, or evidence of pericardial effusion

Renal disorder

Persistent proteinuria greater than 500 mg/24 hours or greater than 3+ if quantitation not performed OR

Typical pleurisy for more than 1 day, pleural effusions, or pleural rub, OR Typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 day, pericardial effusion, pericardial rub, or pericarditis by electrocardiography in the absence of other causes, such as infection, uremia, and Dressler syndrome

Renal

Cellular casts – May be red cell, hemoglobin, granular, tubular, or mixed

Urine protein-to-creatinine ratio (or 24-hour urine protein) representing 500 mg protein/24 hours, OR Red blood cell casts

Neurologic disorder

Seizures OR psychosis – In the absence of offending drugs or known metabolic derangements (uremia, ketoacidosis, or electrolyte imbalance)

Neurologic

Seizures; psychosis; mononeuritis multiplex (in the absence of other known causes, such as primary vasculitis); myelitis; peripheral or cranial neuropathy (in the absence of other known causes, such as primary vasculitis, infection, and diabetes mellitus); OR acute confusional state (in the absence of other causes, including toxic/metabolic, uremia, drugs)

Hematologic disorder

Hemolytic anemia – With reticulocytosis OR

Hemolytic anemia

Hemolytic anemia

Leukopenia or lymphopenia

Leukopenia (0.5 mg/kg/day of prednisone) because of a potential increased risk of scleroderma renal crisis, particularly in patients with diffuse SSc and high or rapidly progressing skin score.

SCORING TOOLS There is significant variability in disease severity in children. Thus, a multidimensional severity score, named "J4S," an acronym which stands for Juvenile Systemic Sclerosis Severity Score, including growth parameters, skin, and internal organ involvement, was designed to follow JSSc patients over time (table 2) [15]. The J4S includes a general category and eight organ system categories: vascular, cutaneous, osteoarticular, muscular, gastrointestinal, respiratory, cardiac, and renal. Each category is scored from 0 to 4 and then weighted based upon the clinical importance of the organ system involved. The parameters that are more sensitive to change are Raynaud phenomenon (RP), number of digital scars, and number of ulcers/gangrene for vascular involvement and the body mass index (BMI) for general assessment. J4S may have several applications for the pediatric age group since it can be used to guide decision making in daily clinical practice, compare study populations, and identify potentially reversible aspects of the disease. Two tools that measure patient function and quality of life have been validated for children with juvenile idiopathic arthritis and juvenile dermatomyositis: the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ-PF50). Although these two instruments also appear to be excellent tools to measure clinical outcomes in children with SSc, especially in clinical trials, validation of these measures is required.

MANAGEMENT OVERVIEW A carefully designed treatment program is based upon disease severity and progression. This multiteam approach includes [16]: ●

Skin care



Vascular protection by avoidance of cold and sudden temperature changes



Exercise program to maintain functional ability



Psychologic and social support



Disease-modifying and organ-targeted pharmacologic therapy including discussions with the patient and family on available options



Surgical procedures, if needed

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Education of the patient and family to help understand the complexity of management decisions, guide decision making, and facilitate adherence with an often difficult and timeconsuming treatment plan

The pharmacologic management of patients with JSSc is challenging because the etiology and pathogenesis are poorly understood and the disease is heterogenous with variable progression [17]. The treatment of JSSc focuses on controlling symptoms and minimizing progression of internal organ involvement. No drug has been shown to be of unequivocal benefit in either children or adults with SSc, and there are no randomized trials or observational studies of these therapies in children with JSSc. In addition, many of these drugs have significant side effects. As a result, careful consideration must be made as to whether or not to initiate treatment, including balancing the known toxicities of the medications against the unknown possible therapeutic gain. Options for therapeutic approaches include: ●

Immunomodulatory therapy, which is directed at controlling the underlying disease process



Organ-targeted therapy, which is directed toward complications of specifically involved organs



Experimental therapy

GENERAL MEASURES Nonpharmacologic measures include the following [16]: ●

General skin care includes avoiding irritating or drying substances and the daily application of lanolin or water-soluble cream as an emollient.



Patients and parents should be told to avoid cold, trauma, heat, and sun exposure. Cold and trauma can exacerbate symptoms. Especially in cold climates, the family should keep the child warm by maintaining a satisfactory household temperature and by use of appropriate clothing, including well-insulated mittens (not gloves), boots, and a hat. These children are also susceptible to hyperpigmentation from sunlight and have difficulty in dissipating heat through sclerotic skin.



The child should be encouraged to be as physically active as possible. Physiotherapy will help maintain functional ability, muscle strength, and joint movement while preventing flexion contractures.



The use of corrective splints may be necessary to treat or prevent contractures.

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In patients with gastrointestinal involvement, small, frequent meals; avoiding eating before bedtime; and raising the head of the bed are advised.

IMMUNOMODULATION An activated immune system may be an important stimulus to both fibrotic and vascular lesions in SSc. The maximum damaging effect is most likely in the early stages of the disease. Initial immune activation may create autocrine loops through the production of cytokines and growth factors, for example, which require no further stimulus to perpetuate fibrotic and vascular lesions. Many immunotherapies are used in adults with SSc with varying degrees of efficacy. These therapies are selected case by case and usually are reserved for patients with severe, refractory diffuse cutaneous SSc (dcSSc) or overlap syndromes. The following have the most reliable efficacy and may be used in children: ●

Mycophenolate – Several observational studies have reported promising results with mycophenolate mofetil (MMF) for skin and pulmonary fibrosis [18-20]. One large observational study, including 326 patients from European centers, found that MMF was well tolerated and associated with improvement in skin disease over 12 months [21]. Another study comparing oral cyclophosphamide with MMF showed benefit for lung fibrosis and skin in both treatment arms [22].



Glucocorticoids – High-dose systemic glucocorticoids are potentially toxic and have been implicated in precipitating renal crisis [23]. Glucocorticoids should be restricted to patients with myositis, active fibrosing alveolitis, symptomatic serositis, the early edematous phase of the skin disease, refractory arthritis, and/or tenosynovitis. The lowest possible effective dose should be used in these settings, preferably below 0.3 mg/kg/day of prednisone.



Cyclophosphamide – The role of cyclophosphamide in SSc remains uncertain. Its efficacy as a single agent is unknown but, in combination with glucocorticoids or plasma exchange, is possibly efficacious in patients with fibrosing alveolitis who do not yet have advanced fibrosis [24].

ORGAN-TARGETED THERAPY The European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) group has established evidence-based recommendations for treatment of specific organ involvement in SSc [25]. These recommendations are based upon observational studies and randomized trials in

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adults. However, there are no validated recommendations for JSSc. As such, a European project called Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE) was carried out to optimize and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases [26]. As part of this effort, an international committee of experts in JSSc was created for the development of specific consensus-based recommendations. Surgical procedures are variable and may include orthopedic procedures for tendon release, gastrointestinal surgical treatments for severe gastroesophageal reflux disease (GERD), and calcium removal in case of tumoral calcinosis. In the following section, we present organ-targeted treatment strategies for JSSc based upon preliminary reports of SHARE experts in International Congresses and meetings and adult patient guidelines [25]. Pediatric-specific literature is reviewed here. A more complete discussion on organbased treatment for SSc is found elsewhere in multiple organ-specific topics and an overview. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults".) Vascular involvement — Vasodilator agents are often used in patients with vascular involvement, mainly manifesting as Raynaud phenomenon (RP) and digital ulcerations or lung vascular disease (pulmonary hypertension). Specific treatment of RP is used in patients who do not respond to avoidance of precipitating circumstances such as cold or emotional stress. (See "Treatment of Raynaud phenomenon: Initial management", section on 'General measures' and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Raynaud phenomenon'.) The use of vasodilator agents in patients with JSSc is rather common, especially for vasospastic phenomenon of the extremities, despite the limited published evidence. The most widely used vasodilators are the calcium channel blockers (CCBs). Of these, nifedipine is the drug most commonly used. An alternative to CCBs is a phosphodiesterase type 5 inhibitor (PDE-5i) such as sildenafil. In view of costs and feasibility, CCBs or PDE-5i are used as first-line drugs when pharmacotherapy is needed in the treatment of RP in children with JSSc. Intravenous prostanoids such as the prostaglandin, iloprost, are used if other therapy fails [25]. Data from a study on a small group of pediatric patients treated with iloprost infusions for ischemic digits and digital ulcerations suggest that these agents are effective and have a good safety profile [12]. Use of these drugs for RP is off label. Treatment of RP is discussed in greater detail separately. (See "Treatment of Raynaud phenomenon: Initial management" and "Treatment of Raynaud phenomenon: Refractory or progressive ischemia".) Digital ulcers are another severe and disabling complication of JSSc. In view of overall risk-to-benefit considerations, CCBs and PDE-5i are typically used as first-line therapy in SSc-related digital ulcers

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[27]. Prostanoids are used as first-choice treatment in rapidly progressive digital ulcers or in case of CCB resistance, with the same modalities as in severe RP. Endothelin 1, a potent vasoconstrictor and smooth muscle mitogen, is a possible target in patients with digital ulcers. Bosentan, a dual endothelin receptor antagonist, is recommended in the adult SSc population both for preventing digital ulcerations and for pulmonary hypertension [25]. Little evidence is available in children regarding use of bosentan for digital ulcerations [28]. However, the SHARE experts committee agree that bosentan is an option in patients with JSSc who have digital ulcerations refractory to other therapies and/or pulmonary hypertension. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Raynaud phenomenon' and "Treatment of Raynaud phenomenon: Refractory or progressive ischemia".) Interstitial lung disease — Pulmonary alveolitis is predominant early in the course of interstitial lung disease (ILD) and later progresses to fibrosis. EULAR guidelines suggest cyclophosphamide for adult patients with SSc-related ILD [25] based upon two randomized trials [22,29]. There are no published studies on cyclophosphamide in children with JSSc. Despite its known toxicity, cyclophosphamide is used in European pediatric scleroderma centers, and clinical practice experience suggests that cyclophosphamide (oral regimen of 1 to 2 mg/kg/ day for one year or 500 to 750 mg/m2 once a month, maximum 1 g, intravenous pulse) is effective for JSSc pulmonary and cardiac involvement. An alternative is mycophenolate mofetil (MMF; 500 to 750 mg/m2/day). In an adult study, the use of both regimens resulted in significant improvements in prespecified measures of lung function, dyspnea, lung imaging, and skin disease [22]. As expected, MMF was better tolerated and associated with less toxicity than cyclophosphamide. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)" and "Overview of pulmonary complications of systemic sclerosis (scleroderma)" and "Approach to the infant and child with diffuse lung disease (interstitial lung disease)" and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Organ involvement'.) Cardiac complications — Cardiac complications of JSSc are either primary (myocardial damage, fibrosis of the conduction system, and pericardial effusion) or secondary to pulmonary arterial hypertension [30]. Although rare, cardiac involvement is a significant cause of morbidity among children with JSSc, and cardiorespiratory complications are the leading cause of death. Thus, cardiac involvement requires prompt and aggressive immunosuppressive therapy. Some patients may also require a pacemaker for arrhythmia. The treatment of the cardiac complications is the same as for ILD. (See 'Interstitial lung disease' above and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Organ involvement'.) Skin involvement — Despite the lack of published data in children, there is a general consensus on the use of low-dose systemic glucocorticoids (eg, prednisone [0.3 to 0.5 mg/kg/day] for two to three months) in the active inflammatory phase of the disease, usually in combination with methotrexate

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(15 mg/m2 as a single oral or subcutaneous dose per week) or an alternative disease-modifying antirheumatic drug (DMARD). The combination of systemic glucocorticoids and methotrexate is widely used in JSSc, especially in skin, subcutaneous, and articular involvement, and appears to have a good safety profile. After the first three months of treatment, prednisone is tapered down until stopping while methotrexate or the alternative DMARD is continued. In adults with SSc, results in randomized trials were inconclusive for methotrexate [31,32]. Nevertheless, the EULAR recommendations for treatment of SSc still support the use of methotrexate for skin disease [25]. (See "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Skin changes' and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Skin'.) The addition of mycophenolate mofetil (MMF) is an option in patients who do not tolerate the prednisone taper and are not controlled on methotrexate alone (methotrexate-refractory disease). Studies in adults have reported positive effects, mainly on cutaneous and pulmonary involvement, with good drug tolerance [18,29,33]. Cyclophosphamide is not indicated for isolated skin involvement. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Skin' and "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)".) Renal disease — The prognosis for renal crisis was uniformly dismal until the introduction of angiotensin-converting enzyme (ACE) inhibitors (eg, captopril or enalapril) brought about a remarkable improvement in the outlook for prevention of vascular damage, effective long-term control of blood pressure, and stabilization of renal function. Conversely, published evidence does not support the preventive use of ACE inhibitors to decrease the risk of development of renal crisis [25]. Management of renal disease in SSc, including renal crisis, is discussed in detail separately. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Renal' and "Renal disease in systemic sclerosis (scleroderma), including scleroderma renal crisis" and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Organ involvement'.) Hemodialysis with or without bilateral nephrectomy and transplantation was an option in cases of irreversible renal failure or uncontrollable hypertension. However, the advent of ACE inhibitors makes this of primarily historic interest. Musculoskeletal involvement — The treatment of musculoskeletal involvement (myositis, arthritis, and tenosynovitis) includes the use systemic glucocorticoids (eg, prednisone/prednisolone 0.3 to 0.5 mg/kg/day for two to three months followed by tapering down until stopping or to the minimal dose that is able to control inflammation) in combination with methotrexate. The use of potential nephrotoxins such as nonsteroidal antiinflammatory drugs (NSAIDs) should be avoided.

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Management of neuromuscular complications of SSc is discussed in detail separately. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Musculoskeletal' and "Neuromuscular manifestations of systemic sclerosis (scleroderma)" and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Musculoskeletal features' and "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders".) Gastrointestinal disease — Few studies in children with JSSc address the most effective management for gastrointestinal disease, which includes GERD, erosive esophagitis, and malabsorption due to bacterial overgrowth. Proton pump inhibitors (PPIs) are still the drugs of choice, even in the early phase of disease, for prevention of SSc-related GERD and esophageal ulcers. JSSc patients on PPIs are at increased risk of hypochlorhydria, gastric bacterial colonization, and enteric infection, in particular, Clostridium difficile, as well as hypomagnesemia and vitamin B12 malabsorption and acute interstitial nephritis; therefore, their use should be closely monitored [34,35]. The management of GERD in children is reviewed in greater detail separately. (See "Management of gastroesophageal reflux disease in children and adolescents" and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Organ involvement'.) Several studies in adults suggest that prokinetic drugs such as domperidone may improve gastrointestinal signs and symptoms (dysphagia, early satiety, bloating, pseudo-obstruction) in SSc patients [36]. There are no published data on efficacy in children, but these drugs are sometimes used when other measures have failed. Malabsorption is difficult to manage. Diarrhea and bloating are most often caused by bacterial overgrowth and are treated by rotating antibiotics because continuous therapy with one agent may result in the emergence of resistant organisms. Treatment is based upon adult SSc data. The choice of antibiotic is usually empirical and includes amoxicillin-clavulanate or oral cephalosporins. In refractory cases, metronidazole can be added for five to seven days to treat anaerobic flora [37]. Hyperalimentation may be necessary but is not an effective long-term choice [36]. (See "Treatment of gastrointestinal disease in systemic sclerosis (scleroderma)".)

EXPERIMENTAL THERAPY Several drugs are under evaluation to treat different aspects of SSc in adults, including imatinib, rituximab, tocilizumab, and abatacept for skin and lung fibrosis and tocilizumab, riociguat, and selexipag for pulmonary arterial hypertension and other possible antifibrotic effects [38,39]. Unfortunately, no experience with these biologic agents have been reported in JSSc, except for

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rituximab. Investigational agents for SSc are discussed in greater detail separately. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Investigational approaches'.) Two small case series have reported on the efficacy of rituximab in patients with JSSc [40,41]. In the first series of six patients with JSSc, treatment with rituximab in combination with cyclophosphamide resulted in subjective improvement in skin tightness and sense of well-being, but no changes in diffusing capacity of the lungs for carbon monoxide (DLCO) were observed [40]. In the second series of four patients treated with rituximab in addition to low-dose oral prednisone and mycophenolate mofetil (MMF) for one year, all patients showed a significant decrease in the number and duration of Raynaud phenomenon (RP) attacks and degree of cutaneous involvement [41]. Two patients showed a global cardiac improvement and decreased Juvenile Systemic Sclerosis Severity Score (J4S). The other two patients had improved respiratory function, and one of these two also had improved muscle strength and resolution of an arrhythmia. One of the most aggressive approaches to therapy is immunoablation followed by reconstitution with autologous hemopoietic cell transplantation (HCT). The rationale for this therapy is the ablation of self-reactive lymphocytic clones that are potentially responsible for the disease process. Studies regarding autologous HCT have demonstrated efficacy in preventing disease progression in adult patients with SSc. However, the high incidence of treatment-related side effects, including a relatively high mortality rate, has limited its use in pediatric patients. The three main complications associated with HCT for SSc include treatment-related mortality (TRM), malignancies, and infections. The particular challenge is that the presence of cardiopulmonary or renal involvement at treatment start may make chemotherapy and fluid load associated with mobilization and conditioning hazardous, increasing the risk for early TRM. Based upon emerging trial data, HCT may be most beneficial in selected patients with early, severe diffuse SSc. These patients may have moderate internal organ involvement and progressive disease despite an initial trial of immunosuppression. The lack of comorbidities, the more defined screening guidelines for JSSc patient selection, and the earlier referral of patients to specialized pediatric centers with expertise in both JSSc and transplantation are reasons for reconsidering HCT as a potential therapeutic strategy for children, particularly those who are early in the disease course (three years or less from the first non-Raynaud sign or symptom) before irreversible damage (eg, fibrosis) has resulted [42]. HCT for SSc is discussed in detail separately. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Autologous stem cell transplantation'.)

PROGNOSIS

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In general, the prognosis of SSc in children appears better than in adults. Survival rates for childhood-onset SSc at 5, 10, 15, and 20 years after diagnosis are 89, 80 to 87, 74 to 87, and 69 to 82 percent, respectively [43-45]. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Mortality'.) Children with SSc have two possible courses. The vast majority manifest a slow disease course with lower mortality. In these patients, JSSc is usually most active during the first three to five years following onset of disease. Typical findings include fatigue, weight loss, rapidly advancing skin induration, arthritis, myositis, and tendonitis. Visceral involvement also commonly occurs during this period. After the first five years of disease, constitutional symptoms often abate, skin abnormalities may stabilize or occasionally improve, but visceral involvement may progress. However, approximately 5 percent of children with JSSc have rapid development of internal organ involvement leading to severe disability and eventually to death. These patients typically present with rapidly progressive disease, for which there are now promising treatments [45,46]. The most common causes of death in children are related to the involvement of the cardiac, renal, and pulmonary systems. Cardiomyopathy is a leading cause of early death, especially in children [45,47]. This complication is rare and usually associated with diffuse cutaneous disease and features of polymyositis. Aggressive immunosuppressive treatment is effective on muscle, skin, and lung involvement but may not prevent progression of myocardial dysfunction [47].

SUMMARY AND RECOMMENDATIONS ●

Treatment is based upon disease severity, activity, and progression. However, laboratory assessment of these is difficult. Thus, regular follow-up and clinical review are used. Sequential skin scores should be recorded, and objective assessment is necessary for organ-based complications, such as pulmonary fibrosis, pulmonary hypertension, or renal involvement. A multidimensional severity score, the Juvenile Systemic Sclerosis Severity Score (J4S), provides a more global index of severity (table 2). (See 'Organ system monitoring' above and 'Scoring tools' above.)



The modified Rodnan skin score (mRSS) is a widely accepted tool for evaluating the extent of skin fibrosis (figure 1 and figure 2). Capillary abnormalities can be detected by nailfold capillaroscopy. Gastrointestinal involvement is often asymptomatic. Thus, imaging such as esophageal technetium scintigraphy is necessary for diagnosis. The assessment of cardiac involvement is traditionally based on periodic monitoring with electrocardiography (ECG) and conventional echocardiography. The diagnosis of interstitial lung disease (ILD) in juvenile

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systemic sclerosis (JSSc) is based on pulmonary function tests and imaging. (See 'Organ system monitoring' above.) ●

Treatment is divided into nonpharmacologic measures and pharmacologic therapy, which includes general immunomodulation and organ-targeted therapy. (See 'Management overview' above.)



Nonpharmacologic measures include skin care, an exercise program, and the use of corrective splints. (See 'General measures' above.)



The pharmacologic management of patients with JSSc is challenging because the etiology and pathogenesis are poorly understood and the disease is heterogenous with variable progression. The treatment of JSSc is mainly symptomatic and is tailored to the individual needs of the patient based upon their specific clinical manifestations of the disease and organ involvement. No drug has been shown to be of unequivocal benefit in either children or adults with SSc, and there are no randomized trials of these therapies in children with JSSc. (See 'Immunomodulation' above and 'Organ-targeted therapy' above and 'Experimental therapy' above.)



Patients with JSSc have a significant risk of severe morbidity and can have a poor prognosis. JSSc is usually most active during the first three to five years following onset of disease. After the first five years of disease, constitutional symptoms often abate and skin abnormalities stabilize or occasionally improve, but visceral involvement may progress. The overall outcome in children with JSSc is better than in adults. The most common causes of death in children are related to the involvement of cardiac, renal, and pulmonary systems. (See 'Prognosis' above.) Use of UpToDate is subject to the Subscription and License Agreement.

Topic 122988 Version 1.0

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GRAPHICS Clinical assessment of skin thickening

The modified Rodnan skin score. Semiquantitative estimates by clinical palpation of the extent and severity of scleroderma skin change. The total skin surface is divided into 17 different areas, and in each of these areas the skin score is estimated by manual palpation. The total skin score is the sum of the skin scores of the individual areas. Original figure modified for this publication. Bolster MB, Silver RM. Clinical features of systemic sclerosis. In: Hochberg MC, Silman AJ, Smolen JS, et al. Rheumatology, 5th ed, Mosby (Elsevier), Philadelphia 2010. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 97759 Version 1.0

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Modified Rodnan skin score for systemic sclerosis

Method used to semiquantify skin thickness in scleroderma. The modified Rodnan skin score is obtained by clinical palpation of 17 different body areas (fingers, hands, forearms, upper arms, face, chest, abdomen, thighs, lower legs, and feet) and subjective averaging of the thickness of each specific site: 0 = normal (A); 1 = mild (B); 2 = moderate (C); and 3 = severe (D). The maximum total score is 51. Reproduced from: Firestein GS, Budd RC, Gabriel SE, et al. Kelley's Textbook of Rheumatology, 9th ed, Saunders, Philadelphia 2012. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 96747 Version 3.0

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Nailfold capillaroscopy in systemic sclerosis (scleroderma)

(A) Normal hairpin-shaped capillaries in a healthy subject. No relevant variation in the thickness of the capillary loops is evident. Systemic sclerosis. Representative examples of architectural disorganization of the nailfold microvascular bed: (B) Striking shape heterogeneity characterized by enlarged loops (*). (C) Heterogeneity with tortuous capillaries, slightly dilated capillary loops (*), and capillary hemorrhages. (D) Architectural derangement dominated by extremely enlarged loops (*) and neoformation of capillaries (arrow). (E) Architectural disorganization characterized by irregular distribution of capillaries that shows a high degree of heterogeneity without loop enlargement. Reproduced from: Walter G, Medico PD, Izzo F, Cervini C. Microvascular involvement in systemic sclerosis: capillaroscopic findings. Semin Arthritis Rheum 2001; 30:397. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 94667 Version 2.0

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Nailfold capillaroscopy - Raynaud phenomenon

(Panel A) The normal nailfold capillaroscopic pattern, showing regular disposition of the capillary loops along the nailbed (original magnification 200x, M Cutolo). (Panel B) A decreased number of loops should be considered highly specific for secondary Raynaud phenomenon and induce "desertification" of the nailbed (original magnification 200x, M Cutolo). Reproduced from: Cutolo M, Pizzorni C, Secchi ME, Sulli A. Capillaroscopy. Best Pract Res Clin Rheumatol 2008; 22:1093. Copyright © 2008. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 79285 Version 5.0

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Childhood Myositis Assessment Scale (CMAS) scoring sheet 1. Head elevation (neck flexion):

Item score ______

0 = Unable 1 = 1 to 9 seconds 2 = 10 to 29 seconds 3 = 30 to 59 seconds 4 = 60 to 119 seconds 5 = ≥2 minutes Number of seconds ______

2. Leg raise/touch object:

Item score ______

0 = Unable to lift leg off table. 1 = Able to clear table, but cannot touch object. 2 = Able to lift leg high enough to touch object.

3. Straight leg lift/duration:

Item score ______

0 = Unable 1 = 1 to 9 seconds 2 = 10 to 29 seconds 3 = 30 to 59 seconds 4 = 60 to 119 seconds 5 = ≥2 minutes Number of seconds ______

4. Supine to prone:

Item score ______

0 = Unable. Has difficulty even turning onto side; able to pull arms under torso only slightly or not at all. 1 = Turns onto side fairly easily, but cannot fully free arms and is not able to fully assume a prone position. 2 = Easily turns onto side; has some difficulty freeing arms, but fully frees them and fully assumes a prone position.

5. Sit-ups:

Item score ______

For each type of sit-up enter either "0" (unable) or "1" (able). Then enter the total subscore. (maximum possible item score 6.) Hands on thighs, with counterbalance ______ Hands across chest, with counterbalance ______ Hands behind head, with counterbalance ______ Hands on thighs, without counterbalance ______ Hands across chest, without counterbalance ______ Hands behind head, without counterbalance ______

6. Supine to sit:

Item score ______

0 = Unable by self. 1 = Much difficulty. Very slow, struggles greatly, barely makes it. Almost unable. 2 = Some difficulty. Able, but is somewhat slow, struggles some. 3 = No difficulty.

7. Arm raise/straighten:

Item score ______

0 = Cannot raise wrists. 1 = Can raise wrists at least up to the level of the acromioclavicular joint, but not above top of head.

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2 = Can raise wrists above top of head, but cannot raise arms straight above head so that elbows are in full extension. 3 = Can raise arms straight above head so that elbows are in full extension.

8. Arm raise/duration:

Item score ______

Can maintain wrists above top of head for: 0 = Unable 1 = 1 to 9 seconds 2 = 10 to 29 seconds 3 = 30 to 59 seconds 4 = 60 to 119 seconds 5 = ≥120 seconds Number of seconds ______

9. Floor sit:

Item score ______

Going from a standing position to a sitting position on the floor. 0 = Unable. Afraid to even try, even if allowed to use a chair for support. Child fears that he/she will collapse, fall into a sit, or harm self. 1 = Much difficulty. Able, but needs to hold onto a chair for support during descent. (Unable or unwilling to try if not able to use a chair for support.) 2 = Some difficulty. Can go from stand to sit without using a chair for support, but has at least some difficulty during descent. Descends somewhat slowly and/or apprehensively; may not have full control or balance as maneuvers into a sit. 3 = No difficulty. Requires no compensatory maneuvering.

10. All-fours maneuver:

Item score ______

0 = Unable to go from a prone to an all-fours position. 1 = Barely able to assume and maintain an all-fours position. 2 = Can maintain all-fours position with straight back and head raised (so as to look straight ahead). But, cannot creep (crawl) forward. 3 = Can maintain all-fours, look straight ahead, and creep (crawl) forward. 4 = Maintains balance while lifting and extending leg.

11. Floor rise:

Item score ______

Going from a kneeling position on the floor to a standing position. 0 = Unable, even if allowed to use a chair for support. 1 = Much difficulty. Able, but needs to use a chair for support. Unable if not allowed to use a chair. 2 = Moderate difficulty. Able to get up without using a chair for support, but needs to place one or both hands on thighs/knees or floor. Unable without using hands. 3 = Mild difficulty. Does not need to place hands on knees, thighs, or floor, but has at least some difficulty during ascent. 4 = No difficulty.

12. Chair rise:

Item score ______

0 = Unable to rise from chair, even if allowed to place hands on sides of chair seat. 1 = Much difficulty. Able, but needs to place hands on sides of seat. Unable if not allowed to place hands on knees/thighs. 2 = Moderate difficulty. Able, but needs to place hands on knees/thighs. Does not need to place hands on side of seat. 3 = Mild difficulty. Able; does not need to use hands at all, but has at least some difficulty.

13. Stool step:

Item score ______

0 = Unable. 1 = Much difficulty. Able, but needs to place one hand on exam table or examiner's hand. 2 = Some difficulty. Able; does not need to use exam table for support, but needs to use hand(s) on knee/thigh. 3 = Able. Does not need to use exam table or hand(s) on knee/thigh.

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14. Pick up:

Item score ______

0 = Unable to bend over and pick up pencil off floor. 1 = Much difficulty. Able, but relies heavily on support gained by placing hand(s) on knees/thighs. 2 = Some difficulty. Needs to at least minimally and briefly place hand(s) on knees/thighs for support and is somewhat slow. 3 = No difficulty. No compensatory maneuver necessary. Total score (maximum possible score 51) ______ From: Lovell DJ, Lindsley CB, Rennebohm RM, et al. Development of validated disease activity and damange indices for the juvenile idiopathic inflammatory myopathies. II. The Childhoold Myositis Assessment Scale (CMAS): A quantitative tool for the evaluation of muscle function. Arthritis Rheum 1999; 42:2213. http://onlinelibrary.wiley.com/doi/10.1002/1529-0131(199910)42:10%3C2213::AID-ANR25%3E3.0.CO;2-8/abstract. Copyright © 1999 American College of Rheumatology. Reproduced with permission of John Wiley & Sons, Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared, or emailed. Please contact Wiley's Permissions Department either via email: [email protected] or use the RightsLink service by clicking on the Request Permission link accompanying this article on Wiley Online Library (www.onlinelibrary.wiley.com). Graphic 104902 Version 1.0

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Juvenile systemic sclerosis severity score

 

0 (normal)

General*

Maximum possible score

1 (mild)

2 (moderate)

3 (severe)

BMI ≥ baseline

BMI 38°C



Association with underlying hematologic or visceral malignancy, inflammatory disease or pregnancy, OR preceded by upper respiratory infection, gastrointestinal infection, or vaccination



Excellent response to treatment with systemic glucocorticoids or potassium iodide



Abnormal laboratory values at presentation (three of four of the following: erythrocyte sedimentation rate >20 mm/hour, positive C-reactive protein, >8000 leukocytes, >70 percent neutrophils)

A separate set of criteria has been proposed for drug-induced Sweet syndrome (table 1) [52].

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Clinical assessment — The clinical assessment of the patient offers valuable clues for diagnosis. The history may reveal a rapid onset of skin lesions and the presence of associated symptoms (eg, painful skin lesions, fever, malaise), findings that are compatible with Sweet syndrome. In addition, the knowledge that a patient has a condition known to occur in association with Sweet syndrome (eg, recent infection, malignancy, pregnancy, or inflammatory bowel disease) raises clinical suspicion for the diagnosis. (See 'Clinical manifestations' above and 'Classification' above.) A complete physical examination that includes surveillance of the entire skin surface should be performed. This aids in determining whether the morphology and distribution of skin lesions is consistent with Sweet syndrome and allows for an assessment of the extent of cutaneous disease as well as an evaluation for signs of extracutaneous involvement. Laboratory studies — In patients in whom the clinical findings suggest the possibility of Sweet syndrome, a skin biopsy and select laboratory tests are indicated. Biopsy — The detection of consistent histologic findings is a major diagnostic criterion for Sweet syndrome (table 1) (see 'Diagnostic criteria' above). Thus, a skin biopsy should be performed whenever feasible. Procedure — In patients with inflammatory papules or plaques, a 4 mm punch biopsy is usually sufficient for obtaining a tissue specimen for histologic examination. Because infection may closely resemble Sweet syndrome, microbial pathology stains should be performed. In addition, we obtain a second 4 mm punch biopsy for bacterial, fungal, and mycobacterial cultures. If pustules are present, a swab specimen can also be sent for culture. In patients with nodules suggestive of subcutaneous Sweet syndrome (a variant in which the pathologic process is primarily located in the subcutaneous fat), an excisional biopsy is preferred because it provides a more generous sample of the subcutaneous fat, which may facilitate the interpretation of the histologic findings. As above, a portion of the tissue specimen should be sent for microbial cultures. (See 'Pathology findings' below and "Skin biopsy techniques" and "Panniculitis: Recognition and diagnosis", section on 'Biopsy'.) Pathology findings — The characteristic histologic features of Sweet syndrome include [102]: ●

Prominent edema in the superficial dermis



Dense infiltrate of neutrophils in the upper and mid-dermis with sparing of the epidermis (picture 5)



Leukocytoclasis



Endothelial swelling

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Absence of vasculitis (see below)

A few eosinophils may also be present. Older lesions may exhibit small numbers of lymphocytes or macrophages [102]. Although the absence of vasculitis is considered a characteristic feature of Sweet syndrome, the identification of vasculitis in a biopsy specimen does not rule out the diagnosis. In a retrospective study of skin biopsies from 21 patients with Sweet syndrome, vasculitis was identified in specimens from 6 patients (29 percent) [103]. The vasculitis seen in Sweet syndrome may be a secondary phenomenon related to the release of noxious products from neutrophils [103]. Pathologic variants of Sweet syndrome include subcutaneous Sweet syndrome and histiocytoid Sweet syndrome [104-109]. Subcutaneous Sweet syndrome is characterized by a dense neutrophilic infiltrate in the subcutaneous tissue. Although lobular inflammation is usually most prominent, both septa and lobules may be involved [89]. In histiocytoid Sweet syndrome, the dermal inflammatory infiltrate is primarily composed of histiocyte-like immature myeloid cells [110]. Histiocytoid Sweet syndrome may be difficult to distinguish from leukemia cutis [111]. (See 'Differential diagnosis' below.) Serologic and other tests — Laboratory evaluation is useful for identifying findings consistent with Sweet syndrome (eg, leukocytosis) and signs of associated diseases or extracutaneous involvement. Our routine laboratory work-up for patients with suspected Sweet syndrome includes the following: ●

Complete blood count with platelets and differential



Complete metabolic panel



Erythrocyte sedimentation rate or C-reactive protein



Urinalysis



Pregnancy test in women of childbearing age

Additional laboratory studies are ordered based upon suspicion for specific sites of extracutaneous disease and associated underlying disorders. For example, patients with pulmonary symptoms, pleuritis, or hypoxia should have a chest radiograph to look for signs of pulmonary involvement. Examples of additional investigations for an underlying disorder include searches for evidence of recent streptococcal infection or an occult malignancy. Evaluation for malignancy — Malignancy testing should only be considered in the setting of reasonable clinical suspicion for an underlying malignancy (eg, constitutional symptoms such as weight loss) and the absence of another explanation for a Sweet syndrome diagnosis (ie, pregnancy,

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drug exposure, recent infection, inflammatory bowel disease, rheumatoid arthritis, etc.). The screening for malignancy should begin with age-appropriate cancer screening guidelines. Some experts have proposed a work-up based upon the most common malignancies reported in association with Sweet syndrome [8]. This includes a physical examination that incorporates thyroid and lymph node examinations, as well as breast, cervical, uterine, and ovarian cancer screening in women and prostate and testicular examinations in men. Additional tests considered by these authors include a carcinoembryonic antigen level, colon cancer screening, and a chest radiograph. Other authors have suggested the use of chest, abdomen, and pelvis CT imaging or PET-CT imaging to evaluate for malignancy in patients with paraneoplastic conditions and reasonable suspicion for a malignancy of unknown source; this is similar to the literature for malignancy work-up of dermatomyositis, which is largely driven by expert opinion [112-114].

DIFFERENTIAL DIAGNOSIS Infection is one of the most important disorders to consider in the patient with clinical and/or histologic findings suggestive of Sweet syndrome. As in Sweet syndrome, fever, leukocytosis, and cutaneous lesions characterized by neutrophil-dense infiltrates may occur in bacterial sepsis. In addition, the lesions of Sweet syndrome can resemble local bacterial, fungal, or atypical mycobacterial infections. The clinical differential diagnosis of Sweet syndrome is dependent upon lesion morphology. Data obtained from the clinical history, physical examination, pathology findings, and microbial studies are useful for distinguishing between Sweet syndrome and other conditions. ●

Erythematous, edematous plaques:

• Cutaneous infection (bacterial, fungal, and mycobacterial) • Urticaria and urticarial vasculitis • Other neutrophilic dermatoses (eg, pyoderma gangrenosum, neutrophilic eccrine hidradenitis, Behçet syndrome, cutaneous metastatic Crohn's disease)

• Drug eruptions • Halogenoderma (eg, bromoderma, iododerma) ●

Nodules (including subcutaneous Sweet syndrome):

• Cutaneous infection (eg, deep fungal infection, Majocchi's granuloma, atypical mycobacterial infection)

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• Malignancy (eg, lymphoma cutis, leukemia cutis, metastatic carcinoma) • Subcutaneous sarcoidosis • Vasculitis (particularly medium-vessel vasculitis such as cutaneous polyarteritis nodosa) • Erythema nodosum ●

Bullous lesions:

• Bullous pyoderma gangrenosum • Bullous leukocytoclastic vasculitis • Autoimmune bullous diseases (eg, bullous pemphigoid, bullous systemic lupus erythematosus, inflammatory epidermolysis bullosa acquisita, linear IgA bullous dermatosis)

• Infection with bullous and hemorrhagic or necrotic changes (eg, bullous cellulitis, vessel invasive infections such as aspergillosis, ecthyma gangrenosum). The findings of a retrospective study in which fluorescence in situ hybridization (FISH) was performed on preserved cutaneous specimens from five of six patients given a diagnosis of hematologic malignancy-associated histiocytoid Sweet syndrome suggest that the clinicopathologic findings of histiocytoid Sweet syndrome may be particularly difficult to distinguish from leukemia cutis [111]. Cytogenic abnormalities in lesional skin were identical to those found in prior bone marrow biopsy specimens in four of the five patients, suggesting that these four patients may have actually had leukemia cutis. Additional studies are necessary to determine the role FISH analysis should play in differentiating histiocytoid Sweet syndrome and leukemia cutis.

SUMMARY AND RECOMMENDATIONS ●

Sweet syndrome (acute febrile neutrophilic dermatosis) is an inflammatory disorder characterized by the presence of inflammatory papules, plaques, or nodules on the skin, systemic symptoms, and neutrophilic infiltration of the skin. Sweet syndrome is often divided into three categories based on etiology: classical Sweet syndrome, malignancy-associated Sweet syndrome, and drug-induced Sweet syndrome (table 3). (See 'Classification' above.)



Classical Sweet syndrome includes cases of Sweet syndrome that are not associated with malignancy or drug exposure. The most common causes of malignancy-associated Sweet

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syndrome and drug-induced Sweet syndrome are acute myelogenous leukemia and granulocytecolony stimulating factor (G-CSF), respectively. (See 'Classification' above.) ●

The cutaneous lesions of Sweet syndrome are typically painful, erythematous to violaceous papules and plaques. Pseudovesiculation and pustule formation are often present. Bullous Sweet syndrome and subcutaneous Sweet syndrome are less common manifestations. (See 'Cutaneous' above.)



Fever, malaise, joint pain, and muscle pain often accompany the cutaneous lesions. Involvement of internal organs may also occur. Leukocytosis and elevations in the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are common laboratory findings. (See 'Associated symptoms' above and 'Extracutaneous disease' above and 'Associated laboratory findings' above.)



A diagnosis of Sweet syndrome is made based upon both clinical and laboratory findings (table 1). Biopsies characteristically demonstrate a dense neutrophilic infiltrate in the dermis without vasculitis. (See 'Diagnosis' above.) Use of UpToDate is subject to the Subscription and License Agreement.

Topic 13784 Version 16.0

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GRAPHICS Diagnostic criteria for Sweet syndrome Classical* 1. Abrupt onset of painful erythematous plaques or nodules 2. Histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis 3. Pyrexia >38°C 4. Association with an underlying hematologic or visceral malignancy, inflammatory disease, or pregnancy, or preceded by an upper respiratory or gastrointestinal infection or vaccination 5. Excellent response to treatment with systemic corticosteroids or potassium iodide 6. Abnormal laboratory values at presentation (three of four): erythrocyte sedimentation rate >20 mm/hr; positive C-reactive protein; >8,000 leukocytes; >70 percent neutrophils

Drug-induced ¶ A. Abrupt onset of painful erythematous plaques or nodules B. Histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis C. Pyrexia >38°C D. Temporal relationship between drug ingestion and clinical presentation, or temporally-related recurrence after oral challenge E. Temporally-related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids

The patients with malignancy-associated Sweet syndrome are included with the patients with classical Sweet syndrome in this list of diagnostic criteria. * The presence of both major criteria (1 and 2), and two of the four minor classical Sweet syndrome. ¶ All five criteria (A, B, C, D, and E) are required for the diagnosis of drug-induced Sweet syndrome. Original figure modified for this publication. Walker DC, Cohen PR. Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet's syndrome. J Am Acad Dermatol 1996; 34:918. Table used with the permission for Elsevier Inc. All rights reserved. Graphic 85940 Version 3.0

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Medications associated with drug-induced Sweet syndrome Antibiotics

Minocycline Nitrofurantoin Norfloxacin Ofloxacin Quinupristin/dalfopristin Trimethoprim-sulfamethoxazole

Antiepileptics

Carbemazepine Diazepam

Antihuman immunodeficiency virus drugs

Abacavir (synthetic carbocyclic nucleoside analogue)

Antihypertensives

Hydralazine

Antineoplastics

Bortezomib Imatinib mesylate Ipilimumab Lenalidomide Topotecan Vemurafenib

Antipsychotics

Clozapine

Antithyroid hormone synthesis drugs

Propylthiouracil

Colony stimulating factors

Granulocyte-colony stimulating factor Granulocyte-macrophage-colony stimulating factor Pegfilgrastim

Contraceptives

Levonorgestrel/ethinyl estradiol (Triphasil) Levonorgestrel-releasing intrauterine system (Mirena)

Diuretics

Furosemide

Immunosuppressants

Azathioprine

Nonsteroidal antiinflammatory agents

Celecoxib Diclofenac

Retinoids

All-trans retinoic acid 13-cis-retinoic acid

The possibility of acyclovir-induced Sweet syndrome cannot be completely ruled out in a 13-year-old girl with systemic lupus erythematosus (that had been diagnosed three months earlier and was being treated with oral prednisolone and azathioprine) whose Sweet syndrome lesions appeared five days after beginning intravenous acyclovir treatment for a herpes zoster infection. Photodistributed neutrophilic dermatosis with overlapping features of Sweet syndrome, acute generalized exanthematous pustulosis and sterile neutrophilic folliculitis with perifollicular vasculopathy developed in a patient who had received antidepressant (amoxapine and citalopram) and anxiolytic (perphenazine) therapy. Adapted from: Cohen PR. Sweet's syndrome - a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis 2007; 2:34. Copyright © 2007 BioMed Central Ltd. Graphic 85942 Version 6.0

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Clinical features of Sweet syndrome Clinical form Characteristic Classical*

Hematologic malignancy*

Solid tumor*

Drug-induced ¶

80

50

59

71

75-90

16

20

21

30

69

41

67

Fever ◊

80-90

88

79

100

Musculoskeletal involvement

12-56

26

34

21

Ocular involvement

17-72

7

15

21

Upper extremities

80

89

97

71

Head and neck

50

63

52

43

Trunk and back

30

42

33

50

Infrequent

49

48

36

2

12

3

7

Neutrophilia §

80

47

60

38

Elevated erythrocyte sedimentation rate ¥

90

100

95

100

Anemia ‡

Infrequent

82

83

100

Abnormal platelet count †

Infrequent

68

50

50

Abnormal renal function**

11-50

15

7

0

Epidemiology Women Prior upper respiratory tract infection Recurrence Δ Clinical symptoms

Lesion location

Lower extremities Oral mucous membranes Laboratory findings

* Percentages for classical, hematologic malignancy, and solid tumor associated Sweet syndrome adapted with permission from Cohen PR, Kurzrock R: Sweet's syndrome and cancer. Clin Dermatol 1993; 11:149-157. Copyright 1993, Reprinted with permission from Elsevier Ltd, Oxford, United Kingdom. ¶ Percentages for drug-induced Sweet syndrome adapted with permission from Walker DC, Cohen PR: Trimethoprim-sulfamethoxazoleassociated acute febrile neutrophilic dermatosis: case report and review of drug induced Sweet's syndrome. J Am Acad Dermatol 1996; 34:918–923. Copyright 1996, Reprinted with permission from the American Academy of Dermatology, Inc., Elsevier Ltd, Oxford, United Kingdom. Δ Recurrence following oral rechallenge testing in the patients with drug-induced Sweet syndrome. ◊ Temperature greater than 38°C. § Neutrophil count greater than 6,000 cells/ul. ¥ Erythrocyte sedimentation rate greater than 20 mm/hr. ‡ Hemoglobin less than 13 g/dl in men and less than 12 g/dl in women. † Platelet count less than 150,000/ul or greater than 500,000/ul. ** This includes hematuria, proteinuria, and renal insufficiency. Original figure modified for this publication. Cohen PR, Kurzrock R. Sweet's syndrome and cancer. Clin Dermatol 1993; 11:149. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 85941 Version 3.0

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Sweet syndrome

A brightly erythematous plaque with a pustular component is visible on this patient with Sweet syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 74393 Version 6.0

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Sweet syndrome

Erythematous, edematous plaques are present on the face. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 85644 Version 4.0

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Sweet syndrome

Plaques with a pustular component are present on the upper extremity. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 85645 Version 5.0

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Sweet syndrome

Inflammatory plaques are present on the extremities. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 85646 Version 4.0

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Sweet syndrome

A brightly erythematous plaque with a pustular component is present on the face of this patient with Sweet syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 79243 Version 6.0

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Sweet syndrome

Multiple inflammatory plaques are present on the face and upper extremities. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 85647 Version 5.0

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Sweet syndrome

Vesiculation is present in this inflammatory plaque of Sweet syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 62314 Version 3.0

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Sweet syndrome

Vesicles and inflammatory papules and plaques are present in this patient with Sweet syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 50526 Version 3.0

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Sweet syndrome

Erythema nodosum-like lesions of the lower extremities in a patient with Sweet syndrome. Courtesy of Samuel Moschella, MD. Graphic 63142 Version 3.0

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Neutrophilic dermatosis of the dorsal hands

Painful plaques that have progressed to ulceration. These developed in a 60-year-old female with seropositive rheumatoid arthritis. The histologic appearance was epithelial hyperplasia with intraepithelial sterile abscesses and dense dermal infiltrate of neutrophils with an absence of leucocytoclastic vasculitis. Courtesy of Samuel L Moschella, MD. Graphic 69295 Version 2.0

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Sweet syndrome

Dense neutrophilic infiltrate in Sweet syndrome. Graphic 66680 Version 2.0

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Sweet syndrome (acute febrile neutrophilic dermatosis): Management and prognosis Author: Joseph F Merola, MD, MMSc, FAAD, FACR Section Editor: Jeffrey Callen, MD, FACP, FAAD Deputy Editor: Abena O Ofori, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Oct 24, 2018.

INTRODUCTION Sweet syndrome (acute febrile neutrophilic dermatosis) is a neutrophilic dermatosis characterized by the abrupt appearance of edematous and erythematous papules, plaques, or nodules on the skin. Fever, leukocytosis, and internal organ involvement can also occur. Sweet syndrome has been associated with infection, malignancy, pregnancy, and drug exposure. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".) Systemic glucocorticoid therapy is a first-line treatment for Sweet syndrome, and usually results in dramatic clinical improvement. Colchicine, dapsone, and potassium iodide are additional effective therapies. The management and prognosis of Sweet syndrome will be discussed here. Information on the clinical features and diagnosis of Sweet syndrome and an overview of other neutrophilic dermatoses are available separately. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis" and "Neutrophilic dermatoses".)

APPROACH TO TREATMENT Although a wide variety of therapeutic interventions have been utilized for Sweet syndrome, there is a paucity of high-quality data on the treatment options. Support for the use of therapies for Sweet syndrome is primarily based on case series and individual reports of clinical experience. Systemic therapies, particularly systemic glucocorticoids, are the mainstays of treatment [1-3].

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Although spontaneous resolution after weeks to months occurs in an unknown proportion of patients with classical Sweet syndrome, the prominent symptoms and the unpredictable disease course lead us to initiate treatment in most patients. In addition, although our experience indicates that drug-induced Sweet syndrome can improve within several weeks after withdrawal of an offending medication, we have found pharmacologic therapy useful for accelerating clinical improvement in these patients [4]. While malignancy-associated Sweet syndrome has resolved following treatment of an underlying cancer [5], the frequency with which this occurs is unknown. Thus, we typically proceed with the treatment of Sweet syndrome in patients with malignancy-associated disease. Sweet syndrome can be managed on an outpatient basis. However, because the signs and symptoms of Sweet syndrome can closely resemble serious infection, patients are often hospitalized for evaluation prior to diagnosis. Outpatient management is appropriate once the diagnosis of Sweet syndrome has been made, provided internal organ involvement that requires inpatient management is not present. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis", section on 'Extracutaneous disease'.)

FIRST-LINE THERAPIES Corticosteroid therapy is considered first-line treatment for Sweet syndrome on the basis of clinical experience that indicates a consistent and rapid response of Sweet syndrome to this intervention. Most patients require systemic therapy to achieve disease control. However, patients who present with a few, localized skin lesions (eg, less than 5 percent body surface area) and without systemic symptoms may respond well to local corticosteroid therapy. Local therapy may also be used as an adjunct to systemic glucocorticoids or other systemic agents in patients with widespread cutaneous lesions. This is often done in an attempt to reduce dependence on systemic drugs and accelerate lesion healing. The efficacy of such combination therapy has not been formally studied. Our experience suggests that combination therapy is useful. Systemic glucocorticoids — The rapid and dramatic response of Sweet syndrome to systemic glucocorticoids documented in multiple case reports and case series supports their status as the treatment of choice for Sweet syndrome [2,4,6-9]. The high likelihood of treatment success is reflected in the inclusion of the response to systemic glucocorticoids in the diagnostic criteria (table 1) (see "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnostic criteria'). Systemic glucocorticoids are effective for both the cutaneous and extracutaneous manifestations of Sweet syndrome.

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In adults, we typically begin treatment with oral prednisone at a dose of 0.5 to 1 mg/kg per day. Symptoms often begin to improve within 48 hours and skin lesions usually resolve within one to two weeks [4,7]. Once disease control is attained, we attempt to taper and discontinue prednisone over the course of four to six weeks [4]. In some patients, disease recurs when the dose of prednisone is reduced, thereby inhibiting the tapering and cessation of therapy. Prednisone at the lowest effective dose (often around 10 mg per day; typical range 5 to 20 mg per day) may be continued for an additional two to three months in these patients. Treatment with an alternative systemic first-line agent can also be initiated as a glucocorticoid-sparing agent. (See 'Alternative first-line therapies' below.) Systemic glucocorticoid therapy, though usually highly effective, is associated with a risk for multiple adverse effects. The risks of systemic glucocorticoid therapy are discussed in greater detail separately. In patients who receive long-term systemic glucocorticoids, measures to protect against osteoporosis are indicated. (See "Major side effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".) Topical and intralesional corticosteroids — Case reports and retrospective studies support the efficacy of local therapy alone in some patients with limited disease [4,6,10]. High potency topical corticosteroids (eg, clobetasol 0.05% ointment) and intralesional corticosteroid injections are utilized (table 2) [6,10]. The comparative efficacy of topical and intralesional administration has not been evaluated. In our experience, intralesional therapy has been useful for thick plaques on the trunk or extremity that do not completely respond to topical therapy. Topical corticosteroids are usually applied twice daily to the affected area for two to three weeks. The use of occlusion may accelerate the response to therapy. For intralesional injection, we utilize triamcinolone acetonide in a concentration between 3 and 10 mg/mL. A dose close to the lower end of this range is preferred for thin plaques or for plaques in sites that are prone to corticosteroid-induced cutaneous atrophy, such as the face. We limit the total injected dose to 20 mg per treatment session. Lesions that respond partially can be retreated after two to four weeks. Patients who fail to respond sufficiently to local therapy are treated with systemic agents. Potential adverse effects of local corticosteroid therapy include cutaneous atrophy and pigmentary alteration. The adverse effects of topical and intralesional corticosteroids are reviewed in greater detail separately. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects' and "Intralesional corticosteroid injection", section on 'Side effects, complications, and pitfalls'.)

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Alternative first-line therapies — Colchicine, dapsone, and potassium iodide are less frequently utilized for Sweet syndrome than systemic glucocorticoids. These agents are used as first-line therapies when avoidance of systemic glucocorticoid therapy is preferred due to patient comorbidities or other factors. As noted above, they can also be used as glucocorticoid-sparing agents. We typically utilize colchicine or dapsone first due to the availability and generally favorable tolerability of these agents. (See 'Systemic glucocorticoids' above.) Colchicine — Case reports and retrospective studies support the use of colchicine in Sweet syndrome [11-14]. Similar to systemic glucocorticoids and potassium iodide, the response to treatment is rapid. In a retrospective study of 20 adults with Sweet syndrome who were treated with colchicine (1 to 1.5 mg per day) for a mean of 15 days (range 10 to 21 days), 18 patients responded to colchicine therapy [13]. Fever resolved within 24 to 72 hours, arthralgias disappeared within two to four days, and cutaneous lesions improved within two to five days. None of the 16 responders who were available for follow-up (range 2 to 10 years post-treatment) reported relapses after the discontinuation of therapy. Of note, patients with malignancy-associated Sweet syndrome were not included in this study, and relapses within 10 years after colchicine therapy were reported in another retrospective study [14]. In the United States, colchicine is available in 0.6 mg capsules or tablets. Patients are generally treated with a total of 1.2 to 1.8 mg of colchicine per day, which can be divided into one to three doses. In locations where colchicine is available in 0.5 mg pills, a total dose of 1 or 1.5 mg per day is sufficient. The drug can be discontinued upon achievement of disease control, which typically occurs within one to three weeks. Gastrointestinal toxicity (nausea, vomiting, diarrhea) are the most frequent complications of colchicine therapy [15]. More severe adverse effects, such as myopathy, neuropathy, and marrow suppression, may occur, especially in the setting of renal insufficiency or hepatic impairment [16]. In addition, colchicine has multiple drug interactions, and concomitant therapies should be reviewed prior to treatment. (See "Treatment of gout flares", section on 'Dosing in renal or hepatic impairment or with risk of drug interactions'.) Dapsone — Dapsone is utilized in the treatment of multiple skin disorders characterized by neutrophilic infiltrates. Case reports document successful treatment of Sweet syndrome with dapsone [4,17-20]. For adults with Sweet syndrome, dapsone is typically initiated at a low dose (eg, 25 mg per day) and increased as tolerated to reach a total daily dose of 100 to 200 mg per day. Dramatic clinical improvement has been noted within one to three weeks in treated patients [18,20]. Major side effects of dapsone include hemolytic anemia, methemoglobinemia, agranulocytosis, and peripheral neuropathy. Due to the increased risk for significant drug-induced hemolytic anemia in

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patients with glucose-6-phosphate (G6PD) deficiency, we test for G6PD deficiency prior to the initiation of dapsone therapy. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Acute hemolytic anemia'.) Potassium iodide — Case series support the efficacy of potassium iodide in Sweet syndrome in adults [6,21]. In one series, seven of eight patients treated with 300 mg of potassium iodide three times daily had a dramatic response to treatment [21]. Tenderness, arthralgias, and high fever resolved within 48 hours, and cutaneous lesions resolved within four days. Five patients, all of whom who began potassium iodide early in the course of Sweet syndrome (within four to eight days), had no relapses after completing a two-week course of treatment. Two patients did well during treatment, but relapsed after drug discontinuation. One patient did not respond to therapy. The mechanism through which potassium iodide leads to improvement in Sweet syndrome and other neutrophilic dermatoses is not well understood. Theories include immune suppression related to potassium-iodide induced release of heparin, inhibition of neutrophil production of oxygen intermediates, or suppression of neutrophil chemotaxis [4]. In adults, potassium iodide may be prescribed as pills (300 mg three times daily) or as a 1000 mg/mL saturated solution (SSKI). The treatment regimen for the solution begins with three drops with a standard medicine dropper (20 drops/mL) three times daily in water or juice to disguise the taste. The dose of potassium iodide is 50 mg per drop, resulting in a total of 450 mg administered per day. The dose is subsequently increased by one drop at each scheduled dosing up to a total of 7 to 10 drops three times daily (1050 to 1500 mg per day) [4]. Potential adverse effects of potassium iodide include gastrointestinal distress, small bowel ulcerations (tablets), hypothyroidism, pulmonary edema, and a serious hypersensitivity reaction [15]. Sipping the medication with a straw may help to avoid drug-related tooth discoloration.

RECALCITRANT DISEASE Clinical experience suggests that pulse glucocorticoid therapy may be effective for severe Sweet syndrome or Sweet syndrome that fails to respond sufficiently to other therapies [22-24]. In adults, intravenous methylprednisolone at doses of up to 500 to 1000 mg per day may be administered for three to five days. Treatment is followed by an oral glucocorticoid taper or another systemic immunosuppressive therapy [23,24]. In addition, oral retinoids [25], cyclosporine [26,27], methotrexate [28], thalidomide [29], and anakinra [30] have been successfully utilized for Sweet syndrome in patients who have failed to respond to standard therapies. Newer case reports have suggested benefit from rituximab and adalimumab in

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refractory cases [31-33]. In patients with myelodysplastic syndrome (MDS)-associated Sweet syndrome, azacitidine has been reported to successfully treat refractory disease [34].

OTHER THERAPIES A variety of additional treatments have been reported to be effective for Sweet syndrome in small numbers of patients [4]. In an open study in which 18 adults with Sweet syndrome were treated with 150 mg per day of indomethacin for one week followed by 100 mg per day for two weeks if initial signs of improvement were detected, 17 of 18 patients responded well to treatment [35]. Fever and arthralgias improved within two days and disease remissions occurred within two weeks. Relapses were not observed during the follow-up period (12 to 36 months). However, the development of Sweet syndrome during indomethacin treatment has been reported [17]. Other agents that have been associated with clinical improvement in Sweet syndrome in case reports include various nonsteroidal antiinflammatory drugs, tetracyclines, clofazimine, and other antibiotics [4,7,22,36].

CHILDREN The initial approach to the treatment of Sweet syndrome is similar in adults and children. As in adults, Sweet syndrome in children usually responds rapidly to systemic glucocorticoid therapy. We typically begin treatment with prednisone at a dose of 1 mg/kg day in children; other authors have utilized initial doses of 2 mg/kg of prednisone per day [2,37]. Experience with other therapies for Sweet syndrome is limited, and data on the efficacy and optimal dosing of other agents considered useful for Sweet syndrome are lacking in children.

PROGNOSIS Without treatment, the duration of Sweet syndrome is unpredictable; spontaneous resolution may occur after weeks to months [38]. The proportion of patients who achieve spontaneous resolution is unknown since no placebo controlled randomized trials have been performed in Sweet syndrome, and most patients receive treatment. In one retrospective study of 80 patients from six different dermatology departments in the United Kingdom, spontaneous resolution was documented in 16 patients who did not happen to receive treatment [10]. Another retrospective study of 48 adults with Sweet syndrome documented resolution without therapeutic intervention in three patients [39].

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The cutaneous lesions of Sweet syndrome usually heal without scarring [22,38] provided ulceration has not occurred. However, postinflammatory hyperpigmentation that takes months to resolve may occur at the sites of recently healed lesions. While major involvement of internal organs can occur in Sweet syndrome, death from Sweet syndrome is rare. Relapse may occur after the tapering or discontinuation of systemic glucocorticoids or other therapies and may be more likely to occur in patients with malignancy-associated disease (table 3). Recurrences of Sweet syndrome occur in approximately 30 percent of patients with classical Sweet syndrome [22]. The rate of recurrence may be as high as 69 percent in the setting of underlying hematologic malignancy [40,41].

SUMMARY AND RECOMMENDATIONS ●

Sweet syndrome (acute febrile neutrophilic dermatosis) is an inflammatory disorder characterized by the presence of inflammatory papules, plaques, or nodules on the skin, systemic symptoms, and neutrophilic infiltration of the skin. Sweet syndrome is often divided into three categories based on etiology: classical Sweet syndrome, malignancy-associated Sweet syndrome, and drug-induced Sweet syndrome (table 3). (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis", section on 'Classification'.)



For adults who present with mild Sweet syndrome (eg, less than 5 percent body surface area involvement and absence of significant systemic symptoms), we suggest the use of high potency topical corticosteroids or intralesional corticosteroid injections as initial treatment due to the relative safety of these interventions (Grade 2C). For adults with more extensive involvement and/or systemic symptoms, we suggest treatment with systemic glucocorticoid therapy (Grade 2C). (See 'First-line therapies' above.)



For adults with Sweet syndrome who cannot be treated with systemic glucocorticoids due to comorbidities or other factors, we suggest treatment with colchicine or dapsone (Grade 2C). Potassium iodide is also effective. (See 'Alternative first-line therapies' above.)



For children with Sweet syndrome, we suggest systemic glucocorticoid therapy (Grade 2C). Data on the use of alternative therapies in children are limited. (See 'Children' above.)



Pulsed intravenous glucocorticoids and other immunomodulatory therapies may be effective for patients with refractory disease. (See 'Recalcitrant disease' above.) Use of UpToDate is subject to the Subscription and License Agreement.

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Topic 86567 Version 9.0

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GRAPHICS Diagnostic criteria for Sweet syndrome Classical* 1. Abrupt onset of painful erythematous plaques or nodules 2. Histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis 3. Pyrexia >38°C 4. Association with an underlying hematologic or visceral malignancy, inflammatory disease, or pregnancy, or preceded by an upper respiratory or gastrointestinal infection or vaccination 5. Excellent response to treatment with systemic corticosteroids or potassium iodide 6. Abnormal laboratory values at presentation (three of four): erythrocyte sedimentation rate >20 mm/hr; positive C-reactive protein; >8,000 leukocytes; >70 percent neutrophils

Drug-induced ¶ A. Abrupt onset of painful erythematous plaques or nodules B. Histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis C. Pyrexia >38°C D. Temporal relationship between drug ingestion and clinical presentation, or temporally-related recurrence after oral challenge E. Temporally-related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids

The patients with malignancy-associated Sweet syndrome are included with the patients with classical Sweet syndrome in this list of diagnostic criteria. * The presence of both major criteria (1 and 2), and two of the four minor classical Sweet syndrome. ¶ All five criteria (A, B, C, D, and E) are required for the diagnosis of drug-induced Sweet syndrome. Original figure modified for this publication. Walker DC, Cohen PR. Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet's syndrome. J Am Acad Dermatol 1996; 34:918. Table used with the permission for Elsevier Inc. All rights reserved. Graphic 85940 Version 3.0

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Comparison of representative topical corticosteroid preparations (classified according to the US system)

Potency group* Super-high potency (group 1)

High potency (group 2)

Corticosteroid

Brand names (United States)

Available strength(s), percent (except as noted)

Betamethasone dipropionate, augmented

Gel, lotion, ointment (optimized)

Diprolene

0.05

Clobetasol propionate

Cream, gel, ointment, solution (scalp)

Temovate

0.05

Cream, emollient base

Temovate E

0.05

Lotion, shampoo, spray aerosol

Clobex

0.05

Foam aerosol

Olux-E, Tovet

0.05

Solution (scalp)

Cormax

0.05

Diflucortolone valerate (not available in United States)

Ointment, oily cream

Nerisone Forte (United Kingdom, others)

0.3

Fluocinonide

Cream

Vanos

0.1

Flurandrenolide

Tape (roll)

Cordran

4 mcg/cm 2

Halobetasol propionate

Cream, lotion, ointment

Ultravate

0.05

Ointment

Cyclocort ¶, Amcort ¶

0.1

Betamethasone dipropionate

Ointment

Diprosone ¶

0.05

Cream, augmented formulation (AF)

Diprolene AF

0.05

Clobetasol propionate

Cream

Impoyz

0.025

Desoximetasone

Cream, ointment, spray

Topicort

0.25

Gel

Topicort

0.05

Ointment

ApexiCon ¶, Florone ¶

0.05

Cream, emollient

ApexiCon E

0.05

Fluocinonide

Cream, gel, ointment, solution

Lidex ¶

0.05

Halcinonide

Cream, ointment

Halog

0.1

Halobetasol propionate

Lotion

Bryhali

0.01

Amcinonide

Cream

Cyclocort ¶, Amcort ¶

0.1

Lotion

Amcort ¶

0.1

Betamethasone dipropionate

Cream, hydrophilic emollient

Diprosone ¶

0.05

Betamethasone valerate

Ointment

Valisone ¶

0.1

Foam

Luxiq

0.12

Cream

Topicort LP ¶

0.05

Diflorasone diacetate

Cream

Florone ¶

0.05

Diflucortolone valerate (not available in United States)

Cream, oily cream, ointment

Nerisone (Canada, United Kingdom, others)

0.1

Fluocinonide

Cream aqueous emollient

Lidex-E ¶

0.05

Amcinonide

Diflorasone diacetate

High potency (group 3)

Vehicle type/form

Desoximetasone

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Fluticasone propionate

Ointment

Cutivate

0.005

Mometasone furoate

Ointment

Elocon

0.1

Cream, ointment

Aristocort HP ¶,

0.5

Triamcinolone acetonide

Kenalog ¶, Triderm Medium potency (group 4)

Lower-mid potency (group 5)

Low potency (group 6)

Betamethasone dipropionate

Spray

Sernivo

0.05

Clocortolone pivalate

Cream

Cloderm

0.1

Fluocinolone acetonide

Ointment

Synalar ¶

0.025

Flurandrenolide

Ointment

Cordran

0.05

Hydrocortisone valerate

Ointment

Westcort

0.2

Mometasone furoate

Cream, lotion, ointment, solution

Elocon ¶

0.1

Triamcinolone acetonide

Cream

Kenalog ¶, Triderm

0.1

Ointment

Kenalog ¶

0.1

Ointment

Trianex

0.05

Aerosol spray

Kenalog

0.2 mg per 2 second spray

Dental paste

Oralone

0.1

Betamethasone dipropionate

Lotion

Diprosone ¶

0.05

Betamethasone valerate

Cream

Beta-Val, Valisone ¶

0.1

Desonide

Ointment

DesOwen, Tridesilon ¶

0.05

Gel

Desonate

0.05

Fluocinolone acetonide

Cream

Synalar ¶

0.025

Flurandrenolide

Cream, lotion

Cordran

0.05

Fluticasone propionate

Cream, lotion

Cutivate

0.05

Hydrocortisone butyrate

Cream, lotion, ointment, solution

Locoid, Locoid Lipocream

0.1

Hydrocortisone probutate

Cream

Pandel

0.1

Hydrocortisone valerate

Cream

Westcort ¶

0.2

Prednicarbate

Cream (emollient), ointment

Dermatop

0.1

Triamcinolone acetonide

Lotion

Kenalog ¶

0.1

Ointment

Kenalog ¶

0.025

Alclometasone dipropionate

Cream, ointment

Aclovate

0.05

Betamethasone valerate

Lotion

Beta-Val ¶, Valisone ¶

0.1

Desonide

Cream

DesOwen, Tridesilon ¶

0.05

Lotion

DesOwen, LoKara

0.05

Foam

Verdeso

0.05

Cream, solution

Synalar ¶

0.01

Shampoo

Capex

0.01

Oil Δ

Derma-Smoothe/FS Body, DermaSmoothe/FS Scalp

0.01

Fluocinolone acetonide

6135

Triamcinolone acetonide Least potent (group 7)

Hydrocortisone (base, ≥2%)

Hydrocortisone (base, 30 mL/kg or >500 mL/day

2

Diarrhea >60 mL/kg or >1000 mL/day

3

Diarrhea >90 mL/kg or >1500 mL/day

4

Diarrhea >90 mL/kg or >2000 mL/day; or severe abdominal pain with or without ileus

Glucksberg grade I – Stage 1 or 2 skin involvement; no liver or gut involvement; ECOG PS 0 II – Stage 1 to 3 skin involvement; Grade 1 liver or gut involvement; ECOG PS 1 III – Stage 2 or 3 skin, liver, or gut involvement; ECOG PS 2 IV – Stage 1 to 4 skin involvement; Stage 2 to 4 liver or gut involvement; ECOG PS 3

International Bone Marrow Transplant Registry Severity Index A – Stage 1 skin involvement; no liver or gut involvement B – Stage 2 skin involvement; Stage 1 to 2 gut or liver involvement C – Stage 3 skin, liver, or gut involvement D – Stage 4 skin, liver, or gut involvement SGOT: serum glutamic oxaloacetic transaminase; ECOG: Eastern Cooperative Oncology Group; PS: performance status. Graphic 68233 Version 7.0

6198

Histologic grade 2 acute graft-versus-host disease

Apoptotic keratinocytes in the epidermis, vacuolization of the basal layer, and lymphocyte exocytosis are present in this specimen of histologic grade 2 acute graft-versus-host disease. A lymphocytic infiltrate at the dermal-epidermal junction and surrounding blood vessels is also present. Graphic 61055 Version 5.0

6199

Exanthematous (morbilliform) drug eruption

Numerous erythematous macules and papules are present in this child with a morbilliform drug eruption. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 54205 Version 8.0

6200

Viral exanthem

Multiple erythematous macules are present on the skin of this patient with a viral exanthem. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 58169 Version 8.0

6201

Acral erythema

Acral erythema of the hand. Reproduced with permission from: Payne AS, James WD, Weiss RB. Dermatologic toxicity of chemotherapeutic agents. Semin Oncol 2006; 33:86. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 77501 Version 5.0

6202

Acral erythema

Bilateral erythema is present on the hands in this patient with acral erythema. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 79857 Version 5.0

6203

Toxic epidermal necrolysis

Multiple bullae and areas of denuded epidermis are present. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 59418 Version 9.0

6204

Toxic epidermal necrolysis

Diffuse erythema and large areas of denuded epidermis are present. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 68458 Version 7.0

6205

Toxic epidermal necrolysis

Multiple bullae overlying diffuse erythema are present. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 82150 Version 5.0

6206

Toxic epidermal necrolysis (TEN)

Usually caused by drugs, TEN demonstrates widespread erythema and confluent vesiculation, leading to sloughing of the skin. Affected patients are at risk for hypernatremic dehydration and sepsis. Courtesy of Lee T Nesbitt, Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.

http://www.lww.com Graphic 66134 Version 6.0

6207

Erythema multiforme

Multiple acrally distributed target lesions and mucosal erosions are present in this patient with erythema multiforme majus. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 62370 Version 7.0

6208

Erythema multiforme

Multiple typical target lesions are present on this extremity. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 57894 Version 8.0

6209

Atypical target lesions in erythema multiforme

A larger lesion is surrounded by multiple oval, atypical target lesions of erythema multiforme. Note the presence of only two zones of color change. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 51037 Version 8.0

6210

Signs and symptoms of chronic graft-versus-host disease

Organ or site

Diagnostic (sufficient to establish the diagnosis of chronic GVHD)

Skin

Distinctive* (seen in chronic GVHD but insufficient alone to establish a diagnosis)

Common Δ (seen with both acute and chronic GVHD)

Other features or unclassified entities ¶

Poikiloderma

Depigmentation

Sweat impairment

Erythema

Lichen planus-like features

Papulosquamous lesions

Ichthyosis

Maculopapular rash

Keratosis pilaris

Pruritus

Sclerotic features

Hypopigmentation

Morphea-like features

Hyperpigmentation

Lichen sclerosus-like features Nails

 

Dystrophy

 

 

Longitudinal ridging, splitting or brittle features Onycholysis Pterygium unguis Nail loss (usually symmetric, affects most nails) Scalp and body hair

 

New onset of scarring or nonscarring scalp alopecia (after recovery from chemoradiotherapy)

Thinning scalp hair, typically patchy, coarse or dull (not explained by endocrine or other causes)

Loss of body hair

Premature gray hair

 

Scaling Mouth

Lichen planus-like changes

Xerostomia

 

Gingivitis

Mucoceles

Mucositis

Mucosal atrophy

Erythema

Ulcers

Pain

Pseudomembranes Eyes

 

New-onset dry, gritty, or painful eyes

Photophobia

 

Periorbital hyperpigmentation

Cicatricial conjunctivitis

Blepharitis (erythema of the eyelids with edema)

KCS Confluent areas of punctate keratopathy Genitalia

Lichen planus-like features

Erosions

 

 

 

 

 

 

Fissures

Lichen sclerosus-like features Females

Vaginal scarring or clitoral/labial agglutination

Males

Phimosis or urethral/meatus scarring or stenosis

 

Esophageal web

 

GI tract

Ulcers

Exocrine pancreatic

6211

Anorexia

Strictures or stenosis in the upper to mid third of the esophagus

insufficiency

Nausea Vomiting Diarrhea Weight loss Failure to thrive (infants and children)

Liver

 

 

 

Total bilirubin, alkaline phosphatase >2 × upper limit of normal ALT >2 × upper limit of normal

Lung

Bronchiolitis obliterans diagnosed with lung biopsy

Air trapping and bronchiectasis on chest CT

Cryptogenic organizing pneumonia

Myositis or polymyositis ¥

Edema

 

Restrictive lung disease §

BOS ◊ Muscles, fascia, joints

Hematopoietic and immune

Fasciitis Joint stiffness or contractures secondary to fasciitis or sclerosis  

 

Muscle cramps Arthralgia or arthritis

 

Thrombocytopenia

 

Eosinophilia Lymphopenia Hypo- or hypergammaglobulinemia Autoantibodies (AIHA, ITP) Raynaud's phenomenon

Other

 

 

Pericardial or pleural effusions

 

Ascites Peripheral neuropathy Nephrotic syndrome Myasthenia gravis Cardiac conduction abnormality or cardiomyopathy GVHD: graft-versus-host disease; KCS: keratoconjunctivitis sicca; GI: gastrointestinal; ALT: alanine aminotransferase; BOS: bronchiolitis obliterans syndrome; CT: computed tomography; AIHA: autoimmune hemolytic anemia; ITP: idiopathic thrombocytopenic purpura. * In all cases, infection, drug effect, malignancy, or other causes must be excluded. ¶ Can be acknowledged as part of the chronic GVHD manifestations if diagnosis is confirmed. Δ Common refers to shared features by both acute and chronic GVHD. ◊ BOS can be diagnostic for lung chronic GVHD only if distinctive sign or symptom present in another organ. § Pulmonary entities under investigation or unclassified. ¥ Diagnosis of chronic GVHD requires biopsy. Reproduced from: Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2015; 21:389. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 115901 Version 1.0

6212

Chronic graft-versus-host disease

Violaceous papules and plaques, many with a reticulated appearance, are present on the trunk and extremities. Graphic 55336 Version 1.0

6213

Keratosis pilaris

Keratosis pilaris. Multiple mildly erythematous, follicularly based papules on the lower leg. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 60786 Version 10.0

6214

Keratosis pilaris

Keratosis pilaris. Close view of multiple follicularly based, hyperpigmented papules on arm. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 68488 Version 7.0

6215

Chronic graft-versus-host disease

Multiple firm, sclerotic plaques are present with areas of shallow ulceration. Dyspigmentation is also present. Graphic 52693 Version 1.0

6216

Lichen sclerosus

Oval, porcelain-white plaques are present on the trunk of this patient with extragenital lichen sclerosus. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 74154 Version 5.0

6217

Chronic graft-versus-host disease

A cellulite-like plaque is present on the upper arm in this patient with subcutaneous fibrosis secondary to chronic graft-versus-host disease. Graphic 64464 Version 2.0

6218

Chronic graft-versus-host disease

Deep sclerosis leading to joint contractures limited the ability to extend the fingers in this patient with chronic graft-versus-host disease ("prayer sign"). The overlying skin appears normal. Graphic 76298 Version 2.0

6219

Chronic graft-versus-host disease

Poikilodermatous changes in chronic graft-versus-host disease. Mottled pigmentation and erythema are present on the extremity. Graphic 66942 Version 2.0

6220

Graft-versus-host disease-associated angiomatosis

Multiple vascular papules and nodules on the instep of the foot of a patient with chronic graftversus-host disease. Graphic 127134 Version 1.0

6221

Graft-versus-host disease-associated angiomatosis

Scattered, vascular papules on the back of a patient with chronic graft-versus-host disease. Graphic 127135 Version 1.0

6222

Oral chronic graft-versus-host disease

Reticulated white plaques and erosions are present on the buccal mucosa. The findings resemble oral lichen planus. Reproduced with permission from: www.visualdx.com. Chronic GVHD buccal mucosa Graphic 73344 Version 4.0

6223

Oral chronic graft-versus-host disease

Multiple white plaques are present on the tongue. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 82463 Version 4.0

6224

Oral chronic graft-versus-host disease

Multiple erosions are present on the tongue. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 61588 Version 4.0

6225

Mucocele

A translucent papule is present on the mucosal surface of the lower lip. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 70332 Version 5.0

6226

Chronic graft-versus-host disease

Dystrophic nails are present in this patient with chronic graft-versus-host disease. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 71229 Version 4.0

6227

Lichen planus

Violaceous, polygonal papules are present on the ventral wrists. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 76383 Version 5.0

6228

Lichen planus

Violaceous and hyperpigmented, polygonal papules are present on ankles and ventral wrists. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 63590 Version 5.0

6229

Lichenoid drug eruption

Erythematous to violaceous papules with fine scale are present in this patient with a lichenoid drug eruption. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 80165 Version 4.0

6230

Lichenoid drug eruption

A lichenoid drug eruption manifesting as violaceous and hyperpigmented papules is present in this patient with dark skin. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 59258 Version 4.0

6231

Pityriasis lichenoides chronica

Multiple small papules with adherent scale are present in this patient with pityriasis lichenoides chronica. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 71210 Version 4.0

6232

Generalized morphea on the trunk

Isomorphic, hyperpigmented, sclerotic plaques are present on the chest and abdomen. Graphic 56113 Version 2.0

6233

Pansclerotic morphea

Sclerosis encompassing the majority of the body surface area, characteristically sparing the fingertips, is present. Graphic 82198 Version 2.0

6234

Eosinophilic fasciitis

Fibrotic changes resembling cellulite are present on the leg in this patient with eosinophilic fasciitis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved Graphic 50218 Version 5.0

6235

Poikiloderma of Civatte

Chronic sun damage is associated with the development of poikiloderma of Civatte, which typically presents as redness, telangiectasias, and mottled hyperpigmentation on the lateral neck. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 81779 Version 6.0

6236

Mycosis fungoides - poikiloderma

A poikilodermatous patch exhibiting red-brown mottled pigmentation, telangiectasias, and subtle atrophy is present on the chest of this patient with mycosis fungoides. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 63888 Version 7.0

6237

Comparison of representative topical corticosteroid preparations (classified according to the US system)

Potency group* Super-high potency (group 1)

High potency (group 2)

Corticosteroid

Available strength(s), percent (except as noted)

Betamethasone dipropionate, augmented

Gel, lotion, ointment (optimized)

Diprolene

0.05

Clobetasol propionate

Cream, gel, ointment, solution (scalp)

Temovate

0.05

Cream, emollient base

Temovate E

0.05

Lotion, shampoo, spray aerosol

Clobex

0.05

Foam aerosol

Olux-E, Tovet

0.05

Solution (scalp)

Cormax

0.05

Diflucortolone valerate (not available in United States)

Ointment, oily cream

Nerisone Forte (United Kingdom, others)

0.3

Fluocinonide

Cream

Vanos

0.1

Flurandrenolide

Tape (roll)

Cordran

4 mcg/cm 2

Halobetasol propionate

Cream, lotion, ointment

Ultravate

0.05

Amcinonide

Ointment

Cyclocort ¶, Amcort ¶

0.1

Betamethasone dipropionate

Ointment

Diprosone ¶

0.05

Cream, augmented formulation (AF)

Diprolene AF

0.05

Clobetasol propionate

Cream

Impoyz

0.025

Desoximetasone

Cream, ointment, spray

Topicort

0.25

Gel

Topicort

0.05

Ointment

ApexiCon ¶, Florone ¶

0.05

Cream, emollient

ApexiCon E

0.05

Fluocinonide

Cream, gel, ointment, solution

Lidex ¶

0.05

Halcinonide

Cream, ointment

Halog

0.1

Halobetasol propionate

Lotion

Bryhali

0.01

Amcinonide

Cream

Cyclocort ¶, Amcort ¶

0.1

Lotion

Amcort ¶

0.1

Betamethasone dipropionate

Cream, hydrophilic emollient

Diprosone ¶

0.05

Betamethasone valerate

Ointment

Valisone ¶

0.1

Foam

Luxiq

0.12

Desoximetasone

Cream

Topicort LP ¶

0.05

Diflorasone diacetate

Cream

Florone ¶

0.05

Diflucortolone valerate (not available in United States)

Cream, oily cream, ointment

Nerisone (Canada, United Kingdom, others)

0.1

Fluocinonide

Cream aqueous emollient

Lidex-E ¶

0.05

Fluticasone propionate

Ointment

Cutivate

0.005

Mometasone furoate

Ointment

Elocon

0.1

Diflorasone diacetate

High potency (group 3)

Vehicle type/form

Brand names (United States)

6238

Medium potency (group 4)

Lower-mid potency (group 5)

Triamcinolone acetonide

Cream, ointment

Aristocort HP ¶, Kenalog ¶, Triderm

0.5

Betamethasone dipropionate

Spray

Sernivo

0.05

Clocortolone pivalate

Cream

Cloderm

0.1

Fluocinolone acetonide

Ointment

Synalar ¶

0.025

Flurandrenolide

Ointment

Cordran

0.05

Hydrocortisone valerate

Ointment

Westcort

0.2

Mometasone furoate

Cream, lotion, ointment, solution

Elocon ¶

0.1

Triamcinolone acetonide

Cream

Kenalog ¶, Triderm

0.1

Ointment

Kenalog ¶

0.1

Ointment

Trianex

0.05

Aerosol spray

Kenalog

0.2 mg per 2 second spray

Dental paste

Oralone

0.1

Betamethasone dipropionate

Lotion

Diprosone ¶

0.05

Betamethasone valerate

Cream

Beta-Val, Valisone ¶

0.1

Ointment

DesOwen, Tridesilon ¶

0.05

Gel

Desonate

0.05

Fluocinolone acetonide

Cream

Synalar ¶

0.025

Flurandrenolide

Cream, lotion

Cordran

0.05

Fluticasone propionate

Cream, lotion

Cutivate

0.05

Hydrocortisone butyrate

Cream, lotion, ointment, solution

Locoid, Locoid Lipocream

0.1

Hydrocortisone probutate

Cream

Pandel

0.1

Hydrocortisone valerate

Cream

Westcort ¶

0.2

Prednicarbate

Cream (emollient), ointment

Dermatop

0.1

Triamcinolone acetonide

Lotion

Kenalog ¶

0.1

Ointment

Kenalog ¶

0.025

Alclometasone dipropionate

Cream, ointment

Aclovate

0.05

Betamethasone valerate

Lotion

Beta-Val ¶, Valisone ¶

0.1

Desonide

Cream

DesOwen, Tridesilon ¶

0.05

Lotion

DesOwen, LoKara

0.05

Foam

Verdeso

0.05

Cream, solution

Synalar ¶

0.01

Shampoo

Capex

0.01

Oil Δ

Derma-Smoothe/FS Body, DermaSmoothe/FS Scalp

0.01

Triamcinolone acetonide

Cream, lotion

Kenalog ¶, Aristocort ¶

0.025

Hydrocortisone (base, ≥2%)

Cream, ointment

Hytone, Nutracort ¶

2.5

Lotion

Hytone, Ala Scalp, Scalacort

2

Desonide

Low potency (group 6)

Fluocinolone acetonide

Least potent (group 7)

6239

Hydrocortisone (base, 5 cm in diameter), irregularly shaped, erythematous, dusky red or brown patches with fine scaling (picture 9A-D). Lesions frequently show epidermal atrophy ("cigarette paper" wrinkling) or poikiloderma (ie, the combination of mottled pigmentation, telangiectasia, and epidermal atrophy) (picture 10A-B). LPP typically involves areas not exposed to the sun (eg, buttocks, thighs, lower trunk, flexural surfaces, and, in women, breasts and inframammary areas).

Histopathology — The histopathology of LPP reveals (picture 11) [17]: ●Variable psoriasiform epidermal hyperplasia (or atrophy in poikilodermatous areas [ie, areas with a combination of mottled pigmentation, telangiectasia, and epidermal atrophy]). ●Vacuolization in the basal keratinocyte layer. ●Capillary dilation. ●Brisk lymphocytic infiltrate with a band-like distribution that can obscure the dermoepidermal junction. The infiltrate is composed of small lymphocytes, some of which may have cerebriform, convoluted nuclei. There is focal lymphocytic epidermotropism, but Pautrier microabscesses (ie, clusters of atypical lymphocytes in the epidermis), a classic histologic characteristic of mycosis fungoides (MF), are usually absent in LPP [17,18]. Immunophenotyping demonstrates normal CD4/CD8 ratio and maintenance of the pan-T cell antigen CD7, a marker of mature T cells [29]. However, some studies have demonstrated that benign T cell infiltrates, including parapsoriasis, may lose CD7 expression [30,31]. Both small plaque

6310

parapsoriasis (SPP) and LPP have increased expression of the dendritic/Langerhans cell marker CD1a [32,33]. Most cases of LPP appear to express the thymocyte selection-associated high-mobility group box protein gene (TOX), a potential marker of MF [34]. However, whether TOX expression is a predictor of progression of LPP to MF or a marker to discriminate those LPP cases that are MF from the outset has not been determined. Clonal T cell receptor gene rearrangements have been identified by polymerase chain reaction analysis in up to 50 percent of LPP cases [4,8]. However, the presence of a predominant T cell clone is not diagnostic of LPP nor is an indication of increased risk of progression to MF.

Diagnosis — A careful clinicopathologic correlation is required for the diagnosis of LPP. Multiple skin biopsies may be required if lesions of diverse morphology (eg, erythematous, atrophic, poikilodermatous) are present. (See 'Clinical manifestations' above.) A diagnosis of LPP is usually made in a patient presenting with multiple, asymptomatic erythematous, scaly, and slightly atrophic patches, mainly located on the trunk (picture 9A-D), showing on histopathologic examination features that are suspicious for MF (eg, dense band-like lymphocytic infiltrate at the dermoepidermal junction, focal epidermotropism) but do not fulfill the morphologic criteria for early MF [9,35]. The diagnosis may be especially difficult in those cases of LPP that show immunophenotypic and molecular features similar to early MF. (See 'Histopathology' above and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Morphology'.) Repeated biopsies over time are needed to monitor for possible progression to MF. (See 'Differential diagnosis' below.)

Differential diagnosis — The differential diagnosis of LPP includes: ●Mycosis fungoides — The clinical differentiation of early (patch stage) MF and LPP may be difficult or impossible in some cases. Clinical monitoring and repeated skin biopsies often are required for definitive diagnosis. The primary patches of LPP are more likely to fade in the summer than the more persistent patches of early MF. Histologically, MF is characterized by a papillary dermal infiltrate of small- to medium-sized atypical mononuclear cells with cerebriform nuclei, single-cell epidermotropism of atypical lymphocytes, or atypical lymphocytes forming intraepidermal aggregates (Pautrier microabscesses) (picture 12). Spongiosis (intercellular edema in the epidermis) is not a feature of MF. However, some of these findings may be missing in early MF. Although there are no universally accepted minimal criteria for the diagnosis of MF, the International Society for Cutaneous Lymphoma and the European Organization of Research and Treatment of Cancer has devised an algorithm for the diagnosis of early MF based upon the integration of clinical, histopathologic,

6311

molecular, and immunophenotypic criteria (table 2) [9]. Cases that fail to meet any specific set of criteria for the diagnosis of early MF may be diagnosed as LPP. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Diagnostic algorithm'.) ●Contact dermatitis — Subacute or chronic allergic contact dermatitis (ACD) may be difficult to differentiate from LPP (picture 13). On histology, both diseases show minimal or absent spongiosis and lymphocytic exocytosis. However, history of allergen exposure, positive patch test results to suspected allergens, and response to treatment and avoidance measures support the diagnosis of ACD. (See "Clinical features and diagnosis of allergic contact dermatitis".) ●Plaque psoriasis — In contrast with the flat lesions of LPP, the psoriasis plaques are erythematous with sharply defined margins raised above the surrounding normal skin (picture 14A-C). There is frequent involvement of elbows and knees, and nail pitting may be seen at close inspection (picture 15). Histology shows prominent epidermal hyperplasia, parakeratosis, neutrophilic exocytosis, and dilated vessels in dermal papillae, which are typically less prominent or absent in LPP. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Chronic plaque psoriasis'.)

Management — Patients with LPP require treatment to control pruritus if present and suppress the skin lesions. They also require close clinical monitoring because of the substantial risk of developing MF. Patients for whom a clear-cut distinction between LPP and early MF cannot be made either clinically or histologically may be treated with skin-directed therapies as indicated for stage IA MF. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Stage IA disease'.)

Initial therapy — We suggest topical corticosteroids as initial treatment for patients with LPP. We typically use high- to super high-potency topical corticosteroids (groups one and two (table 1)) twice daily for 12 weeks and continue once daily or taper off if improvement is noted. Emollients can be used liberally in conjunction with topical corticosteroids. The clearance of all or most skin lesions indicates a good response to treatment. If no response is observed after 12 weeks of treatment, topical corticosteroids should be stopped. Patients who do not respond to topical corticosteroids may be treated with phototherapy. In patients who respond to topical corticosteroids, recurrence is common and may occur weeks to months after stopping the treatment. Recurrent lesions can be treated with another course of topical corticosteroids. The use of topical corticosteroids for the treatment of LPP has not been evaluated in randomized trials. Indirect evidence of efficacy in inducing lesion regression is derived from observational studies of patients with patch stage MF [21,22]. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Topical corticosteroids'.)

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The long-term use of topical corticosteroids, particularly those belonging to the high- and super highpotency groups, may result in skin atrophy, telangiectasia, and striae. In addition, if applied to large skin surfaces, topical corticosteroids may result in systemic absorption and adrenal suppression. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

Extensive or recalcitrant disease — We suggest phototherapy with broadband or narrowband ultraviolet B (UVB) or psoralen plus ultraviolet A (PUVA) for the treatment of LPP in the following situations: ●Patients with LPP who have extensive skin involvement, marked skin atrophy, or poikiloderma. ●Patients who fail to respond to topical corticosteroids (ie, clearance of less than 50 percent of lesions). ●Patients who have disease progression. Phototherapy is generally administered two to three times per week for several months, until clearance of lesions is achieved. The frequency of treatments is gradually tapered to once per week or less and then discontinued. The benefits of a long-term maintenance treatment have not been evaluated. Recurrences may be treated by resuming the initial phototherapy schedule. (See "UVB therapy (broadband and narrowband)" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy".) There are no randomized trials or large observational studies of phototherapy for the treatment of LPP. Its use is based upon limited evidence of efficacy from small case series and indirect evidence of efficacy in early MF [36-38]. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Phototherapy'.) The short-term and long-term adverse effects of phototherapy are discussed in detail separately. (See "UVB therapy (broadband and narrowband)", section on 'Short- and long-term adverse effects' and "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Adverse effects'.) The use of topical nitrogen mustard (mechlorethamine) or topical carmustine has been described in patients with LPP, particularly those in whom LPP cannot clearly be distinguished from MF [39,40]. We generally avoid topical nitrogen mustard and carmustine because of the associated toxicities. These agents and their adverse effects are discussed separately. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Topical nitrogen mustard (mechlorethamine, HN2)' and "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Topical carmustine (BCNU)'.)

Monitoring — Patients with LPP require a close clinical monitoring because of the substantial risk of evolution to MF [3,41]. A total body skin examination ideally should be performed every six months. Patients should be counseled about the risk of developing MF and advised to seek medical attention if thicker plaques or nodules develop. There are no guidelines suggesting how often patients with LPP should be rebiopsied to detect a possible progression to MF. However,

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significant clinical change (eg, thicker plaques, increased atrophy, nodules, ulceration, an "ugly duckling" lesion) is an indication for biopsy. Additionally, presence of a cutaneous T cell clone in LPP may increase the risk of progression to MF [10].

Prognosis — LPP may persist for years or decades. In retrospective observational studies, approximately 10 to 30 percent of cases of LPP evolved to overt MF [2,3,41-43]. Patients with LPP may also have an increased risk of non-Hodgkin lymphomas other than MF and nonhematologic cancers [42].

SUMMARY AND RECOMMENDATIONS ●Parapsoriasis, including small plaque parapsoriasis (SPP) and large plaque parapsoriasis (LPP) is a group of uncommon dermatoses occurring in adults and characterized by erythematous and scaly patches of variable size, chronic course, and poor response to treatment. (See 'Introduction' above and 'Epidemiology' above.) ●SPP presents with round or oval erythematous patches 5 cm, irregularly shaped, frequently atrophic or poikilodermatous, and typically localized in areas not exposed to the sun (eg, lower trunk, buttocks, and thighs) (picture 9A-D). The diagnosis is based upon the clinical presentation and the histologic finding of a dense dermal infiltrate of small lymphocytes, some of which have cerebriform nuclei, and focal single-cell epidermotropism. Differentiating LPP from early mycosis fungoides may be difficult. (See 'Clinical manifestations' above and 'Diagnosis' above and 'Differential diagnosis' above.) ●Patients with LPP require treatment to control pruritus and suppress the skin lesions. They also require close clinical monitoring since they have a substantial risk of developing mycosis fungoides.  

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•For patients with LPP who have limited areas of involvement and mild skin atrophy, we suggest topical corticosteroids as initial treatment (Grade 2C). We use high- to super high-potency topical corticosteroids (groups one and two (table 1)) twice daily for 12 weeks. (See 'Initial therapy' above.) •For patients with LPP who have extensive skin involvement or skin atrophy or poikiloderma, we suggest phototherapy with broadband or narrowband UVB or PUVA rather than topical corticosteroids (Grade 2C). Phototherapy is also appropriate when there is a lack of response to initial treatment with topical corticosteroids or disease progression despite treatment with topical corticosteroids. Phototherapy is generally administered two to three times per week for several months, until clearance of lesions is achieved. (See 'Extensive or recalcitrant disease' above.)

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Classification of primary cutaneous lymphomas uptodate.com/contents/classification-of-primary-cutaneous-lymphomas/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Mar 26, 2020.

INTRODUCTION

Primary cutaneous lymphomas are a heterogeneous

group of T cell and B cell neoplasms that present in the skin without any evidence of extracutaneous disease at the time of diagnosis. In the last two decades, multiple classification systems have been used for these conditions. These include: ●Kiel classification ●European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas ●World Health Organization (WHO) classification 2001 ●WHO-EORTC classification of primary cutaneous lymphomas 2005 ●WHO classification 2008 ●Revised WHO classification 2016 ●Revised WHO-EORTC classification of primary cutaneous lymphomas 2018 In the early 1980s, mycosis fungoides (MF), Sézary syndrome (SS), and some related disorders, collectively termed cutaneous T cell lymphoma (CTCL), were the only types of cutaneous lymphomas that were recognized. Cutaneous lymphomas other than MF/SS were firmly believed to represent skin manifestations of a systemic lymphoma and treated accordingly [1]. The development and application of immunophenotyping and cytogenetic and molecular testing had a major impact on the diagnosis and classification of cutaneous lymphomas. Collaborative studies by dermatologists and pathologists using these new diagnostic techniques demonstrated that malignant lymphomas other than MF/SS can present primarily in the skin without detectable extracutaneous disease. Based upon these studies, several new types of CTCL and cutaneous B cell lymphomas (CBCL) were defined [2]. It became clear that primary cutaneous lymphomas had distinctive immunophenotypic and genetic features, a different clinical behavior, and often a much better prognosis than histologically similar nodal lymphomas with secondary skin involvement. Since in the past primary CTCL and CBCL were not recognized by the classification systems used by hematopathologists for nodal lymphomas (eg, Kiel classification, Working Formulation), they were often inappropriately treated as systemic lymphomas with unnecessarily aggressive therapeutic

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regimens. This observation prompted the EORTC Cutaneous Lymphoma Group to formulate a separate classification for primary cutaneous lymphomas [2]. The 1997 EORTC classification simply listed the different types of CTCL and CBCL that had been defined as separate entities in the decade before. It included a limited number of well-defined types of CTCL and CBCL and some provisional entities. A distinction was made among cutaneous lymphomas with indolent, intermediate, or aggressive clinical behavior. The clinical significance of this classification has been validated by several large studies including more than 1300 patients with a primary cutaneous lymphoma [2-4]. The third edition of the WHO classification for tumors of hematopoietic and lymphoid tissues, published in 2001, included most types of CTCL but did not recognize different types of CBCL [5]. The combined efforts of the EORTC Cutaneous Lymphoma Group and the WHO group resulted in a new consensus classification for primary cutaneous lymphomas, the 2005 WHO-EORTC classification [6]. Several large studies have validated the clinical significance of this new classification [6-9]. The fourth edition of the WHO classification, published in 2008, and its 2016 revision have adopted the terminology and definitions of the WHO-EORTC classification with only minor modifications and now include all types of CTCL and CBCL relevant for dermatologists [10-12]. The 2018 update of the WHO-EORTC classification of primary cutaneous lymphomas is for the most part identical to the 2016 revision of the WHO classification for tumors of hematopoietic and lymphoid tissues [13,14]. The relative frequency and prognosis of the different types of CTCL and CBCL included in the 2018 update of the WHO-EORTC classification are presented in the table (table 1). This topic will briefly discuss the types of primary cutaneous T cell and B cell lymphomas included in the 2018 update of the WHO-EORTC classification of primary cutaneous lymphomas. The classification of other hematopoietic neoplasms is presented separately. (See "Classification of the hematopoietic neoplasms".)

CUTANEOUS T CELL LYMPHOMAS

The

term cutaneous T cell lymphoma (CTCL) describes a heterogeneous group of neoplasms of skinhoming T cells that show considerable variation in clinical presentation, histologic appearance, immunophenotype, and prognosis (table 1). In the Western world, CTCL represent approximately 75 to 80 percent of all primary cutaneous lymphomas [6]. Mycosis fungoides (MF) and primary cutaneous CD30+ lymphoproliferative disorders (LPD) account for approximately 90 percent of CTCL.

Mycosis fungoides — Classic MF is an epidermotropic CTCL clinically characterized by the progression from patch stage to plaques stage and lastly to tumor stage. It is the most common type of CTCL and accounts for approximately 40 percent of all primary cutaneous lymphomas and 60 percent of all CTCL. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

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In addition to the classic type, three variants of MF with distinctive clinicopathologic features have been recognized: ●Folliculotropic MF – This variant of MF is characterized by folliculotropic infiltrates, often with sparing of the epidermis, and preferential involvement of the head and neck area. (See "Variants of mycosis fungoides", section on 'Folliculotropic mycosis fungoides'.) ●Pagetoid reticulosis – Variant of MF characterized by the presence of solitary patches or plaques, usually on the extremities, showing histologically an intraepidermal proliferation of neoplastic T cells. (See "Variants of mycosis fungoides", section on 'Pagetoid reticulosis'.) ●Granulomatous slack skin – Granulomatous slack skin is a very rare variant of MF characterized clinically by the development of folds of lax skin in the intertriginous areas and histologically by a granulomatous infiltrate with clonal T cells. (See "Variants of mycosis fungoides", section on 'Granulomatous slack skin'.)

Sézary syndrome — Sézary syndrome (SS) is a leukemic type of CTCL presenting with erythroderma and peripheral lymphadenopathy and characterized by the presence of neoplastic T cells (Sézary cells) in skin, lymph nodes, and peripheral blood. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

Adult T cell leukemia-lymphoma — Adult T cell leukemialymphoma (ATLL) is defined as a peripheral T cell neoplasm associated with the human T cell leukemia virus 1 (HTLV-1). ATLL is endemic in areas with a high prevalence of HTLV-1 in the population, such as southwest Japan, the Caribbean islands, and parts of South and Central America. Approximately 25 percent of ATLL patients present with skin lesions mimicking MF or Sézary syndrome. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)

Primary cutaneous CD30+ lymphoproliferative disorders — Primary cutaneous CD30

+

lymphoproliferative disorders (LPDs) are the second most common group of CTCL, accounting for approximately 30 percent of CTCL (table 1). This group includes primary cutaneous anaplastic large cell lymphoma (C-ALCL), lymphomatoid papulosis (LyP), and borderline cases. These conditions show overlapping clinical and histologic features and form a spectrum of disease. ●Primary C-ALCL – Primary C-ALCL is characterized histologically by the presence of large cells with an anaplastic or pleomorphic cytomorphology and expression of the CD30 antigen by the majority (greater than 75 percent) of tumor cells. It presents with solitary or localized (ulcerating) skin tumors and has an excellent prognosis in most cases. Unlike systemic ALCL, the vast majority

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of C-ALCL are anaplastic lymphoma kinase (ALK)-negative and do not show the t(2;5) chromosomal translocation. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma".) ●LyP – LyP is defined as a chronic, recurrent, self-healing papulonecrotic or papulonodular skin disease with histologic features suggestive of a CD30+ malignant lymphoma. Several histologic subtypes of LyP mimicking other types of CTCL have been described. Although these variants do not have therapeutic or prognostic implications, it important that pathologists recognize them and include LyP in the differential diagnosis of certain types of CTCL. (See "Lymphomatoid papulosis".)

Subcutaneous panniculitis-like T cell lymphoma — Subcutaneous panniculitis-like T cell lymphoma (SPTCL) was originally defined as an aggressive cytotoxic T cell lymphoma that preferentially infiltrates subcutaneous tissue and is often complicated by a hemophagocytic syndrome [2,5]. In the 2001 World Health Organization (WHO) classification, SPTCL included cases with an alpha-beta T cell phenotype (75 percent) and cases with a gamma-delta T cell phenotype (25 percent) [5]. Studies have shown clinical, histologic, and immunophenotypic differences between cases of SPTCL with an alpha-beta T cell phenotype and those with a gamma-delta T cell phenotype, suggesting that they may represent different entities [15]. While most SPTCL with an alpha-beta T cell phenotype show an indolent clinical behavior, SPTCL with a gamma-delta T cell phenotype runs a very aggressive clinical course, similar to other types of gamma-delta T cell lymphoma. Therefore, in the 2005 WHO-European Organization for Research and Treatment of Cancer (EORTC) classification and in more recent classifications, the term SPTCL is only used for cases with an alpha-beta T cell phenotype, whereas cases with a gamma-delta T cell phenotype are included in the category of primary cutaneous gamma-delta T cell lymphoma (PCGD-TCL). (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

Cutaneous manifestations of chronic active EBV infection — Cutaneous manifestations of chronic active Epstein-Barr virus (EBV) infection include hydroa vacciniforme-like lymphoproliferative disorders (HV-like LPDs) and hypersensitivity reactions to mosquito bites [16-18]. Both disorders carry a risk of progression to systemic EBV-positive T cell or natural killer (NK) cell lymphoma. HV-like LPD is an encompassing term for cases previously referred to as atypical HV and HV-like lymphoma. These disorders are seen mainly in children and adolescents from Asia or in indigenous populations from Central and South America and Mexico. Both conditions are rare in adults. (See "Infectious mononucleosis", section on 'Chronic active EBV infection' and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Hydroa vacciniforme'.)

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Extranodal NK/T cell lymphoma, nasal type — Extranodal NK/T cell lymphoma, nasal type is nearly always an Epstein-Barr viruspositive lymphoma composed of small, medium, or large cells, usually with an NK or, more rarely, a cytotoxic T cell phenotype. The skin is the second most common site of involvement after the nasal cavity/nasopharynx, and skin involvement may be a primary or secondary manifestation of the disease. This lymphoma is more common in Asia, Central America, and South America. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)

Primary cutaneous peripheral T cell lymphoma, rare subtypes Primary cutaneous gamma-delta T cell lymphoma — PCGD-TCL is a rare and most often aggressive CTCL composed of a clonal proliferation of mature, activated gamma-delta T cells with a cytotoxic phenotype. In previous classifications, cases with panniculitis-like lesions were classified as SPTCL with a gamma-delta phenotype. (See "Primary cutaneous T cell lymphomas, rare subtypes", section on 'Primary cutaneous gamma-delta T cell lymphoma'.)

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphoma — Primary cutaneous CD8 aggressive +

epidermotropic cytotoxic T cell lymphoma (CD8+ AECTCL) is a rare and very aggressive type of CTCL characterized by a proliferation of epidermotropic CD8+ cytotoxic T cells. CD8+ AECTCL is included as a provisional entity in the 2016 revision of the WHO classification of hematopoietic neoplasms [11]. (See "Primary cutaneous T cell lymphomas, rare subtypes", section on 'Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphoma'.)

Primary cutaneous acral CD8+ T cell lymphoma — Primary cutaneous acral CD8 T cell lymphoma, initially designated as +

"indolent CD8+ lymphoid proliferation of the ear," has been included as a new provisional entity in the 2018 revision of the WHO-EORTC classification. It is histologically characterized by a diffuse infiltrate of medium-sized CD8+ cytotoxic T cells, suggesting a high-grade malignant lymphoma, and clinically by a solitary skin lesion affecting acral sites (most commonly, the ear) and an indolent clinical behavior. (See "Primary cutaneous T cell lymphomas, rare subtypes", section on 'Primary cutaneous acral CD8+ T cell lymphoma'.)

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Primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder — In the WHO-EORTC and WHO 2008

classification, primary cutaneous CD4+ small/medium T cell lymphoma (PCSM-TCL) was included as a provisional type of CTCL defined by a predominance of small to medium size CD4+ pleomorphic T cells without prior or concurrent patches and plaques typical of MF [6,12]. Almost all cases present with a solitary plaque or tumor, which have the same clinicopathologic features and benign clinical course as cutaneous T cell pseudolymphomas with a nodular growth pattern. Therefore, in the 2018 update of the WHO-EORTC classification, the term primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder, rather than lymphoma, is preferred [11]. (See "Primary cutaneous T cell lymphomas, rare subtypes", section on 'Primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder'.)

CUTANEOUS B CELL LYMPHOMAS

The

term cutaneous B cell lymphoma (CBCL) refers to those cases of B cell lymphoma that present primarily in the skin when there is no evidence of extracutaneous disease at the time of diagnosis and after the completion of an initial staging evaluation. In the 2018 update of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphomas, three main types of CBCL are recognized. In the Western world, CBCL make up approximately 25 percent of primary cutaneous lymphomas.

Primary cutaneous marginal zone lymphoma — Primary cutaneous marginal zone lymphoma (PCMZL) is an indolent lymphoma composed of small B cells, including marginal zone (centrocyte-like) cells, lymphoplasmacytoid cells, and plasma cells. It includes cases previously designated as primary cutaneous immunocytoma, cutaneous follicular lymphoid hyperplasia with monotypic plasma cells, and primary cutaneous plasmacytoma without underlying multiple myeloma (extramedullary plasmacytoma of the skin). Within the group of PCMZL, distinction is made between heavy chain class-switched cases (immunoglobulin G [IgG]-positive), which are the most common and most typical type of PCMZL, and nonclass-switched cases (immunoglobulin M [IgM]-positive), which are uncommon, share many features with mucosa-associated lymphoid tissue (MALT) lymphomas at other extranodal sites, and are more likely to have extracutaneous disease [11,13,14].In the 2016 revision of the WHO classification, PCMZL is not listed separately but is included in the broad group of extranodal marginal zone lymphoma of MALT [10,11]. PCMZL make up approximately 7 percent of all cutaneous lymphomas and approximately 30 to 40 percent of primary CBCL. (See "Primary cutaneous marginal zone lymphoma".)

Primary cutaneous follicle center lymphoma — Primary cutaneous follicle center lymphoma (PCFCL), previously called primary cutaneous follicle center cell lymphoma, is a tumor of neoplastic follicle center cells with a

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predominance of large centrocytes (large cleaved cells) admixed with variable numbers of centroblasts (large noncleaved cells with prominent and usually paracentral nucleoli). PCFCL generally presents with localized lesions on the head, particularly the scalp, or trunk. PCFCL may show a follicular, a follicular and diffuse, or a diffuse growth pattern. In contrast to nodal follicular lymphomas, most PCFCL with a follicular growth pattern are B cell lymphoma 2 (BCL2)-negative and lack the t(14;18) translocation. In previous classifications, PCFCL with a diffuse growth pattern were commonly classified as diffuse large B cell lymphoma. PCFCL accounts for approximately 10 percent of all cutaneous lymphomas and approximately 40 to 50 percent of primary CBCL. (See "Primary cutaneous follicle center lymphoma".)

Primary cutaneous diffuse large B cell lymphoma, leg type — Primary cutaneous diffuse large B cell lymphoma, leg type (PCDLBCL, LT) shows histologically a predominance of confluent sheets of centroblasts and immunoblasts. It typically presents with skin lesions on the lower legs in older adult patients, particularly females. PCDLBCL, LT makes up approximately 4 percent of all cutaneous lymphomas and approximately 20 percent of primary CBCL. (See "Primary cutaneous large B cell lymphoma, leg type".)

EBV-positive mucocutaneous ulcer — Epstein-Barr virus (EBV)-positive mucocutaneous ulcer has been included as a new provisional entity in the 2018 revision of the WHO-EORTC classification [11]. It affects patients with age-related and iatrogenic immunosuppression and usually has a self-limited, indolent course. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'EBV-positive mucocutaneous ulcer'.)

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary cutaneous lymphoma".)

SUMMARY ●Primary cutaneous lymphomas are a heterogeneous group of T cell and B cell neoplasms that present in the skin without any evidence of extracutaneous disease at the time of diagnosis. Because of their distinctive immunophenotypic and genetic features, clinical behavior, and prognosis, primary cutaneous lymphomas are included as separate entities in the 2018 update of the World Health Organization-European Organization for Research and Treatment of Cancer (WHOEORTC) classification and the 2016 revision of the WHO classification (table 1). (See 'Introduction' above.)

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●In the Western world, cutaneous T cell lymphomas (CTCL) represent approximately 75 percent of all primary cutaneous lymphomas. Mycosis fungoides and primary cutaneous CD30+ lymphoproliferative disorders account for approximately 90 percent of all CTCL. Other types of CTCL are rare and may run a very aggressive clinical course. (See 'Cutaneous T cell lymphomas' above.) ●Cutaneous B cell lymphomas represent approximately 25 percent of all primary cutaneous lymphomas. Three main types recognized are primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B cell lymphoma, leg type. (See 'Cutaneous B cell lymphomas' above.)

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Approach to the patient with a diagnosis of atypical lymphocytic infiltrate of the skin uptodate.com/contents/approach-to-the-patient-with-a-diagnosis-of-atypical-lymphocytic-infiltrate-of-the-skin/print

Approach to the patient with a diagnosis of atypical lymphocytic infiltrate of the skin All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Apr 11, 2019.

INTRODUCTION

The clinical and histologic diagnosis of cutaneous

lymphoproliferative disorders is one of the most vexing issues in dermatology and dermatopathology, despite significant advances in their classification, pathogenesis, and treatment [1]. The average delay between initial presentation and the ultimate diagnosis of mycosis fungoides, the most common primary cutaneous T cell lymphoma, is six years [2]. During this period, patients typically undergo numerous skin biopsies, which, in the absence of definite histopathologic criteria for early mycosis fungoides, may be interpreted by the pathologist as "atypical lymphocytic infiltrate" or "atypical lymphocytic proliferation." This nonspecific but potentially serious diagnosis is often a source of anxiety and frustration for both the patient and the clinician.

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This topic will discuss the definition of atypical lymphocytic infiltrate, the difficulties in differentiating reactive lymphocytic infiltrates from early lymphoma from the pathologist and clinician perspective, and the management of patients who receive this ambiguous diagnosis. Mycosis fungoides and other cutaneous lymphoproliferative disorders are discussed separately. ●(See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".) ●(See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".) ●(See "Primary cutaneous marginal zone lymphoma".) ●(See "Primary cutaneous large B cell lymphoma, leg type".) ●(See "Primary cutaneous follicle center lymphoma".) ●(See "Primary cutaneous T cell lymphomas, rare subtypes".) ●(See "Cutaneous T cell pseudolymphomas".) ●(See "Cutaneous B cell pseudolymphomas".) ●(See "Lymphomatoid papulosis".) ●(See "Primary cutaneous anaplastic large cell lymphoma".)

DEFINITION

The term "atypical lymphocytic infiltrate" describes the histologic

finding of a dermal infiltrate of atypical lymphocytes admixed with cytologically banal, reactiveappearing lymphocytes in a pattern that is suggestive of lymphoma or leukemia. Cytologic characteristics that suggest lymphocytic atypia include (picture 1): ●Increased cell size ●Nuclear hyperchromasia ●Nuclear shape (eg, cleaved, folded, cerebriform) that deviates from the typical round morphology of normal lymphocytes Histologic patterns that suggest a lymphoproliferative disorder include: ●Dense band-like infiltrate of lymphocytes within the superficial dermis ●Exocytosis of lymphocytes into the overlying epidermis or adnexa in the absence of spongiosis ●Nodular aggregates of lymphocytes reminiscent of germinal centers

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The term "atypical lymphocytic infiltrate" is generally used when the pathologist cannot reliably differentiate a reactive from a malignant lymphoproliferative disorder on histopathologic grounds alone [3]. In cases where the histologic features are strongly suggestive of malignancy (eg, necrosis, angioinvasion, angiodestruction, diffuse cytologic atypia) but are not entirely consistent with one of the entities included in the current classification of cutaneous lymphomas, the clinician should be alerted that strict clinical and histopathologic monitoring is needed to identify the type of lymphoproliferative disorder and start appropriate treatment.

DIFFICULTIES IN THE DIAGNOSIS OF CUTANEOUS LYMPHOMA

The diagnosis of

cutaneous lymphoma based solely upon histologic features may be extremely difficult, particularly in the early stage of disease [4]. Much of the difficulty stems from the absence of specific markers that can identify a lymphocyte as malignant. In addition, there are numerous conditions that simulate cutaneous lymphoma (eg, drug reactions, inflammatory, and autoimmune skin diseases) or may represent precursor diseases, blurring the line between reactive and malignant lymphoid proliferation (table 1) [3,5-9]. Technical issues such as poor tissue handling during the biopsy procedure, insufficient specimen size, poor processing, and inadequate clinical history also may preclude a precise diagnosis. When a definitive diagnosis cannot be made, it is often more appropriate for the pathologist to render a diagnosis of "atypical lymphocytic infiltrate" rather than label the patient with a possibly lifethreatening condition.

DIFFERENTIATING REACTIVE FROM MALIGNANT LYMPHOPROLIFERATIVE DISORDERS Pathologist perspective Histologic clues — Various histologic clues suggest either a malignant or reactive process [1,3]. For instance, the presence of lymphocyte exocytosis into the epidermis without associated spongiosis suggests mycosis fungoides (picture 2) rather than a reactive dermatosis. In the latter, spongiosis is prominent, whereas lymphocytic exocytosis, if present, is usually limited (picture 3).

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Likewise, if a B cell lymphoma is suspected, the presence of a "bottom-heavy" infiltrate (picture 4) and abnormalities in germinal center architecture (lack of tingible-body macrophages, lack of germinal center polarity, lack of mantle zone, expanded marginal zone, etc) is more consistent with a malignant process than with a B cell pseudolymphoma (picture 5). (See "Cutaneous B cell pseudolymphomas".) However, despite histologic clues, immunohistochemical staining patterns, and molecular data, pathologists are often left without a definitive diagnosis. In such situations, the best approach is to describe the salient histopathologic features and provide the clinician with an extensive differential diagnosis based upon the synthesis of the various findings. In addition, a direct discussion of the case with the clinician may be extremely helpful to both parties, especially if the possibility of a lymphoproliferative disorder was not clinically suspected.

Immunophenotyping — Immunohistochemical detection of specific cellular proteins is commonly used to support or refute the initial histologic diagnosis [10,11]. Common immunohistochemical markers for cutaneous lymphoproliferative disorders are listed in the table (table 2). However, the interpretation of immunohistochemical findings may be difficult, as illustrated in the examples below. ●Atypical lymphocytes are often more immature than their reactive, benign counterparts. Thus, the loss of expression of markers associated with lymphocyte maturity suggests a malignant process. As an example, the loss of the T cell markers CD7, CD2, and CD5 may be found in T cell lymphoma. However, a diminished expression of these markers, especially CD7, is by no means specific and can be observed in numerous reactive processes [12]. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Immunophenotyping'.) ●Expression of markers not commonly observed in reactive infiltrates can also be cause for concern. CD30, a marker of activated lymphocytes, is the hallmark of CD30+ lymphoproliferative disorders including lymphomatoid papulosis and anaplastic large-cell lymphoma. However, CD30 positive cells may be observed in viral infections, drug reactions, arthropod bites, scabies, and inflammatory dermatoses [13]. (See "Lymphomatoid papulosis" and "Primary cutaneous anaplastic large cell lymphoma".) ●The pattern of marker expression is also important. As an example, several markers, including BCL6, CD10, human germinal center associated lymphoma (HGAL), and LIM-only transcription factor 2, are normally expressed by germinal center B lymphocytes. However, the presence of B cells expressing these markers outside of germinal centers raises a concern for malignancy, namely primary cutaneous follicle center B-cell lymphoma or systemic follicular B-cell lymphoma with secondary skin involvement. Likewise, a predominance of intraepidermal CD4+ T lymphocytes over CD8+ T lymphocytes is suggestive of mycosis fungoides. (See "Primary cutaneous follicle center lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Immunophenotyping'.)

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Molecular analysis — Molecular techniques play a key role in the diagnosis of lymphoid neoplasms. Each T and B cell expresses a single T cell receptor (TCR) or immunoglobulin (Ig), respectively. In most reactive lymphocytic infiltrates, T and/or B cells express a variety of TCRs and Igs consistent with polyclonality. In contrast, in lymphoma, the cell population results from the clonal expansion of a single aberrant cell and expresses the same TCR or Ig. The TCR and Ig genes are composed of several separate regions that are combined during maturation (ie, variable [V], diversity [D], and joining [J]) (figure 1) and vary from one individual to another. During the maturation process, one D region is selected and combined with one J region. This pair is then joined to a single V region. By combining the regions in various configurations, the immune system is able to recognize and respond to the extraordinary diversity of proteins to which an individual is exposed over a lifetime. (See "T cell receptor genetics" and "Immunoglobulin genetics".) There are four TCR genes: TCR-alpha, TCR-beta, TCR-gamma, and TCR-delta. T cells express either TCR-alpha and TCR-beta or TCR-gamma and TCR-delta. The pair of resulting proteins (TCRalpha/beta or TCR-gamma/delta) combines to form the TCR protein that resides on the cell surface. Although cells only express two of the TCR genes, all of the genes undergo rearrangement of V, D, and J regions during the maturation process. Of note, the TCR-delta gene resides within the TCRalpha gene and is lost during rearrangement. The detection of the various V, J, and D regions is usually performed by polymerase chain reaction (PCR)-based methods, which have largely replaced the Southern blotting technique used in early studies. PCR primer sets are designed to detect the various regions of the TCR-alpha, TCR-beta or TCR-gamma genes, the last two of which are the most commonly used. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Polymerase chain reaction' and "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Southern and Northern blotting'.) Clonality is present when a single V-D-J region is detected. However, clonality does not equate to malignancy. Clonal T cell and B cell populations have been detected in numerous benign or reactive processes [14-17]. In addition, pseudoclonality (ie, clonal populations that fail to be detected on repeat analysis) has been detected in benign T and B cell processes that histologically resemble lymphoma [18,19]. Pseudoclonality is most commonly seen when only a small population of B cells is present.

Diagnostic accuracy — The sensitivity of molecular tests is not 100 percent. The ability of the assays to detect a clonal population of cells in clinically proven cutaneous lymphoma varies across studies, ranging from 50 to 90 percent [20,21]. Some of this variation is related to the methods used [22]. A protocol for both T cell and B cell processes (BIOMED-2) is used by many laboratories to provide some degree of standardization [23-25].

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The detection of clonality may be hindered when the lymphocytic infiltrate is sparse, as in early disease. In addition, mutations may occur within the PCR primer binding sites, especially in B cell malignancies, preventing the amplification and detection of the clone. Performing two complementary assays (TCR-gamma and TCR-beta or IGH and IGK) on a specimen has been shown to increase sensitivity [26,27]. In addition, next-generation sequencing techniques have shown an increased sensitivity of T cell clone detection over traditional methods [28]. Specificity can be increased by performing clonality studies on specimens from two or more distinct cutaneous lesions [29]. The presence of the same clone at distinct clinical sites is highly suggestive of malignancy. Finally, in situations in which there is a high risk for false-positive results, such as when the lymphocytic infiltrate is sparse or reacting to a limited number of antigens (eg, allergic contact dermatitis, scabietic dermatitis), clonality studies should be repeated at least twice to avoid the detection of pseudoclonality.

Clinician perspective — The clinical diagnosis of cutaneous lymphoma, especially in the setting of early disease, is extremely difficult [30]. The cutaneous lesions of early mycosis fungoides may mimic numerous benign dermatoses and may respond temporarily to topical corticosteroids. Cutaneous B cell lymphomas often present as nonspecific nodules or plaques suggestive of a cyst or basal cell carcinoma. (See "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma".) Despite these challenges, the astute clinician can often alert the pathologist to the possibility of a lymphoproliferative disorder and confirm or refute the pathologist's suspicions.

Skin examination — A full-body skin examination is essential in the evaluation of a patient with suspected lymphoproliferative disorder. Clinical features that suggest a diagnosis of mycosis fungoides include the presence of atrophic, poikilodermatous patches or plaques in geographic, asymmetric patterns and preferential localization of lesions in sun-protected sites. The presence of a nodular lesion on the earlobe, nipple, or scrotum is highly suggestive of Borrelia burgdorferi-associated cutaneous pseudolymphoma [31]. Such clinical clues should always be relayed to the pathologist with an accompanying detailed clinical differential diagnosis. (See "Cutaneous B cell pseudolymphomas" and "Clinical manifestations of Lyme disease in adults", section on 'Borrelial lymphocytoma'.)

Skin biopsy — Providing an adequate tissue sample for histopathologic examination is crucial for the diagnosis of lymphoproliferative disorders. Biopsies should be performed after cessation of any topical therapies, except emollients, for at least two weeks to prevent any treatment-related dampening of the histologic features. It is also important to avoid lesions with significant secondary changes (eg, from scratching or irritation). Biopsying two or more distinct clinical lesions may increase the chance of detecting specific histologic features and improve the accuracy of clonality studies. (See 'Molecular analysis' above.)

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Although small punch or shave biopsies may provide sufficient material for diagnosis, incisional or punch biopsies ≥5 mm in diameter are preferred, since important diagnostic and prognostic features (eg, depth of involvement, folliculotropism, follicular mucinosis) may be missed with a small or superficial biopsy. (See "Skin biopsy techniques".) Skin specimens are generally fixed in formalin as the majority of ancillary studies (eg, immunohistochemistry, PCR-based gene rearrangement studies) can be performed on formalin-fixed tissue. However, if flow cytometry is to be performed, the specimen should be provided to the laboratory on saline-soaked gauze or preferably in Roswell Park Memorial Institute (RPMI) medium.

MANAGEMENT

Several questions arise when a patient receives a

diagnosis of atypical lymphocytic infiltrate. ●What additional steps should the clinician undertake to further clarify the diagnosis? Further clarifying the diagnosis largely depends upon a detailed correlation of histopathologic and clinical features. Several algorithms incorporating clinical and immunohistochemical findings have been proposed for the diagnosis of cutaneous lymphoproliferative disorders in their earliest stages (table 3) [4,12]. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Diagnostic algorithm'.) However, direct discussions between the clinician and the pathologist are essential. Some patients may benefit from evaluation in a multidisciplinary clinic specialized in cutaneous lymphoma [32]. In many of these clinics both the clinician and the pathologist assess the patients and the differential diagnosis is discussed at the bedside. Laboratory or imaging studies typically do not play a role in the evaluation of the patient with suspected lymphoproliferative disorder, since they are expected to be negative in the early stages of the disease. ●What should the patient be told regarding his or her diagnosis and prognosis? Receiving a diagnosis of atypical lymphocytic infiltrate can produce significant anxiety and frustration in a patient. The clinician should discuss with the patient the difficulties in differentiating early lymphoproliferative disorders from reactive conditions and the need of clinical follow-up and repeat biopsies. It is also important to reassure patients that the prognosis of early stage primary cutaneous lymphoma is generally excellent with little effect on their general health, minimal risk for progression to more aggressive disease, and a long-term life expectancy that is similar to that of the general population [33]. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".) ●How should the patient be treated? A "watch and wait" approach with conservative, symptomatic treatment is the most appropriate in patients with a diagnosis of atypical lymphocytic infiltrate. Topical corticosteroids are most commonly used. Intralesional injections of corticosteroids may be useful for localized nodular or plaque-like lesions.

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Phototherapy, especially narrow-band UVB therapy, may be a therapeutic option for patients with widespread skin involvement. (See "UVB therapy (broadband and narrowband)".) Systemic immunosuppressive agents should not be used for the treatment of patients with atypical lymphocytic infiltrate. There are several reports of nonspecific dermatoses treated with cyclosporine who later transformed into aggressive T cell lymphomas [34-36]. A close clinical follow-up with a low threshold for repeat biopsy is required for all patients with a diagnosis of atypical lymphocytic infiltrate. We typically see patients every two to three months; the frequency of follow-up visits may be reduced if clinical improvement is noted or the condition remains stable. Patients should be educated to alert the clinician for more urgent evaluation if a change in their condition occurs.

SUMMARY AND RECOMMENDATIONS ●The term "atypical lymphocytic infiltrate" is generally used when the pathologist cannot reliably differentiate a reactive from a malignant lymphoproliferative disorder on histopathologic grounds alone. It describes the histologic finding of a dermal infiltrate of atypical lymphocytes admixed with cytologically banal, reactive-appearing lymphocytes in a pattern that is suggestive of lymphoma or leukemia. (See 'Definition' above.) ●Clinicians suspecting a cutaneous lymphoproliferative disorder should provide adequate tissue samples for histopathologic examination, immunophenotyping, and molecular studies. Incisional or punch biopsies ≥5 mm in diameter taken from two or more distinct lesions may increase the chance of a correct diagnosis. (See 'Histologic clues' above and 'Immunophenotyping' above and 'Molecular analysis' above.) ●Communication between the pathologist and the clinician, as well as between the clinician and the patient, is essential for the management of patients with a diagnosis of atypical lymphocytic infiltrates of the skin. A "watch and wait" approach with symptomatic treatment of the skin lesions is appropriate for most patients. (See 'Management' above.)

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Variants of mycosis fungoides - UpToDate uptodate.com/contents/variants-of-mycosis-fungoides/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Aug 27, 2019.

INTRODUCTION

Mycosis fungoides (MF) is the most common

cutaneous T cell lymphoma (CTCL) [1]. Patients with classic MF, as originally described by Alibert and Bazin two centuries ago, initially present with erythematous patches and/or plaques (picture 1AB), which represent the early stage of MF. Clinically, the patches and plaques vary in size and shape, have a scaly atrophic surface, and are often located on sun-protected areas of the body. Histologically, they are characterized by a superficial lymphoid infiltrate and epidermotropism of lymphocytes with various degree of atypia. Although in many cases the diagnosis of MF is based upon the combination of clinical and histologic features, immunohistochemical and molecular studies are usually needed to confirm the diagnosis in equivocal cases [2,3]. It has long been recognized that early MF can mimic common dermatoses, such as psoriasis and atopic dermatitis. However, in the last few decades, the list of differential diagnoses has considerably widened, due to the description of numerous atypical variants of MF that show the clinical features and/or histopathologic patterns of all the major inflammatory skin diseases [4-7]. Among them, the 2005 World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of primary cutaneous T cell lymphomas recognizes only three variants/subtypes of MF with distinctive clinicopathologic features, clinical behavior, and prognosis: folliculotropic MF, pagetoid reticulosis, and granulomatous slack skin [1,8].

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In this topic, we will review the clinical features, diagnosis, and management of these three welldefined subtypes of MF as well as of a number of rare MF variants. Classic MF and Sézary syndrome are discussed separately. ●(See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".) ●(See "Staging and prognosis of mycosis fungoides and Sézary syndrome".) ●(See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".) ●(See "Treatment of early stage (IA to IIA) mycosis fungoides".) ●(See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

GENERAL CONSIDERATIONS

Most clinical

variants of MF mimic clinically and/or histopathologically benign inflammatory skin diseases. This is not unexpected, as in the early stage of MF the number of malignant T cells is small and the dermal infiltrate consists mainly of reactive T lymphocytes, which produce inflammatory cytokines that are partly responsible for the large variety of histologic patterns observed in MF. All major histopathologic patterns described for inflammatory skin diseases have been also found in MF [9]. As MF can be a "great imitator," a high index of suspicion, as well as clinical, histopathologic, immunohistochemical, and molecular studies, are necessary for the accurate diagnosis of unusual variants of MF. The principles of staging for MF variants are similar to those used for classic MF [2]. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

FOLLICULOTROPIC MYCOSIS FUNGOIDES

Folliculotropic mycosis fungoides (FMF) is the most common

subtype of MF in adults. It is categorized as a distinct clinicopathologic variant in the 2005 classification of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) and characterized by the presence of follicle-based lesions and folliculotropism with or without follicular mucinosis as the dominant histopathologic findings [1,10]. FMF can also affect children and adolescents. In a review of 50 MF patients younger than 18 years, 18 (36 percent) had features of FMF [11]. FMF may be the sole manifestation of the disease or may occur in conjunction with classic or other variants of MF.

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Clinical presentation — The clinical manifestations are variable and include follicle-based patches, plaques, infiltrated plaques (picture 2), tumors, and prurigo nodularis-like lesions, as well as keratosis pilaris-like lesions (picture 3) and acneiform lesions (comedones, cysts) [11-21]. Alopecia is a common accompanying feature, although it is not infrequently seen also in classic MF (picture 4). In children, the most common manifestation is the presence of hypopigmented patches with follicular accentuations and alopecia. FMF preferentially involves the head and neck [13-15]. However, a significant portion of patients display lesions on the trunk and limbs as the sole site of involvement [11,18-20]. Patients with FMF experience significant pruritus [12-20] and occasional superimposed Staphylococcus aureus infection [11].

Diagnosis and differential diagnosis — The diagnosis of FMF is based upon clinical findings and the examination of a skin biopsy. One study reported a mean time of 2.8 (range 0.3 to 10) years between the onset of the eruption and the biopsy-proven diagnosis of FMF [20]. Histology shows perifollicular infiltrates of variable density around the infundibulum and/or infrainfundibulum, which usually spare the bulbar area, accompanied by folliculotropism of atypical T cells. In most cases, the epidermis is only minimally involved or spared (folliculotropism instead of epidermotropism). Immunohistochemistry shows in almost all cases a CD4+ phenotype [11-20]. The clinical differential diagnosis of FMF depends upon the clinical presentation [4,11,16,21]: ●Alopecic lesions on the scalp: alopecia areata, trichotillomania, and cicatricial alopecias. ●Follicular spiky papules: keratosis pilaris, lichen spinulosus, pityriasis rubra pilaris, and lichen planopilaris. ●Hairless patches/flat plaques: alopecia mucinosa, also known as idiopathic follicular mucinosis (picture 5A-B). ●Acneiform lesions: Favre-Racouchot syndrome, chloracne, follicular-comedogenic graft-versushost disease, and adult onset acne. In children, in whom FMF most often presents with hypopigmented patches with follicular accentuation and associated alopecia, the main differential diagnosis is alopecia mucinosa, which may mimic FMF both clinically and histopathologically [11].

Staging and prognosis — FMF has been traditionally considered an aggressive variant of MF, based upon earlier series reporting a greater risk of disease progression and worse prognosis, similar to that of tumor-stage MF [13-15]. However, subsequent studies suggest that this is not always the case [11,16,17,20,21].

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One study performed by the authors of this topic review, including a series of 49 consecutive FMF patients, revealed that FMF may present with two distinct patterns of clinicopathologic features, each with different prognostic implications [20]: ●Early-stage FMF, characterized by patches and/or flat plaques, keratosis pilaris-like lesions, and/or acneiform lesions mainly located on the trunk and/or limbs; relatively sparse perifollicular infiltrates on histology; and a favorable prognosis, similar to that of early MF. ●Tumor-stage/advanced-stage FMF, characterized by infiltrated plaques and/or tumors located mainly in the head and neck region, much heavier perifollicular infiltrates than early-stage FMF on histology, and survival rates similar to those of classic tumor-stage MF. The estimated five-year survival rate was 94 percent for early-stage and 69 percent for tumor-stage FMF [20]. These observations have been confirmed by an additional study of 203 patients with FMF [22]. Among the 186 patients with skin-limited disease at the time of the diagnosis, 67 (36 percent) presented with lesions of early-stage FMF. The 10-year disease-specific survival rates for patients with early-stage FMF and advanced-stage FMF were 93 and 40 percent, respectively. In addition to clinical stage, other unfavorable prognostic factors included age >60 years at diagnosis and presence of extensive secondary bacterial infection. Interestingly, in almost all juvenile cases reported in one study, FMF presented with early-stage superficial lesions on the trunk or limbs and had an indolent course [11]. Taken together, the results of these studies suggest that the clinical staging system used for classic MF (table 1A-B) may not be suitable for FMF, as it does not capture the unique clinicopathologic features of FMF lesions. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

Management — Based upon the prevailing notion that FMF is associated with higher risk of disease progression and that the perifollicular neoplastic infiltrates are less accessible to skin-targeted therapies alone, it has been suggested that FMF be treated as tumor-stage MF. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".) However, several studies suggest that psoralen and ultraviolet A (PUVA) phototherapy, as monotherapy or in combination with interferon or systemic retinoids, may be beneficial for patients with superficial lesions who have in fact early-stage FMF [11,16-18]. ●A large retrospective study of 203 patients with FMF from the Dutch Cutaneous Lymphoma Registry examined the response to various types of treatments in patients with early-stage FMF (n = 84), advanced-stage, skin-limited FMF (n = 102), and extracutaneous localizations at first presentation (n = 17) [23]. Among patients with early-stage FMF treated with skin-directed therapies only, including topical corticosteroids, topical nitrogen mustard, ultraviolet B (UVB) phototherapy, and PUVA therapy, 29 and 57 percent experienced complete remission (CR) or partial remission (PR), respectively; the 10-year disease-specific survival was 93 percent. None of these patients had disease progression. The majority of patients with advanced, skin-limited FMF were treated with

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PUVA with or without systemic retinoids, interferon-alpha, or local radiotherapy, local radiotherapy alone, or total skin electron beam therapy. In this group, the CR and PR rates were 25 and 50 percent, respectively, with a 10-year disease-specific survival of 40 percent. ●The authors of this topic reported on the treatment outcomes in a retrospective cohort of 27 adults with early-stage FMF treated with PUVA monotherapy [24]. Seventy percent achieved CR and 26 percent achieved PR. The CR rate was similar to that achieved in a series of 18 adult patients with classic plaque-stage MF, although the early-stage FMF group required more treatments and a higher cumulative dose of ultraviolet A (UVA). It should be emphasized that narrowband UVB phototherapy is inadequate for the treatment of FMF, as the UVB radiation penetrates the epidermis and superficial dermis but cannot reach the deep adnexal neoplastic component of FMF, thus leaving residual disease despite the improvement of the epidermal component [11,23,24].

PAGETOID RETICULOSIS

Pagetoid reticulosis (PR), also

called Woringer-Kolopp disease, is a variant of MF presenting with slowly growing, localized patches or plaques with a psoriasiform or hyperkeratotic appearance, usually located on the distal extremities [1]. Histopathology reveals a psoriasiform and sometimes verrucous hyperplasia with marked pagetoid (intraepidermal) spread of highly epidermotropic, large atypical lymphocytes, singly or in nests, which occupy the entire thickness of the epidermis. The neoplastic cells are CD3+ expressing a CD4+,CD8- or CD4-,CD8+ or CD4-,D8- phenotype [25-28]. The clinical differential diagnosis of PR includes papulosquamous, infectious, and neoplastic conditions. On histopathology, PR may mimic superficial spreading melanoma, pagetoid squamous cell carcinoma in situ, or extramammary Paget disease. PR generally follows a benign course, usually with no recurrence after curative intent treatment (ie, excision, localized radiotherapy). Rare cases of local recurrence or relapses at distant cutaneous sites have been reported [29].

GRANULOMATOUS SLACK SKIN

Granulomatous slack skin (GSS) is an extremely rare clinicopathologic subtype of MF

[1]. It is characterized by the slow development of bulky, infiltrated, pendulous folds of atrophic skin in the intertriginous areas (axillae and groins) reminiscent of cutis laxa [30]. GSS shares the histopathologic features of granulomatous mycosis fungoides (GMF), although the number of multifocal giant cells is much greater in GSS than in GMF, and many display 20 to 30 nuclei per cell, which is considered an almost pathognomonic sign of GSS [5]. (See 'Granulomatous mycosis fungoides' below.)

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Loss of elastic fibres, elastophagocytosis, and emperipolesis (engulfment of lymphocytes) are additional characteristic findings in GSS [1,5,30]. Neoplastic lymphocytes can display a CD4+ or, less commonly, a CD8+ phenotype. Despite the diffuse infiltrate that involves the entire dermis, GSS has a slowly progressive course with rare cases developing extracutaneous infiltration. There is no standard of therapy for GSS. Topical nitrogen mustard, psoralen and ultraviolet A (PUVA), radiotherapy, surgical excision, and systemic therapies have all been used, depending upon the disease stage. Patients with GSS require lifelong observation due to the increased risk of a second lymphoid malignancy, most commonly Hodgkin lymphoma [30,31].

OTHER CLINICOPATHOLOGIC VARIANTS Unilesional (solitary) mycosis fungoides — MF is typically a multifocal disease. However, rare cases of solitary lesions with the clinicopathologic features of MF have been reported in both adults and children [29,32-35]. Unilesional or solitary MF usually manifests as a single erythematous, scaly patch or plaque predominantly located on non-sun-exposed areas [32]. However, hypopigmented, eczematoid, psoriasiform, poikilodermatous, and folliculotropic solitary lesions have also been reported [29,32,33,36-40]. In many patients, the lesion has been present for several years before the diagnosis. In the context of a solitary lesion, the evaluation of clinical, morphologic, and histologic features are essential for the diagnosis of MF. The demonstration of T cell clonality may support the diagnosis. Clinical differential diagnosis of unilesional MF includes papulosquamous or eczematous lesions, dermatophyte infection, and Bowen's disease. Unilesional MF generally follows a benign course, usually with no recurrence over variable follow-up periods after curative intent treatment (ie, excision or localized radiotherapy). Rare cases of local recurrence or, even more rarely, relapse at distant cutaneous sites have been reported [29,30,32,33,36,37]. In contrast with classic MF, extracutaneous spread of unilesional MF has never been reported. Whether unilesional MF is a localized manifestation of MF or a cutaneous T cell pseudolymphoma is still unclear. (See "Cutaneous T cell pseudolymphomas".) Only pagetoid reticulosis (PR) but not unilesional MF is listed as an MF subtype in the 2005 World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classifications [1]. It remains to be seen whether the historical term PR will be included within

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unilesional MF in future classifications.

Granulomatous mycosis fungoides — Granulomatous reactions can be detected in MF cases, either at the time of the initial diagnosis or years later [9,41,42]. The pathogenesis of granuloma formation in MF is unknown, although it is recognized that granulomas can be induced by Th1 or Th2 cells in various diseases, including lymphoproliferative disorders [41]. Treatment of MF with interferon or bexarotene has been associated with the development of a granulomatous reaction [43,44]. Granulomatous mycosis fungoides (GMF) is mainly a histopathologic variant that may be found in histologic sections from patients with otherwise classical MF (including erythrodermic MF), as well as in unusual variants such as poikilodermatous, follicular, ichthyosiform, and hyperpigmented MF [2,30,41]. In some cases, the clinical features may be suggestive of a granulomatous disease, as it may present as nonscaly, thick plaques or nodules, without the cutis laxa-like features typical of granulomatous slack skin. GMF may mimic benign granulomatous skin diseases, such as granuloma annulare, sarcoidosis, or granulomatous rosacea [4,45]. The EORTC pathologic criteria for GMF include prominent granuloma formation or numerous histiocytic giant cells or a histiocyte rich infiltrate defined by histiocytes accounting for more than 25 percent of the entire infiltrate [30]. The histopathologic patterns of GMF may vary and include epithelioid/sarcoidal, tuberculoid, periadnexal, granuloma annulare-like, palisaded, necrobiotic granuloma-like, and diffuse granulomatous infiltrate [30,41]. Loss of elastic fibers is a common finding, but elastophagocytosis is rare [30]. Immunohistochemically, most cases have a CD4+ phenotype [30]. The diagnosis of GMF may be difficult, particularly in cases in which the atypical lymphoid infiltrate is obscured by a predominant granulomatous component [46]. Moreover, in some cases epidermotropism, which is the major diagnostic clue for MF, may be absent, leading to a significant delay in the diagnosis and treatment [30,41]. The finding of a monoclonal T cell receptor gene rearrangement can support the diagnosis, although a monoclonal T cell clone can occasionally be found in non-neoplastic granulomatous disorders [47]. Scant data are available as to whether patients with GMF have a different prognosis compared with classic MF. In a retrospective case-control study of 27 patients with GMF and 54 age and stagematched controls with classic MF, patients with GMF experienced more frequently disease progression and a poorer response to skin-directed therapies than those with classic MF [41]. GMF is associated with an increased risk of a second hematologic malignancy, most frequently a Hodgkin lymphoma, which can precede or follow the diagnosis of GMF by years or even decades [30,41].

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Poikilodermatous mycosis fungoides — Poikiloderma is the combination of cutaneous atrophy, telangiectasia, and macular pigmentary changes, which result in a mottled skin appearance [48]. Poikilodermatous MF is usually a clinical variant of patchstage MF, accounting for approximately 11 percent of all MF cases, according to one study [10]. It is predominantly located on the breast, hips, and buttocks and may be associated with patches and/or plaques of either classic MF or unusual variants [49]. On histopathologic examination, poikilodermatous MF shows findings of classic MF combined with changes of poikiloderma, such as epidermal atrophy, basal hydropic degeneration, pigment incontinence, and telangiectatic vessels [50,51]. Immunophenotypic analysis reveals overexpression of CD8+, compared with classic MF [52,53].   Most reported patients had early-stage disease with nonaggressive clinical behavior and good response to phototherapy [52,53], although a few cases of tumor stage and erythroderma have been described [48,52,53]. In a large cohort study examining the outcome of 1502 MF patients, poikilodermatous MF was associated with a reduced risk for disease progression and increased disease-specific survival [10].

Hypopigmented mycosis fungoides — Hypopigmented mycosis fungoides (HMF) accounts for approximately 3 percent of all MF cases in adults, according to one large cohort study [10]. It is the most common variant in childhood/adolescent MF and predominantly affects people with dark complexions [11,54,55]. HMF was the most common subtype (33 percent) in an Asian cohort of 239 MF patients [56]. The loss of pigmentation has been attributed to a decrease in the number of melanocytes in lesional skin, due to a cytotoxic effect of CD8+ T cells, as in vitiligo [57,58]. (See "Vitiligo: Pathogenesis, clinical features, and diagnosis".) HMF presents as round or irregular hypopigmented patches or flat plaques covered by fine scale, usually without atrophy. Lesions are usually asymptomatic or slightly pruritic and are mainly located on the trunk, buttocks, and limbs. On the upper limbs, in contrast with classic MF, lesions show a predilection for the dorsal, rather than the volar sun-protected surface [5,6,11,54,55,59-66]. Hypopigmented lesions may be the sole manifestation of MF or may occur in association with lesions of classic MF or other variants [11,64]. In the pediatric age group, hypopigmented lesions may be seen in combination with early-folliculotropic lesions [11]. Histopathologically, HMF lesions are indistinguishable from classic MF [11,54,55,60-63]. Striking epidermotropism of atypical lymphocytes as well as decreased melanin in the basal layer of the epidermis and melanin incontinence with melanophages in the dermis are observed in some cases [55]. In contrast with classic MF, which usually has a CD4+,CD8- phenotype, HMF is often CD8+ [11,55,60]. The diagnosis of HMF may be difficult or delayed, due to its indolent course and close clinical resemblance to a wide range of benign conditions presenting with hypopigmented macules or patches, including vitiligo, tinea corporis, tinea versicolor, pityriasis alba, postinflammatory

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hypopigmentation, progressive macular hypomelanosis, idiopathic guttate hypomelanosis, sarcoidosis, and leprosy [5,11,55,64]. (See "Vitiligo: Pathogenesis, clinical features, and diagnosis" and "Acquired hypopigmentation disorders other than vitiligo".) Because of the lack of specific signs and symptoms, a high index of suspicion and the examination of a skin biopsy are necessary for the diagnosis of HMF. Multiple skin biopsies may occasionally be needed for a definitive diagnosis. HMF shows a good response to skin-directed therapies and favorable prognosis [10,11,54,55,6063,65]. However, progression to tumor stage has been reported in a few cases.

Hyperpigmented mycosis fungoides — Hyperpigmented mycosis fungoides (HPMF) is a rare variant of MF, reported in a few cases and case series [67]. In dark-skinned individuals, it may not be as rare as reflected in the literature. HPMF is usually characterized by hyperpigmented patches and/or plaques, some with ill-defined borders, with various degrees of skin atrophy and scaling [67-70]. These hyperpigmented lesions are usually the sole manifestation of MF, although some patients may have concomitant lesions of classic, purpuric, hypopigmented, poikilodermatous, or ichthyosiform MF [67-70]. Histopathologically, in addition to features of typical MF, basal hydropic degeneration changes together with melanophages are observed [67]. Diffuse vacuolar degeneration of basal keratinocytes mimicking "interface dermatitis" has been found in the majority of cases [67,71]. A band-like lymphocytic infiltrate lining up directly opposite to the dermoepidermal junction may also be noted [72]. Immunohistochemically, most cases of HPMF show a CD8+ phenotype [67]. These cytotoxic T cells may affect neighboring melanocytes or basal keratinocytes, causing interface changes and marked melanin incontinence that results in hyperpigmentation [67]. HPMF may mimic a wide range of benign conditions, including postinflammatory hyperpigmentation, fixed drug eruption, pigmented contact dermatitis, erythema dyschromicum perstans (ashy dermatosis), cutaneous amyloidosis, atrophoderma of Pasini and Pierini, and idiopathic eruptive macular hyperpigmentation [73-75]. Hyperpigmentation induced by topical mechlorethamine, an alkylating agent used for the treatment of early-stage MF, should also be excluded [76]. Based upon very limited data, the clinical course of HPMF seems to be similar to that of classic early-stage MF, with good response to topical therapies and phototherapy and favorable prognosis [67-70].

Syringotropic mycosis fungoides — Involvement of the eccrine epithelium may be seen in some biopsies of folliculotropic mycosis fungoides (FMF) [1]. The term syringotropic MF refers to cases with prominent involvement of eccrine structures. Whether it

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constitutes a separate entity or falls within the spectrum of FMF is still matter of debate [77,78].

Ichthyosiform mycosis fungoides — Ichthyosiform MF may represent a specific clinical variant of MF rather than a paraneoplastic eruption [5,79-84]. (See "Cutaneous manifestations of internal malignancy", section on 'Acquired ichthyosis'.) Patients typically present with diffuse, dry, scaling skin or well-circumscribed scaly patches or flat plaques affecting the trunk and extremities. The diagnosis of MF can be clinically suspected only in patients showing concomitant lesions of classic MF or other variants, usually FMF lesions [79,80,84]. Histologically, in addition to the typical features of MF, findings suggestive of coexistent ichthyosis vulgaris, such as parakeratosis and focally compact orthokeratosis with thinning or absence of the granular layer [79,84] and diminished filaggrin expression in the thin granular layer, are noted [85]. Most cases of ichthyosiform MF have a CD3+,CD4+ phenotype, with only a few showing a predominance of CD8+ lymphocytes [79-84]. Ichthyosiform MF is characterized in most cases by an indolent course and good prognosis [79,84]. Progression to tumor stage and large cell transformation have been reported in a few cases [85].

Mycosis fungoides palmaris et plantaris — Specific involvement of the palms and soles can be seen in the course of MF in approximately 10 percent of cases [86]. Yet MF that is limited predominantly to or initially presents on the palms and/or soles, a condition referred to as mycosis fungoides palmaris et plantaris (MFPP), has been only rarely reported [86]. Lesions are usually bilateral and present as erythematous hyperkeratotic patches and plaques with fissures and scales, with or without pruritus. Unusual clinical variations of MFPP include annular, hyperpigmented, vesicular, dyshidrotic, pustular, verrucous, psoriasiform, and ulcerative lesions and nail dystrophy [86-93]. If these changes are not accompanied by typical MF lesions elsewhere on the body, the diagnosis may be challenging. On histology, the usual features of MF are found in MFPP. However, in the authors' experience, spongiosis may be more pronounced than in classic MF, making it difficult to differentiate MFPP from a spongiotic dermatitis. Immunophenotyping and analysis of T cell receptor clonality should be performed to confirm the diagnosis. The differential diagnosis of MFPP includes primarily dermatophyte infection or inflammatory skin diseases localized to the palms and soles, such as psoriasis and eczematous dermatitides [94]. The diagnosis of MFPP should be suspected in long-standing cases of hand/foot dermatitis or psoriasis that are unresponsive to standard therapies or have atypical presentations [59,89,90]. Other possible differential diagnoses include secondary syphilis, hyperkeratotic lichen planus, verrucae, and granuloma annulare [59,90].

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MFPP is predominantly a localized stage IA disease and as such has an indolent course, although cases with rapid progression beyond acral regions have been described [89]. Treatment modalities that have been used for MFPP include topical steroids, nitrogen mustard, topical or systemic retinoids, phototherapy, laser treatments, radiotherapy, methotrexate, and combinations of multiple agents and treatment modalities [89,90,92,95]. (See "Treatment of early stage (IA to IIA) mycosis fungoides".)

Papular and pityriasis lichenoides chronicalike mycosis fungoides — The papular variant of MF was initially defined in 2005 as papules with histopathologic findings of MF, absence of spontaneous regression, and no other evidence of MF or lymphomatoid drug reaction [96]. So far, less than 20 cases have been reported in the literature, with only a few subsequently developing typical patches or plaques of classic MF [97-105]. Lesions were typically widespread, often symmetric, and without apparent predilection for sun-protected areas. All reported cases of papular MF were CD30- [97]. The differential diagnosis of papular MF includes primarily other clonal T cell lymphoproliferative disorders, such as lymphomatoid papulosis (LyP) type B and pityriasis lichenoides chronica (PLC) and, less often, persistent arthropod bite reactions and lymphomatoid drug eruption [97,106,107]. Whether papular MF is actually a variant of MF or an atypical form of LyP type B is still controversial [97]. (See "Lymphomatoid papulosis" and "Pityriasis lichenoides chronica".) PLC-like MF is a unique expression of papular MF, reported in a few adults and children [107-109]. It is characterized by papules that resemble PLC and histopathologic findings consistent with MF, including a dermal infiltrate composed of lymphocytes that are CD30-. The main differential diagnoses are LyP type B and PLC. Because evolution into typical MF has not been documented for any of the reported PLC-like MF cases, the alternative term "lymphomatoid PLC" has been proposed to describe this condition [96,106].

Pigmented purpuric dermatosis-like mycosis fungoides — Pigmented purpuric dermatosis (PPD)-like MF is a rare purpuric variant of MF, reported both in adults and children. It may be the sole manifestation of the disease or may appear in conjunction with classic lesions or unusual variants of MF [110-117]. It is unclear whether PPD-like MF represents a purpuric dermatosis evolving to MF or a primary MF presenting with clinical and histopathologic features of PPD [110-117]. (See "Pigmented purpuric dermatoses (capillaritis)", section on 'Relationship to mycosis fungoides'.) On histopathologic examination, PPD-like MF reveals features of MF (ie, lichenoid infiltrate, epidermotropism, atypical lymphocytes) as well as extravasation of erythrocytes in the papillary dermis and presence of siderophages typically seen in PPD. Immunohistochemical analysis

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performed in a minority of the published cases showed CD4+, CD8+, or CD4-,CD8- double negative phenotypes [67,116,118]. Clinical clues to the diagnosis of PPD-like MF are the extensive distribution of lesions (in PPD, lesions are usually limited to the lower limbs), presence of reticular arrangement, and/or the coexistence of other lesions suspicious of large plaque parapsoriasis or MF [119,120]. Although MF-like histopathologic patterns can be observed in classic cases of PPD [120-122], the presence of intraepidermal lymphocytes larger than those in the dermis along with atypical lymphocytes in the dermis and papillary dermal fibrosis favor the diagnosis of MF [71]. The finding of a monoclonal T cell receptor gene rearrangement can be helpful to confirm the diagnosis, although T cell clonality may also be detected in otherwise classic cases of PPD [121,122]. It has been suggested that cases of PPD with T cell clonality but histopathologic features not consistent with MF should be regarded as cases of cutaneous T cell lymphoid dyscrasia and undergo a close clinical and histopathologic follow-up [5].

Bullous mycosis fungoides — Vesiculobullous lesions are a rare manifestation of MF, usually appearing months to years after the onset of classic MF/Sézary syndrome [123-127]. In rare instances, bullous lesions may be the primary manifestation of MF. Bullous MF presents with flaccid or tense, often multiple blisters appearing on both lesional and normal-looking skin, sometimes with a tendency to form ulcers. The trunk and limbs are the areas predominantly affected. Histopathology reveals subcorneal, intraepithelial, or subepidermal blisters, which may contain atypical T cells. The presence of typical features of MF (ie, epidermotropism with atypical lymphocytes) is the main clue to the diagnosis [124-128]. The differential diagnosis includes bacterial or viral infections, autoimmune bullous disorders, and drug eruptions. The coexistence of bullous pemphigoides or pemphigus foliaceous with MF has been reported in a few cases [123,129]. Of note, bulla formation can be an adverse effect of treatments for MF, such as topical mechlorethamine, systemic interferon, and psoralen and ultraviolet A (PUVA) [126]. The limited literature on this rare phenotype of MF generally portrays a negative prognosis [124-128].

Interstitial mycosis fungoides — Interstitial MF is a rare variant that may mimic histopathologically and, less often, clinically interstitial granuloma annulare (IGA), inflammatory morphea, or interstitial granulomatous dermatitis (IGD) [130-134]. (See "Granuloma annulare" and "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults".)

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In the largest published series of interstitial MF, which included 21 patients, this histopathologic variant was detected in biopsies of otherwise conventional patches or plaques of MF and mostly as a transient histopathologic pattern [134]. However, based upon earlier reports and the authors' experience, the interstitial pattern is found in flat or slightly elevated plaques that, in contrast with classic MF, lack scaling and atrophy.   On histopathology, interstitial MF shows a dermal interstitial infiltrate composed mainly of CD3+ lymphocytes with variable amounts of CD68+ histiocytes that do not outnumber the lymphocytes and occasional mucin deposition. Epidermotropic lymphocytes are present at least focally in many but not in all cases. In a series of 21 patients with interstitial MF, a CD8+ phenotype was found in 9 of 18 tested cases [134]. IGA and IGD can be differentiated from interstitial MF by the predominance of histiocytes. Inflammatory morphea is differentiated from interstitial MF by the relative predominance of B cells and plasma cells in the interstitium and presence of sclerosis. The detection of T cell clonality by polymerase chain reaction (PCR) favors the diagnosis of MF. However, clonality has been detected, albeit rarely, also in granuloma annulare [135]. A rare coexistence of MF and IGA has been reported [136]. The clinical behavior, prognosis, and treatment are not established due to the rarity of this variant.

SUMMARY AND RECOMMENDATIONS ●Many atypical variants of mycosis fungoides (MF) that share the clinical features and histopathologic patterns of all the major inflammatory skin diseases have been described. Among them, the 2005 World Health Organization-European Organization for Research and Treatment of Cancer classification of primary cutaneous T cell lymphomas recognizes three variants with distinctive clinicopathologic features, clinical behavior, and prognosis: folliculotropic MF (FMF), pagetoid reticulosis (PR), and granulomatous slack skin (GSS). (See 'Introduction' above.) ●FMF is characterized by the presence of follicle-based patches, plaques, infiltrated plaques (picture 2), tumors, and prurigo nodularis-like lesions, or keratosis pilaris-like lesions (picture 3). Although FMF has been traditionally considered an aggressive variant of MF, an early-stage form, characterized by patches and/or flat plaques, keratosis pilaris-like or acneiform lesions, and favorable prognosis has been recognized. (See 'Folliculotropic mycosis fungoides' above.) ●PR, also called Woringer-Kolopp disease, presents as slowly growing, localized patches or plaques with a psoriasiform or hyperkeratotic appearance, usually located on the distal extremities. PR generally follows a benign course, with no recurrence after curative intent treatment. (See 'Pagetoid reticulosis' above.)

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●GSS is an extremely rare clinicopathologic subtype of MF characterized by the slow development of bulky, infiltrated, pendulous folds of atrophic skin in the intertriginous areas reminiscent of cutis laxa. Treatments include topical nitrogen mustard, phototherapy, radiotherapy, surgical excision, and systemic therapies. GSS is associated with an increased risk of a second lymphoid malignancy, most commonly Hodgkin lymphoma. (See 'Granulomatous slack skin' above.)   ●Other uncommon clinicopathologic variants include unilesional, granulomatous, poikilodermatous, and hypopigmented MF. Rare variants mimicking ichthyosis vulgaris, pityriasis lichenoides chronica, and pigmented purpuric dermatosis have also been described. (See 'Other clinicopathologic variants' above.)

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Primary cutaneous T cell lymphomas, rare subtypes uptodate.com/contents/primary-cutaneous-t-cell-lymphomas-rare-subtypes/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Mar 26, 2020.

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INTRODUCTION

The term primary cutaneous T cell lymphoma (CTCL)

refers to T cell lymphomas that present primarily in the skin without evidence of extracutaneous disease at the time of diagnosis. The group of classical CTCLs (mycosis fungoides, variants of mycosis fungoides, and Sézary's syndrome) and the group of primary cutaneous CD30+ lymphoproliferative disorders (anaplastic large cell lymphoma and lymphomatoid papulosis) encompass the most common forms of CTCLs, accounting for approximately 90 percent of CTCLs in the Western world [1]. However, different distributions have been observed in other parts of the world [2,3]. Other types of CTCLs recognized in the 2018 update of the World Health Organization (WHO)European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas [1] and in the 2016 revision of the WHO classification of tumors of hematopoietic and lymphoid tissue [4] include uncommon entities, such as subcutaneous panniculitis-like T cell lymphoma; extranodal natural killer/T cell lymphoma, nasal type; primary cutaneous peripheral T cell lymphoma (PTCL), not otherwise specified; and rare subtypes of PTCL [1,4]. This topic will focus on rare subtypes of primary cutaneous PTCL, which include: ●Primary cutaneous gamma-delta T cell lymphoma ●Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T cell lymphoma ●Primary cutaneous acral CD8+ T cell lymphoma ●Primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder Mycosis fungoides, Sézary syndrome, primary cutaneous CD30+ lymphoproliferative disorders, and other uncommon types of CTCL are discussed separately. ●(See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".) ●(See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".) ●(See "Primary cutaneous anaplastic large cell lymphoma".) ●(See "Lymphomatoid papulosis".) ●(See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".) ●(See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)

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PRIMARY CUTANEOUS GAMMADELTA T CELL LYMPHOMA

Primary cutaneous

gamma-delta T cell lymphoma (PCGD-TCL) is a rare lymphoma composed of a clonal proliferation of mature, activated gamma-delta T cells with a cytotoxic phenotype and characterized by rapid progression and poor prognosis [1,4]. This group includes cases previously known as subcutaneous panniculitis-like T cell lymphoma (SPTCL) with a gamma-delta phenotype.

Epidemiology — PCGD-TCL is rare, representing less than 1 percent of all cutaneous T cell lymphomas (CTCLs) [1]. Most patients are adults, with a median age of approximately 60 years (range 25 to 91) [5].

Pathogenesis — Consistent with the prevalence of V-delta-2 gamma-delta T cells in the skin, the tumor cells of PCGD-TCL usually express V-delta-2 [6,7]. Since V-delta-2 gamma-delta T cells may act as antigen-presenting cells, chronic antigenic stimulation is thought to play a role in the pathogenesis of PCGD-TCL [6,7].

Clinical features — PCGD-TCL usually presents with disseminated, rapidly progressing plaques and/or ulceronecrotic nodules or tumors, preferentially located on the extremities (picture 1) [8,9]. Mucosal and other extranodal sites are frequently involved, but involvement of lymph nodes, spleen, or bone marrow is uncommon. PCGD-TCL may be associated with a hemophagocytic syndrome, particularly in patients with panniculitis-like tumors [8,9]. B symptoms, including fever, night sweats, and weight loss, are seen in most patients. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Pathology Morphology — In contrast with SPTCL, the neoplastic infiltrates of PCGD-TCL are not confined to the subcutaneous tissue but generally involve the epidermis and/or dermis as well [810]. Epidermal infiltration may occur as mild epidermotropism to marked pagetoid reticulosis-like infiltrates, which may be associated with intraepidermal vesiculation and necrosis. Angiocentricity, angiodestruction, and tissue necrosis are common. The neoplastic cells are generally medium to large in size with coarsely clumped chromatin (picture 2).

Immunophenotype — The neoplastic cells of PCGD-TCL characteristically have a T cell receptor (TCR)-gamma/delta+, beta-F1-, CD3+, CD2+, CD5-, CD4-, CD8-, CD56+ phenotype with strong expression of cytotoxic proteins (picture 3) [7-9,11]. Coexpression of TCR-gamma/delta and beta-F1 has been reported in some cases [12]. Epstein-Barr virus is negative.

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Genetics — Most cases of PCGD-TCL show clonally rearranged TCR-gamma and TCR-delta genes. No other genetic features have been reported.

Diagnosis — The diagnosis of PCGD-TCL requires the integration of clinical, histologic, phenotypic, and molecular genetic data. Deep punch biopsies (≥4 mm) or incisional biopsies can be performed for routine histopathology, immunophenotyping, and molecular analysis. A new commercially available TCR-delta antibody has been extremely helpful in differentiating between PCGD-TCL and other aggressive primary CTCLs with a cytotoxic T cell phenotype [13]. However, it should be noted that TCR-gamma/delta expression is found not only in PCGD-TCL but also in other types of CTCLs, including rare cases of otherwise classical mycosis fungoides (MF) and lymphomatoid papulosis type D [12,14,15].

Differential diagnosis — The differential diagnosis of PCGD-TCL includes: Subcutaneous panniculitis-like T cell lymphoma — Both PCGD-TCL and SPTCL may present on histopathologic examination as nodular lesions with panniculitis-like features with rimming of fat cells (picture 4A-B). In contrast to SPTCL, PCGD-TCL commonly involves not only the subcutis but also the dermis and/or epidermis, either in the same biopsy or in different biopsies of lesional skin, and may show ulceration. While SPTCL has an alpha-beta T cell phenotype, PCGD-TCL has a gamma-delta T cell phenotype, is generally negative for both CD4 and CD8, and commonly expresses CD56 (table 1). The differentiation of these two entities is important, since PCGD-TCL with panniculitis-like features generally has a poor prognosis and requires systemic combination chemotherapy [8,9]. (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

Mycosis fungoides — The histopathologic differentiation of PCGD-TCL from tumorstage MF and, uncommonly, plaque-stage MF may be difficult. Clinicopathologic correlation is essential. While the neoplastic T cells in MF have TCR-gamma/delta-, beta-F1+, CD4+, or, less commonly, a CD8+ T cell phenotype, the T cells in PCGD-TCL have a TCR-gamma/delta+, beta-F1-, CD4-, CD8- T cell phenotype. However, rare cases of otherwise classical MF expressing TCR-gamma have been reported [12,14]. Documentation of previous or concurrent presence of patch or plaquelike lesions strongly suggests a diagnosis of MF. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

Treatment and prognosis — Because of its rarity, there are no randomized trials addressing the treatment of PCGD-TCL. These patients should be treated with combination chemotherapy using the regimens suggested for peripheral T cell lymphoma, not

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otherwise specified (PTCL, NOS). Pretreatment evaluation, initial treatment, and treatment of PTCL, NOS are presented elsewhere. (See "Initial treatment of peripheral T cell lymphoma" and "Treatment of relapsed or refractory peripheral T cell lymphoma".) PCGD-TCL usually has an aggressive clinical course, is resistant to multiagent chemotherapy, and has a poor prognosis, with a median survival of approximately 15 months [8,9]. Patients with subcutaneous fat involvement tend to have a poorer prognosis than patients with epidermal or dermal disease only [9,10]. Rare cases of PCGD-TCL following a more indolent clinical course have been reported [5,16,17].

PRIMARY CUTANEOUS CD8+ AGGRESSIVE EPIDERMOTROPIC CYTOTOXIC T CELL LYMPHOMA

Primary

cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphoma (AECTCL) is a rare cutaneous lymphoma characterized by a proliferation of epidermotropic CD8+ cytotoxic T cells, an aggressive clinical behavior, and poor prognosis [18]. CD8+ AECTCL is included as a provisional entity in the 2018 update of the World Health Organization (WHO)-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas and in the 2016 revision of the WHO classification of hematopoietic neoplasms [1,4].

Epidemiology — CD8

+

AECTCL is rare, representing less than 1 percent of all

cutaneous T cell lymphomas (CTCL) [1]. Most patients are adults.

Clinical features — Patients with CD8

+

AECTCL present with localized or

disseminated eruptive papules, nodules, and tumors showing central ulceration and necrosis (picture 5) or with superficial, hyperkeratotic patches and plaques [18-20]. CD8+ AECTCL progresses rapidly over weeks to months and shows a propensity to disseminate to visceral sites such as the lung, testis, central nervous system, and oral mucosa, but lymph nodes are often spared [18,20]. Some patients may have a prodrome of chronic patches prior to the development of aggressive ulcerative lesions [21].

Pathology Morphology — The histopathologic appearance of CD8

+

AECTCL is variable, ranging from

a lichenoid pattern with marked, pagetoid epidermotropism and subepidermal edema in early patchlike lesions to diffuse dermal infiltrates in nodular and tumor-like lesions (picture 6). Epidermal

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necrosis and ulceration as well as invasion and destruction of adnexal skin structures are commonly found [18-20,22]. Angiocentricity and angioinvasion may be present. Tumor cells are small-medium or medium-large with pleomorphic or blastic nuclei.

Immunophenotype — The neoplastic T cells of CD8

+

AECTCL have a beta-F1+,

CD3+, CD8+, granzyme B+, perforin+, TIA-1+, CD45RA+/-, CD45RO-, CD2-/+, CD4-, CD5-, CD7+/phenotype (picture 7) [18-20]. CD30 is rarely expressed [20,23]. Epstein-Barr virus is negative [20,24].

Genetics — The neoplastic T cells of CD8

+

AECTCL show clonal T cell receptor gene

rearrangements. Specific genetic abnormalities have not been described.

Diagnosis — The diagnosis of CD8

+

AECTCL is based upon the combination of the

clinical, histopathologic, and immunophenotypic findings described above. Deep punch biopsies (≥4 mm) or incisional biopsies can be performed for routine histopathology, immunophenotyping, and molecular analysis. Since several types of primary CTCLs express a CD8+ cytotoxic T cell phenotype (table 2), a careful clinicopathologic correlation is key to the correct diagnosis [23,25].

Differential diagnosis — The differential diagnosis of CD8

+

includes several subtypes of CTCL that show infiltration of

CD8+

AECTCL

neoplastic T cells (table 2).

Lymphomatoid papulosis — Lymphomatoid papulosis (LyP) type D is a newly described histologic subtype of LyP that shows the same histologic and immunophenotypic characteristics as CD8+ AECTCL [26]. However, in contrast with CD8+ AECTCL, LyP type D has a clinical indolent behavior characterized by the recurrence of self-healing papulonecrotic lesions limited to the skin, without involvement of extracutaneous sites. (See "Lymphomatoid papulosis".)

Primary cutaneous anaplastic large cell lymphoma — Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) usually shows

a CD4+ CD30+ T cell phenotype, but in rare instances it may express CD8 [27]. In contrast with CD8+ AECTCL, which in most cases presents with multiple disseminated lesions, PC-ALCL usually presents with a solitary or a few clustered skin lesions. Rare cases of CTCL showing coexpression of CD8 and CD30 most likely belong to the spectrum of primary cutaneous CD30+ lymphoproliferative disorders, although CD8+ AECTCL may occasionally also express CD30 [20,23]. (See "Primary cutaneous anaplastic large cell lymphoma".)

Mycosis fungoides — Early lesions of CD8

+

AECTCL should be differentiated from

patch- or plaque-stage mycosis fungoides (MF). Although in most cases MF has a CD4+, CD8- T cell phenotype, approximately 15 percent of cases of early-patch/plaque-stage MF show a CD4-, CD8+ T cell phenotype with strong expression of cytotoxic proteins [28]. Differentiating CD8+ AECTCL from rare cases of CD8+ tumor-stage MF, which may also present with ulcerating tumors, is much more

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difficult. Clinical and histopathologic documentation of previous or concurrent patch or plaque lesions is essential for a correct diagnosis. Strong expression of CD30 in such cases argues against a diagnosis of CD8+ AECTCL [23]. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

Pagetoid reticulosis — On histology, early lesions of CD8

+

AECTCL that show

CD8+

marked pagetoid epidermotropism of neoplastic cytotoxic T cells may closely resemble pagetoid reticulosis, a rare variant of MF characterized by intraepidermal proliferation of neoplastic T cells. Pagetoid reticulosis typically presents with a solitary, slowly progressive, psoriasiform or hyperkeratotic patch or plaque at the distal extremities. Unlike CD8+ AECTCL, the neoplastic T cells in pagetoid reticulosis may have either a CD4+, CD8- or a CD4-, CD8+ T cell phenotype and often express CD30 [29,30].

Subcutaneous panniculitis-like T cell lymphoma — Subcutaneous panniculitis-like T cell lymphoma (SPTCL) presents with nodular skin lesions most often located on the legs. The neoplastic T cells express CD8 and the cytotoxic proteins TIA-1, granzyme B, and perforin. However, in contrast with CD8+ AECTCL, the infiltrates of SPTCL are restricted to the subcutis, and epidermotropism is absent [8]. (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

Primary cutaneous acral CD8+ T cell lymphoma — The

main differences between primary cutaneous acral CD8+ T cell lymphoma and tumor-like lesions of CD8+ AECTCL include the presence of a solitary lesion at acral sites (particularly the ears), an indolent clinical behavior, lack of epidermotropism, negative staining for granzyme B, and low proliferation rate. (See 'Primary cutaneous acral CD8+ T cell lymphoma' below.)

Treatment and prognosis — Because of its rarity, there are no

randomized trials addressing the treatment of CD8+ AECTCL. Patients are usually treated with combination chemotherapy, using the regimens for peripheral T cell lymphoma (PTCL), not otherwise specified. Pretreatment evaluation, initial treatment, and treatment of relapsed or refractory PTCL are presented elsewhere. Complete and durable remissions after allogeneic stem cell transplantation have been reported in selected cases [21,31,32]. (See "Initial treatment of peripheral T cell lymphoma" and "Treatment of relapsed or refractory peripheral T cell lymphoma".) The clinical course of CD8+ AECTCL is aggressive, and the response to chemotherapy is often disappointing. The reported median survival is less than two years [18-21].

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PRIMARY CUTANEOUS ACRAL CD8+ T CELL LYMPHOMA

Primary cutaneous acral

CD8+ T cell lymphoma is a newly described entity histologically characterized by a diffuse infiltrate of medium-sized CD8+ cytotoxic T cells suggesting a high-grade malignant lymphoma and an indolent clinical behavior [33]. This condition, initially designated "indolent CD8-positive lymphoid proliferation of the ear," has been included as a provisional entity in the 2018 update of the World Health Organization (WHO)-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas and in the 2016 revision of the WHO classification [1,4].

Epidemiology — Primary cutaneous acral CD8

+

T cell lymphoma is rare. It has been

reported only in adults and shows a male predominance.

Clinical features — Patients with primary cutaneous acral CD8

+

T cell lymphoma

typically present with a solitary, slowly progressive papule or nodule, most commonly located on the ear (picture 8). Similar lesions may occur at other acral sites including the nose and the foot [33-37]. In rare cases, both ears or feet may be affected [33,36-39]. One report describes a patient with recurrent and multifocal lesions on several acral sites [37].

Pathology Morphology — The lesions of primary cutaneous acral CD8

+

T cell lymphoma show a

diffuse proliferation of monomorphous, medium-sized blast cells throughout the dermis and subcutis, separated from the epidermis by a clear grenz zone (picture 9) [33].

Immunophenotype — The tumor cells have a CD3 , CD4 , CD8 , TIA-1 , granzyme B , +

-

+

+

-

CD30- T cell phenotype (picture 9) [33,36]. CD68 often shows a positive Golgi dot-like staining [39]. Loss of pan-T cell antigens (CD2, CD5, CD7) may occur. In almost all cases, the proliferation rate is very low (30 g over six months. ●Women with localized skin thickening/hyperkeratosis unresponsive to topical steroids. ●Women previously treated for usual or differentiated type vulvar intraepithelial neoplasia (VIN) and/or SCC. (See "Vulvar intraepithelial neoplasia".)

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●Women with vulvar biopsy showing carcinoma or precancerous changes. Biopsy should be performed in women with clinical evidence of localized skin thickening/hyperkeratosis. ●Women with biopsies where the pathologist expresses concern, but cannot make a definite diagnosis of differentiated VIN [6].

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lichen sclerosus".)

INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topics (see "Patient education: Lichen sclerosus (The Basics)") ●Beyond the Basics topics (see "Patient education: Lichen sclerosus (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS ●Lichen sclerosus refers to a benign, chronic, progressive dermatologic condition characterized by marked inflammation, epithelial thinning, and distinctive dermal changes accompanied by pruritus and pain. Lichen sclerosus usually occurs in the anogenital region, but can develop on any skin surface and in women, men, and children (picture 1A-B). (See 'Introduction' above and "Extragenital lichen sclerosus".) ●The classic appearance is thin, white, wrinkled skin localized to the labia minora and/or labia majora (picture 1A, 1D), although the whitening may extend over the perineum and around the anus in a keyhole fashion (picture 1B). Areas of epithelial hyperplasia from chronic rubbing are often seen. Fissuring is frequently present perianally, in the intralabial folds, or around the clitoris. At the end-stages, the vulva is pallid and featureless due to midline fusion. (See 'Signs' above.)

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●Vulvar pruritus is a common symptom of vulvar lichen sclerosus and can be so intense that it interferes with sleep. Other symptoms include pruritus ani, painful defecation, rectal bleeding, dyspareunia, and dysuria. However, some patients are asymptomatic. (See 'Symptoms' above.) ●The diagnosis of vulvar lichen sclerosus is based upon the presence of characteristic clinical manifestations plus histologic confirmation. (See 'Diagnosis' above.) ●There is a small increased risk of squamous cell cancer of the vulva in patients with lichen sclerosus. Adequate treatment of the disease seems to be associated with a reduced risk of development of neoplasia. The skin of patients with vulvar lichen sclerosus should be examined at least yearly, with biopsy of suspicious lesions, and women themselves should look at their skin and touch with fingertips monthly to search for thickened lumps or sores that do not heal. (See 'Associated malignancy' above.) ●Educating women with vulvar disorders about vulvar hygiene is important with any chronic vulvar condition, including lichen sclerosus (table 2). (See 'Patient education' above.) ●Medical therapy for vulvar lichen sclerosus will lead to symptomatic relief in most women; however, the effectiveness of medical therapy for preventing long-term sequelae, such as scarring and squamous cell cancer, is unclear. (See 'Management' above.) ●We recommend initial treatment of vulvar lichen sclerosus with a superpotent topical corticosteroid ointment (Grade 1B). We typically administer clobetasol propionate 0.05% ointment or halobetasol propionate 0.05% ointment daily at night for 6 to 12 weeks, followed by maintenance therapy two to three times per week if symptoms improve. Thickened hypertrophic plaques may respond best to intralesional corticosteroid therapy. (See 'Medical therapy' above.) ●In patients with persistent symptoms, we suggest a careful evaluation for causes of treatment failure. (See 'Treatment failure' above.) ●Surgical intervention is indicated for treating the postinflammatory sequelae of lichen sclerosus, and for diagnosis and treatment of an associated malignancy. (See 'Treatment of adhesions and scarring' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like

to acknowledge Elizabeth G Stewart, MD, who contributed to an earlier version of this topic review.

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Extragenital lichen sclerosus - UpToDate uptodate.com/contents/extragenital-lichen-sclerosus/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jul 17, 2019.

INTRODUCTION

Lichen sclerosus (also known as lichen sclerosus et

atrophicus) is a chronic inflammatory disorder characterized by the presence of porcelain-white, atrophic plaques on the skin (picture 1A-C). Most cases of lichen sclerosus involve the female genitalia; extragenital manifestations occur in a minority of patients. The epidemiology, clinical manifestations, and treatment of extragenital lichen sclerosus will be reviewed here (algorithm 1). Anogenital lichen sclerosus is discussed separately. (See "Vulvar lichen sclerosus" and "Balanitis in adults".)

EPIDEMIOLOGY

Extragenital manifestations are estimated to occur in

approximately 15 to 20 percent of patients with lichen sclerosus [1]. Similar to genital lichen sclerosus, extragenital disease appears to be more common in women than in men. In a retrospective review, 17 out of 20 patients with histopathologic findings consistent with extragenital lichen sclerosus were female [2]. The disorder is rare in children.

PATHOGENESIS

The pathogenesis of lichen sclerosus is not well

understood, and most information on this subject has been derived from studies in genital disease. Proposed etiologic factors for lichen sclerosus have included immune dysfunction, genetic

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predisposition, infectious agents, and trauma [3-12]. (See "Vulvar lichen sclerosus", section on 'Etiology'.)

CLINICAL MANIFESTATIONS

Extragenital lichen

sclerosus can occur in any location on the skin and infrequently appears in the oral cavity. Concomitant vulvar or penile lichen sclerosus may or may not be present. Conjunctival lesions do not occur.

Cutaneous lesions — Extragenital lesions are most commonly found on the back, shoulder, neck, wrist, thigh, and inframammary areas [1,13]. Disease following the lines of Blaschko (figure 1) also has been reported [14,15]. Early, active skin lesions of extragenital lichen sclerosus often appear as flat-topped and slightly scaly, hypopigmented, white, or mildly erythematous, polygonal papules that may coalesce to form larger plaques with peripheral erythema (picture 2A-C). Over time, as activity subsides, lesions develop a porcelain white color, variable degrees of palpable sclerosis, and a cigarette paper-like, wrinkled appearance that correlates with epidermal atrophy (picture 1A-C). In individuals with dark skin, established lesions may demonstrate hyperpigmentation and hypopigmentation rather than a porcelain white color (picture 3A-B) [16]. Telangiectasias, follicular keratotic plugs, and hemorrhagic or nonhemorrhagic bullae may also be present (picture 4) [17,18]. Extragenital lichen sclerosus may be asymptomatic but may also be severely disabling. Patients can experience pruritus or painful fissuring, particularly when lesions are located in areas subject to friction or tension, such as the inframammary folds, antecubital fossae, axillae, waist, inguinal creases, and popliteal fossae. Bullae may develop, often with hemorrhage resulting in erosions. In addition, trauma to unaffected skin, such as injury from tight clothing, injections, radiation therapy, herpes zoster, or other factors, may precipitate new lesions (Koebner phenomenon) (picture 5) [11,12,19-21].

Oral lesions — Oral lichen sclerosus is a rare manifestation of this disorder that involves the lips, gingiva, palate, tongue, or buccal mucosa in children and adults [22-25]. Lesions often appear as irregular, white or hypopigmented plaques. Most patients are asymptomatic, but occasional patients experience pruritus, burning, or tightness in affected areas [22,23,26]. Oral lesions may present independently or in association with lichen sclerosus in other sites [27].

Concomitant morphea — Clinical findings consistent with genital or extragenital lichen sclerosus may occur in patients with morphea (picture 6A-B) [28-31]. It is unclear whether the appearance of lesions consistent with lichen sclerosus represents the simultaneous occurrence of two separate disorders or the development of clinical findings that simply resemble lichen sclerosus in lesions of morphea. (See "Pathogenesis, clinical manifestations, and diagnosis of

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morphea (localized scleroderma) in adults", section on 'Lichen sclerosus' and "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults", section on 'Generalized morphea'.) The frequency of extragenital lichen sclerosus in patients with morphea was evaluated in a retrospective study of 381 adults and 91 children with morphea [29]. Extragenital lichen sclerosus was detected in 19 patients (4 percent). Additional studies are necessary to confirm the frequency of extragenital lichen sclerosus in this population.

HISTOPATHOLOGY

The characteristic pathologic features of lichen

sclerosus include (picture 7) [2]: ●Epidermal hyperkeratosis with follicular plugging ●Epidermal atrophy with flattening of rete ridges ●Vacuolization of the basal layer of the epidermis ●Marked edema in the superficial dermis (early lesions) ●Homogenized collagen in the upper dermis (established lesions) ●Lymphohistiocytic infiltrate underlying the zone of homogenized collagen

DIAGNOSIS

The diagnosis of extragenital lichen sclerosus can often be made

based upon the clinical appearance of lesions. The finding of atrophic, porcelain-white plaques on the skin is consistent with the diagnosis. When the diagnosis is uncertain, such as when features suggestive of other disorders are also present, a punch biopsy is useful for confirming the diagnosis. (See 'Differential diagnosis' below and "Skin biopsy techniques", section on 'Punch biopsy'.) Patients with skin findings consistent with extragenital lichen sclerosus should undergo complete examination of the skin, oral cavity, and external genitalia. This allows for assessment of the extent of skin disease and identification of patients with associated oral or genital lichen sclerosus or morphea. The recognition of genital lichen sclerosus is particularly important because of an association with increased risk for squamous cell carcinoma. (See "Vulvar lichen sclerosus", section on 'Associated malignancy'.) The identification of characteristic histopathologic findings in biopsies of lesions suspicious for extragenital lichen sclerosus is almost always indicative of the diagnosis (picture 7). Although similar histopathologic findings occur in the lichen sclerosus-like variant of chronic graft-versus-host disease, the clinical history facilitates the differentiation of these disorders. (See 'Histopathology' above and "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Diagnosis' and 'Differential diagnosis' below.)

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DIFFERENTIAL DIAGNOSIS

A variety of disorders

may present with clinical features that resemble extragenital lichen sclerosus. Examples include: ●Vitiligo – Vitiligo is characterized by the presence of well-demarcated, depigmented patches on the skin (picture 8A-B). In contrast to extragenital lichen sclerosus, skin texture is normal, without signs of atrophy or sclerosis. (See "Vitiligo: Pathogenesis, clinical features, and diagnosis", section on 'Clinical features'.) ●Lichen planus – Extragenital lichen sclerosus may present as violaceous, polygonal papules on the wrists or ankles that closely resemble lichen planus (picture 9A-B) [32,33]. Unlike extragenital lichen sclerosus, lichen planus often is pruritic. A skin biopsy can be used to distinguish between these disorders. (See "Lichen planus".) ●Tinea versicolor – Tinea versicolor presents with hypopigmented macules and patches primarily located on the trunk and proximal upper extremities (picture 10A-B). Fine scale is often evident, and a potassium hydroxide preparation will reveal the presence of fungal elements. Signs of cutaneous atrophy and sclerosis are absent. (See "Tinea versicolor (pityriasis versicolor)" and "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.) ●Anetoderma – In anetoderma, loss of elastin in the dermis contributes to reduced skin elasticity and the appearance of circumscribed, 1 to 3 cm areas of depressed, flaccid, wrinkled, or bulging skin (picture 11). Anetoderma may occur as a primary disorder or as a result of a preceding inflammatory process or other skin abnormality. The neck, trunk, and upper extremities are most frequently affected. (See "Anetoderma".) ●Cutaneous T cell lymphoma – Like extragenital lichen sclerosus, lesions of patch-stage mycosis fungoides may present with epidermal atrophy manifesting as fine, cigarette paper-like wrinkling (picture 12A-B). Lesions of mycosis fungoides are often erythematous, resembling an eczematous dermatitis.(See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Skin lesions'.) ●Chronic graft-versus-host disease – Patients who have received hematopoietic cell transplants may develop lesions that closely resemble extragenital lichen sclerosus as a manifestation of chronic graft-versus-host disease (picture 13). Knowledge of the patient's transplant history is useful for diagnosis. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Sclerotic manifestations'.) ●Morphea – Skin lesions that resemble the classic, atrophic, white patches of extragenital lichen sclerosus may develop in individuals with morphea, an idiopathic inflammatory disorder that causes sclerotic changes in the skin. The relationship between morphea and lichen sclerosus remains unclear. (See 'Concomitant morphea' above.)

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MANAGEMENT

There are few data on the efficacy of treatments for

extragenital lichen sclerosus. Recommendations for the use of specific agents are primarily based upon case reports, small uncontrolled studies, and data from studies in genital disease.

Overview — Topical medications, phototherapy, and systemic agents have been used for treatment. Topical corticosteroids and phototherapy are the mainstays of treatment for limited and extensive disease, respectively. Systemic therapy is rarely utilized due to the paucity of efficacy data and the potential for severe adverse effects. Systemic agents are primarily reserved for severe disease that fails to respond to other treatments (algorithm 1). Patients with both morphea and extragenital lichen sclerosus are managed similarly to patients with morphea. (See 'Concomitant morphea' above and "Treatment of morphea (localized scleroderma) in adults".)

Decision to treat and patient counseling — Lichen sclerosus is a benign condition, and deferring treatment is a reasonable option for limited skin involvement. Common reasons for initiating treatment include symptomatic, cosmetically distressing, extensive, or progressively worsening disease. Providing patients with realistic expectations for treatment outcomes is important. Although symptoms and the appearance and texture of lesions can improve with treatment, lesions usually do not completely resolve. In our experience, active inflammatory lesions respond best, while inactive lesions with hypopigmentation and atrophy are unlikely to improve.

Inactive skin disease — If lesions are inactive (eg, stable, atrophic plaques without associated erythema), supportive therapy with emollients and wound care for fissures and erosions is indicated. Bland emollients (eg, petrolatum) and nonstick dressings are useful.

Active limited skin disease — Potent topical corticosteroids are typically used as initial therapy for patients with active limited disease (eg, inflammatory but relatively stable skin disease involving less than 10 percent of the body surface area). This is due to their consistent efficacy in genital lichen sclerosus, reports of clinical experience documenting improvement in patients with extragenital lesions, and the ease of administration and relative safety of these agents. Patients who respond poorly to topical corticosteroids are typically treated with phototherapy (algorithm 1).

Topical corticosteroids — Although the efficacy of topical corticosteroids in extragenital lichen sclerosus has not been formally studied, improvement in genital disease during topical corticosteroid therapy has been reported in a randomized treatment comparison trial as well as uncontrolled and retrospective studies [34-37]. Multiple reports of clinical experience

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documenting successful treatment of extragenital lichen sclerosus with superpotent topical corticosteroids also support use for this disease [13,17,32,38-42]. Still, clinical experience suggests topical corticosteroids are less consistently effective for extragenital lesions than for genital lesions [13]. ●Administration – We typically prescribe once-daily application of a superpotent agent, such as clobetasol propionate (table 1) [13]. If there is no improvement after two months (four to six weeks for intertriginous sites), or if adverse effects are noted, we discontinue treatment and consider alternative therapies. For patients who respond sufficiently within this period, we reduce the frequency of application to two days per week for maintenance therapy. If the response is maintained over the subsequent three months, the frequency of application can continue to be tapered as tolerated. ●Adverse effects – Potential adverse effects of topical corticosteroid therapy include local cutaneous atrophy and systemic absorption resulting in suppression of the hypothalamic-pituitary axis. Intertriginous skin and facial skin areas are at greatest risk for corticosteroid-induced atrophy. Hypothalamic-pituitary axis suppression is most likely to occur with the use of high-potency agents or during treatment of large areas. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

Phototherapy — Phototherapy is our preferred second-line treatment option for patients with limited disease that cannot be effectively treated with topical corticosteroids. (See 'Phototherapy' below.)

Active extensive or spreading skin disease — In the setting of widespread active disease (eg, inflammatory skin disease involving more than 10 percent of the body surface area), application of topical corticosteroids to all lesions is often impractical. Phototherapy is typically used for the initial treatment of active disease in these patients (algorithm 1). We also tend to use phototherapy for more limited disease when patients are actively developing multiple new lesions in an attempt to suppress disease progression. Topical corticosteroids can be used as an adjunctive treatment for the more bothersome lesions during phototherapy. (See 'Topical corticosteroids' above.)

Phototherapy — Phototherapy offers the ability to treat large areas of skin, thereby facilitating the treatment of patients with widespread lesions. The mechanism through which phototherapy improves extragenital lichen sclerosus is unknown but may involve factors such as the stimulation of matrix metalloproteinases and the depletion of proinflammatory cytokines [43]. Whether exposure of uninvolved skin during phototherapy prevents the development of new lesions has not been proven. However, we believe this might be a benefit of phototherapy and use this treatment for patients with progressive development of new lesions.

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Several forms of phototherapy have been used for extragenital lichen sclerosus. The largest study involved the treatment of 10 patients with 40 sessions of ultraviolet A1 (UVA1) light at a dose of 20 J/cm2 four times per week [44]. All patients exhibited lesion softening and improvement in pigmentation. In addition, a few case reports have documented marked improvements in disease severity following treatment with narrowband ultraviolet B (UVB) light [39,43]. Psoralen plus ultraviolet A light (PUVA) photochemotherapy involves the administration of an oral or topical photosensitizer (psoralen) prior to light treatment. Case reports document responses to oral PUVA used alone or in combination with topical tacrolimus [45,46]. (See "UVA1 phototherapy" and "UVB therapy (broadband and narrowband)" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy".) ●Administration –We favor UVA1 phototherapy. If UVA1 phototherapy is not available, we suggest use of narrowband UVB phototherapy. PUVA photochemotherapy is a less favorable option due to the additional precautions and side effects associated with this therapy. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Safety measures' and "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Drug interactions' and "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Adverse effects'.) Phototherapy is usually given two to five times per week. Our typical dose range for UVA1 is 60 to 100 J/cm2, and we administer narrowband UVB according to the standard regimen. (See "UVA1 phototherapy", section on 'Dosimetry' and "UVB therapy (broadband and narrowband)", section on 'Dosimetry and treatment protocols'.) Improvement from phototherapy (transitioning of erythema to postinflammatory hyperpigmentation and reduction in the development of new lesions) is usually evident within approximately 15 treatments. Our usual treatment course is 40 to 50 treatments. We typically stop treatment at this point. Treatment success is characterized by resolution of erythema and the cessation of both lesion expansion and new lesion formation. We continue to follow patients closely after the end of treatment. Responders often exhibit continued improvement in skin texture over the subsequent six months after treatment. ●Adverse effects – Adverse effects of phototherapy include burning or blistering of skin and potential increased risks for premature skin aging and cutaneous malignancy. The risk for malignancy appears to be highest with long-term PUVA treatment. (See "UVA1 phototherapy", section on 'Adverse effects' and "UVB therapy (broadband and narrowband)", section on 'Short- and long-term adverse effects' and "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Adverse effects'.)

Refractory extensive skin disease — Systemic immunosuppressive therapy is rarely used for the management of extragenital lichen sclerosus. It is a treatment option for extensive disease in patients who have failed to respond to topical corticosteroids and phototherapy or who are unable to receive phototherapy (algorithm 1). We typically treat these patients with a combination of systemic glucocorticoids and methotrexate.

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Methotrexate and systemic glucocorticoids — The efficacy of glucocorticoids plus methotrexate is supported by a retrospective study of seven patients with progressively worsening extragenital lichen sclerosus that failed to respond to a potent topical corticosteroid (all patients) and phototherapy (six patients) [47]. Patients were treated with 15 mg per week of oral methotrexate and 1000 mg of intravenous methylprednisolone sodium succinate on three consecutive days per month. Treatment was continued for 6 months in six patients and for 10 months in one patient who had a delayed response to treatment. A significant decrease in a nonvalidated clinical disease severity score was detected at the end of treatment. In most patients, signs of improvement were first noted after three months of therapy. ●Administration – Our typical treatment regimen includes 10 to 20 mg of oral methotrexate administered once per week plus oral prednisone (1 mg/kg per day or 40 to 60 mg per day). Folic acid supplementation (1 mg per day) is typically given during methotrexate therapy to reduce risk for some side effects of methotrexate. Because absorption of oral methotrexate may be reduced at higher doses [48], we often give methotrexate subcutaneously rather than orally when doses exceed 15 mg per week or when patients fail to respond adequately to oral therapy. Alternatively, we split the total dose of oral methotrexate into a morning and an evening dose or instruct the patient to take the second half of the dose on the following day. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Folic acid supplementation' and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Pharmacology' and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Parenteral therapy'.) Regimens for initiating methotrexate vary. The author typically begins with a dose of 10 to 15 mg per week; some clinicians begin with a lower dose followed by dose increases every one to two weeks in the absence of evidence of significant toxicity. (See "Methotrexate: Drug information".) Patients are clinically assessed for a satisfactory response to methotrexate and prednisone (cessation of disease progression, resolution of erythema, and lesion improvement) after receipt of 10 to 15 mg of methotrexate per week for one month. If this endpoint has not been reached, we increase the dose of methotrexate to 17.5 to 20 mg per week, continue 1 mg/kg of prednisone per day, and reassess after an additional month. In our experience, most patients achieve satisfactory improvement within this period and tapering of prednisone can begin. We typically taper and discontinue prednisone slowly over the course of two months while continuing the same dose of methotrexate. The optimum duration of therapy with methotrexate is not established. After cessation of prednisone, we generally maintain patients on the lowest effective dose, tapering over time as tolerated. Our patients who have not achieved a satisfactory response to methotrexate and prednisone within two months continue treatment for an additional month. If the response remains unsatisfactory, this treatment is unlikely to be effective and can be discontinued. (See "Glucocorticoid withdrawal".) Monotherapy with methotrexate has also been used successfully in a patient with extragenital disease [49]. We generally reserve initial treatment with methotrexate alone for patients who have slow disease progression or who are poor candidates for systemic glucocorticoid therapy.

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●Adverse effects – A variety of potential adverse effects are associated with treatment with methotrexate and glucocorticoids, and close monitoring for toxicity is needed. Gastrointestinal distress is a common dose-related side effect of oral methotrexate therapy that may occur less frequently when methotrexate is given as parenteral therapy. We typically attempt subcutaneous therapy in patients who develop gastrointestinal side effects during oral therapy. (See "Major side effects of low-dose methotrexate" and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Parenteral therapy'.) Use of methotrexate is contraindicated in pregnancy, and relative contraindications for methotrexate therapy include alcohol abuse and pre-existing liver disease. Dose adjustments of methotrexate are necessary in patients with renal insufficiency. The adverse effects of systemic glucocorticoids are reviewed separately. (See "Major side effects of low-dose methotrexate" and "Major side effects of systemic glucocorticoids".)

Oral disease — Treatment of oral lesions of lichen sclerosus often is not required and is usually only initiated in the setting of cosmetic concerns or symptoms. Treatments that have been associated with improvement in this disorder include superpotent or medium-potency topical corticosteroids [24,50], intralesional corticosteroid injections (10 mg/mL triamcinolone acetonide) [51], topical tacrolimus [27], topical pimecrolimus [26], topical corticosteroids followed by topical testosterone [52], surgical excision [23], oral colchicine [23], and oral griseofulvin [53]. In our opinion, topical or intralesional corticosteroids and topical calcineurin inhibitors are reasonable first-line treatments. We typically involve an oral maxillofacial surgeon or dentist in the care of these patients.

Morphea with lichen sclerosus features — Patients with morphea who present with coexisting lesions consistent with extragenital lichen sclerosus should be managed similarly to other morphea patients (algorithm 1). (See 'Differential diagnosis' above and "Treatment of morphea (localized scleroderma) in adults" and "Localized scleroderma in childhood", section on 'Treatment'.)

Other therapies — Although topical tacrolimus is an accepted treatment for genital lichen sclerosus, it appears less likely to be effective in extragenital lichen sclerosus. In a prospective uncontrolled study in which 16 patients with lichen sclerosus applied tacrolimus 0.1% ointment twice daily to affected areas, a partial or complete response was observed in 9 of 10 patients with anogenital lesions but only 1 of 6 patients with extragenital lesions [54]. The solitary patient with extragenital lichen sclerosus who improved achieved only a partial response. Topical pimecrolimus, which has also been used successfully for vulvar disease [34], was not effective for extragenital lichen sclerosus in a case report [55]. We typically do not use topical tacrolimus or pimecrolimus for treatment of extragenital lichen sclerosus. (See "Vulvar lichen sclerosus", section on 'Topical calcineurin inhibitors'.)

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Local treatments reported to be effective in small numbers of patients include topical calcipotriol [56], pulsed dye laser [57,58], photodynamic therapy [58], and carbon dioxide laser vaporization [59]. Additional studies are necessary to determine the efficacies of these treatments for extragenital disease. The efficacy of other systemic therapies used in genital lichen sclerosus (eg, oral retinoids, cyclosporine) for extragenital disease is unknown. Improvement in extragenital lichen sclerosus complicated by bullae and ulceration during hydroxychloroquine therapy was reported in one patient [60].

PROGNOSIS AND FOLLOW-UP

The natural

history of extragenital lichen sclerosus has been poorly characterized. In our experience, the disease process often continues over the course of years, with unpredictable periods of exacerbation and stability. Periodic follow-up is indicated given that some patients who present with isolated plaques progress to extensive disease. Although there is a strong link between genital lichen sclerosus and the development of genital squamous cell carcinoma, reports of the development of squamous cell carcinoma in sites of extragenital lichen sclerosus are rare [61,62]. (See "Vulvar lichen sclerosus", section on 'Associated malignancy'.)

INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topics (see "Patient education: Lichen sclerosus (The Basics)")

SUMMARY AND RECOMMENDATIONS 6695

●Extragenital lichen sclerosus is an uncommon disorder that may involve the skin or oral cavity. The disorder occurs more frequently in women than in men, and the occurrence in children is rare. (See 'Epidemiology' above.) ●Early active skin lesions of extragenital lichen sclerosus often present as flat-topped, polygonal papules that may coalesce into large plaques (picture 2A-C). Inactive lesions frequently develop a porcelain white color, a finely wrinkled surface, and variable degrees of sclerosis (picture 1A-C). In individuals with dark skin, lesions may be hyperpigmented or hypopigmented (picture 3A-B). Oral lichen sclerosus presents as irregular, white or hypopigmented plaques on the lips or in the oral cavity. (See 'Clinical manifestations' above.) ●A variety of other skin disorders share clinical features with extragenital lichen sclerosus. When the diagnosis is uncertain based upon clinical examination, a skin biopsy should be performed. (See 'Diagnosis' above and 'Differential diagnosis' above.) ●Extragenital lichen sclerosus is a benign condition, and treatment may be deferred by patients who do not desire intervention. Common indications for proceeding with therapy include symptomatic, cosmetically distressing, extensive, or progressively worsening disease. (See 'Decision to treat and patient counseling' above.) ●For patients with limited extragenital lichen sclerosus who desire treatment, we suggest treatment with a superpotent topical corticosteroid, such as clobetasol propionate (Grade 2C). (See 'Topical corticosteroids' above.) ●For patients with widespread or progressive lesions, in whom application of topical therapy is impractical, or for patients who fail treatment with a superpotent topical corticosteroid, we suggest treatment with ultraviolet A1 (UVA1) phototherapy (algorithm 1) (Grade 2C). If UVA1 phototherapy is not available, patients may be treated with narrowband ultraviolet B (UVB) phototherapy. (See 'Phototherapy' above.) ●For patients with severe disease that fails to respond to topical corticosteroids and phototherapy, we suggest treatment with a combination of methotrexate and systemic glucocorticoids (algorithm 1) (Grade 2C). Other systemic treatments that have been reported to be effective in single patients include methotrexate alone and hydroxychloroquine. (See 'Refractory extensive skin disease' above.) ●Wound care is important in the presence of fissures and erosions and should include bland emollients (eg, petrolatum) and nonstick dressings. (See 'Inactive skin disease' above.)

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Primary focal hyperhidrosis - UpToDate uptodate.com/contents/primary-focal-hyperhidrosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jan 02, 2020.

INTRODUCTION

Hyperhidrosis (excessive sweating) is a common

condition rarely due to significant underlying pathology that may have serious social, emotional, and professional consequences. The diagnosis and treatment of primary focal hyperhidrosis is reviewed here. Night sweats and menopausal hot flashes are discussed separately. (See "Evaluation of the patient with night sweats or generalized hyperhidrosis" and "Menopausal hot flashes".)

DEFINITION

Hyperhidrosis is the secretion of sweat in amounts greater than

physiologically needed for thermoregulation. It is most commonly a chronic idiopathic (primary) condition; however, secondary medical conditions or medications should be excluded. Idiopathic hyperhidrosis localized to certain areas of the body is called primary focal hyperhidrosis. Primary focal hyperhidrosis usually affects the axillae, palms, and soles. The condition may also affect other sites, such as the face, scalp, inguinal, and inframammary areas. A consensus panel suggested the following diagnostic criteria for primary focal hyperhidrosis [1]: ●Focal, visible, excessive sweating of at least six months duration without apparent cause Plus at least two of the following characteristics: ●Bilateral and relatively symmetric ●Impairs daily activities ●At least one episode per week ●Onset before age 25 ●Family history of idiopathic hyperhidrosis ●Focal sweating stops during sleep

SYMPTOMS

Patients with primary focal hyperhidrosis generally develop

symptoms in childhood or adolescence that persist throughout life. Patients have focal symptoms most often localized to the palms, soles, and axillae [2-4]. Less commonly, primary focal

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hyperhidrosis may affect the scalp and face, or other sites [4]. While primary focal hyperhidrosis is made worse by heat or emotional stimuli, it is not considered a psychological disorder. Patients with axillary hyperhidrosis report skin maceration and staining of clothes. Palmar hyperhidrosis often leads to a fear of shaking hands and soiling of papers, and patients may have difficulty with work or recreational tasks that require a dry grip. Patients report that hyperhidrosis often results in social problems on both a private and professional level. Hyperhidrosis is associated with an increased incidence of other cutaneous disorders. In a retrospective case-control study involving 387 patients with primary focal hyperhidrosis, patients with hyperhidrosis were more likely to suffer from dermatophytosis, pitted keratolysis, and viral warts at the sites of hyperhidrosis [4]. In addition, atopic dermatitis and other eczematous dermatitides were present at a greater frequency in subjects with hyperhidrosis. The reason for this association is unknown; one theory is that hyperhidrosis is an exacerbating factor for dermatitis [4].

EPIDEMIOLOGY AND ETIOLOGY

Hyperhidrosis prevalence estimates range from 1 to 5 percent of the

population [3,5-8]. A study of patients with primary palmar hyperhidrosis who had been treated with thoracoscopic sympathectomy found that 49 of 58 patients and none of 20 controls reported a family history of hyperhidrosis [9], which suggests a genetic component to the disease.

PATHOGENESIS

Sweating assists thermoregulation, skin hydration, and

fluid and electrolyte balance. Three types of sweat glands, eccrine, apocrine, and apoeccrine glands have been described in humans [10]. Eccrine sweat glands are responsible for hyperhidrosis, although apoeccrine glands might play a role in axillary hyperhidrosis [11]. The primary function of eccrine sweat glands is thermoregulation, with cooling resulting from evaporation of eccrine sweat. Eccrine sweat glands are located throughout the body, but they are found in greatest quantity in the palms, soles, and (to a lesser degree) axillae. Sweating on the face, chest, and back is generally due to heat stimuli, while sweating of the palms and soles is due to emotional stress. The axillae have eccrine, apocrine, and apoeccrine glands. Thermal sweating can occur throughout the day, but emotional sweating (palms, soles, and to some degree axillae) stops while sleeping [12,13]. Eccrine glands are innervated by the sympathetic nervous system but utilize acetylcholine as the primary neurotransmitter. Thermal and emotional sweating are controlled by different regions of the brain. Thermal sweating is controlled by the hypothalamus via the thermosensitive preoptic sweat center, while emotional sweating is regulated by the cerebral cortex. A sympathetic signal is carried to endocrine glands via cholinergic autonomic neurons. In patients with primary focal hyperhidrosis,

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the sweat glands are usually histologically and functionally normal. Rather, the cause of hyperhidrosis appears to be an abnormal or exaggerated central response to normal emotional stress.

DIFFERENTIAL DIAGNOSIS

Patients with primary

focal hyperhidrosis generally have hyperhidrosis involving the face, scalp, palms, soles, or axillae. Generalized sweating suggests an etiology other than primary focal hyperhidrosis.

Secondary hyperhidrosis — The most common cause of generalized sweating is excessive heat. Generalized hyperhidrosis can be due to systemic diseases or medications. Unlike primary focal hyperhidrosis, patients with generalized, secondary hyperhidrosis usually present as adults and report sweating that occurs both while awake and sleeping. A history of generalized hyperhidrosis requires a careful evaluation for systemic causes. The differential diagnosis for generalized hyperhidrosis is similar to the differential diagnosis of night sweats (see "Evaluation of the patient with night sweats or generalized hyperhidrosis"). One should evaluate for signs and symptoms of an infectious cause such as tuberculosis [14], HIV [15], or endocarditis; a malignant etiology such as lymphoma [16,17]; or an endocrinopathy such as carcinoid syndrome [18], pheochromocytoma [19], or hyperthyroidism [20]. Medications should be carefully reviewed, as many can cause generalized sweating (table 1). While menopause is a common cause of excessive sweating, clinicians should perform a careful history and examination before concluding that excessive sweating in a woman of perimenopausal age is due to hot flashes. (See "Menopausal hot flashes".) Other causes of excessive sweating include: ●Patients with previous spinal cord injuries may occasionally develop episodes of diffuse sweating long after their injury. These sweating episodes can be due to an autonomic dysreflexia, orthostatic hypotension, or a posttraumatic syringomyelia. Hyperhidrosis attributed to autonomic dysreflexia is caused by an exaggerated autonomic response to normal stimuli such as bowel and bladder distention or skin irritation. In addition to sweating of the face, neck, and trunk, patients generally have flushing of the face and a throbbing headache. Their spinal cord lesion is usually at or above the sixth thoracic level. A post-traumatic syringomyelia may occur months to years after the development of paraplegia from a spinal cord injury of any level. The syrinx may develop above or below the level of the transection and may be associated with progressive numbness of the hyperhidrotic areas [12,13]. ●Gustatory sweating (mild sweating around the lips, nose, and forehead) occurs normally with the consumption of hot, spicy foods. However, pathologic gustatory sweating may be caused by sympathetic nerve damage, either due to invasion (such as a Pancoast tumor), or by

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sympathectomy (see 'Sympathectomy' below). It can also be due to a diabetic neuropathy, herpes zoster of the preauricular region, or misdirection of autonomic nerve fibers following parotid surgery (Frey's syndrome) [12,13].

Colored sweat — Chromhidrosis is an uncommon, idiopathic, nonhyperhidrotic condition in which apocrine glands secrete colored sweat (eg, yellow, blue, green, or black). Chromhidrosis can occur on the face (particularly malar cheeks), axillae, areolae, groin, and other areas [21-23]. Chromhidrosis is reviewed in detail separately. (See "Chromhidrosis".)

TREATMENT

Selection of the appropriate approach to treatment begins with

consideration of the location of involvement (ie, axillary, palmar, plantar, or craniofacial location). Additional factors, such as the patient's goals, expectations, and preferences, as well as safety concerns, disease severity, cost, and treatment availability also impact treatment selection.

Axillary hyperhidrosis — The major therapeutic options for axillary hyperhidrosis include antiperspirants, botulinum toxin, microwave thermolysis, topical glycopyrronium, oral medications, and surgery.

First-line therapy — Topical antiperspirants are the preferred initial treatment for axillary hyperhidrosis because they are widely available, inexpensive, and well-tolerated therapies. Topical glycopyrronium is an alternative first-line treatment and an option for patients who present with a history of poor responses to prescription antiperspirants.

Antiperspirants — Most commercially available nonprescription antiperspirants contain a low-dose metal salt (usually aluminum) that physically obstructs the opening of sweat gland ducts. Nonprescription products are only successful in treating patients with very mild hyperhidrosis. Treatment with prescription antiperspirants, such as 20% aluminum chloride hexahydrate or 6.25% aluminum chloride hexahydrate, may provide adequate therapy for patients with axillary hyperhidrosis that fails to respond to nonprescription antiperspirants [24,25]. (See 'Palmar or plantar hyperhidrosis' below.) ●Efficacy – The mechanism through which aluminum salts are thought to improve hyperhidrosis involves precipitation of the metal ions with mucopolysaccharides after application to the skin, leading to damage of epithelial cells within of the lumina of sweat ducts and the formation of plugs that occlude the ducts [26]. ●Administration – Prescription strength antiperspirants should be applied nightly to the area of hyperhidrosis until improvement is noted; significant improvement may be noted within one week. The interval between applications then can be gradually lengthened. Once-weekly applications are typically needed for maintenance therapy [27].

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Unfortunately, treatment with strong antiperspirants is often limited by skin irritation, especially in the axillary region. Low-potency corticosteroid creams (such as 2.5% hydrocortisone cream) can help alleviate axillary irritation. To reduce the risk of irritation, these products should be applied to dry skin between episodes of sweating. Ideally, aluminum chloride hexahydrate should be applied at bedtime when hyperhidrosis is at a minimum, allowed to remain in place for six to eight hours, and washed off in the morning [26]. Others have recommended using a hair dryer to quickly dry the skin before application and immediately after application, or to use baking soda powder in the morning to neutralize any remaining aluminum chloride [13]. We do not instruct patients to occlude treated areas with plastic wrap or other occlusive materials after the application of prescription antiperspirants. Occlusion is not necessary and may increase risk for irritation. Use of an additional antiperspirant product during the daytime also is not necessary. Patients who desire to use a fragranced product may apply a nonmedicated deodorant to the axillae in the morning after bathing [26].

Topical glycopyrronium — Topical glycopyrronium is an anticholinergic drug that inhibits sweating through inhibiting the action of acetylcholine on sweat glands. Topical glycopyrronium 2.4% is applied once daily to the axillae using a premoistened cloth. Local skin irritation and anticholinergic symptoms are potential adverse effects. Randomized trial data support benefit of topical glycopyrronium. The identical ATMOS-1 (n = 344) and ATMOS-2 (n = 353) trials randomly assigned patients ≥9 years of age with primary axillary hyperhidrosis to once-daily application of either glycopyrronium tosylate 3.75% (equivalent to 2.4% glycopyrronium) or vehicle in a 2:1 ratio [28]. Primary endpoints were assessed after four weeks and included the rate of response (≥4 point improvement from baseline) on patient-reported sweating severity in the Axillary Sweating Daily Diary (ASDD) and the mean absolute change from baseline in axillary gravimetric sweat production. Both trials found that more patients in the glycopyrronium tosylate groups achieved the specified ASDD measure of response than in the vehicle groups; pooled response rates were 60 versus 28 percent. In ATMOS-2, patients in the glycopyrronium tosylate group had a greater mean absolute change in sweat production compared with the vehicle group (-110±131 versus -92±153 mg/5 min). In ATMOS-1, the difference in the mean reduction in sweat production (105±285 versus 92±128 mg/5 min) was not statistically significant; a sensitivity analysis suggested a single analysis center with extreme outlier data may have contributed. Treatment-emergent adverse effects were more frequent in the glycopyrronium tosylate groups but were generally transient and mild to moderate in severity. Dry mouth and mydriasis were the most common anticholinergic adverse effects.

Second-line therapy — Patients who do not achieve sufficient improvement in axillary hyperhidrosis with topical antiperspirants may benefit from botulinum toxin injections or microwave thermolysis.

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Botulinum toxin — Periodic botulinum toxin injection into affected skin is a safe and effective method for improving axillary hyperhidrosis. However, treatment can be painful and expensive. ●Efficacy –Botulinum toxin blocks the release of neuronal acetylcholine from the presynaptic junction of both neuromuscular and cholinergic autonomic neurons. By blocking the release of acetylcholine, botulinum toxin can temporarily reduce sweat production. Although other formulations of botulinum toxin may improve hyperhidrosis, most studies have used onabotulinumtoxinA or abobotulinumtoxinA [29]. Dosing of these agents is not equivalent; 1 unit of onabotulinumtoxinA is equal to approximately 3 units of abobotulinumtoxinA [30]. US Food and Drug Administration (FDA) approval for botulinum toxin for hyperhidrosis is limited to onabotulinumtoxinA for axillary hyperhidrosis. Several studies support the efficacy of BTX-A in the treatment of axillary hyperhidrosis [30-36]. Examples include: •In a randomized trial involving 320 patients with bilateral primary axillary hyperhidrosis, response rates after four weeks were significantly higher with onabotulinumtoxinA, 50 units per axilla, than placebo (94 versus 36 percent) [33]. After 16 weeks, 82 percent of the onabotulinumtoxinA group still had an effective response compared with 21 percent of the placebo group. •In a randomized trial involving 145 patients with primary axillary hyperhidrosis unresponsive to topical therapy with aluminum chloride, patients were injected with 200 units of abobotulinumtoxinA in one axilla and placebo in the other; after two weeks, the treatments were revealed, and the axilla that had been treated with placebo was injected with 100 units of abobotulinumtoxinA [30]. Two weeks after the initial injection, the rate of sweat production was significantly less on the side treated with abobotulinumtoxinA (24 versus 144 mg/min). Two weeks after the injection with 100 U, the rate of sweat production decreased from 144 to 32 mg/min. The mean reduction in sweating was greater with the 200 units injection (81.4 versus 76.5 percent). Although the above study found a statistically greater reduction in sweating with 200 units of abobotulinumtoxinA, it is not clear that this difference is clinically important. A study of 43 patients found no difference in the degree or duration of reduction in sweating with 100 or 200 units of abobotulinumtoxinA [37]. A response to treatment is usually evident within two to four days and improvement in sweating typically persists for three to nine months or longer [29]. The duration of efficacy may increase with subsequent injections. In a retrospective study of 83 patients given an average of four abobotulinumtoxinA injection sessions for axillary hyperhidrosis (range 2 to 17 sessions) and followed for an average of 2.7 years (range 3 months to 9 years), the median duration of effect (as reported by patients) was 5.5 months after the initial injection and 8.5 months after the last injection [38]. An increase in the duration of effect of botulinum toxin may result from lengthening of the time required for regrowth of the axon terminal [38]. Additional studies are needed to confirm the findings of this study.

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Neutralizing antibody development, which occasionally has been linked to reduced therapeutic effectiveness in patients treated with botulinum toxin for other indications [39,40], appears to be infrequent among patients treated for axillary hyperhidrosis and does not necessarily result in a failure to respond to treatment. In an analysis of data from trials of onabotulinumtoxinA therapy for various indications, only 4 of 871 patients (0.5 percent) treated for axillary hyperhidrosis developed neutralizing antibodies against botulinum toxin, and the two patients who received subsequent injections after developing neutralizing antibodies continued to respond to treatment [41]. ●Administration – Optimal treatment of hyperhidrosis with botulinum toxin is dependent upon accurate identification of the specific areas of hyperhidrosis. Hyperhidrotic areas of the axilla do not necessarily correlate with the distribution of terminal axillary hair [29]. The Minor iodine starch test, a simple method to identify the responsible areas, is performed with the following steps: •Dry the affected region with absorbent paper •Apply a 3 to 5% iodine solution to the axilla and adjacent skin •Apply dry starch over the area of iodine application •Note areas in which a dark purple color appears (areas of sweat production) •Mark the areas of sweat production with a marking pen A 30-gauge needle is used to inject the botulinum toxin into the dermis or superficial fat. Typically 10 to 20 injections spaced 1 to 2 cm apart are performed in each axilla. For onabotulinumtoxinA the average dose used per axilla is 50 to 100 U; abobotulinumtoxinA treatment usually requires 100 to 300 units per axilla [29]. Pain during injections is one of the most common complaints with this therapy. A topical anesthetic may be applied after the Minor iodine starch test to reduce pain. Cryoanalgesia (refrigerant sprays or ice packs) or vibration anesthesia also may be of some benefit in decreasing pain [42-46].

Microwave thermolysis — Microwave energy can be utilized to destroy eccrine glands and relieve hyperhidrosis in the axilla [47-51]. A commercial device designed to focus microwave energy onto the dermal-adipose interface has been approved by the FDA and is commercially available. Limited availability and cost may limit access to this therapy. The use of microwave energy for axillary hyperhidrosis is supported by a randomized trial of 120 adults with primary axillary hyperhidrosis who were given one to three treatments with a microwave energy device (n = 81) or a sham device (n = 39) [49]. Patients treated with the microwave device were more likely to notice a subjective reduction in the severity of axillary hyperhidrosis 30 days after treatment than patients in the sham treatment group (89 versus 54 percent). The difference in favor of active treatment remained statistically significant for up to six months. In addition, more patients in the active group achieved at least a 50 or 75 percent reduction in a gravimetric

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measurement of sweat production through six months after treatment. However, this difference was only statistically significant for patients who achieved ≥75 percent improvement at the 30 day time point (62 versus 39 percent). Microwave thermolysis is typically administered in two 20- to 30-minute treatment sessions separated by three months [52]. The most common side effects of treatment are altered skin sensation (median duration 25 days, range 4 to 225 days), discomfort, and other local reactions. Transient median and ulnar neuropathy after microwave thermolysis also has been reported in a patient treated for axillary hyperhidrosis [53].

Other therapies — Additional therapies that may improve axillary hyperhidrosis include systemic agents, surgical interventions, and iontophoresis. Concern for adverse effects or limited efficacy data make these agents less favorable options for initial therapy. We agree with the stepwise approach outlined by the International Hyperhidrosis Society for patients who cannot be managed with first-line and second-line therapies. Patients are first considered for an alternative local treatment (suction curettage), followed by systemic agents, then endoscopic thoracic sympathectomy (ETS) [54].

Suction curettage — For many years axillary hyperhidrosis was surgically treated with subcutaneous curettage or excision of the skin containing eccrine glands. However, this procedure has a significant failure rate and is associated with permanent scarring and the risk of restricted arm movement [55]. Minimally invasive suction curettage, a newer local surgical technique for removing axillary eccrine and apocrine sweat glands, may have improved outcomes and decreased morbidity [56-64]. Suction curettage involves the use of tumescent anesthesia followed by cannula suction of the superficial subcutis to remove sweat glands. Additional studies are necessary to determine the role of suction curettage in the therapeutic algorithm for hyperhidrosis. We consider suction curettage as a therapeutic option for patients who cannot be managed with topical therapies or botulinum toxin injection and as an alternative to thoracic sympathectomy. The first randomized trial to evaluate the efficacy of suction curettage compared suction curettage to botulinum toxin injection and found a trend towards better results with botulinum toxin treatment [62]. In this study, 20 patients with axillary hyperhidrosis were randomly assigned to receive suction curettage in the right axilla and injection of 50 units of onabotulinumtoxinA in the left axilla or vice versa. Three months after treatment, there were nonstatistically significant trends toward greater reductions in resting and exercise-induced sweat rates in axillae treated with botulinum toxin (72 and 74 percent reductions, respectively) than in axillae treated with suction curettage (60 and 59 percent reductions, respectively). In a subgroup of "heavy sweater" axillae, exercise-induced sweat rates were significantly lower after botulinum toxin injection than after suction curettage, indicating a better response to botulinum toxin treatment. Among all patients, a validated quality of life questionnaire revealed significantly greater patient satisfaction with botulinum toxin therapy three and six months after treatment.

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Ideally, the permanent removal of axillary sweat glands via suction curettage would result in permanent improvement of hyperhidrosis, unlike nonsurgical local interventions. However, the limited amount of outcomes data on suction curettage and variation in surgical technique among studies preclude definitive conclusions about the long-term efficacy of the procedure. The potential for long-term benefit is supported by a prospective study of 28 patients that found reductions in resting and exercise-induced sweat rates of 70 and 86 percent one month after treatment, and 58 and 87 percent, respectively, after one year [61]. Treatment results at one year were graded as excellent, good, or satisfactory by 25, 14, and 24 percent of patients, respectively. Continued hyperhidrosis after suction curettage may occur as a result of skipped areas or compensatory sweating. The skill of the surgeon performing the procedure also may influence treatment efficacy. Recurrences of hyperhidrosis may be related to reinnervation of remaining sweat glands [64]. Posttreatment soreness is a transient and expected side effect of suction curettage. Additional potential side effects include bruising, infection, hematoma, scar, hyperpigmentation at incision sites, compensatory sweating, and dysesthesia [61,62,65].

Systemic agents — Systemic therapies (anticholinergics, clonidine, beta-blockers, and benzodiazepines) can be effective for primary focal hyperhidrosis. The potential adverse effects of systemic agents inhibit the routine use of these therapies. The most common anticholinergic agents prescribed for primary focal hyperhidrosis are oral glycopyrrolate (glycopyrronium bromide) and oral oxybutynin [66-69]. Glycopyrrolate is utilized more frequently than oxybutynin. However, only oxybutynin has been evaluated in randomized trials [70,71]. ●Oral glycopyrrolate– The use of oral glycopyrrolate for hyperhidrosis is supported by retrospective case series [67,68,72]. In one retrospective series in which 45 patients with primary hyperhidrosis (axillary, palmoplantar, generalized, or craniofacial) received treatment with glycopyrrolate alone (11 patients) or in combination with local therapies (34 patients), 67 percent of patients reported symptomatic improvement [68]. In addition, a retrospective study of 31 children with hyperhidrosis (mean age of 15 years) found that 71 percent achieved major improvement in symptoms during treatment with glycopyrrolate (with or without concomitant topical aluminum chloride) [73]. The children in this study were treated with an average total dose of 2 mg of glycopyrrolate per day. Typical doses for adults range from 1 to 2 mg once or twice daily (ie, 1 to 4 mg per day). However, doses of up to 8 mg per day occasionally are required for improvement in symptoms [74]. ●Oral oxybutynin– The efficacy of oxybutynin for hyperhidrosis was documented in a six-week randomized trial of 50 patients with palmar or axillary hyperhidrosis [70]. At six weeks, great or moderate improvement in symptoms occurred in 48 and 26 percent of patients treated with oxybutynin (2.5 mg per day for one week, 2.5 mg twice daily for two weeks, and 5 mg twice daily for three weeks), respectively. In contrast, great or moderate improvement was reported by 0 and 27 percent of patients treated with placebo, respectively. Uncontrolled studies performed by the same authors also support the efficacy of oxybutynin for facial, palmar, and axillary hyperhidrosis [75-77].

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In addition, a placebo-controlled randomized trial in which most study participants had generalized hyperhidrosis involving more than one body area (among palms, plantar feet, axillae, face, and trunk) demonstrated efficacy of oxybutynin for primary hyperhidrosis [71]. Typical adult doses of oxybutynin are a total dose of 5 to 10 mg per day; this is given in two divided doses for immediaterelease oxybutynin or once daily for extended-release oxybutynin [74]. However, doses up to 20 mg per day have been utilized [74]. Responses to systemic anticholinergics usually take about one week for the maximum effect. Dose adjustments may be needed to achieve sufficient improvement for individual patients; dosing is typically titrated to achieve satisfactory improvement in sweating while minimizing adverse effects. Continued treatment is necessary to maintain the response to treatment. Potential adverse effects of anticholinergic agents include dry mouth (most common), blurred vision, headache, and urinary retention [67,73]. Although the side effects of glycopyrrolate and oxybutynin are often tolerable, discontinuation of glycopyrrolate may be necessary in up to one-third of treated patients [67]. Additional studies are necessary to confirm the long-term efficacy and safety of anticholinergic drugs when utilized for this indication. As noted above, other drugs have been employed for the treatment of hyperhidrosis. Evidence for the efficacy of clonidine, an alpha-2 adrenergic agonist that reduces sympathetic outflow, for hyperhidrosis is limited to case reports and a small retrospective case series [68,78,79]. A typical dose for adults is 0.1 mg twice daily [74]. Reduced blood pressure is a potential adverse effect of this agent. In patients with hyperhidrosis related to specific emotional events, beta-blockers or benzodiazepines may be useful in reducing the emotional stimulus that leads to the excessive sweating [27,74,80,81].

Iontophoresis — Iontophoresis, a treatment based upon the use of electrical current to inhibit sweating, is most often used for palmar and plantar hyperhidrosis. Although a special axillary electrode can be used to treat axillary hyperhidrosis [82], treatment of the axillae is often less effective because it is difficult to obtain uniform contact of the electrode with axillary skin. (See 'Iontophoresis' below.)

Sympathectomy — The endoscopic thoracic sympathectomy (ETS) procedure for upper extremity or cervicofacial involves the interruption of the upper thoracic sympathetic chain through cauterization, cutting, or clipping. ETS is primarily reserved for patients with severe and debilitating symptoms that cannot be managed with other therapies. Based upon review of the literature, a Society for Thoracic Surgeons expert panel proposed that the ideal candidates for ETS also possess the following characteristics: ●Onset before age 16 years and younger than 25 years at the time of surgery ●Body mass index (BMI) 25 percent of the mast cells in bone marrow sections, bone marrow aspirate, or other extracutaneous tissues. ●Mutational analysis of KIT (the gene for c-kit) showing a codon 816 mutation (eg, Asp816Val) in bone marrow, peripheral blood, or extracutaneous organs. ●Bone marrow or other extracutaneous mast cells expressing the surface markers CD2, CD25, or both. ●Serum tryptase levels >20 ng/mL (when the patient is in a baseline state). Values >11.4 ng/mL are considered elevated in most diagnostic laboratories. However, the WHO criterion is defined as a value >20 ng/mL. Of note, the serum tryptase criterion does not apply to patients with the subtype of SM called "systemic mastocytosis with an associated hematologic neoplasm," since tryptase in such patients can originate from myeloid precursor cells.

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If criteria for the diagnosis of SM are met, the next step is to determine the type of systemic disease present. This evaluation is discussed separately. (See "Systemic mastocytosis: Determining the subtype of disease".)

Solid mast cell tumors — Solid mast cell tumors do not fulfill the criteria for either SM or CM. Malignant and benign variants of these tumors exist.

Mast cell sarcoma — Mast cell sarcoma is a rare disorder with few welldocumented cases [28,29]. Subsequent evolution to mast cell leukemia may occur. The sarcoma is a locally destructive lesion without systemic (bone marrow) involvement at the time of the diagnosis. Mast cell sarcomas may be located in skin, bone, extramedullary space, colon, larynx, and meninges [30-32].

Extracutaneous mastocytomas — Extracutaneous mastocytomas are also rare and are characterized by accumulation of mature mast cells in an organ other than the skin without aggressive features. These are typically detected accidentally or discovered because they can cause a mass effect and have been described in the skull and lungs [33]. Evolution of extracutaneous mastocytomas to mast cell sarcoma has not been described.

DIFFERENTIAL DIAGNOSIS ●Epidermolysis bullosa (EB) simplex is an inherited disease characterized by skin fragility and blister formation following minor skin trauma (picture 7). It can mimic blistered CM. EB is diagnosed by skin biopsy of a fresh blister analyzed by immunofluorescence microscopy. (See "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Epidermolysis bullosa' and "Diagnosis of epidermolysis bullosa".) ●Diffuse CM with blistering can be mistaken for scalded skin syndrome or impetigo bullosa, and patients may receive antibiotics inappropriately [34]. ●Café-au-lait macules are pigmented lesions that appear during the first year of life. The presence of six or more is highly suggestive of neurofibromatosis type 1 (picture 8). Café-au-lait spots do not urticate when rubbed. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".) ●Linear immunoglobulin A bullous dermatosis is a rare autoimmune blistering disease that can affect children or adults (picture 9). Most cases are idiopathic, although some are associated with drug exposure. (See "Linear IgA bullous dermatosis".) ●Increased mast cell numbers can be found in other inflammatory and neoplastic conditions of the skin, such as dermatofibromas, psoriasis, atopic dermatitis, and nevi. However, these disorders are each associated with characteristic pathologic changes in the skin that differ from those of

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mastocytosis.

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mast cell disorders".)

SUMMARY AND RECOMMENDATIONS ●Mastocytosis is a group of disorders caused by excessive mast cell proliferation. This process is limited to the skin in cutaneous mastocytosis (CM) and involves extracutaneous tissues in systemic mastocytosis (SM) with or without skin involvement. In children, cutaneous forms of disease account for approximately 90 percent of cases. The most common type of CM is maculopapular cutaneous mastocytosis (MPCM), which includes urticaria pigmentosa as well as rare nodular and plaque forms. Many children with CM have episodes of systemic symptoms (eg, pruritus, flushing, abdominal pain, diarrhea), which result from the release of mediators from cutaneous mast cells, so the presence of systemic symptoms does not distinguish between cutaneous and systemic disease. (See 'Overview' above.) ●The evaluation of a child with suspected mastocytosis begins with a skin examination for characteristic lesions, such as MPCM (picture 1), mastocytomas (picture 3), or skin thickening consistent with diffuse cutaneous mastocytosis (picture 4). The patient should also be assessed for hepatosplenomegaly. (See 'History and physical examination' above.) ●A complete blood count with differential, liver function tests, and a baseline serum tryptase should be obtained. Patients with persistent and unexplained abnormalities in any of these initial tests should be evaluated further for systemic forms of mastocytosis. (See 'Initial testing' above.) ●Generalists should perform a history and physical examination (with careful attention to the skin and elicitation of a Darier's sign), obtain the basic laboratories mentioned above if possible, and obtain a biopsy of suggestive skin lesions if possible. Further evaluation usually requires specialty referral. (See 'When to refer' above.) ●If there is any doubt about the diagnosis, children with lesions consistent with CM should undergo a punch biopsy of skin lesions with specific histopathologic stains. (See 'Skin biopsy' above.) ●The diagnosis of CM is confirmed when the morphology of the skin lesions and the skin biopsy findings (if obtained) are consistent with CM and if the patient has no unexplained laboratory abnormalities or evidence of hepatosplenomegaly or lymphadenopathy on physical examination (table 2 and algorithm 1). (See 'Diagnosis' above.)

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●The small minority of children who have abnormalities in initial laboratories, including unexplained cytopenias or liver function abnormalities, persistently elevated tryptase >20 ng/mL, hepatosplenomegaly, or lymphadenopathy on physical examination, should be evaluated further for systemic disease. This evaluation consists of imaging studies that may include an abdominal ultrasound or computed tomography (for hepatosplenomegaly) and a bone marrow biopsy (algorithm 1). Some experts perform bone marrow biopsy in prepubertal children if systemic symptoms are very severe and difficult to control with pharmacologic therapy. In adolescents, an additional indication for bone marrow biopsy is the failure of skin lesions to improve or regress after puberty or baseline serum tryptase levels that remain above the normal range (usually >20 ng/mL) after puberty. (See 'Bone marrow examination' above and 'Additional evaluation for systemic disease' above.) ●The diagnosis of SM requires either the presence of the major criterion and one of the minor criteria or three of the minor criteria (in the absence of the major criterion) (table 2). (See 'Diagnosis' above.)

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Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults uptodate.com/contents/mastocytosis-cutaneous-and-systemic-evaluation-and-diagnosis-in-adults/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Dec 06, 2017.

INTRODUCTION

Mastocytosis describes a group of disorders in which

there is pathologic accumulation of mast cells in tissues. These diseases can be limited to the skin (cutaneous mastocytosis [CM]) or involve extracutaneous tissues (systemic mastocytosis [SM]). The evaluation and diagnosis of the different forms of CM and SM in adults are reviewed here. The evaluation and diagnosis in children, the clinical manifestations of mastocytosis, the treatment of mastocytosis, and the biology of mast cells are discussed separately: ●(See "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in children".) ●(See "Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations".) ●(See "Treatment and prognosis of cutaneous mastocytosis".) ●(See "Systemic mastocytosis: Determining the subtype of disease".) ●(See "Advanced systemic mastocytosis: Management and prognosis".)

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●(See "Mast cell disorders: An overview".) ●(See "Mast cells: Development, identification, and physiologic roles".)

OVERVIEW

Mastocytosis is diagnosed according to the World Health

Organization's (WHO) published diagnostic criteria for cutaneous and systemic forms of mastocytosis (table 1) [1]. ●The diagnosis of cutaneous mastocytosis (CM) in a patient with an appropriate clinical presentation is based upon characteristic skin findings, supported by findings on skin biopsy. Evidence for systemic disease must be absent. ●The diagnosis of systemic mastocytosis (SM) requires the presence of the major criterion plus one minor criterion, or the presence of three minor criteria. In a patient with an appropriate clinical presentation, fulfilling these criteria requires both laboratory testing and biopsy of one or more involved tissues (most commonly bone marrow). The diagnostic criteria are discussed in more detail below. (See 'Diagnosis' below.)

INDICATIONS FOR EVALUATION

An

evaluation for mastocytosis is appropriate in an adult with any of the following presentations: ●Characteristic skin lesions of urticaria pigmentosa, also called maculopapular cutaneous mastocytosis (MPCM) (picture 1) or (rarely) mastocytoma. (See 'Skin examination' below.) ●Episodic signs and symptoms of mast cell activation affecting at least two organ systems (such as flushing, tachycardia, diarrhea, fatigue, or musculoskeletal pain) (table 2). Symptoms can be present on a daily basis or can be relatively infrequent. Symptoms and triggers are reviewed elsewhere. (See "Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations".) ●Signs/symptoms of mast cell activation associated with hypotensive syncope or near syncope, including hypotension in response to the sting of a bee, wasp, or other Hymenoptera insect, with or without skin lesions of mastocytosis. ●Osteoporosis in a young adult, pathologic bone fracture, or radiographic diffuse skeletal abnormalities (lytic or sclerotic lesions) are additional rare presentations (in which signs and symptoms of mast cell activation may or may not be present). ●Unexplained hepatosplenomegaly, abnormal CBC with differential or presence of mast cells in peripheral blood smear with any other signs and symptoms of mast cell activation. These different presentations result from the release of mast cell mediators and/or infiltration of various organs by mast cells (table 2). More detailed descriptions of the clinical manifestations of cutaneous and systemic forms of mastocytosis are found separately. (See "Mastocytosis

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(cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations".)

HISTORY AND PHYSICAL EXAMINATION

Each episode of symptoms that the patient can describe

should be reviewed to determine if the signs and symptoms are consistent with mast cell activation.

Skin examination — The skin should be examined for lesions or plaques of urticaria pigmentosa, which is also called maculopapular cutaneous mastocytosis (MPCM) (picture 2 and picture 3 and picture 1). MPCM is the most common presentation in adults. Descriptions and additional images of characteristic skin lesions are presented elsewhere. (See "Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations", section on 'Skin findings and symptoms'.)

Darier's sign — If lesions of UP are detected, then the examiner may lightly rub, scratch, or stroke a small area of the affected skin. The development of erythema or urticaria over/around the lesion is called Darier's sign and is suggestive of the presence of mast cells within the lesion. Darier's sign may not be present in patients taking antihistamines. It may also be more difficult to elicit urtication from older, brown-colored, lesions. The examiner should concentrate on more recent, reddish lesions.

Skin biopsy — An experienced clinician can diagnose mastocytosis in the skin based upon the characteristic appearance of MPCM lesions. However, if there is any doubt about the nature of the lesion, a punch biopsy should be performed and evaluated with the specific histopathologic stains discussed below. Specimens should be fixed in formalin and undergo histopathologic staining with Giemsa and/or immunohistochemical staining for tryptase and KIT (also known as, CD117, the receptor for stem cell factor). These mast cells also stain-positive for chymase and carboxypeptidase A3, although these stains are not routinely performed [2]. Degranulated mast cell can be difficult to identify without these specialized stains. Techniques for identifying mast cells in tissues are presented in more detail separately. (See "Mast cells: Development, identification, and physiologic roles", section on 'Cellular identification'.) Mast cells in the skin are most easily identified with stains for tryptase and KIT (ie, CD117), which identify both normal and abnormal mast cells. Mast cells in lesions of UP may have irregular shapes, sometimes with bilobed nuclei, which may be seen on light microscopy. Infiltrating eosinophils may also be present.

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Mast cells may form small or large clusters or appear in sheets. There are four patterns of mast cell infiltrates that are observed in cutaneous mastocytosis, which only partially correlate with the type of clinical lesion [3]: ●Perivascular infiltrates in the papillary and upper dermis ●Sheet-like infiltrates in the papillary body and upper reticular dermis ●Interstitial infiltrates ●Nodular infiltrates CD25 (interleukin-2 [IL-2] receptor alpha chain) may be aberrantly expressed by a subset of skin mast cells in those with systemic disease [4].

Interpretation — Abnormal skin biopsy findings in the context of the morphologic lesion are diagnostic of cutaneous mastocytosis (CM) (table 1) [5]. However, CM should not be diagnosed based upon biopsy findings alone, without the characteristic skin lesions, because mast cells can be found around blood vessels and in telangiectasias in otherwise healthy skin. In addition, mast cell numbers may be increased in inflammatory or neoplastic skin diseases, such as psoriasis, urticaria, eczema, and dermatofibromas. There is no specific cut-off value for numbers of mast cells in the skin that is considered abnormal. In addition, skin biopsy does not provide information about systemic involvement. Analysis of cutaneous mast cells for the presence of mutations in KIT does not fulfill the diagnostic criteria and is not a standard part of the evaluation of skin biopsies, but it has been performed in investigational protocols [6-8]. Instead, KIT mutational analysis is usually performed on peripheral blood or bone marrow. (See 'KIT mutational analysis of peripheral blood' below and 'Mutational analysis' below.) Activating mutations of KIT have been implicated in the pathogenesis of both cutaneous and systemic mastocytosis, although no consistent correlation between the type of mutation and either phenotype or prognosis has been recognized. The significance of KIT mutations is reviewed separately. (See "Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations", section on 'Mutations in KIT'.)

LABORATORY STUDIES

Adult patients presenting with skin

lesions of mastocytosis almost always have systemic disease, in contrast to children with skin lesions, who usually have disease limited to skin. Therefore, evaluation for systemic disease should be strongly considered in all adults.

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Initial testing — The tests discussed in this section should be performed in all adult patients to evaluate for abnormalities due to systemic disease or organ infiltration by mast cells and to detect the presence of mast cell mediators: ●Complete blood count with differential to evaluate for cytopenias, immature or abnormal myeloid and lymphoid leukocytes, leukocytosis, polycythemia, anemia, thrombocytopenia, thrombocytosis, eosinophilia, and circulating mast cells. ●Liver function tests (including serum aminotransferases and alkaline phosphatase) to evaluate for liver involvement. ●Serum total tryptase when the patient is in his/her baseline state – Tryptase is a protease produced predominantly in mast cells, although a small amount is made by basophils and myeloid precursors as well. The presence of elevated serum concentrations of tryptase >20 ng/mL is one of the minor criteria for the diagnosis of systemic mastocytosis (SM) [9]. (See 'Diagnosis' below.) Of note, serum tryptase should be assayed when the patient is in a baseline state (ie, not immediately following an episode of symptoms) for the purposes of diagnosing mastocytosis, because elevations in mediators obtained immediately after a symptomatic episode (such as flushing or syncope) indicate mast cell activation, but do not distinguish between anaphylaxis and mastocytosis. (See 'Differential diagnosis' below.) Total serum tryptase can be measured with a commercially available assay (ImmunoCAP tryptase), which is performed at many clinical laboratories. Normal levels are between 1 and 11.4 ng/mL (some laboratories consider 15 ng/mL to be the upper limit of normal). However, the value must be >20 ng/mL to fulfill the World Health Organization's (WHO) criterion. Tryptase is usually normal in cutaneous mastocytosis (CM) and elevated in the majority of patients with systemic mastocytosis (SM). However, up to 10 percent of patients with SM (with or without urticaria pigmentosa [UP]) have tryptase levels 20 ng/mL on at least two

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occasions [15]. The absolute level of total tryptase does not predict the category of SM [16]. Aggressive mastocytosis and mastocytosis associated with hematologic malignancies can have similar elevations of tryptase as indolent systemic mastocytosis. However, mast cell leukemia (MCL) is generally associated with extremely elevated tryptase levels, sometimes >1000 ng/mL. Other laboratory abnormalities are variable. The laboratory abnormalities that may be present in different systemic forms of mastocytosis are discussed elsewhere. (See "Systemic mastocytosis: Determining the subtype of disease", section on 'C findings'.)

KIT mutational analysis of peripheral blood — The presence of a mutation in the KIT gene (which codes the receptor for stem cell factor) is one of the minor criteria for SM (table 1). All adults suspected of having SM should undergo a mutational analysis of KIT, which can be performed on peripheral blood or bone marrow (and occasionally on other tissues) [17,18]. Bone marrow lesional tissue has the highest sensitivity for detection of somatic KIT mutations due to the higher concentration of mast cell precursors and mature mast cells, and a bone marrow evaluation is the most useful means of evaluating for KIT mutations. However, analysis of peripheral white blood cells is convenient and available through at least two commercial laboratories (in the United States, Quest Diagnostics and Mayo Clinic Laboratories) [19]. One situation in which the peripheral blood KIT analysis can be helpful is the evaluation of a patient with normal or slightly elevated serum tryptase, no suggestive skin lesions, and persistent clinical suspicion for SM, as a positive result would further argue for the need for bone marrow biopsy, although a negative peripheral blood result would not necessarily rule out SM [20]. Peripheral blood KIT testing is also useful in the evaluation of monoclonal and idiopathic mast cell activation syndromes. (See "Mast cell disorders: An overview".) The tests performed by commercial laboratories for diagnosis of mastocytosis detect the most common KIT mutation (D816V) only and will miss less common mutations [19]. It is our experience that KIT mutations can be detected in peripheral blood in 30 to 50 percent of patients with SM, with the available commercial tests, while approximately 90 percent of patients with SM have detectable mutations if bone marrow is analyzed with a sensitive assay. Mutational assays using D816Vspecific polymerase chain reaction (PCR) primers have the highest sensitivity of detection and usually can detect less than 1 percent of the mutated allele in a sample, whereas sequencing-based techniques have poor sensitivity and should not be used for routine mutational analysis. However, sequencing of the entire KIT gene is recommended in patients with advanced forms of SM when KIT D816V-specific testing is negative, as this information can also inform treatment with targeting therapies [21]. If the KIT D816V mutation is detected in peripheral blood in the evaluation of an adult who presents without skin lesions, then bone marrow should be performed to evaluate for additional diagnostic criteria. If the mutation is not detected in peripheral blood (which is common in patients with low mast cell burden) and there is a high index of suspicion due to compatible clinical symptoms, then a bone marrow biopsy should be performed to obtain material for the evaluation of the KIT D816V and to look for other diagnostic criteria. (See 'Bone marrow examination' below.)

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EVALUATION OF COMMON PRESENTATIONS

Some experts have suggested the following

practical guide to evaluation based upon clinical presentation [22,23].

Urticaria pigmentosa — Systemic disease is present in most adults with urticaria pigmentosa (UP) or maculopapular cutaneous mastocytosis (MPCM). Thus, adults with MPCM should have the laboratory studies mentioned above and undergo a bone marrow examination [22]. (See 'Laboratory studies' above and 'Bone marrow examination' below.)

Symptoms related to mast cell mediators without skin lesions — In patients with this presentation, the initial laboratories mentioned previously should be performed. If tryptase levels are >20 ng/mL, we perform a bone marrow examination. Bone marrow examination may also be appropriate in selected patients with tryptase ≤20 ng/mL, such as in those with hypotensive anaphylaxis.

Unexplained severe allergic or anaphylactic reaction — Anaphylactic reactions with hypotension and without hives or angioedema, in response to Hymenoptera stings, other allergens, or unexplained, should raise the suspicion for SM. Some experts recommend a bone marrow biopsy in all such patients, as a subset of these patients may have clonal mast cell disease [24]. (See 'Differential diagnosis' below.) In addition, patients with unexplained anaphylaxis should undergo a thorough allergy evaluation if an underlying allergy seems possible from the clinical history [25]. It should be noted that some of these patients may be on scheduled antihistamines that would interfere with skin testing, but antihistamines should not be discontinued for the sole purpose of skin testing unless it is determined to be safe by an allergy specialist. The evaluation of idiopathic anaphylaxis is reviewed elsewhere. (See "Idiopathic anaphylaxis".)

WHEN TO REFER

Generalists should perform a history and physical

examination (with careful attention to the skin) and obtain the initial laboratory studies mentioned above if possible. (See 'Initial testing' above.) Further evaluation and skin biopsy usually requires specialty referral. When feasible, the following patients should be referred to an allergy/immunology, dermatology, or hematology expert with knowledge of mast cell disorders: ●Any patient suspected of having MPCM.

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●Patients with signs or symptoms suggestive of systemic disease, (eg, recurrent episodic flushing attacks with tachycardia, lightheadedness, and abdominal complaints). Note that patients can have systemic symptoms due to mediator release from cutaneous mast cells, so it is often difficult to tell if the patient has systemic disease based on symptoms alone. If there is uncertainty, it is prudent to refer. ●Patients with elevated tryptase levels (>20 ng/mL). If the patient also has symptoms of mast cell activation, a lower threshold for referral is appropriate (>11.4 ng/mL). ●Patients with recurrent unexplained anaphylaxis presenting with hypotension.

BONE MARROW EXAMINATION

Bone marrow

examination is performed to determine if abnormal mast cells are present. Certain bone marrow findings constitute the major criterion for the diagnosis of systemic mastocytosis (SM) (table 1). (See 'Major criterion' below.)

Indications for bone marrow biopsy Bone marrow biopsy and aspiration should be strongly considered in all adult patients with MPCM, even if other signs and symptoms of systemic disease are not apparent, as the incidence of systemic disease is high. In addition, patients with the symptoms or laboratory features below may be considered for work-up for SM regardless of the presence of skin lesions, particularly if there is an elevated baseline tryptase level. These symptoms and laboratory features include: ●Unexplained flushing or anaphylaxis, particularly associated with documented hypotensive episodes ●Unexplained gastrointestinal abnormalities (eg, peptic ulcer disease, malabsorption, or diarrhea) ●Unexplained peripheral blood abnormalities, such as liver function abnormalities or cytopenias ●Unexplained hepatomegaly, splenomegaly, or lymphadenopathy ●Unexplained pathologic bone fractures, osteopenia, osteoporosis, or osteosclerosis ●Systemic reactions to Hymenoptera presenting with hypotension ●The detection of a KIT D816V mutation in peripheral blood However, in patients without skin lesions or symptoms of mast cell activation, in whom the indication for bone marrow biopsy is an elevated tryptase, other nonmast cell etiologies (such as renal disease) should be explored before proceeding to bone marrow biopsy.

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In patients with systemic mastocytosis, there is a good correlation between an elevated total tryptase level and the mast cell burden in the bone marrow biopsy. A simple bone marrow biopsy with routine histologic studies is more likely to be diagnostic of mastocytosis in patients with serum tryptase levels >20 ng/mL. However, even in patients with elevated serum tryptase levels, the bone marrow may have relatively low numbers of pathologic mast cells and the disease may not be detected due to sampling of uninvolved areas, and thus the diagnosis can require some expertise [26]. Such patients should be offered referral to a center with expertise in diagnosing mastocytosis if there is a strong suspicion of SM based on the presentation [27].

Bone marrow analysis — The bone marrow examination includes an evaluation of the histology of the core sample and of aspirated cells. Both types of samples should be examined for morphologically abnormal mast cells (eg, spindle-shaped, hypogranular forms).

Histochemistry — Mast cells (both normal and abnormal) within the bone marrow core biopsy specimen are identified by immunohistochemical staining with antibodies to tryptase and/or KIT (CD117). Mast cells in other tissues stain with metachromatic dyes, such as Giemsa or toluidine blue, but mast cells in the bone marrow core sections may not, because fixation and decalcification of the specimen can interfere with these stains. In addition, degranulated mast cells may lose their metachromatic staining properties. For these reasons, bone marrow mast cells are best identified with specialized stains, including antibodies for CD117 and tryptase [28]. Stains to detect CD25 (interleukin-2 [IL-2] receptor alpha chain) and CD2 (lymphocyte function antigen-2 [LFA-2]) should also be performed, as mast cells from patients with SM can inappropriately express these surface markers, while normal or reactive mast cells do not [22,29]. Staining for CD25 can be done in histopathology sections in most hospital pathology laboratories in formalin-fixed bone marrow tissue. CD2 stains usually yield weaker results than CD25. The expression of one or both of these markers is a minor criterion for the diagnosis (see 'Diagnosis' below). The functionality of CD2 and CD25 expression is unknown, although CD2 may be involved in clustering of the mast cells. The typical phenotype in SM is an increase in mast cells that are positive for CD117, tryptase, and CD25 [30]. Normal bone marrow mast cells are round cells with small central nuclei and granulated cytoplasm and have a morphology similar to mature mast cells in other tissues. In patients with SM, bone marrow mast cells often have a spindle or fusiform shape, cytoplasmic projections, eccentric, oval nuclei, hypogranular cytoplasm with focal accumulation of granules with or without granule fusion, and a high nucleus to cytoplasm ratio [31]. Mast cells in SM may also appear immature (multilobated or clefted nuclei, hypogranulated). Paratrabecular and perivascular localization is common, with thickened bony trabeculae, although interstitial infiltrates are also observed. The major criterion for SM is the presence of multifocal aggregates of spindle-shaped mast cells that contain at least 15 mast cells per aggregate. Smaller aggregates with round mast cells of normal morphology, as well as diffuse increases of mast cells, may also be observed (figure 1 and

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picture 4). One of the minor criteria is the presence of mast cells with a spindle-shape or atypical morphology that comprise >25 percent of the mast cells in the bone marrow aspirate or in the infiltrate (either in aggregated or interstitially distributed mast cells) on a bone marrow section. In healthy individuals, bone marrow mast cells represent less than 1 percent of all nucleated cells [32]. In patients with SM, the bone marrow ranges from normocellular to markedly hypercellular [31,33]. The clinical significance of the marrow burden of mast cells is unclear, but advanced forms of disease, such as aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL), are associated with extensive bone marrow infiltration. Morphologically immature bone marrow mast cells comprising more than 20 percent of cells in a nonspicular area of the bone marrow smear or >10 percent in peripheral blood is diagnostic for MCL [1,31]. (See "Systemic mastocytosis: Determining the subtype of disease", section on 'Mast cell leukemia'.)

Flow cytometry — Analysis of the bone marrow aspirate by flow cytometry (ie, fluorescence activated cell sorting [FACS]) should be performed if possible. Mast cells make up less than 1 percent of cells in bone marrow aspirate samples and are identified as a CD117high immunoglobulin E (IgE)positive population [29,34,35]. Acquisition of at least 1 million cell events is preferred to capture enough mast cells. Expression of CD2 and CD25 should be assessed [34]. CD2 expression may be variable or absent in advanced disease, whereas CD25 is more reliable. Doublepositive cells expressing both KIT (CD117) and CD25 are considered aberrant mast cells, which fulfills a World Health Organization (WHO) minor criteria.

Mutational analysis — Analysis for mutations in the KIT gene should be performed on bone marrow aspirate samples. Enrichment for mast cells can increase the sensitivity of the test but is not routinely done. Whole cell sequencing-based methods have a low sensitivity and frequently yield false-negative results. The most common KIT mutation is an adenine-to-thymine base substitution (A>T) at nucleotide position 2468, which results in an aspartic acid-to-valine change in the protein. This is called the Asp816Val or D816V mutation. D816V KIT mutational analysis is commercially available in the United States, and it is also performed at several academic centers [27]. The assay of choice is a polymerase chain reaction (PCR) assay using a mutationspecific primer with a sensitivity of 25 percent of the mast cells in bone marrow sections, bone marrow aspirate, or other extracutaneous tissues. ●Mutational analysis of KIT (the gene for c-kit) showing a codon 816 mutation (commonly Asp816Val) in bone marrow, peripheral blood, or extracutaneous organs. ●Bone marrow or other extracutaneous mast cells expressing the surface markers CD2, CD25, or both.

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●Serum tryptase levels (when the patient is in a baseline state) >20 ng/mL. Values >11.4 ng/mL are considered elevated in most diagnostic laboratories. However, the WHO criterion is defined as a value >20 ng/mL. Of note, the serum tryptase criterion does not apply to patients with an associated clonal hematologic nonmast cell lineage disorder (AHNMD), since tryptase in such patients can originate from myeloid precursor cells. Once a patient has been diagnosed with SM, further evaluation is needed to determine the category of disease present. This evaluation is presented separately. (See "Systemic mastocytosis: Determining the subtype of disease".)

DIFFERENTIAL DIAGNOSIS

Mastocytosis can be

confused either clinically or histologically with a variety of disorders, although application of the World Health Organization's (WHO) criteria to pathologic samples confirms or rules out the diagnosis of systemic mastocytosis (SM).

Disorders with similar clinical manifestations — Mastocytosis is a histopathologic and genetic diagnosis and should not be based solely on clinical presentation. In addition to mastocytosis, there are three other disorders of mast cell activation with overlapping clinical and pathologic features (table 3): ●Monoclonal mast cell activation syndrome – The term "monoclonal mast cell activation syndrome" (MMAS) has been accepted by a consensus panel as appropriate for patients who experience episodes of mast cell activation symptoms, such as recurrent flushing, gastrointestinal cramping, and hypotension, and meet one or two of the minor diagnostic criteria for SM (KIT D816V or aberrant CD25 expression on mast cells), but do not fully meet diagnostic criteria for SM. (See 'Minor criteria' above.) Patients with MMAS may present with recurrent unexplained anaphylaxis or hypotensive reactions to Hymenoptera stings. Baseline serum tryptase values are normal or mildly increased. Bone marrow findings do not meet the full criteria for SM, although some cells express the aberrant markers CD2 and CD25 and/or KIT mutations. MMAS is reviewed in greater detail separately. (See "Mast cell disorders: An overview".) ●Idiopathic mast cell activation syndrome – "Idiopathic mast cell activation syndrome" (IMCAS) is a term proposed to describe an idiopathic disorder in which patients present with recurrent episodes of signs and symptoms that are consistent with mast cell activation and affect at least two organ systems (ie, cutaneous, gastrointestinal, cardiovascular, respiratory, or naso-ocular) [44]. Of note, the signs and symptoms should not fulfill criteria for anaphylaxis (table 4). If the criteria for anaphylaxis are met, then the diagnosis of idiopathic anaphylaxis is more appropriate. In addition, elevations in mast cell mediators in serum or urine should be documented as follows:

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•A serum tryptase level obtained within four hours of the suspected mast cell activation episode showing a value greater than Baseline + 0.2 x baseline + 2 ng/mL is preferred as a proof of mast cell activation [45]. •Elevations in a 24-hour urine N-methylhistamine or prostaglandin D2 (PGD2) (or its metabolite 11beta-prostaglandin F2-alpha [PGF2-alpha]) should be demonstrated on at least two occasions during a symptomatic period. However, these mediators (especially PGD2 and PGF2-alpha) are less specific to mast cell activation. Finally, patients should exhibit a favorable clinical response to medications that counteract mast cell mediators, including H1 and H2 antihistamines, antileukotriene medications, or oral cromolyn sodium. Mast cell activation syndrome (MCAS) can be further classified into clonal and nonclonal subtypes. MCAS is reviewed in more detail separately. (See "Mast cell disorders: An overview".) ●Anaphylaxis – Clinical criteria for the diagnosis of anaphylaxis have been defined (table 4). Patients with anaphylaxis may have elevations of serum beta tryptase during (or for several hours after) acute events. In contrast, patients with SM have persistent elevations in total tryptase in the baseline state, which increase further during anaphylaxis. We suggest that patients with Hymenoptera anaphylaxis should be evaluated with a baseline serum tryptase. If the tryptase is greater than 11.4 ng/mL, or if the patient experienced hypotensive syncope (regardless of the tryptase level), then an evaluation for SM should be performed. Idiopathic anaphylaxis is a diagnosis of exclusion. (See "Idiopathic anaphylaxis".) During an anaphylactic event (in a patient without SM), beta tryptase rises and, if sufficiently high, can result in elevations of total tryptase. Beta tryptase levels >1 ng/mL and a ratio of total to mature of 20, whereas it is often 20 ng/mL) in SM. If there is uncertainty about the skin lesions, skin biopsy should be performed. A test to detect mutations in the KIT (the gene coding for the receptor for stem cell factor, an essential mast cell growth factor) can be obtained on a sample of peripheral blood, although there are limited clinical scenarios in which this test is useful. (See 'Laboratory studies' above.) ●In most cases, referral to an allergy/immunology, dermatology, or hematology expert with knowledge of mast cell disorders will be needed for definitive diagnosis. (See 'When to refer' above.)

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●Bone marrow biopsy and aspiration is indicated in adult patients with MPCM, an elevated serum tryptase level, or signs and symptoms of systemic involvement. Most adult patients require bone marrow evaluation. Bone marrow sections should be stained for tryptase, CD117 and CD25, and aspirate analyzed for D816V KIT mutation. (See 'Bone marrow examination' above.) ●In CM, laboratory studies are typically normal and the diagnosis is confirmed by skin biopsy findings (table 1). Bone marrow studies are normal. (See 'Cutaneous mastocytosis' above.) ●In SM, abnormalities include a persistently elevated total tryptase (>20 ng/mL), characteristic bone marrow findings, and variable other findings of systemic involvement. The diagnosis of SM requires either the presence of the major criterion and one of the minor criteria, OR three of the minor criteria (in the absence of the major criterion) (table 1). (See 'Systemic mastocytosis' above.) ●The differential diagnosis of mastocytosis is broad. Disorders that can mimic mastocytosis may be divided into those with similar clinical manifestations, those with similar bone marrow findings, and other causes of elevated tryptase. (See 'Differential diagnosis' above.)

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Treatment and prognosis of cutaneous mastocytosis uptodate.com/contents/treatment-and-prognosis-of-cutaneous-mastocytosis/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Apr 03, 2020.

INTRODUCTION

Cutaneous mastocytosis describes a group of disorders

characterized by the presence of excessive numbers of mast cells in the skin. Patients with cutaneous mastocytosis do not fulfill diagnostic criteria for systemic mastocytosis and show no evidence of organ involvement other than the skin. Forms of cutaneous mastocytosis include three variants recognized by the World Health Organization (WHO) [1]: ●Maculopapular cutaneous mastocytosis (MPCM) or urticaria pigmentosa (UP) with two variants – Monomorphic and polymorphic [2] ●Diffuse cutaneous mastocytosis ●Solitary cutaneous mastocytoma There are two additional disorders about which there is some controversy surrounding classification: ●Telangiectasia macularis eruptive perstans (TMEP) – This variant is rarely seen without MPCM, and the 2016 classification discontinued use of the term TMEP [2] ●Nodular mastocytosis There are no therapies that change the natural course of cutaneous mastocytosis, although the prognosis in children is generally good. The treatment and prognosis of the different forms of cutaneous mastocytosis will be presented here. The clinical manifestations, classification, and diagnosis of cutaneous mastocytosis are reviewed separately. (See "Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations" and "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults".) The specific mediators released from mast cells and the symptoms caused by these mediators are reviewed separately. (See "Mast cells: Surface receptors and signal transduction" and "Pathophysiology of anaphylaxis".)

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GENERAL MEASURES

The management of cutaneous

mastocytosis begins with practical measures, such as the use of lukewarm water for bathing, air conditioning during hot weather, and avoidance of triggers for mast cell degranulation. All patients/caretakers should be periodically trained in how to recognize and treat anaphylaxis and should carry an epinephrine autoinjector at all times.

Preparation for treating possible anaphylaxis — Children with extensive skin involvement or elevated serum baseline tryptase may be at increased risk for anaphylaxis from a variety of triggers [3,4], although the risk of anaphylaxis in children with cutaneous mastocytosis is much smaller than that of adult patients with systemic disease (9 versus 49 percent cumulative incidence according to one series) [5]. One series found that children with tryptase levels >6 ng/mL are more likely to require daily antimediator treatment to manage symptoms and prevent severe episodes, and those with levels >15.5 ng/mL were at risk for hospitalization due to severe symptoms [3]. Epinephrine is the primary treatment for anaphylaxis. Mastocytosis patients or their caretakers should have at least two doses of epinephrine in a self-injectable form available at all times for treatment of possible anaphylaxis, since a single dose may be inadequate to counteract a massive release of mediators. Clinicians should also make patients and caregivers aware of the importance of lying down with the legs elevated during anaphylaxis involving hypotension. Hypotension during anaphylaxis is more common than asthma or laryngeal edema in patients with mastocytosis, and ensuring that patients are placed in this position as soon as possible is an important therapeutic intervention. The treatment of anaphylaxis in adults and children is discussed elsewhere. (See "Anaphylaxis: Emergency treatment".) Mastocytosis patients should consider wearing a medical identification bracelet and should carry an anaphylaxis emergency action plan or wallet card that identifies the condition and describes the proper treatment of anaphylaxis (Anaphylaxis Emergency Action Plan – English) (Anaphylaxis Emergency Action Plan – Spanish) (Anaphylaxis Emergency Action Plan – Wallet card).

Trigger avoidance — Patients should avoid exposures that trigger or aggravate their symptoms, to the extent possible. These exposures may include heat, humidity, cold, emotional stress, exercise, alcohol, and lack of sleep. In infants and young children, irritability (fussing, whining, anger), overexcitement, fever, teething, and skin rubbing can induce symptoms [3]. Spicy foods, such as those containing capsaicin, may cause flushing, nasal congestion, and gastrointestinal symptoms in some patients. Patients should avoid only those triggers that bother them. Empiric avoidance of these factors by all patients is not necessary.

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Problematic medications — There are various medications that may cause mast cell activation in patients with either cutaneous or systemic mastocytosis. As a precaution, these medications should be avoided when possible, unless the patient's tolerance for a specific agent is already known. Potentially problematic medications include the following: ●Opioid analgesics, such as morphine and codeine [6]. ●Vancomycin [7,8]. ●Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), including ketorolac. ●Radiocontrast agents. ●Certain muscle relaxants – Succinylcholine is more likely to cause immunoglobulin E (IgE)mediated anaphylaxis than nondepolarizing agents, such as pancuronium or vecuronium. In addition, atracurium can cause direct mast cell activation, and rocuronium has been implicated as an etiology of anaphylactic reactions [9]. Despite the potential for problems with the medications listed above, the majority of patients do tolerate these drugs. A study reviewed anesthetic management of 22 children with mastocytosis (14 with cutaneous and 8 with systemic disease) [10]. Most of these patients were receiving medications to counteract mast cell mediators, which were continued before and after the procedures, although other medications were administered at the discretion of the anesthesiologist. The study found that the perioperative courses were uncomplicated and without serious adverse events. Another retrospective series found that among 45 children with mastocytosis, most of whom had cutaneous disease, general anesthesia was usually well-tolerated [11].

Medications that are usually tolerated — Most patients tolerate acetaminophen, local anesthetics, and benzodiazepines. Fentanyl appears to be a less potent mast cell degranulator than morphine in equimolar concentrations in vitro, although fentanyl has not been specifically studied in patients with mastocytosis. If anesthesia is required in a patient with no previous history of exposure to anesthetics, certain agents, such as propofol, etomidate, ketamine, fentanyl, cisatracurium, and pancuronium, are recommended over others [12]. A volatile anesthetic, such as sevoflurane, can be used to maintain anesthesia. However, allergic reactions to any medication can develop without precedent, and the clinician must be prepared to handle any such reaction.

Premedication before anticipated trigger exposure — Patients can be premedicated in advance of an anticipated exposure to a possible or known trigger. The approach for patients with cutaneous mastocytosis is similar to that

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for those with systemic mastocytosis and is presented elsewhere. Children with diffuse cutaneous mastocytosis can be especially sensitive to all provoking factors and vaccinations, and exposure can trigger exacerbations and bullous eruptions. Premedication is recommended for procedures involving general anesthesia or radiocontrast injection and before the administration of vaccines. We suggest the combination of prednisone (up to 0.5 to 1 mg/kg), as well as both H1 and H2 antihistamines.

Treatment of coexistent allergic disease — Patients with mastocytosis may have concomitant allergic diseases, including allergic rhinitis, asthma, food allergies, and drug allergies [13-16]. However, the incidence of allergic disease in patients with mastocytosis does not appear to be increased, compared with the general population. In most cases, these conditions should be managed as they would be in patients without mastocytosis. (See "Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations" and "Pharmacotherapy of allergic rhinitis" and "An overview of asthma management".) The administration of subcutaneous immunotherapy for respiratory allergies warrants careful consideration in patients with mastocytosis, because they are at greater risk for systemic reactions and anaphylaxis as a consequence of the therapy itself.

Hymenoptera venom hypersensitivity — Patients with systemic mastocytosis are at increased risk for anaphylaxis in response to Hymenoptera stings, compared with patients who are sensitive to these venoms but do not have mastocytosis. Patients with elevated tryptase levels are at greater risk for anaphylaxis [3,17]. Less is known about the risk of sting-induced anaphylaxis in children with cutaneous mastocytosis. Patients with IgE-mediated systemic reactions to Hymenoptera stings should be offered venom immunotherapy to reduce the risk of anaphylaxis upon subsequent stings. (See 'Treatment of coexistent allergic disease' above.) Despite the risk of systemic allergic reactions to immunotherapy, venom immunotherapy has been shown to be beneficial for patients with cutaneous (or systemic) mastocytosis who have evidence of venom-specific IgE (ie, positive skin or IgE tests to Hymenoptera venoms) [16]. Therefore, venom immunotherapy is recommended for patients with cutaneous or systemic mastocytosis, who also have a history of systemic symptoms following a known or suspected sting, and evidence of venomspecific IgE. The evaluation and management of Hymenoptera venom reactions in patients with mastocytosis are discussed separately. The use of omalizumab, anti-IgE, has helped during immunotherapy to provide maintenance to patients with severe initial reactions and reactions with build-up of immunotherapy [18]. The optimal approach in children with cutaneous mastocytosis and Hymenoptera reactions is not known, and management should be guided by recommendations for children with Hymenoptera allergy but without mastocytosis. (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Indications and patient selection'.)

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PHARMACOLOGIC THERAPIES

The

pharmacologic treatment of cutaneous mastocytosis is comprised of medications to prevent mast cell-mediator release and when mediator release does occur, to reduce the resulting symptoms. There are no large randomized, controlled trials evaluating different therapies in cutaneous mastocytosis, and recommendations are based upon extrapolation from allergic diseases, small series, and expert opinion.

Diffuse cutaneous disease and urticaria pigmentosa — For both children with cutaneous disease and adults with urticaria pigmentosa (UP), oral antihistamines are administered to control itching and flushing [19]. Oral sodium cromolyn is helpful for patients with gastrointestinal symptoms (which are reported by over one-third of patients with cutaneous mastocytosis).

Antihistamines — Both H1 and H2 antihistamines are useful in the treatment of cutaneous mastocytosis. H1 antihistamines are administered to prevent flushing and itching. H2 antihistamines are helpful in controlling abdominal pain, heartburn, cramping, and/or diarrhea and may enhance the antipruritic effects of H1 antihistamines. ●Commonly used H1 antihistamines (adult dosing) include oral cetirizine (10 mg daily), fexofenadine (180 mg daily), loratadine (10 mg daily), levocetirizine (5 mg daily), desloratadine (5 mg daily), or hydroxyzine (25 mg every six hours) [20]. Each of these agents may be used in children at age/weight-appropriate doses. In some patients, a combination of two or more H1 antihistamines may provide better symptom control than the use of a single agent. Some patients may benefit from twice daily dosing of nonsedating antihistamines. ●H2 antihistamines (adult dosing) include oral famotidine (20 mg twice daily) and cimetidine (400 mg twice daily) [20]. Famotidine may be used in children at age/weight-appropriate doses. ●Ketotifen, which has been reported to have both mast cell-stabilizing and H1 antihistamine properties, is used to control mast cell activation and pruritus and can be used as a first-line agent where available, although it can be quite sedating for some patients. This drug is not available in oral form in the United States. The adult dose is 2 to 4 mg orally every 12 hours [21]. Ketotifen may be used in children at age/weight-appropriate doses. A double-blind, placebo-controlled trial showed no advantage of ketotifen over hydroxyzine in pediatric mastocytosis [22].

Cromoglycates — Anecdotal evidence suggests that topical cromoglycate ointments may be symptomatically effective for the diffuse skin disease seen in some children with mastocytosis, as well as in adults with UP, although formal studies have not been performed [3,23]. Cromoglycates have been shown to have mast cell-stabilizing properties in vitro, and topical preparations have been studied in the treatment of atopic dermatitis [24,25].

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Cromoglycate ointments at strengths ranging from 0.21 to 4 percent have been used in children with mastocytosis [22]. One of the authors (MC) has cromolyn sodium (powder) compounded into hydrated petrolatum to generate a 4 percent ointment. This is applied twice daily to the affected areas to alleviate pruritus and reduce flares. Similar products are available commercially in Europe. Cromoglycates have an excellent safety record in the treatment of pediatric asthma and other diseases, as they are not believed to be systemically absorbed to a significant degree. However, these agents do not cause permanent regression of the skin lesions or alter the natural history of the disease. In infants with diffuse skin involvement, resolution of pruritus and bullae formation with topical cromoglycates can be seen within three months, although this may vary depending upon severity. Use of the ointment is then tapered to once daily for another month and then continued at the lowest dose that controls symptoms. Adverse effects have not been reported with this therapy. Cromolyn can also be administered orally (Gastrocrom, 200 mg up to four times daily in patients 13 years or older or 100 mg up to four times daily in patients ages 2 to 12 years) to treat gastrointestinal symptoms caused by mast cell-mediator release, which are present in 20 to 30 percent of patients with cutaneous disease. This medication is generally mixed into a glass of water and taken one hour before meals and then before bed. We typically begin with one or two doses daily and increase gradually to three to four times daily. Some patients do not tolerate this medication because of bloating, cramping, and diarrhea.

Leukotriene-modifying agents — Antileukotriene drugs (eg, montelukast, zafirlukast, or zileuton) may be added in patients with symptoms, such as flushing, itching, abdominal cramping, and recurrent anaphylaxis that are suboptimally controlled by H1 and H2 antihistamines and cromoglycates. These medications rarely cause mood-related side effects, which should be discussed before initiating the therapy. Monitoring of liver function tests is needed with zafirlukast.

Treatment of refractory symptoms — In selected patients with symptoms refractory to cromoglycates, antihistamines, and leukotriene-modifying agents, aspirin and limited use of topical corticosteroids may be helpful. ●Aspirin (in adults only) (up to 325 mg four times daily) may be administered to control flushing, provided the patient is known to tolerate nonsteroidal anti-inflammatory drugs (NSAIDs). This should be administered with caution, because NSAIDs can trigger mediator release in some patients and may precipitate peptic ulcer disease. Techniques for safely administering aspirin to patients with mastocytosis are reviewed separately. Aspirin should not be used concomitantly with other NSAIDs. (See "Advanced systemic mastocytosis: Management and prognosis".) ●Short-term use of topical corticosteroids may be useful for temporarily decreasing the number of skin mast cells and reducing refractory symptoms of mediator release. However, the benefit is shortlived, and this should not be considered a form of long-term management because of the side effects associated with chronic glucocorticoid use, including adrenal suppression if they are applied

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to large areas. Glucocorticoid creams or ointments may be applied to the skin of children older than two years. For areas 10 percent BSA, some experts recommend that the topical corticosteroid be diluted one part to three parts and applied for three to six weeks [26]. ●Psoralen-ultraviolet A therapy (PUVA) or narrow band UVB decreases the number of mast cells and controls pruritus that cannot be managed with antihistamines alone [27-30]. However, long-term use is associated with an increased risk of skin cancer, and the skin lesions usually recur after therapy is stopped. Phototherapy may be considered for temporary symptomatic relief in patients with diffuse cutaneous mastocytosis with extensive skin involvement refractory to medical management. ●The oral multikinase inhibitor midostaurin (PKC412) appears to reduce skin lesions in patients with indolent systemic mastocytosis and may be similarly useful in cutaneous mastocytosis, although trials have been focused on advanced forms of systemic disease with associated hematopathology. (See "Advanced systemic mastocytosis: Management and prognosis", section on 'Midostaurin'.)

Therapies that are not recommended — With adult forms of UP, several forms of therapy have been used to decrease the number of mast cells in the skin. These therapies provide only temporary relief, do not affect the development of systemic disease, and are associated with side effects. Thus, they are not recommended, although they are included here because their use is a common source of inquiries: ●Systemic glucocorticoids are not recommended for routine management of skin lesions in patients with cutaneous mastocytosis, although brief courses may be considered to control severe symptoms during acute flares, especially in bullous outbreaks of diffuse cutaneous mastocytosis. ●Mast cell cytoreductive therapies, including imatinib, are not indicated in patients with disease limited to skin.

Cutaneous mastocytomas — Physical irritation of the mastocytoma lesion should be avoided, as it may lead to generalized symptoms of mediator release, such as flushing, urticaria, and wheezing. Surgical removal of mastocytomas is potentially curative if the lesion is resectable, although this is usually not necessary unless patients suffer from uncontrollable symptoms due to mediator release. Mastocytomas rarely recur.

Pharmacotherapy — Oral antihistamines are helpful for symptoms caused by mediator release, as with other forms of cutaneous mastocytosis. (See 'Antihistamines' above.) Localized application of topical corticosteroids may be beneficial in patients with cutaneous mastocytomas who experience local or generalized symptoms. We suggest a medium-to-high potency preparation initially, applied under an occlusive dressing for 7 to 10 days. (See "Topical

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corticosteroids: Use and adverse effects".)

MONITORING

Yearly monitoring is appropriate for children with cutaneous

mastocytosis and stable symptoms. A complete blood count (CBC) with differential, chemistry panel including alkaline phosphatase, and serum tryptase level are generally sufficient. If the serum tryptase level is found to be consistently >20 ng/mL or if there is an unexplained persistent abnormality in the CBC with differential, hepatomegaly or splenomegaly, or unexplained lymphadenopathy, an evaluation for systemic mastocytosis should be considered. In all patients who experience onset of skin lesions in adulthood, an evaluation for systemic work-up with a bone marrow biopsy and aspiration should be considered. (See "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults".)

PROGNOSIS

The prognosis of cutaneous forms of mastocytosis is related to

the age at presentation. The presence of kit mutations in lesional skin samples obtained from children with cutaneous mastocytosis has not been found to provide useful prognostic information and is essentially a research tool, but the presence of the KIT D816V mutation in the skin biopsies has been associated with an increased risk for progression to systemic forms [31]. The monomorphic variant of the maculopapular lesions has a prognostic value in children, since children with this presentation have a tendency to progress to systemic mastocytosis [2].

Infants and young children — The prognosis is excellent for children with cutaneous forms of mastocytosis who have onset of skin lesions within the first two years of life, because spontaneous resolution is common after several years (usually before the onset of puberty) [32]. ●Mastocytomas in children usually involute spontaneously after several years. ●The lesions of urticaria pigmentosa (UP) in children resolve during adolescence in over 50 percent of patients, with fading or improvement of the lesions in most of the remaining patients. Overall, more than 80 percent of children with cutaneous mastocytosis experience spontaneous resolution [33,34]. The remaining children may have persistent cutaneous disease or may progress to systemic forms of the disease. ●In a series of 15 patients with onset of mastocytosis in childhood, complete regression of cutaneous findings and symptoms occurred in 10 (67 percent) [33]. Of the remaining 5 patients, 3 had major and 2 had partial regression. Three of those with persistent disease underwent bone marrow examinations and 1 (7 percent of the group) was found to have systemic mastocytosis.

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●In a large retrospective series of 1747 pediatric patients (published between 1950 and 2014), the disease regressed or stabilized 94 percent after variable periods of follow-up (1.5 to 55 years) [34]. Aggressive forms of systemic disease (mast cell leukemia or mast cell sarcoma) developed in 3 percent and ultimately proved fatal. Three of these patients also developed germ cell tumors. These findings underline the need for continued monitoring in patients whose symptoms do not completely resolve. Risk factors for the development of systemic disease include [2]: ●Late onset of skin lesions (beyond two years of age) ●Monomorphic variant ●Persistence of skin lesions beyond adolescence ●Presence of unexplained hepatomegaly, splenomegaly, or lymphadenopathy ●Abnormal blood counts (to detect anemia, leukocytosis, leukopenia, presence of blast forms, or abnormal numbers of platelets) Evaluation of patients for possible systemic disease is reviewed in detail elsewhere. (See "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults".)

Older children and adults — Cutaneous mastocytosis that develops after the age of two years or in adulthood tends to persist. Approximately 90 percent of adult patients with skin lesions have evidence of systemic disease at the time of diagnosis, with the majority belonging to the category of indolent systemic mastocytosis. Rare cases of progression of pediatric-onset cutaneous disease to aggressive forms of mast cell disease such as mast cell sarcoma and mast cell leukemia have been reported [35,36]. (See "Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations".)

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mast cell disorders".)

SUMMARY AND RECOMMENDATIONS ●There are no therapies that alter the natural course of cutaneous mastocytosis or urticaria pigmentosa (UP), and management consists of avoiding triggers of mast cell degranulation and pharmacotherapy for symptomatic relief. (See 'Introduction' above.)

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●For patients with itching or flushing due to diffuse cutaneous involvement or UP, we suggest H1 antihistamines as initial therapies (Grade 2C). Antihistamines may be administered on a scheduled or as-needed basis, depending upon symptom frequency. We typically begin treatment with nonsedating antihistamines and reserve sedating agents for refractory symptoms or as-needed use. Cromoglycate ointments may also help control cutaneous disease. (See 'Antihistamines' above and 'Cromoglycates' above.) ●For patients with gastrointestinal symptoms, such as abdominal pain, heartburn, cramping, and/or diarrhea, we suggest H2 antihistamines and/or oral cromolyn as initial therapies (Grade 2C). (See 'Antihistamines' above and 'Cromoglycates' above.) ●For patients with flushing, itching, or abdominal symptoms despite the above measures, we suggest the addition of an antileukotriene agent (Grade 2C). (See 'Leukotriene-modifying agents' above.) ●The management of isolated cutaneous mastocytomas involves avoiding physical contact or rubbing of the lesion(s), as this causes mediator release and systemic symptoms. Systemic symptoms are managed primarily with antihistamines. Surgical removal is rarely necessary, unless the patient experiences uncontrollable systemic symptoms. (See 'Cutaneous mastocytomas' above.) ●The prognosis for young children with cutaneous mastocytosis is excellent, because the majority will experience spontaneous resolution before puberty. However, such children should be followed to assure that symptoms have stabilized or resolved. In contrast, cutaneous disease that first develops after two years of age tends to be persistent, and many patients will develop systemic forms of mastocytosis. (See 'Prognosis' above.)

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Systemic mastocytosis: Determining the subtype of disease uptodate.com/contents/systemic-mastocytosis-determining-the-subtype-of-disease/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Oct 17, 2019.

INTRODUCTION

Mastocytosis describes a group of disorders in which

pathologic mast cells accumulate in tissues. In the 2016 revisions of the World Health Organization's classification of tumors of the hematopoietic and lymphoid tissues, "mastocytosis" was removed as one of the subtypes under the major category of "myeloproliferative neoplasms" and is classified as its own major category [1]. In systemic mastocytosis (SM), mast cells infiltrate extracutaneous tissues. Once the diagnosis of SM has been reached, the subtype (variant) of disease must be determined, as treatment and prognosis differ for each disorder. Topics related to other aspects of mastocytosis are found separately: ●(See "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults".) ●(See "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in children".) ●(See "Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations".) ●(See "Advanced systemic mastocytosis: Management and prognosis".)   ●(See "Indolent and smoldering systemic mastocytosis: Management and prognosis".)

SUBTYPES OF SYSTEMIC MASTOCYTOSIS

The World Health Organization's classification system

defines five subtypes of systemic mastocytosis (SM) (table 1) [1,2]: ●Indolent systemic mastocytosis (ISM) ●Smoldering systemic mastocytosis (SSM) ●Aggressive systemic mastocytosis (ASM) ●Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) ●Mast cell leukemia (MCL) Each subtype of SM is distinguished by various features. (See 'Determining the subtype' below.)

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EVALUATION Basic evaluation — The basic evaluation of all patients with systemic mastocytosis (SM) should include the following: ●Laboratory studies, including a complete blood count with differential, chemistries with liver and renal function, albumin, calcium, lactate dehydrogenase, serum tryptase level, and beta-2 microglobulin. ●Bone marrow aspirate and biopsy should be sent for pathologic review, immunophenotyping by immunohistochemistry (for CD25, tryptase, and the receptor for stem cell factor, KIT [also known as CD117]) and/or flow cytometry (for CD117, CD25, and CD2), and KIT mutational analysis (preferably on bone marrow aspirate cells). If well-differentiated SM is suspected, CD30 staining is helpful, as mast cells in this variant do not express CD25. The KIT D816V mutation should be assessed by a sensitive technique, such as polymerase chain reaction employing mutation-specific primers, before concluding that it is negative [3]. Metaphase cytogenetics should be performed in patients with suspected coexistent hematologic disease [4]. ●Fluorescence in situ hybridization for cysteine-rich hydrophobic domain 2 deletion should be performed to detect Fip1-like1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) fusion gene in patients with a suspected chronic myeloid neoplasm with eosinophilia (chronic eosinophilic leukemia)/myeloproliferative hypereosinophilic syndrome. These patients can have increased numbers of loosely scattered, atypical mast cells in the bone marrow and an increased serum tryptase level but is not considered a World Health Organization subtype of mastocytosis. Also, it is very rare for the FIP1L1-PDGFRA fusion to be found in tandem with the KIT D816V mutation. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".) ●Bone densitometry (T score by dual-energy X-ray absorptiometry) to evaluate for bone loss, since mastocytosis is a risk factor for osteoporosis. Individuals with bone pain should have radiographs to evaluate for fracture or a skeletal survey. Although not a standard component of the evaluation, combined positron emission tomography/computed tomography (CT) may help to further assess patients found to have lytic lesions on other imaging studies. In most cases, some of these studies will have been obtained in order to make the diagnosis of SM. Interpretation of abnormalities in these tests is reviewed separately. (See "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults", section on 'Laboratory studies' and "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults", section on 'Bone marrow examination'.)

Advanced testing — Depending on the clinical presentation, the following additional studies may be indicated:

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●Abdominal imaging, such as ultrasound or CT scan in patients suspected of having systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), aggressive systemic mastocytosis (ASM), or mast cell leukemia (MCL). Abdominal CT is also indicated in patients with abnormal blood counts (suggestive of an AHN), palpable hepatomegaly, splenomegaly, or lymphadenopathy on examination and in those with a moderate or higher mast cell burden (>30 percent, consistent with smoldering systemic mastocytosis [SSM]) or tryptase level that is >100 ng/mL. ●Gastrointestinal endoscopy with biopsies in patients with gastrointestinal signs/symptoms. ●Next-generation sequencing myeloid mutation panels in patients with suspected ASM, MCL, and SM-AHN to evaluate for additional molecular abnormalities (eg, TET2, SRSF2, ASXL1, RUNX1, CBL) that may impart further prognostic information [5-7]. Such testing could also be considered in SSM. Mutations in SRSF2, ASXL1, RUNX1, and DNMT3A have been shown to have poorer prognostic significance in SM [7]. ●Biopsy of enlarged lymph nodes is not routine, although it can be helpful in specific situations. As an example, in patients with suspected SM-AHN, lymph node biopsy may confirm and identify the hematologic neoplasm subtype. Similarly, if a patient with SM-AHN has lymphadenopathy causing local signs/symptoms of disease, biopsy would be helpful in determining which process is causing symptoms in that individual. ●Liver biopsy should be considered in patients with signs of liver dysfunction, such as elevated transaminases or bilirubin, ascites, or portal hypertension, if there is doubt about whether liver disease is caused by mastocytosis or another entity.

Evaluation for organ enlargement or dysfunction — All patients with SM should be evaluated for B and C findings. B findings refer to significant organ involvement without organ dysfunction. C findings denote organ dysfunction due to excessive mast cell infiltration. C findings are associated with aggressive disease and a poorer prognosis.

B findings — B findings refer to signs of significant organ involvement (manifest as enlargement due to mast cell infiltration) without organ dysfunction and are a marker of increased mast cell burden [8]. B findings are not common in patients with indolent systemic mastocytosis (ISM) but may be found in those with high mast cell burden. The presence of two or more B findings is used to distinguish SSM from ISM. Patients with ASM may have B findings, but unlike SSM or ISM, they will also have at least one marker of organ dysfunction related to the organ with mast cell infiltration (C findings). (See 'C findings' below.) B findings include the following (table 1) [9]:

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●Infiltration of bone marrow, such that mast cells comprise >30 percent of cells in bone marrow biopsy sections and/or serum tryptase is >200 ng/mL. ●Hypercellular bone marrow with loss of fat cells or discrete signs of myelodysplasia or myeloproliferation (but insufficient to diagnose myelodysplastic syndromes or other myeloproliferative neoplasms), normal blood counts, or a mild cytopenia without progression. ●Extramedullary involvement defined as one or more of the following: •Palpable hepatomegaly without ascites or other signs of liver impairment •Palpable lymphadenopathy or visceral node enlargement (>2 cm) found on ultrasound or CT •Palpable splenomegaly without hypersplenism

C findings — C findings denote organ function impairment due to excessive mast cell infiltration and are associated with aggressive disease and a poorer prognosis. They are absent in patients with ISM and SSM. The presence of at least one C finding is required for the diagnosis of ASM. In addition, C findings may be observed in MCL and SM-AHN. C findings include [9]: ●Cytopenias due to bone marrow infiltration by mast cells, as defined by one or more of the following [10]: •Absolute neutrophil count 28 days: Evaluation and management", section on 'Purulent/fluctuant SSTI'.)

DEFINITIONS

Skin abscesses can be differentiated from folliculitis, furuncles,

and carbuncles as follows: ●Folliculitis – Folliculitis is a superficial bacterial infection of the hair follicles with purulent material in the epidermis (picture 1). ●Furuncle – A furuncle is a well-circumscribed, painful, suppurative inflammatory nodule involving hair follicles that usually arises from preexisting folliculitis. A furuncle can occur at any site that contains hair follicles, especially in regions that are subject to friction and maceration (eg, face, neck, axillae, groin, thighs, and buttocks). The lesion may extend into the dermis and subcutaneous tissues and often serves as a nidus for cellulitis and skin abscess. ●Carbuncle – A carbuncle is a coalescence of several inflamed follicles into a single inflammatory mass with purulent drainage from multiple follicles (picture 2).

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●Skin abscess – A skin abscess is a collection of pus within the dermis and deeper skin tissues. Skin abscesses manifest as painful, tender, fluctuant, and erythematous nodules frequently surmounted by a pustule and surrounded by a rim of erythematous swelling (picture 3).

DIFFERENTIAL DIAGNOSIS

Historical features and

appearance usually help to distinguish skin abscesses from the other conditions in the differential diagnosis. As a rule, incision and drainage is not indicated for these diseases: ●Vascular malformation – Abscesses located near major blood vessels must be differentiated from aneurysms or arteriovenous malformations before incision and drainage is performed (picture 4). Incision of an aneurysm that mimics an abscess can lead to fatal hemorrhage [1,2]. Identification of a vascular malformation can be made in several ways, including physical examination (eg, bruit or thrill may be present; distal pulses may be diminished) and Doppler ultrasound, which is the test of choice [1]. (See "Acquired arteriovenous fistula of the lower extremity".) ●Myiasis – Botfly myiasis is a skin infection caused by larvae of the botfly that should be suspected in travelers returning from Central or South America [3-5]. Patients typically note an apparent insect bite that, instead of healing, slowly enlarges over time to a nodule measuring 1 to 3 cm in diameter (picture 5 and picture 6). Patients may have a sensation of irritation, crawling, or episodic lancinating pain. Small amounts of serosanguineous fluid may drain from the lesion. (See "Skin lesions in the returning traveler", section on 'Myiasis'.) ●Kerion – Patients with the fungal infection tinea capitis may develop a boggy, tender, exudative scalp mass called a kerion. This is an allergic inflammatory response to the fungal infection and not a true cutaneous abscess (picture 7). Although antibiotic therapy for possible superinfection with Staphylococcus aureus may be indicated, incision and drainage should not be performed. (See "Tinea capitis".) ●Herpetic whitlow – Herpetic whitlow (herpes simplex virus [HSV] infection of the finger) occurs as a complication of primary oral or genital herpes infection via a break in the skin. In addition to erythema, swelling, and pain, herpetic whitlow is characterized by the presence of vesicular or pustular lesions (picture 8). Patients may also experience fever, lymphadenitis, and epitrochlear or axillary lymphadenopathy. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Cutaneous manifestations'.) The diagnosis of herpetic whitlow is suspected by an exposure history as well as the presence of vesicles that, on Tzanck smear, reveal multinucleated giant cells. It is important to distinguish whitlow from felon; incision and drainage should not be performed in the former because it may lead to secondary bacterial infections that delay healing. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Diagnosis' and "Paronychia", section on 'Diagnosis'.)

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●Hidradenitis suppurativa – Hidradenitis suppurativa is a chronic relapsing inflammatory disease affecting the apocrine glands. It should be considered in any patient who presents with recurrent furunculosis of the groin, buttocks, and axillae (picture 9 and picture 10 and picture 11). Hidradenitis suppurativa may be associated with multiple and recurrent skin abscesses. (See "Hidradenitis suppurativa: Pathogenesis, clinical features, and diagnosis".) ●Sexually transmitted infection – Several sexually transmitted infections may present with one or more genital ulcers and matted suppurative inguinal lymph nodes including granuloma inguinale, chancroid, and lymphogranuloma venereum. Diagnosis may require specialized testing. (See "Approach to the patient with genital ulcers".) ●Botryomycosis – Botryomycosis, also known as bacterial pseudomycosis, is a chronic, suppurative infection characterized by a granulomatous inflammatory response to bacterial pathogens (picture 12). Its name came from the erroneous presumption that it was a fungal infection. The most common organism identified in botryomycosis lesions is S. aureus. (See "Botryomycosis".) ●Sporotrichosis – Lymphocutaneous sporotrichosis is the most common form of sporotrichosis seen in clinical practice. Days to weeks after cutaneous inoculation of the fungus, a papule develops at the site of inoculation. This primary lesion usually ulcerates but may remain nodular with overlying erythema; drainage from the lesion is not grossly purulent and has no odor (picture 13A-B). (See "Clinical features and diagnosis of sporotrichosis", section on 'Lymphocutaneous sporotrichosis' and "Treatment of sporotrichosis".) ●Cat scratch disease – Cat scratch disease is typically a self-limited disease characterized by painful regional lymphadenopathy following a cat scratch. Bartonella henselae is the organism that causes this illness. Pustules may occur at the site of the scratch, and 25 to 30 percent of patients develop lymph nodes that suppurate. Incision and drainage should be avoided due to scarring and fistula formation. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease", section on 'Cutaneous manifestations' and "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease", section on 'Lymphadenopathy'.)

INDICATIONS

Approximately 2 percent of emergency department visits are

for the evaluation of skin abscesses. Most lesions are caused by Staphylococcus aureus, and many of these patients require incision and drainage. (See "Cellulitis and skin abscess: Clinical manifestations and diagnosis", section on 'Microbiology'.) Most patients with skin abscesses should undergo incision and drainage [6-9]. In patients with small abscesses that are spontaneously draining, the clinician may choose to observe for resolution. Needle aspiration is insufficient for adequate abscess drainage. As an example, in an unblinded trial of incision and drainage versus ultrasound-guided needle aspiration of cutaneous abscesses in 101 adults, incision and drainage was much more likely to successfully resolve an abscess at seven days when compared with needle aspiration (80 versus 26 percent, respectively) [10].

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Observed patients may be treated with oral antibiotics that have activity against methicillin-resistant S. aureus (MRSA), depending upon the clinical scenario and the local prevalence of MRSA. The role of antibiotics in skin abscesses and the management of abscesses infected with MRSA are discussed separately. (See "Cellulitis and skin abscess in adults: Treatment".) Observed patients should apply warm compresses to the infected area several times per day to promote drainage.

CONTRAINDICATIONS

Although most patients with

cutaneous abscesses may safely undergo incision and drainage in a monitored setting (eg, emergency department), they should first be assessed for possible contraindications, including the following [11]: ●Abscess location – The following abscesses have a high rate of complication or require anatomical expertise and should be drained by a surgeon: •Perirectal abscesses. •Anterior and lateral neck abscesses potentially arising from congenital cysts (eg, thyroglossal duct cyst, branchial cyst, cystic hygroma). •Hand abscesses (excluding paronychias and felons). •Abscesses adjacent to vital nerves or blood vessels (eg, facial nerve, carotid artery, femoral artery). •Abscesses in the central triangle of the face formed by the corners of the mouth and the nasal bridge. These lesions pose a risk of septic phlebitis and intracranial extension through the cavernous sinus. They are treated with warm compresses, broad spectrum antibiotic therapy, and close follow-up with otolaryngology [12]. •Breast abscesses, particularly those near the areola and nipple. (See "Primary breast abscess".) ●Abscess type – Recurrent and multiple interconnected abscesses warrant removal in the operating room by a surgeon to assess and manage any fistulas (picture 11). Large abscesses (>5 cm by palpation or ultrasound) may be best managed by surgery. Mycotic abscesses should not be treated with incision and drainage. (See "Tuberculous lymphadenitis".) ●Patient factors – Individuals who may pose difficulty in airway or ventilatory management or present an aspiration risk have relative contraindications to abscess drainage under procedural sedation. (See "Procedural sedation in adults outside the operating room" and "Procedural sedation in children outside of the operating room".)

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Patients with an underlying bleeding disorder should undergo correction of their coagulopathy prior to the procedure. The clinician should determine if the patient is allergic to lidocaine, epinephrine, or latex and avoid exposure during the procedure.

PREPARATION Evaluation with bedside ultrasonography — The clinician should examine the area of infection and determine the presence of any abscess by fluctuance or drainage. For patients with a skin and soft tissue infection in which the clinician is certain an abscess is present, and when device and trained providers are available, we suggest bedside ultrasonography to identify the presence, size, and location of the abscess and to facilitate adequate drainage (image 1). Incision and drainage without the use of ultrasound is a reasonable alternative [13]. In patients with uncertainty regarding the presence of an abscess, we recommend bedside ultrasonography to aid in the diagnosis of abscess (image 1) versus cellulitis (image 2) and to facilitate drainage [1,1318]. In a prospective observational study of over 1200 adults with skin and soft tissue infections (827 with abscess), bedside ultrasonography changed management in approximately 1 percent of cases when clinicians were certain about the presence or absence of an abscess, and these changes were appropriate in 10 of 13 individuals [13]. By contrast, in the 105 patients for whom clinicians were uncertain, ultrasound changed management in 24 percent of patients, and changes were appropriate in 21 of 25 individuals. Thus, bedside ultrasonography was much better than clinical judgement for determining the presence of an abscess or cellulitis in patients for whom the clinical diagnosis was uncertain but added minimal benefit when the clinical diagnosis was certain. However, this study did not report on clinical outcomes of drainage. Even when the diagnosis is certain, evidence suggests that bedside ultrasound may reduce clinical failure. As an example, in a trial of 107 patients undergoing abscess drainage in the emergency department (ED), clinical failure rates 10 days after the procedure were lower in patients evaluated with physical examination and ultrasonography compared with physical examination alone (4 versus 17 percent [risk difference 13 percent, 95% CI 0-19 percent, adjusted odds ratio 0.2, 95% CI 0.04-0.97]) [19]. All providers performing point-of-care ultrasonography in this study were highly experienced. Furthermore, bedside ultrasound may have a greater beneficial role in children where clinical examination may be limited and clinical certainty of the presence or absence of an abscess is harder to achieve. As an example, in a prospective observational study of over 380 children younger than 19 years of age with skin and soft tissue infections undergoing evaluation in a children's hospital ED, bedside ultrasound had a much higher sensitivity and specificity than clinical examination for the

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almost 160 children in whom abscesses were not clinically evident (sensitivity 78 versus 44 percent and specificity 61 versus 42 percent, respectively), although, similar to findings in adults, bedside ultrasound did not significantly change the sensitivity and specificity for the detection of clinically evident abscesses when compared with physical examination (sensitivity 93 versus 95 percent and specificity 81 versus 84 percent, respectively) [20]. In a separate prospective, observational study of nearly 150 children with skin and soft tissue infection presenting to a pediatric emergency department, bedside ultrasonography had higher sensitivity (96 versus 84 percent) and specificity (87 versus 60 percent) than clinical evaluation alone and correctly changed management in approximately 25 percent of patients [21]. In addition, ultrasonography is a useful adjunct for determining which patients with cellulitis also have multiple connected abscesses (a contraindication to simple incision and drainage, which does not provide adequate treatment of fistulas). Rarely, it may identify abnormalities (eg, adjacent vessels or atypical findings suggesting an alternative diagnosis) that contraindicate simple incision and drainage in the ED [14,22]. (See 'Contraindications' above.)

Endocarditis prophylaxis — In patients who are at risk for bacterial endocarditis (eg, patients with unrepaired cyanotic congenital heart disease, prosthetic valves, central line, or rheumatic heart disease), antibiotic prophylaxis with activity against staphylococci and beta-hemolytic streptococci is warranted prior to incision and drainage. (See "Cellulitis and skin abscess in adults: Treatment", section on 'Drainable abscess present' and "Infective endocarditis in children", section on 'Risk factors' and "Antimicrobial prophylaxis for the prevention of bacterial endocarditis", section on 'Skin or soft tissue procedures'.)

Patient counseling — Before beginning the procedure, explain in full the nature of the procedure and the possible risks and consequences. With children, explain the procedure in an age-appropriate manner and perform informed consent with the patient or caregiver. Emphasize the following important features of incision and drainage: ●An abscess may be much larger than it appears on the surface. Thus, it may require a longer incision than the patient expects. ●Scarring should be expected, including the possibility of keloid formation. ●Recurrence is relatively common, particularly in patients with hidradenitis suppurativa or an infected sebaceous cyst.

Sedation and analgesia — Lack of adequate pain control is the most common limiting factor in achieving adequate incision and drainage [6,23]. Most patients can receive appropriate sedation and analgesia in the ED. Local anesthesia is sufficient for most simple abscesses in adolescents and adults. Young children and patients with large abscesses, especially those in the pilonidal region, frequently require parenteral sedation and analgesia in addition to local

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anesthesia to achieve adequate pain control and to permit successful completion of the procedure. (See "Procedural sedation in children outside of the operating room" and "Procedural sedation in adults outside the operating room".)

Local anesthesia — To augment procedural sedation, use a regional block, if possible. Local infiltration is less effective than a regional block due to the lower pH of infected tissue, which reduces the proportion of anesthetic in the more active uncharged form. (See "Subcutaneous infiltration of local anesthetics".) Alternatively, use a field block with a local anesthetic (eg, 1 or 2 percent lidocaine). The injection can be performed with one puncture if the needle is inserted into the dome of the abscess and the syringe is held parallel to the skin and rotated to distribute the anesthetic circumferentially. Topical local anesthetics (eg, prilocaine-lidocaine, liposomal lidocaine, or tetracaine gel) may be applied prior to local injection or anesthetic blocks to further reduce the pain of the procedure. (See "Clinical use of topical anesthetics in children".) Be careful to avoid injecting toxic doses of anesthetic. For lidocaine, the toxic dose is 4 mg/kg; for lidocaine with epinephrine, the toxic dose is 7 mg/kg. (See "Subcutaneous infiltration of local anesthetics".)

INCISION AND DRAINAGE Equipment — Assemble the following materials for the procedure: ●Sterile gloves, drapes, and 4x4 inch gauze ●Goggles or other eye protection (eg, surgical mask with integrated visor) ●Antiseptic solution (eg, povidone-iodine or chlorhexidine solution) ●Local anesthetic (eg, 1 or 2 percent lidocaine) ●3 to 10 mL syringe and needle of 25, 27, or 30 gauge ●Culture swab ●Number 11 blade and scalpel holder ●Curved hemostats ●Forceps ●Scissors

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●Needleless 30 to 60 mL syringe with 19 gauge intravenous (IV) catheter or needleless irrigation device with splash protection (eg, Zerowet Splashield) ●Basin with sterile saline solution ●Packing material (eg, iodoform or plain gauze packing tape) ●Dressing of choice

Incision — After adequate analgesia is achieved, incise the skin with a number 11 scalpel blade. (See 'Sedation and analgesia' above and 'Local anesthesia' above.) Make a simple linear incision through the total length of the abscess with the incision conforming to the natural folds of the skin. Avoid cruciate or elliptical incisions because they can cause unsightly scars. If the abscess is in a cosmetic area or an area of skin tension, a stab incision may be used to limit tissue injury and scarring.

Culture — Prior to the emergence of community-acquired methicillin-resistant Staphylococcus aureus (cMRSA) infection, cultures were not routinely obtained when performing incision and drainage of a simple abscess, and when obtained did not typically change the care of otherwise healthy patients. Wound cultures are still not necessary in healthy patients who will not receive antibiotics after abscess drainage. However, given the increased prevalence of cMRSA infection and developing resistance patterns, we suggest that specimens for Gram stain, culture, and susceptibility testing be obtained if the patient will be treated with antibiotics and meets one of the following criteria [24]: ●Severe, local infection (eg, extensive cellulitis, pilonidal cyst) ●Systemic signs of infection (eg, fever or hemodynamic instability) ●History of recurrent or multiple abscesses ●Failure of initial antibiotic treatment ●Extremes of age (young infants or the elderly) ●Immunocompromised Wound culture may also be appropriate for otherwise healthy patients receiving antibiotics after abscess drainage who reside in regions where S. aureus antibiotic susceptibility is unknown or rapidly changing. (See "Suspected Staphylococcus aureus and streptococcal skin and soft tissue

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infections in children >28 days: Evaluation and management", section on 'Laboratory evaluation' and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections", section on 'Clinical approach'.) For abscesses requiring incision and drainage, fluid for cultures may be obtained by swabbing purulent material. In selected patients, such as immunocompromised hosts or IV drug users, isolation of possible anaerobic organisms can be enhanced by needle aspiration with a syringe through appropriately cleaned (eg, with chlorhexidine) skin prior to incision and drainage [6,23]. (See "Microbiology specimen collection and transport", section on 'Specimen collection'.) The role of antibiotics in patients undergoing cutaneous abscess drainage and antibiotic selection is discussed in greater detail separately. (See "Cellulitis and skin abscess in adults: Treatment".)

Probing and irrigation — After incision, probe the abscess cavity with a hemostat to break up loculations, identify foreign bodies, and ensure proper drainage. Do not probe with a gloved finger or scalpel. A gloved finger may be injured by a sharp foreign body, and a scalpel may cause tissue damage or create a false passage or fistula. Probing of the wound is painful and may require additional anesthesia. Irrigate the abscess cavity copiously with isotonic saline solution until all visible pus is removed [25]. (See "Minor wound preparation and irrigation", section on 'Irrigation'.)

Closure — After incision, drainage, probing, and irrigation, we suggest that abscesses be left open to heal by secondary intention (secondary closure). In previously healthy adults without significant surrounding erythema >5 cm wide or signs of systemic infection, primary closure using nonabsorbable sutures and vertical mattress technique is an option (figure 1). However, available evidence is of low quality and does not indicate a clear benefit for primary closure of abscesses over healing by secondary intention [26,27]. If sutures are placed, close wound follow-up must be assured to evaluate for reaccumulation of pus. Also, primary closure should be avoided in patients with the following conditions: ●Immunocompromised (eg, diabetes mellitus, chronic immunosuppressive therapy, or HIV) ●Signs of systemic infection (eg, fever, chills, hypotension) ●Significant cellulitis (>5 cm of surrounding erythema) Furthermore, studies evaluating primary closure have not been performed in children. Given the lack of clear benefit in adults and the potential anxiety and pain associated with suture removal, the available evidence does not support primary closure after skin abscess drainage in pediatric patients.

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Closure by secondary intention is the traditional approach to abscess management and is based upon the principle of avoiding the placement of foreign bodies in contaminated wounds. Evidence for primary closure of abscesses is as follows: ●In one meta-analysis of seven trials (915 patients), primary vertical mattress closure of abscesses after drainage using nonabsorbable sutures had clinically significantly faster healing (8 versus 15 days) and fewer recurrences (8 versus 11 percent, although not statistically significant) than healing by secondary intention [26]. However, these studies differed from each other with respect to site and size of abscess, location of drainage (outpatient versus operating room), and use of antibiotics. Furthermore, most of these studies were performed before the advent of methicillin-resistant S. aureus and were judged to be of poor quality [26]. ●In a more recent trial of 56 healthy adults undergoing incision and drainage for abscesses in the emergency department (ED), healing or treatment failure was not significantly different between primary or secondary closure (60 to 70 percent healing and approximately 30 percent treatment failures with both outcomes evaluated at seven days) [27]. However, 6 of 27 patients who underwent primary closure required suture removal by 48 hours because of reaccumulation of pus.

Packing or drain placement Indications — After incision and drainage, we suggest packing any abscess cavity that meets any of the following criteria: ●Abscess >5 cm in diameter ●Pilonidal abscess ●Abscess in an immunocompromised or diabetic patient In contrast to abscesses more than 5 cm in diameter, packing of wounds 5 cm in diameter or pilonidal abscesses) should undergo packing and further management as described above. In one trial of primary versus secondary closure of abscesses, 6 of the 27 healthy patients who received primary closure after incision and drainage of an abscess required suture removal by 48 hours because of reaccumulation of pus [27].

Loop drainage technique — Drainage after placement of a loop may persist for up to 7 to 10 days and is acceptable. The patient or caregiver should be encouraged to wiggle the loop daily to encourage drainage. However, increased erythema surrounding the abscess or increased swelling of the affected area suggests extensive infection and warrants timely reevaluation to determine the need for formal incision and drainage and, depending upon the degree of illness, the need for intravenous (IV) antibiotics. Once drainage has ceased, then the loop can be cut and removed.

COMPLICATIONS

Complications of incision and drainage are

uncommon [6,23]. They typically result from either inadequate or overaggressive drainage:

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●Inadequate drainage may result in local extension, leading to development of a larger abscess that may be followed by osteomyelitis, tenosynovitis, septic thrombophlebitis, necrotizing fasciitis, or fistula formation. ●Overaggressive drainage, especially with sharp dissection, may damage adjacent structures (eg, nerves and vessels) and may lead to bacteremia. Complications are particularly likely to occur with incision and drainage of facial abscesses in the triangle formed by the bridge of the nose and the corners of the mouth. This approach poses a risk of septic phlebitis and intracranial extension through the cavernous sinus [12]. (See 'Contraindications' above.) Infections involving the nose and perioral area can be complicated by orbital abscesses [37] or cavernous sinus thrombosis. Bacteremia leading to development of secondary infection at distant sites may result in considerable morbidity or even mortality.

ADDITIONAL RESOURCES

A high-quality instructional

video of this procedure is available elsewhere [11].

SOCIETY GUIDELINE LINKS

Links to society and

government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Skin and soft tissue infections".)

SUMMARY AND RECOMMENDATIONS ●Skin abscesses are collections of pus within the dermis and deeper skin tissues. Skin abscesses manifest as painful, tender, fluctuant, and erythematous nodules frequently surmounted by a pustule and surrounded by a rim of erythematous swelling (picture 3). (See 'Definitions' above.) ●Prior to performing incision and drainage, check for other skin conditions that can mimic abscesses. (See 'Differential diagnosis' above.) ●In patients with an abscess, when device and trained providers are available, we suggest bedside ultrasound to identify the presence, size, and location of the abscess and to facilitate adequate drainage (image 1). (See 'Evaluation with bedside ultrasonography' above.) ●For patients with a skin and soft tissue infection in which the clinician is certain an abscess is present, and when device and trained providers are available, we suggest bedside ultrasonography to identify the presence, size, and location of the abscess and to facilitate adequate drainage (image 1). Incision and drainage without the use of ultrasound is a reasonable alternative [13]. In patients

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with uncertainty regarding the presence of an abscess, we recommend bedside ultrasonography to aid in the diagnosis of abscess (image 1) versus cellulitis (image 2) and to facilitate drainage. (See 'Evaluation with bedside ultrasonography' above.) ●Incision and drainage warrants provision of proper analgesia. Most simple abscesses in adolescents and adults can be managed with local anesthesia. Young children and patients with large abscesses, especially those in the pilonidal region, frequently require parenteral sedation and analgesia in addition to local anesthesia to achieve adequate pain control and to allow for successful completion of the procedure. (See 'Sedation and analgesia' above.) ●The procedure of incision and drainage is summarized in the table (table 2). A list of the necessary equipment is provided in the text. (See 'Equipment' above and 'Incision and drainage' above.) ●We suggest that specimens for Gram stain, culture, and susceptibility testing be obtained if the patient will be treated with antibiotics and meets one of the following criteria (Grade 2C) (see 'Culture' above): •Severe, local infection (eg, extensive cellulitis, pilonidal cyst) •Systemic signs of infection (eg, fever or hemodynamic instability) •History of recurrent or multiple abscesses •Failure of initial antibiotic treatment •Extremes of age (young infants or the elderly) •Immunocompromised ●Wound culture may also be appropriate for otherwise healthy patients receiving antibiotics after abscess drainage who reside in regions where Staphylococcus aureus antibiotic susceptibility is unknown or rapidly changing. (See 'Culture' above.) ●Wound cultures are not necessary in healthy patients who will not receive antibiotics after abscess drainage. (See 'Culture' above.) ●We suggest that patients with the following characteristics undergo packing of the abscess cavity after incision and drainage (Grade 2C): •Abscess >5 cm in diameter •Pilonidal abscess •Abscess in an immunocompromised patient ●We suggest that abscesses be left open to heal by secondary intention (secondary closure) (Grade 2C). (See 'Closure' above.)

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●Decisions about antibiotic therapy for skin abscesses are discussed separately. (See "Cellulitis and skin abscess in adults: Treatment".) ●The loop drainage technique is an alternative to traditional incision and drainage that may be less painful for the patient, avoids packing, and may reduce the need for follow-up. This method also leaves less scarring and may prevent recurrence of the abscess, especially in children. (See 'Loop drainage technique' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like

to acknowledge Rana Kronfol, MD, who contributed to an earlier version of this topic review.

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Management of ingrown toenails - UpToDate uptodate.com/contents/management-of-ingrown-toenails/print

Management of ingrown toenails Authors: Beth G Goldstein, MD Adam O Goldstein, MD, MPH Section Editors: Robert P Dellavalle, MD, PhD, MSPH Moise L Levy, MD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 02, 2019.

INTRODUCTION

Ingrown toenails (or onychocryptosis) occur when a

spicule of the lateral nail plate pierces the lateral nail fold and penetrates into the skin, with subsequent foreign-body inflammatory reaction and secondary infection (picture 1). The great toenail is most commonly affected. Characteristic signs and symptoms include pain, edema, exudate, and granulation tissue. Predisposing factors include poorly fitting shoes, excessive trimming of the lateral nail plate, pincer nail deformity (picture 2), and trauma. The diagnosis is based upon clinical appearance and rarely is difficult. This topic will discuss the management of ingrown toenails. Paronychia and other skin disorders are discussed separately. (See "Paronychia" and "Overview of nail disorders".)

Treatment — The treatment of ingrown toenails depends upon the severity of the lesion. All patients should be educated about proper nail trimming; the lateral nail plate should be allowed to grow well beyond the lateral nail fold before trimming horizontally. Patients should also be educated about the importance of well-fitting shoes.

Mild to moderate lesion — Mild to moderate lesions are characterized by minimal to moderate pain, little erythema, and no discharge. Options for conservative treatment include [1,2]: ●Placing a cotton wedging or dental floss underneath the lateral nail plate to separate the nail plate from the lateral nail fold, or use tape to pull the lateral nail fold away from a spicule [3], thereby relieving pressure. An additional option called "cotton nail cast" has been proposed for mild ingrown

7101

toenail. Without anesthesia, a piece of cotton (u-shaped), is placed with forceps between the nail plate and inflamed tissue, secured with a cyanoacrylate liquid glue, and allowed to harden to form a "cast" [4]. ●Soaking the affected foot in warm, soapy water for 10 to 20 minutes three times per day for one to two weeks, pushing the lateral nail fold away from the nail plate [5]. Alternatively, a solution of water mixed with 1 to 2 teaspoons of Epsom salts can be used [6]. A medium- to high-potency topical corticosteroid can be applied after soaking to reduce inflammation (table 1). ●Toe taping, using a sticky elastic tape to pull the lateral nail fold away from the nail plate. The tape is placed on the nail fold, stretched around the toe over the volar surface, and fixed on the contralateral side, proximally to the nail [3,7]. ●Nail bracing, using various devices (hook, adhesive, or composite), depending on the accessibility of the nail folds (picture 3) [8,9].   Over 70 percent of patients respond to conservative therapy. Nonresponders may need to undergo more aggressive therapy. (See 'Moderate to severe lesion' below.)

Moderate to severe lesion — Moderate to severe lesions are characterized by substantial erythema and pus (picture 4). Treatment consists of the following: ●Perform an appropriate digital block with lidocaine 1% without epinephrine (see "Digital nerve block"). EMLA (eutectic mixture of lidocaine [2.5 percent] and prilocaine [2.5 percent] in a cream base) has not been proven helpful in reducing the pain of injection. ●Using nail-splitting scissors or a hemostat, insert the instrument under the nail plate and remove the involved nail wedge with nail clippers or scissors (picture 5). (See "Nail avulsion and chemical matricectomy".) ●Remove any granulation tissue with a curette and/or silver nitrate sticks. ●Dilute hydrogen peroxide 1:1 with tap water and cleanse the surgical site with cotton swabs two or three times a day, followed by application of either bacitracin or mupirocin ointment. ●Many elect to treat secondary infections with oral antibiotics. However, in a study of 54 patients with ingrown toenails (patients who were immunocompromised, had peripheral vascular disease, or had cellulitis were excluded), the use of antibiotics in association with nail border resection did not decrease healing time nor postprocedure morbidity [10]. ●Follow up in three to four days to assess treatment and possible spicule formation with nail regrowth. Remember to educate the patient that when the lesion heals and the lateral nail fold is no longer edematous, they should allow the lateral nail plate to grow beyond the lateral nail fold. ●An additional option is the placement of a soft plastic tube stent along the affected nail edge (gutter method).

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Recurrent ingrown toenail — For patients who suffer recurrent ingrown toenails, consider permanent nail ablation of the lateral nail horn. This is best achieved with the combination of surgical excision plus phenol ablation (chemical matricectomy). In one study, for example, 163 patients (204 ingrowing nail edges) who had not had previous surgery were randomized and treated by total nail avulsion, nail edge excision, or nail edge excision with phenolization of the germinal matrix [11]. Recurrence rates one year postoperatively were 73, 73, and 9 percent, respectively. A systematic review and meta-analysis concluded that nail avulsion combined with phenol leads to a 75 to 91 percent reduction in the recurrence of ingrowing toenails compared with excisional techniques alone, although there is a higher rate of postoperative secondary infections [12]. One study described more rapid healing with the use of sodium hydroxide [13], but until additional studies are performed demonstrating efficacy, safety, and ease of use, we continue to use phenol. To perform the procedure, surgical nail avulsion of the involved lateral nail is performed prior to the application of phenol 88% or trichloroacetic acid 100% [14]. The central nail plate and uninvolved lateral nail plate is usually left in place. The procedures for partial nail avulsion and chemical matricectomy are discussed separately (see "Nail avulsion and chemical matricectomy", section on 'Nail avulsion' and "Nail avulsion and chemical matricectomy", section on 'Chemical matricectomy'). The possibility of partial regrowth, including nail spicules, should be discussed with the patient. Surgical ablation with electrocautery, radiofrequency, or carbon dioxide laser are alternatives to destruction of the nail matrix with phenol [5].

INFORMATION FOR PATIENTS

UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topics (see "Patient education: Ingrown toenail (The Basics)" and "Patient education: Paronychia (The Basics)")

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SUMMARY AND RECOMMENDATIONS ●Ingrown toenails occur when the lateral nail plate pierces the lateral nail fold. Patients may present with pain or swelling surrounding the nail. (See 'Introduction' above.) ●Mild lesions can be treated conservatively, with soaks several times per day, the use of cotton or dental floss to separate the nail plate from the nail fold, nail taping, or nail bracing. (See 'Mild to moderate lesion' above.) ●Surgical intervention for removal of the involved nail wedge may be required for more severe cases. In patients with frequent recurrences, permanent nail ablation of the lateral nail horn by partial nail avulsion and chemical matricectomy can be beneficial. (See 'Moderate to severe lesion' above and 'Recurrent ingrown toenail' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 112847 Version 2.0

GRAPHICS

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Ingrown toenail

The nail plate is entering the lateral nail groove, causing erythema, granulation tissue, and discomfort. Reproduced with permission from: Stedman's Medical Dictionary. Copyright © 2008 Lippincott Williams & Wilkins. Graphic 60056 Version 2.0

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Pincer nails deformity

Transverse overcurvature of the nail is seen in pincer nail deformity. The disorder may be hereditary or acquired. In cases of acquired pincer nails, poorly fitting shoes are often responsible. The condition can be painful. Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2003. Copyright © 2003 Lippincott Williams & Wilkins. Graphic 59295 Version 2.0 Comparison of representative topical corticosteroid preparations (classified according to the US system)

Potency group*

Corticosteroid

Vehicle type/form

Brand names (United States)

Available strength(s), percent (except as noted)

Superhigh potency (group 1)

Betamethasone dipropionate, augmented

Gel, lotion, ointment (optimized)

Diprolene

0.05

Clobetasol propionate

Cream, gel, ointment, solution (scalp)

Temovate

0.05

Cream, emollient base

Temovate E

0.05

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High potency (group 2)

Lotion, shampoo, spray aerosol

Clobex

0.05

Foam aerosol

Olux-E, Tovet

0.05

Solution (scalp)

Cormax

0.05

Diflucortolone valerate (not available in United States)

Ointment, oily cream

Nerisone Forte (United Kingdom, others)

0.3

Fluocinonide

Cream

Vanos

0.1

Flurandrenolide

Tape (roll)

Cordran

4 mcg/cm2

Halobetasol propionate

Cream, lotion, ointment

Ultravate

0.05

Amcinonide

Ointment

Cyclocort¶, Amcort¶

0.1

Betamethasone dipropionate

Ointment

Diprosone¶

0.05

Cream, augmented formulation (AF)

Diprolene AF

0.05

Clobetasol propionate

Cream

Impoyz

0.025

Desoximetasone

Cream, ointment, spray

Topicort

0.25

Gel

Topicort

0.05

Ointment

ApexiCon¶, Florone¶

0.05

Cream, emollient

ApexiCon E

0.05

Fluocinonide

Cream, gel, ointment, solution

Lidex¶

0.05

Halcinonide

Cream, ointment

Halog

0.1

Halobetasol propionate

Lotion

Bryhali

0.01

Diflorasone diacetate

7107

propionate High potency (group 3)

Medium potency (group 4)

Cream

Cyclocort¶, Amcort¶

0.1

Lotion

Amcort¶

0.1

Betamethasone dipropionate

Cream, hydrophilic emollient

Diprosone¶

0.05

Betamethasone valerate

Ointment

Valisone¶

0.1

Foam

Luxiq

0.12

Desoximetasone

Cream

Topicort LP¶

0.05

Diflorasone diacetate

Cream

Florone¶

0.05

Diflucortolone valerate (not available in United States)

Cream, oily cream, ointment

Nerisone (Canada, United Kingdom, others)

0.1

Fluocinonide

Cream aqueous emollient

Lidex-E¶

0.05

Fluticasone propionate

Ointment

Cutivate

0.005

Mometasone furoate

Ointment

Elocon

0.1

Triamcinolone acetonide

Cream, ointment

Aristocort HP¶, Kenalog¶, Triderm

0.5

Betamethasone dipropionate

Spray

Sernivo

0.05

Clocortolone pivalate

Cream

Cloderm

0.1

Fluocinolone acetonide

Ointment

Synalar¶

0.025

Flurandrenolide

Ointment

Cordran

0.05

Hydrocortisone valerate

Ointment

Westcort

0.2

Mometasone furoate

Cream, lotion, ointment, solution

Elocon¶

0.1

Amcinonide



7108

Cream

Kenalog¶, Triderm

0.1

Ointment

Kenalog¶

0.1

Ointment

Trianex

0.05

Aerosol spray

Kenalog

0.2 mg per 2 second spray

Dental paste

Oralone

0.1

Betamethasone dipropionate

Lotion

Diprosone¶

0.05

Betamethasone valerate

Cream

Beta-Val, Valisone¶

0.1

Desonide

Ointment

DesOwen, Tridesilon¶

0.05

Gel

Desonate

0.05

Fluocinolone acetonide

Cream

Synalar¶

0.025

Flurandrenolide

Cream, lotion

Cordran

0.05

Fluticasone propionate

Cream, lotion

Cutivate

0.05

Hydrocortisone butyrate

Cream, lotion, ointment, solution

Locoid, Locoid Lipocream

0.1

Hydrocortisone probutate

Cream

Pandel

0.1

Hydrocortisone valerate

Cream

Westcort¶

0.2

Prednicarbate

Cream (emollient), ointment

Dermatop

0.1

Triamcinolone acetonide

Lotion

Kenalog¶

0.1

Ointment

Kenalog¶

0.025

Alclometasone dipropionate

Cream, ointment

Aclovate

0.05

Triamcinolone acetonide

Lowermid potency (group 5)

Low potency (group

7109

(group 6)

Betamethasone valerate

Lotion

Beta-Val¶, Valisone¶

0.1

Desonide

Cream

DesOwen, Tridesilon¶

0.05

Lotion

DesOwen, LoKara

0.05

Foam

Verdeso

0.05

Cream, solution

Synalar¶

0.01

Shampoo

Capex

0.01

OilΔ

Derma-Smoothe/FS Body, DermaSmoothe/FS Scalp

0.01

Triamcinolone acetonide

Cream, lotion

Kenalog¶, Aristocort¶

0.025

Hydrocortisone (base, ≥2%)

Cream, ointment

Hytone, Nutracort¶

2.5

Lotion

Hytone, Ala Scalp, Scalacort

2

Solution

Texacort

2.5

Ointment

Cortaid, Cortizone 10, Hytone, Nutracort

1

Cream

Cortaid¶, Cortizone 10, Hytone, Synacort

1

Gel

Cortizone 10

1

Lotion

Aquanil HC, SarnolHC, Cortizone 10

1

Spray

Cortaid

1

Solution

Cortaid, Noble, Scalp Relief

1

Cream, ointment

Cortaid

0.5

Cream

MiCort-HC

2.5

Lotion

Nucort

2

Fluocinolone acetonide

Least potent (group 7)

Hydrocortisone (base, 34 weeks: 25 mg/kg IV every 8 hours

Nafcillin

Age 8 through 28 days: GA ≤34 weeks: 25 mg/kg IV every 8 hours GA >34 weeks: 25 mg/kg IV every 6 hours

Gentamicin*

GA 14 days : 5 mg/kg IV every 36 hours GA 30 to 34 weeks: Age ≤14 days: 5 mg/kg IV every 36 hours Age >14 says: 5 mg/kg IV every 24 hours GA ≥35 weeks: Age ≤7 days: 4 mg/kg IV every 24 hours Age >7 days: 5 mg/kg IV every 24 hours

Linezolid

Age ≤7 days: GA ≤34 weeks: 10 mg IV every 12 hours GA >34 weeks: 10 mg IV every 8 hours Age 8 through 28 days: 10 mg IV every 8 hours (independent of GA)

Vancomycin ¶

Loading dose: 20 mg/kg IV Maintenance dosing according to GA and serum creatinine as indicated below. The interval between the loading dose and the first maintenance dose should be the same as the dosing interval for the maintenance regimen. GA ≤28 weeks: 1.4 mg/dL: 15 mg/kg IV every 48 hours GA >28 weeks 1.6 mg/dL: 15 mg/kg IV every 48 hours

Refer to UpToDate content on S. aureus infections in neonates for additional information about choice of therapy. Unless otherwise specified, age refers to postnatal age. GA: gestational age; IV intravenous. * Gentamicin is necessary to provide coverage for possible gram-negative pathogens. The optimal, individualized dose should be based on determination of serum concentrations. Doses may differ from those recommended by the package insert. ¶ Serum creatinine concentration will take approximately five to seven days after birth to reasonably reflect neonatal renal function. Cautious use of creatinine-based dosing strategy with frequent assessment of renal function and vancomycin serum concentrations are recommended in neonates ≤7 days old [1]. A vancomycin dosing method based upon postnatal age and weight is provided as an alternative to the serum creatinine-based method listed above and may be useful in some clinical situations. This particular algorithm was provided in the 2009 edition of the Red Book [2]. Postnatal age 5 cm in diameter of the head, including scalp PLUS one minor criteria

Hemangioma of the neck, upper trunk or trunk, and proximal upper extremity PLUS two major criteria

Hemangioma of the neck, upper trunk or trunk, and proximal upper extremity PLUS one major criteria or two minor criteria No hemangioma PLUS two major criteria

PHACE: posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. * Internal carotid artery, middle cerebral artery, anterior cerebral artery, posterior cerebral artery, or vertebrobasilar. ¶ Includes kinking, looping, tortuosity, and/or dolichoectasia. Reproduced from: Garzon MC, Epstein LG, Heyer GL, et al. PHACE Syndrome: Consensus-Derived Diagnosis and Care Recommendations. J Pediatr 2016; 178:24. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 110054 Version 3.0

8260

Nascent infantile hemangioma

In some newborns, a patch of telangiectasias with surrounding pallor is a premonitory cutaneous mark of infantile hemangiomas. Graphic 89391 Version 1.0

8261

Morning glory disc anomaly

The disc is large and there is a central, white tuft of glial tissue. The retinal vessels proceed radially from the disc. Courtesy of Karl C Golnik, MD. Graphic 55325 Version 1.0

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Initial screening, follow-up, and referral of patients with PHACE syndrome

The initial screening tests should be performed in every patient suspected to have PHACE syndrome. The decision regarding additional evaluation or referral should be made for the individual patient, based upon the results of the screening tests. PHACE: posterior fossa anomalies, hemangiomas, arterial anomalies, cardiac anomalies, and eye anomalies; MRI: magnetic resonance imaging; MRA: magnetic resonance angiography. * Ocular abnormalities that have been associated with PHACE syndrome: Retinal vascular abnormalities Persistent fetal vasculature Iris vessel hypertrophy "Morning-glory" disc Peripapillary staphyloma Optic nerve hypoplasia Microphthalmia Coloboma Congenital cataracts Sclerocornea Iris hypoplasia Exophthalmos Congenital third nerve palsy Horner syndrome ¶ Risk stratification in patients with PHACE syndrome based on severity of cerebral arterial anomalies: Low risk: Anomalous origin of arteries Variants in the circle of Willis Persistent fetal vessels Intermediate risk: Narrowing proximal to the circle of Willis but intact circle of Willis Stenosis of the proximal internal carotid artery if there is normal collateral flow in anterior cerebral artery and posterior cerebral artery High risk: >25% narrowing of principal cerebral vessels in association with an incomplete circle of Willis Tandem stenosis that causes a risk of diminished cerebral perfusion Signs of chronic or silent ischemia, existing infarction, border zone ischemic changes, presence of lenticulostriate collateral dilation, pial collaterals Original figure modified for this publication. Garzon MC, Epstein LG, Heyer GL, et at. PHACE Syndrome: Consensus-Derived Diagnosis and Care Recommendations. J Pediatr 2016; 178:24. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 110437 Version 3.0

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Risk stratification in patients with PHACE syndrome   Low risk

Description

Surveillance

Anomalous origin of arteries

Baseline scan only. Repeat imaging as needed for new symptoms.

Variants in the circle of Willis Persistent fetal vessels Intermediate risk

Narrowing proximal to the circle of Willis*

Referral to neurologist.

Stenosis of the proximal ICA if there is normal collateral flow in ACA and PCA

Repeat imaging when sedation no longer needed or sooner for new signs or symptoms. May be at increased risk later in life if additional risk factors arise (atherosclerosis or traumatic injury). Avoid contact sports and sports with extreme neck positions.

High risk

>25% narrowing of principal cerebral vessels

Referral to neurology.

In association with an incomplete circle of Willis

Repeat imaging at six months and one year. Then to be determined based on symptoms and progression.

Tandem stenosis that causes a risk of diminished cerebral perfusion Signs of chronic or silent

Avoid contact sports and sports with extreme neck positions. Aspirin 4 to 5 mg/kg/day up to 81 mg per day.

Ischemia

If progressive moyamoya, refer to tertiary care center with experienced neurologist and neurosurgeon.

Existing infarction Border zone ischemic changes Presence of lenticulostriate collateral dilation Pial collaterals

PHACE: posterior fossa anomalies, hemangiomas, arterial anomalies, cardiac anomalies, and eye anomalies; ICA: internal carotid artery; ACA: anterior cerebral artery; PCA: posterior cerebral artery. * Must have intact circle of Willis. Adapted from: Garzon MC, Epstein LG, Heyer GL, et al. PHACE Syndrome: Consensus-Derived Diagnosis and Care Recommendations. J Pediatr 2016; 178:24. Graphic 110883 Version 3.0

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH) Authors: Ilona J Frieden, MD, Denise Adams, MD Section Editor: Moise L Levy, MD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Sep 18, 2019.

INTRODUCTION Congenital hemangiomas (CHs) are rare, benign vascular tumors that, unlike infantile hemangiomas (IHs), are present and fully grown at birth. They present as bossed plaques or exophytic masses located on the head, neck, or limbs (picture 1A-B). Based upon their natural history, two major subtypes of CH have been recognized: rapidly involuting congenital hemangiomas (RICHs) and noninvoluting congenital hemangiomas (NICHs) [1,2]. In most cases, RICH involute completely by the age of 14 months, whereas NICH never regress but grow in proportion with somatic growth or, in rare cases, slowly expand. Infrequently, they require treatment due to pain or expanded size [3,4]. A third intermediate subtype, the so-called partially involuting congenital hemangioma (PICH), shows overlapping features of RICH and NICH [5]. CH will be discussed in this topic. IH and other vascular tumors of childhood and capillary malformations are discussed separately. ●

(See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications".)



(See "Infantile hemangiomas: Evaluation and diagnosis" and "Infantile hemangiomas: Management".)



(See "Infantile hemangiomas: Management".)



(See "Tufted angioma, kaposiform hemangioendothelioma, and the Kasabach-Merritt phenomenon".)



(See "Pyogenic granuloma (lobular capillary hemangioma)".)

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(See "Capillary malformations (port wine stains) and associated syndromes".)

EPIDEMIOLOGY The precise incidence of congenital hemangioma (CH) is unknown. In a prospective study, RICH occurred in 2 of 594 newborns (0.3 percent) [6]. In a retrospective review of 6459 children with vascular anomalies seen in a vascular anomalies center, CHs were diagnosed in 14 percent, infantile hemangiomas (IHs) in 43 percent, and capillary malformations in 30 percent [7]. In contrast with IH, there is no known association between CH and premature birth or multiple gestation [8].

PATHOGENESIS There is increasing evidence that most (or perhaps all) congenital hemangiomas (CHs), whether rapidly involuting, noninvoluting, or partially involuting, are due to somatic activating mutations in GNAQ and its paralog GNA11. Mutations that alter glutamine at amino acid 209 (Gln209) in GNAQ or GNA11 were found in all tested frozen-tissue samples from eight CHs collected during a clinically indicated procedure, at frequencies ranging from 3 to 33 percent [9]. The same mutations were found in three out of seven paraffin-embedded samples. The authors noted that since the same mutations are found in both NICH and RICH, other factors must account for the differing clinical presentations and postnatal behaviors. Mutations in this allele are also common in uveal melanoma and blue nevi and have been shown to constitutively activate mitogen-activated protein kinase (MAPK) and/or Yesassociated protein (YAP) signaling [10]. Mutations in GNAQ and GNA11 are a common cause of port wine stains, but they are typically found in other alleles, such as R183Q. In one case report, an infant with a very large CH, as well as innumerable small vascular tumors, was found to have a GNA11 mutation in the same allele in both the large tumor and in two of the smaller tumors [11]. Two other types of hemangiomas have also been described as being due to Gln209 GNAQ mutations: congenital hepatic hemangiomas [9] and anastomosing hemangiomas, a type of vascular tumor with adult onset that occurs mostly in the genitourinary tract and paravertebral soft tissues [12]. These genomic findings, together with immunohistochemical differences between CHs and infantile hemangiomas (IHs), as well as differing biomarker expression, confirm that they are distinct entities rather than variants of the same vascular tumor [13-15]. At the same time, they link together RICH, NICH, and partially involuting congenital hemangioma (PICH) as related entities, but the reasons they differ in clinical behavior are not well understood.  

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HISTOPATHOLOGY Both RICH and NICH consist of small to large lobules of capillary proliferations lined by endothelial cells with "hobnailed" nuclei, embedded in a dense fibrous stroma and surrounded by large dysplastic vessels (picture 2) [3,13]. Focal thromboses and calcifications may be seen; stromal hemosiderin deposits are common. Immunohistochemical staining for glucose transporter protein-1 (GLUT-1) is negative. This finding helps distinguish CH from infantile hemangiomas (IH), whose endothelial cells uniformly express GLUT-1 [14]. The lobular components of NICH and RICH stain for Wilms tumor 1 (WT1) protein, a transcription factor activated during angiogenesis, but the larger dysplastic vessels are WT1 negative [2,3,13,16-18].

CLINICAL FEATURES Overview — CH are present and fully grown at birth. They usually present as solitary, plaque-like or exophytic lesions of size varying from a few centimeters to more than 10 cm (picture 1A-D). The observation of a rapid involutive process beginning in the first days or weeks of life allows the distinction between RICH and NICH. Rapidly involuting congenital hemangiomas — RICH are most often located in the head and neck region (picture 1A) or lower extremities [1,19,20]. They vary in size from a few centimeters to 10 cm or more and are nearly always solitary, although multifocal lesions have been reported [21]. Several morphologic variants have been described, including: ●

A raised, violaceous, soft-tissue mass with prominent peripheral veins (picture 1A)



A soft-tissue mass with overlying prominent, coarse telangiectasias admixed with a blanched skin, including a halo of blanched skin at the periphery of the tumor (picture 1C)



A pink to violaceous tumor with a deeper dermal or subcutaneous infiltration



Exophytic vascular tumor with central ulceration [22]



A vascular tumor with overlying pustules [23]

On palpation, lesions are typically warmer than the surrounding skin; occasionally, a bruit can be heard or a thrill can be felt. The involution of RICH typically starts a few days to a few weeks after birth and, in most cases, is complete in 6 to 14 months. In rare instances, involution may occur in utero [24]. Involution leaves areas of skin redundancy with dermal or subcutaneous atrophy, textural and color changes, and

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persistent telangiectasias or scattered veins (picture 3). Other local sequelae include permanent alopecia, superficial scarring, and milia formation [1,16,25]. In a small proportion of patients with RICH, involution is incomplete and leaves a vascular plaque with coarse telangiectasias on the surface and a peripheral, bluish-white border indistinguishable from NICH [2]. (See 'Partially involuting congenital hemangiomas' below.) Hepatic rapidly involuting congenital hemangioma — RICH can also occur in the liver [26-28]. They present as an abdominal mass in an otherwise healthy infant. Transient thrombocytopenia and anemia are observed in some infants, presumably due to intralesional thrombosis. Arteriovenous shunting may result in heart failure and pulmonary hypertension. Although rare, these lesions can lead to instability in some neonates, with progressive liver failure and death. Ultrasonography demonstrates a well-circumscribed vascular mass with large feeding and draining vessels; coarse subcapsular calcifications can be seen after involution. On magnetic resonance imaging (MRI), the lesions are hyperintense on T2 imaging and hypointense on T1 imaging, with postcontrast imaging demonstrating early peripheral enhancement with eventual diffuse enhancement. Noninvoluting congenital hemangiomas — NICH are well-circumscribed, round to oval, plaque-like or bossed, soft-tissue masses; the color varies from pink to blue-red or purple [2]. Overlying telangiectasias and a rim of pallor are characteristic. NICH are typically flatter than RICH. Two morphologic variants have been described: a patch type, characterized by a flat or slightly atrophic surface, resembling a vascular stain (picture 4), and a nodular/plaque type, associated with prominent tissue swelling (picture 1B, 1D) [3]. The tumor size ranges from a few centimeters to more than 10 cm. In many cases, peripheral enlarged draining veins can be seen in the surrounding skin (picture 4). Ulceration, scarring, and atrophy are uncommon. On palpation, lesions are typically warm and may have areas of induration with well-circumscribed borders. NICH do not resolve spontaneously, but tend to enlarge proportionately with the child's growth (picture 5). Doppler examination shows persistent fast flow. Nearly half of patients in one retrospective case series reported some degree of pain within their lesions [3]. Although classically thought of as static in size, one case series found that 9 of 80 NICH (11 percent) had postnatal growth after an initial stable period, at ages 2 to 10 years (mean 5.3 years) [4]. Partially involuting congenital hemangiomas — In rare instances, CH involute rapidly during the first year of life, fulfilling the criteria for RICH, but fail to regress completely (picture 6). The residual tumor has the clinical, ultrasonographic, and histologic features of NICH [5,29]. In a series of eight patients with partially involuting congenital hemangiomas (PICH) followed up for 2.5 to 10 years, the hemangiomas decreased in size and thickness in 12 to 30 months and then stabilized [5]. The

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residual lesions appeared as red-purple patches or plaques with telangiectasias, prominent veins, and a pale rim; Doppler ultrasound imaging revealed low-resistance, high-velocity arterial flow. Complications ●

Ulceration – Ulceration with minor bleeding is a frequent complication of large CH, particularly during the involution phase. Severe bleeding due to ulceration involving large feeding vessels or trauma is a rare occurrence and may require early surgical excision [22,30-32].



Thrombocytopenia and coagulopathy – Transient thrombocytopenia and coagulopathy with hypofibrinogenemia and anemia are potential complications of RICH, especially in liver lesions. The thrombocytopenia is usually mild and typically resolves without treatment in a few weeks [33,34]. In a case series of seven patients with large RICH presenting with thrombocytopenia, low fibrinogen, and high fibrin split products, only one developed petechiae [33]. In all cases, thrombocytopenia and coagulopathy resolved in two weeks. Occasionally, transient thrombocytopenia in combination with coagulopathy and hypofibrinogenemia mimics the Kasabach-Merritt phenomenon (KMP), a life-threatening complication of other rare congenital vascular tumors (eg, tufted angioma [TA], hemangioendothelioma) characterized by profound and protracted thrombocytopenia and disseminated intravascular coagulation [33,35,36]. (See "Tufted angioma, kaposiform hemangioendothelioma, and the Kasabach-Merritt phenomenon".)



Heart failure – High-output heart failure from arteriovenous shunting and cardiac overload has been reported in a small number of infants with large CH (>7 cm) [34,37]. Heart failure is present at birth or develops in the first days of life. There are rare reports of prenatal diagnosis of heart failure in association with a CH [34]. (See "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Diagnostic evaluation'.)



Pain – A minority of NICH cause local pain, occasionally to the point where treatment is needed [3,4].

DIAGNOSIS In most cases, the diagnosis of CH is based upon history and physical examination. Imaging studies (eg, ultrasonography, magnetic resonance imaging [MRI], arteriography) may be helpful when the diagnosis is unclear. A biopsy for histologic examination is necessary if a malignant lesion is suspected. Additional evaluation, including laboratory and cardiac evaluation, may be needed in infants with suspected coagulopathy or congestive heart failure.

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Clinical examination — In most cases, the diagnosis of CH is made clinically in a newborn presenting with a fully grown soft-tissue mass with overlying telangiectasias and peripheral vasoconstriction (picture 1A-D). The presence of the tumor at the time of birth is an important clue to the diagnosis and an important criterion for differentiating CH from infantile hemangiomas (IH), which are usually not clinically evident at the time of delivery [1,38]. The observation of a rapid involution starting a few days after birth is usually sufficient to differentiate RICH from NICH. Imaging studies — Imaging studies (eg, ultrasonography, MRI, arteriography) may be needed when the diagnosis is unclear: ●

On ultrasonography, both RICH and NICH show a predominantly heterogeneous sonographic structure, diffuse vascularity, high vessel density, and, occasionally, calcifications [39]. Doppler examination reveals a high-flow vascular lesion [3]. In involuting lesions, long, tortuous, and compressible channels with a venous flow signal become a dominant feature [40]. The presence on B-mode and Doppler ultrasound of visible vessels, venous ectasia, venous lakes, and arteriovenous shunting in patients with RICH suggest increased risk of ulceration, bleeding, and, in the case of arteriovenous shunting, high-output congestive heart failure [41].



On MRI, RICH and NICH show heterogeneous enhancement, hyperintensity on T2-weighted sequences, flow voids, and absence of peripheral edema. Less defined borders and more fat stranding help distinguish CH from IH [39].



Angiography reveals heterogeneous parenchyma; large, irregular feeding arteries; venous ectasia; and, in some cases, micro-shunting [42]. Arterial aneurysms and arteriovenous shunts can also be seen.

Prenatal diagnosis — Because of their volume and vascularity, RICH are increasingly detected during prenatal ultrasound investigations, usually during the third trimester of pregnancy. Sonographic features include solid appearance with a homogeneous or slightly heterogeneous pattern isoechoic with the placenta, venous lakes mimicking a cystic component, hemosiderin deposits, and small calcifications [43]. If a RICH is noted on prenatal ultrasound, an antenatal MRI is recommended to define better the characteristics of the tumor. On fetal MRI, the signal of the lesion is slightly hyperintense or hypointense on T2-weighted sequences [43]. Biopsy — A biopsy for histopathologic examination should be performed if the diagnosis is uncertain or there is a clinical suspicion of malignant tumor (firmness on palpation, rapid growth, ulceration, and fixation to the fascia). Both RICH and NICH show similar histopathologic findings. The histologic finding of lobules of capillary proliferations embedded in a fibrous stroma containing hemosiderin

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deposits and surrounded by large dysplastic vessels confirms the diagnosis of CH. In contrast with IH, both RICH and NICH are glucose transporter protein-1 (GLUT-1) negative, but lobular areas may show positive staining for Wilms tumor 1 (WT1) protein [3]. Gene testing on frozen or paraffinembedded tissue for GNAQ or GNA11 mutations can help to confirm the diagnosis in uncertain cases [9,11]. Additional evaluation — Laboratory blood tests are not routinely performed in infants with small, uncomplicated CH. However, a complete blood cell count with platelet count and evaluation of the coagulation status (eg, fibrinogen concentration, fibrin split products [d-dimer]) may be warranted in newborns with large tumors at risk of thrombocytopenia and coagulopathy, especially tumors of the liver. (See "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management", section on 'Diagnostic evaluation to identify underlying cause'.) Comprehensive cardiac evaluation should be performed in infants with clinical signs of heart failure. (See "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Diagnostic evaluation'.)

DIFFERENTIAL DIAGNOSIS The differential diagnosis of CH includes other benign vascular tumors, vascular malformations, and benign and malignant nonvascular tumors [38]. ●

Infantile hemangioma – A diagnostic dilemma often arises when the patient’s parents report that a certain vascular growth "has been there since birth." It is particularly important to ascertain whether a palpable mass (suggesting CH) or just a flat area of discoloration was present at birth since the latter could represent a premonitory mark of infantile hemangioma (IH) (picture 7). A history of rapid postnatal growth usually differentiates IH from CH. When the diagnosis is uncertain, a tissue biopsy for immunohistochemical staining for glucose transporter protein-1 (GLUT-1) can clarify the diagnosis. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications", section on 'Clinical features'.)



Tufted angioma – Tufted angioma (TA) is an uncommon, benign vascular tumor that usually develops in early infancy but may be present at birth. It presents as an infiltrated, firm, dusky, red to violaceous plaque or nodule with typical, overlying hypertrichosis (picture 8). Histology shows vascular tufts of tightly packed capillaries, randomly dispersed throughout the dermis in a typical "cannonball distribution." TA is GLUT-1 negative. (See "Tufted angioma, kaposiform hemangioendothelioma, and the Kasabach-Merritt phenomenon", section on 'Tufted angioma'.)

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Kaposiform hemangioendothelioma – Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor that can be present at birth. KHE appears as a slightly raised, subcutaneous mass with a purpuric, bruised appearance (picture 9). It is often associated with the KasabachMerritt phenomenon (severe thrombocytopenia and coagulopathy). Histologically, KHE is characterized by spindled cells with minimal atypia and infrequent mitoses lining slit-like or crescentic vessels containing hemosiderin. The tumor is GLUT-1 negative. (See "Tufted angioma, kaposiform hemangioendothelioma, and the Kasabach-Merritt phenomenon", section on 'Kaposiform hemangioendothelioma'.)



Vascular malformations – Venous malformations are often present at birth as soft, compressible, blue soft-tissue mass or plaque. Doppler ultrasonography demonstrates a slowflow, ill-defined vascular lesion that is compressible on palpation. Histology shows ectatic venous-like channels with anomalies in mural cells. In contrast to CH, vascular malformations do not stain for cytoplasmic Wilms tumor 1 (WT1) [18]. (See "Capillary malformations (port wine stains) and associated syndromes".)



Infantile myofibromatosis/hemangiopericytoma – Infantile myofibromatosis is a rare, fibrous tissue tumor of infancy. In most cases, it presents at birth as solitary or multiple nodules from one-half to several centimeters in diameter of firm or rubbery consistency and variable colors (brown, blue, purple, or red) (picture 10) [44]. A biopsy is necessary to differentiate infantile myofibromatosis from CH. Histopathology shows a biphasic pattern of peripheral smooth muscle-like fascicles of spindle cells and central areas resembling hemangiopericytoma with rounded pericytes. Given their considerable clinical and histologic overlap, infantile myofibromatosis and infantile hemangiopericytoma are thought to be related entities or identical conditions in different maturation stages [45-47]. (See "Skin nodules in newborns and infants", section on 'Infantile myofibromatosis'.)



Lipoblastoma and lipoblastomatosis — Lipoblastoma is a rare, benign, infantile tumor that may be present at birth [48]. It presents as a well-circumscribed soft-tissue mass located in the subcutaneous tissue on the extremities, trunk, and head and neck area. Histology shows an admixture of mature and immature adipocytes.



Malignant tumors — Highly vascular malignant tumors (eg, infantile fibrosarcoma, rhabdomyosarcoma, dermatofibrosarcoma protuberans, metastatic neuroblastoma, angiosarcoma) may be present at birth and mimic CH [44]. Clinical signs that raise the suspicion of a malignant lesion and prompt a biopsy for histopathologic examination include firmness on palpation, rapid growth, ulceration, fixation to the fascia, and an atypical appearance on imaging. (See "Skin nodules in newborns and infants", section on 'Malignant tumors'.)

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MANAGEMENT Approach — The approach to the management of CH must be individualized based upon the tumor size and location, tendency to spontaneous involution, and presence of local or systemic complications. Consultation with a specialist or multidisciplinary group with special expertise in vascular anomalies may be warranted for infants with large tumors that are at increased risk of complications (eg, bleeding, thrombocytopenia, high-output cardiac failure) or tumors that do not show a tendency to regress in the first weeks of life [49]. Large, complicated liver CH should be evaluated by an interdisciplinary vascular anomaly team. It is important to educate the family about the natural history of CH, potential complications, and treatment options for noninvoluting lesions or residual skin changes after involution. Rapidly involuting congenital hemangiomas — RICH typically involute by age 14 months. Because RICH are self-resolving, treatment is usually not necessary, unless there are complications such as ulceration or bleeding. (See 'Treatment of complications' below.) Periodic clinical examinations are performed until complete involution has taken place. The time to involution has not been precisely determined. Evidence from small case series and case reports indicates that most RICH undergo complete regression in 12 to 14 months [1,8,19]. It is our practice to examine infants with RICH for at least 12 to 18 months, usually at monthly intervals, to confirm the expected decrease in size. Further assessment may be needed to evaluate any unexpected complications such as pain, ulceration, or infection and to assess whether involution is complete or partial. We do not recommend routine laboratory monitoring, unless abnormalities (eg, thrombocytopenia) were previously noted. However, once thrombocytopenia has resolved, laboratory testing is no longer necessary. During the rapid involution phase, the application of petrolatum to the lesion surface multiple times per day may be helpful in preventing ulceration [8]. Persistently ulcerated lesions or lesions with a history of repeated bleeding may require early surgical excision. (See 'Treatment of complications' below.) After involution is completed, residual skin changes can be corrected surgically. Pulsed-dye laser treatment may be helpful in reducing the appearance of superficial telangiectasias [50]. (See "Laser and light therapy for cutaneous vascular lesions", section on 'Involuting and resolved lesions'.) Noninvoluting congenital hemangiomas — NICH do not resolve over time, but treatment is not necessarily needed if they remain asymptomatic and do not bother the patient [2]. Pain or increased size may increase the need for treatment. In cases where treatment is indicated, pulsed-dye laser

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may help diminish superficial discoloration. For larger, thicker, or more symptomatic lesions, surgical excision is the treatment of choice. In a series of 53 patients (age 2 to 30 years) with NICH, 28 underwent surgical excision [2]. Preoperative arterial embolization was performed in seven patients. No intraoperative or postoperative complications were reported. The optimal timing for surgical excision has not been determined. Most experts recommend surgical excision during the preschool age, when the child begins to manifest a facial or body image [50]. Treatment of complications ●

Ulceration – Superficial ulcerations can be treated conservatively with meticulous wound care, which involves the use of topical antibiotics (eg, mupirocin 2% cream), barrier creams (eg, petrolatum), and nonadherent dressings [51]. Crusting should be debrided with diluted hydrogen peroxide or saline soaks two to three times daily since crusting prevents re-epithelization and favors infection. Pulsed-dye laser treatment may be a treatment option for ulcerations that do not respond to topical therapy. Pain associated with ulceration may be severe. Appropriate analgesia with oral acetaminophen or a topical anesthetic agent (ie, lidocaine hydrochloride 2% ointment) may be warranted. (See "Prevention and treatment of neonatal pain", section on 'Local analgesia' and "Prevention and treatment of neonatal pain", section on 'Systemic analgesia'.)



Bleeding – Minor bleeding can be controlled with compression. Persistent or major bleeding from ulceration or trauma may require arterial embolization and/or surgical excision of the tumor [22,31,32]. In two reported cases, control of minor bleeding from superficial ulcerations was successfully achieved with topical tranexamic acid and compression [30].



Thrombocytopenia and coagulopathy – The thrombocytopenia associated with CH is transient and usually resolves in a few weeks without treatment. Systemic corticosteroids have been used in a small number of infants with RICH and thrombocytopenia, but their role in the normalization of the platelet count remains uncertain [33].



Heart failure – For infants who develop CH-induced heart failure, embolization and/or surgical excision of the tumor in addition to medical treatment is required in most cases [34]. The medical management of congestive heart failure in infants and children is discussed separately. (See "Heart failure in children: Management".)

PROGNOSIS

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Infants with uncomplicated RICH have a favorable prognosis. The prognosis is guarded for infants with severe bleeding and infants who develop heart failure. In a review of 17 patients with large CH and heart failure, four died in the first weeks of life despite embolization or excision of the tumor and medical treatment of heart failure [34]. The prognosis of NICH is generally favorable. Lesions that are not excised grow in proportion with the child and persist unchanged throughout adulthood [2].

SUMMARY AND RECOMMENDATIONS ●

Congenital hemangiomas (CH) are rare, benign vascular tumors that are present and fully grown at birth. Based upon their natural history, two major subtypes have been recognized: rapidly involuting congenital hemangiomas (RICH) and noninvoluting congenital hemangiomas (NICH). (See 'Introduction' above.)



RICH usually present as solitary, violaceous, soft-tissue masses with coarse telangiectasias and prominent peripheral veins, most often located on the head, neck, or lower extremities (picture 1A, 1C). Involution typically starts a few days to weeks after birth and, in most cases, is complete in 6 to 14 months (picture 3). In some patients, involution may be incomplete, and the residual lesion is indistinguishable from NICH. (See 'Rapidly involuting congenital hemangiomas' above and 'Partially involuting congenital hemangiomas' above.)



NICH present as well-circumscribed, plaque-like or bossed, soft-tissue masses with overlying telangiectasias and a characteristic rim of pallor (picture 1B, 1D). NICH do not resolve spontaneously, but tend to grow proportionately with the child’s somatic growth. (See 'Noninvoluting congenital hemangiomas' above.)



The diagnosis of CH is made clinically in a newborn presenting with a fully grown, soft-tissue mass with overlying telangiectasias and peripheral vasoconstriction (picture 1A-D). The rapid involution starting a few days after birth differentiates RICH from NICH. Imaging studies (eg, ultrasonography, magnetic resonance imaging [MRI], arteriography) and/or a biopsy for histopathologic examination may be warranted if the diagnosis is unclear or a malignant tumor is suspected. (See 'Diagnosis' above.)



Because RICH are self-resolving, treatment is usually not necessary, unless there are complications. Periodic clinical examinations are performed until complete involution has taken place. (See 'Rapidly involuting congenital hemangiomas' above and 'Treatment of complications' above.)



NICH do not resolve over time, but treatment may be not necessary if they remain asymptomatic and do not bother the patient. For larger, thicker, or more symptomatic lesions, surgical excision

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is the treatment of choice. Most experts recommend surgical excision during the preschool age, when the child begins to manifest a facial or body image. (See 'Noninvoluting congenital hemangiomas' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 13727 Version 9.0

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GRAPHICS Rapidly involuting congenital hemangioma

A large scalp vascular mass was present at birth in this infant. Graphic 88800 Version 1.0

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Noninvoluting congenital hemangioma

A 40 x 55 mm bluish patch on the right clavicular area with an overlying red telangiectatic vascular mass in a two-year-old boy. The child was born with a vascular nodule on the right clavicular area. Contrary to expectations, this asymptomatic lesion has continued to slowly increase in size in proportion to the growth of the patient. Copyright © Albert Yan, MD, Dermatlas; http://www.dermatlas.org. Graphic 88907 Version 5.0

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Histopathologic features of congenital hemangiomas

(A) Large lobules of varying size. (B) Lobules composed of thin-walled capillaries. (C) "Hobnailed" endothelial cells. (D) Eosinophilic globules. (E) Dilated, malformed vessels. (F) Endothelial cells immunonegative for GLUT-1. Graphic 89836 Version 3.0

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Rapidly involuting congenital hemangioma

This healthy newborn had a congenital 4 cm subcutaneous purplish-blue rubbery tumor on the left leg, just below the knee. Note the surrounding pallor and overlying telangiectasias. Copyright © Jennifer Sawyer-Butler, Dermatlas; http://www.dermatlas.org. Graphic 88803 Version 4.0

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Noninvoluting congenital hemangioma

A 6 x 8 cm partially compressible bluish tumor with overlying red and purple papules and telangiectasias and surrounding pallor in a 10-month-old boy. The lesion was present at birth and showed no signs of growth or regression. Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org. Graphic 88908 Version 3.0

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Rapidly involuting congenital hemangiomas

This healthy 13-month-old boy had a firm bluish-purple plaque on his left leg at birth. The lesion flattened and lightened in color within six months and continued to regress without therapy, leaving a slightly atrophic 5 cm pale purple plaque with overlying telangiectasias. Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org. Graphic 88807 Version 3.0

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Noninvoluting congenital hemangioma (NICH)

Noninvoluting congenital hemangiomas presenting as a flat bluish lesion with overlying telangiectasias resembling a vascular stain.   Graphic 89389 Version 2.0

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Noninvoluting congenital hemangioma (NICH)

An 8 cm diameter soft compressible blue subcutaneous mass with overlying coarse telangiectasias and surrounding pallor on the arm of a 10-year-old girl. This soft-tissue mass was unchanged since birth. Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org. Graphic 89041 Version 3.0

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Noninvoluting congenital hemangioma (NICH)

A 10 cm soft partially compressible subcutaneous mass with central overlying scar and telangiectasias at the border. This three-year-old girl was thought to have a rapidly involuting congenital hemangioma. However, after some apparent regression following ulceration of the center of the lesion in early infancy, it changed little over the ensuing 2.5 years. Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org. Graphic 88948 Version 3.0

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Nascent infantile hemangioma

In some newborns, a patch of telangiectasias with surrounding pallor is a premonitory cutaneous mark of infantile hemangiomas. Graphic 89391 Version 1.0

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Tufted angioma

A large violaceous infiltrated plaque involving the left leg of an infant with tufted angioma. Graphic 89065 Version 1.0

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Kaposiform hemangioendothelioma (KHE)

An infant with kaposiform hemangioendothelioma associated with the Kasabach-Merritt phenomenon. Graphic 89100 Version 1.0

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Infantile myofibromatosis

Multiple scattered and disseminated 0.5 to 1.5 cm colorless, rubbery, subcutaneous nodules and red to violaceous, dermal nodules in a newborn with myofibromatosis. Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org. Graphic 89023 Version 4.0

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Sclerema neonatorum Author: Raegan Hunt, MD, PhD Section Editor: Moise L Levy, MD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Oct 16, 2018.

INTRODUCTION Sclerema neonatorum is an uncommon severe panniculitis that manifests as a diffuse skin hardening in critically ill, premature, and low-birthweight infants [1]. The hardened skin and subcutaneous fat become bound down and adherent to underlying muscle and bone, such that the basic functions of breathing, feeding, and movement are restricted. Affected infants suffer from comorbid illnesses, such as sepsis, dehydration, severe respiratory or gastrointestinal disease, and congenital malformations. Mortality is high; however, with current standards of neonatal intensive care, sclerema neonatorum is thought to be exceptionally uncommon. Regardless, cases of sclerema neonatorum occurring in neonatal intensive care settings continue to be reported [2], and it is important that clinicians are able to diagnose and treat this entity. This topic discusses the pathogenesis, clinical manifestations, diagnosis, and management of sclerema neonatorum. Subcutaneous fat necrosis of the newborn is discussed separately. (See "Subcutaneous fat necrosis of the newborn".)

EPIDEMIOLOGY Sclerema neonatorum characteristically affects newborn infants and typically develops within the first week of life, although a few cases have been reported to occur beyond the neonatal period. Aggregation of case reports suggests that males may be affected slightly more often than females (male to female ratio, 1.6:1) [1]. Maternal parity does not appear to be a risk factor [3].

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The incidence of sclerema neonatorum is not known. The largest case series have been published between 1940 and 1970, while fewer cases have been reported in last few decades [4]. It has been postulated that improved perinatal intensive care has substantially reduced the number of affected infants, rendering sclerema neonatorum a rare diagnosis in the setting of modern neonatal intensive care [5]. Limited data suggest that the incidence of sclerema neonatorum may be higher in areas with less access to high acuity neonatal care. A study evaluating premature newborns at a tertiary pediatric hospital in Bangladesh from 1998 to 2003 reported a 10 percent incidence of sclerema neonatorum [6].

PATHOGENESIS The pathogenesis of sclerema neonatorum remains unknown. Subcutaneous adipose tissue in neonates is enriched in saturated fats as compared with the subcutaneous fat composition of older individuals. This special biochemical property of neonatal fat makes it more likely to harden in a cold environment. It has been suggested that decreased body temperatures encountered in clinical shock trigger subcutaneous adipose hardening in sclerema neonatorum [7]. However, fat hardening should not occur until skin temperature is below the freezing point, which argues against this explanation. Additional theories propose that sclerema neonatorum is a consequence of abnormal fat metabolism, results from dysfunction of the connective tissue surrounding the adipocytes, or is a downstream effect triggered by systemic toxicity [8-10].

CLINICAL MANIFESTATIONS The affected skin in sclerema neonatorum is waxy-appearing, tight, and adherent to underlying tissues. In some infants, the skin may be purple or mottled. It cannot be lifted, pinched, or depressed. Sclerema neonatorum classically develops symmetrically on the trunk, thighs, or buttocks, but the skin hardening quickly spreads to involve the subcutaneous fat of the entire body except for the fatfree areas of the genitalia, palms, and soles. The hardening of the facial skin may manifest as a mask-like, fixed facies. The diffuse skin tightening limits the chest wall expansion and thus respiration, and it may also restrict feeding and other movement. Joint contractures are frequently noted. A case of severe extremity ischemia from a compartment syndrome-like effect in sclerema neonatorum has been described [11]. (See "Acute compartment syndrome of the extremities".) Clinical course — As sclerema neonatorum develops in seriously ill newborns and further restricts respiration and other vital functions, it is associated with a high mortality rate. Case series estimated

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that approximately 13 to 39 percent of affected neonates survive [1]. Among survivors, typically there are no long-term skin complications [12].

DIAGNOSIS The diagnosis of sclerema neonatorum is usually made clinically, based upon the observation of diffuse skin hardening in a gravely ill newborn. The affected skin is fixed to underlying tissue and cannot be folded, pinched, or pitted. If the diagnosis is in question, a skin biopsy may be valuable for histopathologic confirmation. (See 'Pathology' below.) Pathology — Histopathologic findings that support a diagnosis of sclerema neonatorum include [5,13]: ●

Necrosis of subcutaneous fat without significant inflammatory infiltrate and with no prominent granulomatous changes



Formation of needle-shaped clefts in adipocytes, sometimes in a radial arrangement



Fibrous thickening of tissue surrounding fat lobules

DIFFERENTIAL DIAGNOSIS Conditions that may mimic sclerema neonatorum include: ●

Subcutaneous fat necrosis of the newborn – Subcutaneous fat necrosis of the newborn typically presents around one to four weeks of life as circumscribed hardened areas of red-brown-tan skin in healthy-term or post-term neonates (picture 1). As opposed to sclerema neonatorum, lesions tend to remain localized, develop later in life, and, although firm, the skin freely moves over the underlying tissue (table 1). Risk factors for subcutaneous fat necrosis of the newborn include hypoxia, perinatal distress, and therapeutic hypothermia [14,15]. On histopathology, subcutaneous fat necrosis of the newborn demonstrates fat necrosis as well as numerous histiocytes, eosinophils, and multinucleated giant cells. Crystal cleft spaces similar to those in sclerema neonatorum may be observed within adipocytes, and calcification may be present [5,13]. In general, the clinical findings and the extensive inflammatory infiltrate encountered in subcutaneous fat necrosis of the newborn help distinguish it from sclerema neonatorum. (See "Subcutaneous fat necrosis of the newborn".)



Cold panniculitis – Cold panniculitis is characterized by erythematous, firm, well-demarcated plaques that develop at sites where the skin has been subjected to cold temperatures (picture 2)

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[14]. It appears within hours to a few days after cold exposure and resolves spontaneously. Cases of cold panniculitis in infants have been reported after application of ice to the face to treat supraventricular tachycardia and also after use of cooling blankets during cardiac surgery [16]. Whereas the clinical findings may be very similar, the histopathology of cold panniculitis lacks the characteristic needle-shaped clefts observed in subcutaneous fat necrosis of the newborn, and cystic spaces are often apparent where fat cells have presumably ruptured [13]. ●

Scleredema – Scleredema has been rarely described in neonates, particularly among infants exposed to cold temperatures or those with severe diarrhea or infection during the first week of life [17,18]. Affected skin is visibly thickened and wax-like. The legs are involved more frequently than other body sites. In contrast to sclerema neonatorum, the skin is edematous and exhibits easy pitting [1]. The dermis and subcutaneous fat appear edematous on histopathology with lymphohistiocytic inflammation noted in the fat lobules. Scleredema in adults (scleredema adultorum of Buschke) differs from that described in infants. Scleredema adultorum is associated with increased mucin disposition and thickened collagen. (See "Scleredema".)



Restrictive dermopathy – Restrictive dermopathy is a lethal genetic disease characterized by abnormally tight skin from birth. Affected newborns are usually premature and present with diffusely hard skin that may shear or tear at areas of skin folding, such as the neck, inguinal folds, and lower abdomen (picture 3A-B). Additional clinical findings include joint contractures, ectropion, chest wall narrowing, hypoplastic clavicles, and a fixed O-shaped mouth. This condition is associated with polyhydramnios and pulmonary hypoplasia and is generally fatal in the newborn period. Histopathology shows flattened rete ridges, thin dermis with horizontally oriented collagen, and incompletely developed skin appendages [19]. Recessive mutations in ZMPSTE24, which encodes a zinc metalloproteinase that processes the important nuclear envelope protein lamin A (encoded by LMNA), are responsible for most cases; however, dominant LMNA mutations have been found in restrictive dermopathy as well [20,21].



Hutchinson-Gilford progeria syndrome – Sclerodermatous skin tightening has been uncommonly reported in infants with Hutchinson-Gilford progeria, with the youngest reported affected child being approximately two weeks of age [22]. Findings of prominent skin veins, alopecia, frontal bossing, bird-like nose, and micrognathia support the diagnosis. Skin biopsy typically demonstrates thickened dermal collagen but is nonspecific. Most cases are due to an autosomal dominant LMNA mutation [23].

MANAGEMENT

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Diagnosis and treatment of concurrent illnesses is paramount for infants affected by sclerema neonatorum. Infections, metabolic disturbance, cardiac disease, and other congenital malformations must be treated promptly. Body temperature, fluid status, and electrolyte levels should be monitored and actively maintained within normal ranges. In the 1960s and 1970s, the use of systemic corticosteroids for sclerema neonatorum did not appear to improve survival, although in some cases systemic corticosteroids may have limited the extension of existing lesions [3,24-26]. A case report describes successful treatment of a 1550 g preterm infant with progressive sclerema neonatorum in the context of hypoglycemia and sepsis with parenteral hydrocortisone, antibiotics, and supportive intensive care management [27]. However, additional study is needed to determine the efficacy of systemic corticosteroids for treatment of sclerema neonatorum in the context of neonatal intensive care practices. Exchange transfusion has also been employed in the treatment of sclerema neonatorum [28-30]. One randomized clinical study reported 50 percent mortality in infants treated with exchange transfusion versus 95 percent in untreated infants. In a single case report, intravenous immunoglobulin infusion in a full-term infant with biopsy-proven sclerema neonatorum induced a transitory, mild clinical improvement of the skin, although the child died of respiratory failure secondary to chest wall skin tightening at six weeks of age [31].

SUMMARY AND RECOMMENDATIONS ●

Sclerema neonatorum is an uncommon severe panniculitis that develops in critically ill neonates. Premature and low-birthweight infants are the most susceptible. Affected infants suffer from comorbid disease including sepsis, congenital malformations, and severe respiratory or gastrointestinal illness. (See 'Introduction' above and 'Epidemiology' above.)



The affected skin in sclerema neonatorum is waxy, tight, and adherent to underlying tissues. The skin-hardening develops symmetrically on the trunk, thighs, and buttocks but quickly spreads to involve the subcutaneous fat of the entire body symmetrically, sparing the areas that lack subcutaneous fat, such as palms, soles, and genitalia. (See 'Clinical manifestations' above.)



The diagnosis of sclerema neonatorum is usually made clinically. If the diagnosis is uncertain, a skin biopsy may be helpful for confirmation. On histopathology, sclerema neonatorum shows needle-shaped clefts in adipocytes and fibrotic change around fat lobules without significant inflammation or granulomatous infiltrate. (See 'Diagnosis' above and 'Pathology' above.)



Sclerema neonatorum is associated with a high mortality rate. As the condition develops within the context of serious illness in premature and low-birthweight neonates, prompt diagnosis and

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treatment of associated disease is critical. Limited available data suggest that exchange transfusion may help reduce mortality in affected infants. (See 'Management' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 13737 Version 7.0

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GRAPHICS Subcutaneous fat necrosis of the newborn

Erythematous nodules and plaques in subcutaneous fat necrosis of the newborn. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 83790 Version 5.0

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Subcutaneous fat necrosis of the newborn versus sclerema neonatorum Clinical features

Subcutaneous fat necrosis of the newborn

Sclerema neonatorum

Onset

0 to 4 weeks of age

0 to 7 days of age

Gestational age

Usually term

Usually preterm

Associated conditions

Birth trauma, including asphyxia, mechanical trauma, thermal trauma

Serious underlying disease, including congenital malformations, sepsis, respiratory and gastrointestinal disease

Site and spread

Bony prominences; remains localized

Begins on trunk or lower limb and may become generalized; spares palms and soles

Morphology

Circumscribed subcutaneous plaques or nodules

Hard, wax-like skin and subcutaneous tissue; does not pit

Mobility

Move freely over muscles and bone

Bound to underlying muscle and bone

Histopathology

Fat necrosis; extensive granulomatous inflammatory infiltrate; needle-shaped clefts within adipocytes

Thickened fibrous septae; sparse nongranulomatous inflammatory infiltrate; needle-shaped clefts within adipocytes

Adapted from: Zeb A, Darmstadt GL. Sclerema neonatorum: a review of nomenclature, clinical presentation, histological features, differential diagnoses and management. J Perinatol 2008; 28:453. Graphic 70556 Version 5.0

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Cold panniculitis

An erythematous plaque is present on the cheek of this child with cold panniculitis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 83785 Version 4.0

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Restrictive dermopathy

Hard, adherent, and shiny skin in a premature neonate with restrictive dermopathy. Note the erosions at flexures sites. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 110284 Version 2.0

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Restrictive dermopathy

Hard, adherent, and shiny skin in a premature neonate with restrictive dermopathy. Courtesy of Moise Levy, MD. Graphic 112139 Version 1.0

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Skin lesions in the newborn and infant Authors: Erin Mathes, MD, Leah Lalor, MD Section Editors: Moise L Levy, MD, Leonard E Weisman, MD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Sep 03, 2019.

INTRODUCTION Benign skin and mucosal lesions seen in the newborn and infant are reviewed here. Vesicular, pustular, and bullous disorders; nodular lesions; cutaneous developmental anomalies; vascular lesions; and vascular tumors in the newborn and infant are discussed in more depth separately. Congenital nevi are also discussed separately. ●

(See "Vesicular, pustular, and bullous lesions in the newborn and infant".)



(See "Skin nodules in newborns and infants".)



(See "Cutaneous developmental anomalies in the newborn and infant".)



(See "Vascular lesions in the newborn".)



(See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications".)



(See "Rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH)".)



(See "Congenital melanocytic nevi".)

SKIN EXAMINATION OF THE NEWBORN AND INFANT Newborn skin may display a variety of findings [1]. These may be physiologic and transient or may represent a sign of a more serious condition, such as a genetic or developmental anomaly. Careful examination not only of the skin and mucous membranes, but also of the entire body for any associated abnormalities, is of utmost importance. (See "Assessment of the newborn infant".)

TRANSIENT PAPULAR AND PUSTULAR LESIONS

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Milia — Milia are white papules caused by retention of keratin and sebaceous material in the pilaceous follicles. They are frequently found on the nose and cheeks and resolve in the first few weeks of life [2]. Miliaria — Miliaria is a transient cutaneous eruption in newborns due to obstruction of sweat ducts. Hot and humid environments are particularly common causes. There are three different presentations (ie, miliaria crystallina (picture 1), miliaria rubra (picture 2), and miliaria profunda), depending on the depth of the obstruction. Miliaria is discussed separately. (See "Miliaria".) Sebaceous hyperplasia — Sebaceous hyperplasia presents with small (1 to 2 mm), white-yellow, smooth papules occurring most prominently on the face, particularly on the nose and upper lip, in up to one-half of normal newborns (picture 3) [1]. They gradually involute in the weeks after birth. Erythema toxicum neonatorum — Erythema toxicum neonatorum is a common pustular eruption seen more commonly in term neonates within the first 72 hours of life that resolves spontaneously within one week (picture 4). It is discussed separately. (See "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Erythema toxicum neonatorum'.) Neonatal cephalic pustulosis (neonatal acne) — Neonatal cephalic pustulosis (also called neonatal acne) is a pustular eruption on the head and neck of newborns with onset around three weeks of life (picture 5). Some studies have shown an association with Malassezia colonization. It resolves spontaneously without scarring in a few months but may be treated with topical azole antifungal preparations or mild topical steroids to speed clearance. (See "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Neonatal cephalic pustulosis'.) Benign cephalic histiocytosis — Benign cephalic histiocytosis (BCH), also called papular histiocytosis of the head, is a rare, self-healing type of non-Langerhans cell histiocytosis that typically occurs in infants and young children, with an average age of onset of 15 months [3,4]. BCH presents with small, yellow-red or yellow-brown, asymptomatic macules and/or papules located mostly on the head and neck (picture 6A-B). In some cases, lesions may extend to involve the trunk and upper and lower extremities. There is no visceral involvement. The diagnosis is in most cases clinical. However, if the diagnosis is in doubt, a skin biopsy for histology and immunostaining should be performed. The histopathologic hallmark of BCH is a well-circumscribed, histiocytic infiltrate in the superficial and reticular dermis [4]. Immunohistochemical staining of lesional cells demonstrates positive staining for factor XIIIa, fascin, and CD68 but negative staining for CD1a, langerin, and S100 (table 1). The differential diagnosis may include multiple Spitz nevi, juvenile xanthogranuloma, Langerhans cell histiocytosis, urticaria pigmentosa, and generalized eruptive histiocytosis. (See "Spitz nevus and atypical Spitz tumors" and "Juvenile xanthogranuloma (JXG)" and "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis" and "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in children".)

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Given the self-limiting nature of BCH, no treatment is needed. Lesions spontaneously regress over several months to years. Some resolve with superficial epidermal atrophy.

FOCAL PAPULES, VESICLES, AND BLISTERS Sucking blisters — Sucking blisters are typically single, noninflammatory vesicles or bullae on the wrists, hands, or fingers of newborns due to vigorous sucking in utero (picture 7). Sucking blisters are discussed separately. (See "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Sucking blisters'.) Oral inclusion cysts — Intraoral inclusion cysts are small, keratin-filled cysts, analogous to milia, presenting on the oral mucosa of up to nearly 90 percent of newborns [5,6]. They are called Epstein pearls when located on the palate and Bohn nodules when on the vestibular or lingual surfaces of the alveolar ridge (picture 8) [7]. They resolve spontaneously within a few months after birth. (See "Congenital anomalies of the jaw, mouth, oral cavity, and pharynx".) Median raphe cysts — Median raphe cysts are uncommon epidermal inclusion cysts that occur on the foreskin and ventral surface of the penis and scrotum [8,9]. They may enlarge throughout infancy and may require surgical removal if large or if they become infected.

SKIN COLOR CHANGES Benign causes of color changes in neonates include physiologic changes and vascular and melanocytic lesions. Pigmentary anomalies Melanin Dermal melanocytosis — Congenital dermal melanocytosis, also called Mongolian spot, is the most frequently encountered pigmented lesion in newborns. There are marked ethnic differences in prevalence [10-13]: ●

85 to 100 percent in Asian neonates



>60 percent in black neonates



46 to 70 percent in Hispanic neonates



2 cm, orthopedic referral may be warranted [15]. No sex predominance has consistently been demonstrated [14,17]. Associated abnormalities have been reported to occur in 27 to 80 percent of cases [18-20]. These include port-wine stain, body and limb asymmetry, glaucoma (especially with facial involvement), localized aplasia cutis congenita, cleft palate, or other malformations [17,19]. Capillary malformation-arteriovenous malformation syndrome — Capillary malformationarteriovenous malformation syndrome (CM-AVM, MIM #608354) is an autosomal dominant disorder caused by mutations in the RASA1 gene [21]. CM-AVM presents with multiple small capillary malformations associated with high-flow arteriovenous malformations and arteriovenous fistulas located in the soft tissues, bone, or central nervous system. Red punctate spots surrounded by pale halos, often with associated hypotrichosis, are frequent findings [22]. (See "Capillary malformations (port wine stains) and associated syndromes", section on 'Capillary malformation-arteriovenous malformation syndrome'.) Macrocephaly-capillary malformation syndrome — Macrocephaly-capillary malformation (M-CM) syndrome, previously named macrocephaly-cutis marmorata telangiectatica congenita (MIM #602501), is a genetic syndrome characterized by an enlarged head circumference and patchy, reticular capillary malformations that sometimes resemble CMTC, but with a finer, livedo-like pattern and no atrophy [23-25]. Other clinical features may include polydactyly/syndactyly, neonatal hypotonia, developmental delay, and structural brain abnormalities [23,26,27]. The vascular lesions often fade during the first few years of life. (See "Capillary malformations (port wine stains) and associated syndromes", section on 'Microcephaly-capillary malformation syndrome'.) Phakomatosis pigmentovascularis — Phakomatosis pigmentovascularis (PPV) is a rare syndrome characterized by the association of a capillary malformation with dermal melanocytosis (Mongolian spot, nevus of Ota), nevus spilus, or epidermal nevus. The etiology is thought to be a developmental abnormality of the vasomotor nerves and melanocytes, both derived from neural crest [28]. All ethnic groups may be affected [29]. Five types of PPV have been identified (table 1), the most common being type II or phakomatosis cesioflammea (port-wine stain plus blue spots such as nevus of Ota or

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Mongolian spots), formerly known as PPV types IIa and IIb [30,31]. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Dermal melanocytoses' and "Epidermal nevus and epidermal nevus syndrome".) Capillary malformation is present in most PPV types and is usually extensive. In one series of 15 PPV cases, all had facial capillary malformations, and 80 percent had additional capillary malformations in other areas [30]. As many as half of patients have other associated cutaneous lesions, most commonly nevus anemicus and café-au-lait spots [30]. It has been estimated that approximately 50 percent of patients have systemic involvement; neurologic, ocular, and skeletal abnormalities occur most frequently [30,32]. Neurologic abnormalities usually present in the first few months of life and include psychomotor retardation, seizures, intracranial calcifications, or cerebral atrophy [33]. Ocular involvement, such as blue-gray scleral discoloration, is also common. Management and outcome depend upon the presence of other associated conditions. Proteus syndrome — Proteus syndrome is an extremely rare disorder caused by somatic activating mutations in the AKT1 oncogene and characterized by asymmetric and disproportionate progressive overgrowth of body parts (picture 15) [34]. Cutaneous findings are present in approximately 40 percent of neonates and include capillary, lymphatic, or venous malformations; epidermal nevi; connective tissue nevi; lipomas; and café au lait macules. The vascular malformations are usually extensive, covering a large portion of the body, and may be associated with visceral vascular malformations. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Proteus and Proteus-like syndromes'.) CLOVES syndrome — Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies/scoliosis (CLOVES) syndrome (MIM #6129180) is a rare disorder caused by somatic mosaicism for postzygotic activating mutations in the PIK3CA gene on chromosome 3q26 [35]. The term PIK3CA-related overgrowth spectrum (PROS) is used to encompass multiple clinical syndromes with segmental tissue and/or vascular overgrowth associated with somatic PIK3CA mutations, including CLOVES, M-CM syndrome, fibroadipose overgrowth, and KTS [36,37]. (See "Klippel-Trenaunay syndrome: Clinical manifestations, diagnosis, and management", section on 'CLOVES syndrome'.) Patients with CLOVES syndrome present at birth with truncal, lipomatous masses of various sizes infiltrating the adjacent tissues; combined vascular malformations, including capillary, lymphatic, venous (phlebectasias), and arteriovenous malformations (geographic stains); hand and feet deformities (macrodactyly, "sandal gap" toe deformity); and scoliosis [38]. In contrast with Proteus syndrome, the overgrowth present at birth is nonprogressive.

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Patients with CLOVES syndrome have an increased risk of developing Wilms tumor (WT). In a review of 122 patients with CLOVES syndrome, 4 (3.3 percent) developed WT by the age of two years [39]. This incidence was significantly higher than that observed in the general population (1 in 10,000 births). Maffucci syndrome — Maffucci syndrome is a rare developmental disorder characterized by venous vascular malformations that may be present at birth and multiple enchondromas in early childhood [40]. Maffucci syndrome is caused by somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 and is associated with a substantial risk of malignant transformation of enchondroma to chondrosarcoma later in life [41]. (See "Venous malformations", section on 'Maffucci syndrome'.)

OTHER VASCULAR LESIONS Nevus anemicus — Nevus anemicus is a vascular anomaly presenting at birth as a pale area of the skin of various size and shape, usually located on the trunk (picture 16). It is caused by a localized, increased vascular sensitivity to endogenous catecholamines resulting in persistent vasoconstriction. On diascopy, which consists in applying pressure to the lesion and adjacent normal skin with a glass slide, nevus anemicus is indistinguishable from the surrounding skin. Nevus anemicus is in most cases an isolated finding but may occur in association with several genetic syndromes, including phakomatosis pigmentovascularis, neurofibromatosis, and tuberous sclerosis complex [42-45]. (See 'Phakomatosis pigmentovascularis' above and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis".) STING-associated vasculopathy with onset in infancy — Stimulator of interferon genes (STING)associated vasculopathy with onset in infancy (SAVI, MIM #615934) is an autoinflammatory disease caused by gain-of-function heterozygous mutations in the gene encoding STING (TMEM173, transmembrane protein 173, on chromosome 5q31.2), resulting in the upregulation of type 1 interferon signaling and elevated levels of interferon-induced cytokines in the peripheral blood [46]. Patients presents in early infancy with a hyperinflammatory state, severe cutaneous vasculopathy, and interstitial lung disease. (See "Periodic fever syndromes and other autoinflammatory diseases: An overview", section on 'STING-associated vasculopathy with onset in infancy'.) Cutaneous lesions include purple-red telangiectatic plaques, pustules, and blisters involving the cheeks, helix and lobule of the ears, tip of the nose, and dorsal side of the hands, fingers, and toes [46,47]. These lesions worsen with cold weather and may ulcerate, leading to tissue loss and severe scarring. Skin biopsy reveals microthrombotic vascular changes and a dense pericapillary lymphocytic and neutrophilic infiltrate with nuclear dust.

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SUMMARY AND RECOMMENDATIONS ●

Vascular lesions, including vascular neoplasms and vascular malformations, are common in newborns. Although the majority of these lesions are benign and self-limited conditions, some may be part of complex syndromes or systemic disorders or may be associated with complications. (See 'Introduction' above and 'Classification of vascular anomalies' above.)



Infantile hemangiomas are the most common benign tumors of infancy. Rare vascular tumors of the newborn include congenital hemangioma, tufted angioma and kaposiform hemangioendothelioma, and pyogenic granuloma. These tumors are discussed in detail separately. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications" and "Rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH)" and "Tufted angioma, kaposiform hemangioendothelioma, and the Kasabach-Merritt phenomenon".)



Vascular malformations are anomalies of vessel morphogenesis. Depending upon the type of involved vessels and flow characteristics, vascular malformation can be divided into low flow (capillary, venous, lymphatic, or combination) and high flow (arterial, arteriovenous). They may occur in isolation or in the setting of complex inherited and congenital disorders. (See 'Vascular malformations' above.)

• Capillary malformations appear as pink-red macular lesions on the skin or mucosa (picture 17). They are present at birth and generally persist throughout life, although some variants, such as nevus simplex, may fade and disappear during the first few years of life. Capillary malformations may be an isolated finding or occur in association with other cutaneous or systemic abnormalities in complex inherited or sporadic disorders. (See 'Capillary malformations' above and "Capillary malformations (port wine stains) and associated syndromes".)

• Lymphatic malformations (LM) are benign, slow-flow vascular lesions composed of dilated lymphatic channels or cysts lined by endothelial cells with a lymphatic phenotype. They are classified as macrocystic (cystic hygroma) (picture 6), microcystic (lymphangioma circumscriptum) (picture 7), and mixed type. (See 'Lymphatic malformations' above.)

• Venous malformations are low-flow vascular malformations presenting as bluish, ill-defined, compressible nodules or masses (picture 8). They may involve the skin, mucosa, deep soft tissues, and internal organs. Large lesions may develop a chronic localized intravascular coagulopathy that results in thrombosis or bleeding. (See 'Venous malformations' above.)

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• Arteriovenous malformations are composed of abnormal arteries, veins, and capillaries, with direct arteriovenous communications resulting in arteriovenous shunting. The may present clinically as capillary malformation-like lesions (picture 9) or purple-red, warm, painful lesions that may become ulcerated and bleed (picture 10). ●

Nevus anemicus is a vascular anomaly presenting at birth as a pale area of the skin of various size and shape, usually located on the trunk (picture 16). It is caused by a localized increased vascular sensitivity to endogenous catecholamines resulting in persistent vasoconstriction. Nevus anemicus is in most cases an isolated finding but may occur in association with phakomatosis pigmentovascularis, neurofibromatosis, or tuberous sclerosis complex. (See 'Nevus anemicus' above.)



STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease presenting in early infancy with a hyperinflammatory state, severe cutaneous vasculopathy, and interstitial lung disease. Vascular lesions include telangiectatic plaques, pustules, and blisters involving the cheeks, ears, tip of the nose, and dorsal side of the hands, fingers, and toes. (See 'STING-associated vasculopathy with onset in infancy' above.)

ACKNOWLEDGMENT The editorial staff at UpToDate would like to acknowledge Josie A Pielop, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Subscription and License Agreement. Topic 5789 Version 20.0

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GRAPHICS Noninvoluting congenital hemangioma

A 6 x 8 cm partially compressible bluish tumor with overlying red and purple papules and telangiectasias and surrounding pallor in a 10-month-old boy. The lesion was present at birth and showed no signs of growth or regression. Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org. Graphic 88908 Version 3.0

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Rapidly involuting congenital hemangioma

A large scalp vascular mass was present at birth in this infant. Graphic 88800 Version 1.0

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Pyogenic granuloma

Pyogenic granuloma presenting as friable, easily bleeding lesion on the nasal bridge of an infant. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 105762 Version 2.0

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Nevus simplex (also called "salmon patch" or "stork bite")

This splotchy pink mark fades with age. Reproduced with permission from: Fletcher M. Physical Diagnosis in Neonatology. Lippincott-Raven Publishers, Philadelphia 1998. Copyright ©1998 Lippincott Williams & Wilkins. Graphic 70234 Version 4.0

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Macular stain

An erythematous patch is present on the posterior scalp and neck of this infant. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 72513 Version 5.0

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Macular stain

Erythematous patches are present on the forehead and eyelids of this infant. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 81729 Version 5.0

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Port wine stain

A port wine stain in the V2 distribution is present on the face of this infant. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 59124 Version 6.0

8440

Port wine stain

A port wine stain, represented by an erythematous patch, is present in the V2 distribution on the face of this child. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 73978 Version 5.0

8441

Port wine stain

A port wine stain, manifesting as an erythematous patch with multiple small, vascular papules, is present on the leg of this adult. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 54078 Version 4.0

8442

Macrocystic lymphatic malformation (cystic hygroma)

Cystic hygroma presenting in a neonate as a large, soft mass in the axilla with overlying normal skin. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 105718 Version 4.0

8443

Microcystic lymphatic malformation (lymphangioma circumscriptum)

Multiple tense vesicles, some of which hemorrhagic, in the perianal area of an infant with microcystic lymphatic malformation. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 105768 Version 2.0

8444

Venous malformation

Venous malformation presenting in an infant as a bluish compressible lesion. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 105862 Version 2.0

8445

Cutaneous arteriovenous malformation

Arteriovenous malformation presenting as an erythematous patch on the leg of a young child. Superficial veins are visible. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 83553 Version 5.0

8446

Arteriovenous malformation

Arteriovenous malformation presenting as a vascular patch on the gluteus of a child. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 83576 Version 7.0

8447

Sturge-Weber syndrome

Bilateral port wine stains involving V1 are present on this infant with Sturge-Weber syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 60560 Version 4.0

8448

Bilateral port wine stains in a child with Sturge-Weber syndrome

Bilateral port wine stains are present on the face of this patient with Sturge-Weber syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 73343 Version 6.0

8449

Klippel-Trenaunay syndrome

A capillary malformation and limb hypertrophy are present on the right leg of this child with Klippel-Trenaunay syndrome. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 51296 Version 4.0

8450

Cutis marmorata

A net-like, violaceous pattern is visible on the legs of this infant. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 50846 Version 5.0

8451

Cutis marmorata telangiectatica congenita

Reticular, red patches with telangiectasias and focal atrophy are present on the arm. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 64092 Version 5.0

8452

Cutis marmorata telangiectatica congenita

Reticular, red patches with areas of atrophy and ulceration are present on the leg of this infant. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 74935 Version 5.0

8453

Classification of phakomatosis pigmentovascularis Type

Clinical features

I

Capillary malformation, epidermal nevus

II (Cesioflammea)

Capillary malformation, dermal melanosis (Mongolian spots, nevus of Ota)

III (Spilorosea)

Capillary malformation, nevus spilus, nevus anemicus

IV (Unclassified)

Capillary malformation, dermal melanosis (Mongolian spots, nevus of Ota), nevus spilus, nevus anemicus

V (Cesiomarmorata)

Cutis marmorata telangiectatica congenita, dermal melanosis

Data from: 1. Hasegawa Y, Yasuhara M. Phakomatosis pigmentovascularis type IVa. Arch Dermatol 1985;121:651. 2. Happle R. Phacomatosis pigmentovascularis revisited and reclassified. Arch Dermatol 2005;141:385. Graphic 105804 Version 2.0

8454

Proteus syndrome

Proteus syndrome presenting in a newborn with an asymmetric enlargement of the hand. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 83559 Version 6.0

8455

Nevus anemicus

A hypopigmented macule with irregular border is visible on the trunk of this infant. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 105713 Version 3.0

8456

Port wine stain in an infant

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 83601 Version 5.0

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Vasculitis in children: Evaluation overview Authors: David Cabral, MBBS, FRCPC, Kimberly Morishita, MD, MHSc, FRCPC Section Editor: Robert Sundel, MD Deputy Editor: Elizabeth TePas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 15, 2019.

INTRODUCTION Vasculitis is defined as the presence of inflammation in a blood vessel that may occur as a primary process or secondary to an underlying disease. Clinical symptoms vary widely depending upon the type and location of the vessels involved and the extent of inflammation [1]. Because of the multisystem nature of these disorders, many pediatric subspecialties, including rheumatology, dermatology, nephrology, pulmonology, and cardiology, may be involved in the diagnostic work-up and ongoing care of a child with vasculitis. Prompt recognition and treatment of these disorders are important as these can be severe and life-threatening conditions without appropriate management. The approach to evaluating a child with suspected vasculitis is reviewed here. The classification and overview of the management of childhood vasculitis are discussed separately. (See "Vasculitis in children: Incidence and classification" and "Vasculitis in children: Management overview".)

CLINICAL PRESENTATION Clinical symptoms vary widely depending upon the types and location of vessels involved, the extent of inflammation, and the degree to which vascular integrity has been compromised. Many patients ultimately diagnosed with a specific vasculitis will have presented initially with a combination of fever or other constitutional symptoms or signs (eg, weight loss, weakness, fatigue) and laboratory evidence of inflammation in addition to skin lesions. These early features are neither specific nor sensitive for vasculitis and may be found in other conditions including common infections. In patients with such nonspecific systemic symptoms, vasculitis should be suspected if symptoms do not resolve or improve within days to weeks, as would be expected in a "self-limited" infectious

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illness. In addition to systemic symptoms, the presence of multiorgan involvement should heighten one's suspicion of vasculitis, and certain patterns of organ involvement in the presence of inflammation may be diagnostic. (See "Vasculitis in children: Incidence and classification", section on 'Classification criteria'.) Kawasaki disease and immunoglobulin A (IgA) vasculitis (Henoch-Schönlein purpura), the most common forms of primary vasculitis in childhood, are described as acute vasculitides [2]. Although their disease courses are usually self-limited, the risk for sustained cardiac damage in Kawasaki disease and potential for persisting nephritis in IgA vasculitis (Henoch-Schönlein purpura) demand early recognition to mitigate the effects of these potential problems. Thus, familiarity with the characteristic features of these diseases is imperative. The combination of lower-extremity purpura, abdominal pain, joint pain, and glomerulonephritis suggests the diagnosis of IgA vasculitis (HenochSchönlein purpura) (picture 1), whereas the syndrome of persistent fever, conjunctivitis, rash, mucocutaneous changes, and swelling of the hands and feet suggests the diagnosis of Kawasaki disease (picture 2 and picture 3 and picture 4 and picture 5). Recognition of these combinations of features is often sufficient to make a "syndromic" diagnosis. Caregivers should be alert to evolving combinations of features when only a few features are initially present. (See "IgA vasculitis (HenochSchönlein purpura): Clinical manifestations and diagnosis", section on 'Diagnosis' and "Kawasaki disease: Clinical features and diagnosis".) The other primary vasculitides are chronic (eg, granulomatosis with polyangiitis, polyarteritis nodosa, microscopic polyangiitis, Takayasu arteritis) and relatively rare in childhood. Although characteristic patterns of clinical findings typical for individual vasculitides have been described for adults, the differentiating presenting features in children may be less clear. Often, children present with either incomplete or overlapping diagnostic features. As a result, many children with vasculitis have an "unclassifiable" disease. This was illustrated in reviews of two pediatric rheumatology registries from the early 1990s, which reported that up to two-thirds of children with chronic primary vasculitis did not fulfill diagnostic classification criteria [3,4]. In a survey of pediatric rheumatologists from the United States and Canada performed in 2005, clinicians reported that one-third of patients were categorized as having "unclassified vasculitis" [5].

REFERRAL Children who present with features consistent with IgA vasculitis (Henoch Schönlein purpura) or Kawasaki disease can be managed for the most part by general pediatricians. For those patients with more severe manifestations, or with vasculitis features that are less typical of IgA vasculitis

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(Henoch Schönlein purpura) or Kawasaki disease, referral should be made to a tertiary care center where the expertise of pediatric rheumatologists, nephrologists, dermatologists, and other subspecialists can be sought.

DIFFERENTIATING PRIMARY VASCULITIS FROM OTHER DISORDERS The majority of children with vasculitis are diagnosed by pattern recognition because the most common vasculitides, IgA vasculitis (Henoch-Schönlein purpura) and Kawasaki disease, have typical combinations of features that are diagnostic (see 'Clinical presentation' above). However, the diagnosis is more challenging in children with clinical features seen in chronic systemic vasculitis. These cases require a high index of suspicion since the features may overlap with common disorders, vasculitis may occur as a feature of other systemic disorders, and vasculitic features may be mimicked by other conditions [6]. In addition, the clinical presentation varies widely depending upon the type and location of the vessels involved, the extent of inflammation, and subsequent vessel wall damage with associated hemodynamic changes (table 1) [1]. Differential diagnosis — Because of the rarity of the primary vasculitides, when patients with overt, recognizable vasculitis syndromes such as Kawasaki disease or IgA vasculitis (Henoch-Schönlein purpura) have been excluded, a patient with clinical features "suggestive" of chronic vasculitis is more likely to have another disease. In the early stages of presentation, the differential diagnosis is broad (table 2): ●

Drugs – Antimicrobials, biologic agents, diuretics, anticonvulsants, and antithyroid medications



Infections:

• Bacterial/fungal – Subacute bacterial endocarditis and bacteremia, particularly meningococcemia, Group A streptococcal infections (see "Clinical manifestations of meningococcal infection")

• Viral – Human immunodeficiency virus (HIV), hepatitis, cytomegalovirus, Epstein-Barr virus, parvovirus B19, and herpes zoster/varicella

• Other organisms – Tuberculosis, syphilis, Rocky Mountain spotted fever, typhus, and rickettsial pox ●

Malignancy – Lymphoma, leukemia



Rheumatologic disorders:

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• Systemic lupus erythematosus (SLE) (see "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis")

• Systemic juvenile idiopathic arthritis (see "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis")

• Juvenile dermatomyositis (see "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations")

• Sarcoidosis (see "Clinical manifestations and diagnosis of pulmonary sarcoidosis") ●

Renal disorders – Anti-glomerular basement membrane (GBM) disease (Goodpasture's)



Monogenic disorders:

• Adenosine deaminase 2 (ADA2) deficiency (see "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis")

• STING-associated vasculopathy with onset in infancy (SAVI) (see "Periodic fever syndromes and other autoinflammatory diseases: An overview", section on 'STING-associated vasculopathy with onset in infancy') Differentiating the above listed mimics and secondary causes of vasculitis from primary vasculitis often requires a comprehensive evaluation while considering the differential diagnostic possibilities, including taking a complete history of symptoms and recent exposures (drugs or infectious) and thorough review of systems, alongside a careful physical examination and investigative work-up. A diagnosis of primary vasculitis can only be made once secondary causes or mimics of vasculitis have been eliminated. Monogenic disorders mimicking vasculitis are rare but should be considered in cases that present in infancy or very early childhood [7-10]. Even in the presence of apparent vasculitic lesions, there are noninflammatory mechanisms involving blood vessels that may cause similar findings [11,12]. For example, cutaneous lesions (eg, purpura) may be caused by vascular occlusion. The following noninflammatory mechanisms may mimic vasculitis by virtue of blood vessel occlusion: ●

Lesions outside the vessel wall – Neurofibromatosis (see "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis")



Lesions inside the vessel wall – Thrombocytopenia, thrombotic conditions (eg, antiphospholipid syndrome), and embolic conditions (eg, atrial myxoma) (see "Approach to the child with unexplained thrombocytopenia" and "Clinical manifestations of antiphospholipid syndrome")

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Spasm of the vessels – Drug-induced vasospasm (eg, ergot, cocaine, phenylpropanolamine) and Raynaud phenomenon (see "Clinical manifestations and diagnosis of Raynaud phenomenon")



Abnormal vessels themselves – Coarctation of the aorta and fibromuscular dysplasia (see "Clinical manifestations and diagnosis of coarctation of the aorta")

Further evaluation including imaging or histologic review of tissue samples from involved organs may be necessary to make a more definitive diagnosis, especially in children with severe disease who may require therapy that has potentially serious adverse effects. The diagnostic approach for each individual primary vasculitis is discussed in detail separately. (See appropriate topic reviews.) Initial evaluation — The initial evaluation while differentiating other disorders (see 'Differential diagnosis' above) includes a detailed history, comprehensive physical examination, and basic laboratory testing for all children and adolescents suspected of having vasculitis. History — Constitutional symptoms, such as malaise, fatigue, and fever, are frequently present; however, they are nonspecific. A careful and detailed history should identify which organ systems are affected and the extent and severity of their involvement. The history should include the following: ●

A thorough review of each major organ system to determine whether organs other than those implicated by the presenting complaint are involved and also to determine if there is a specific pattern of findings that may be suggestive or diagnostic of a particular disease.



Recent illness, particularly infections, either in the patient or in close contacts.



Recent travel to a tuberculosis-endemic country, which would raise suspicion of a mycobacterial infection.



Exposure to any medications or toxins that may cause secondary vasculitis.



History of any predisposing condition for secondary vasculitis, such as hepatitis, SLE, juvenile dermatomyositis, or malignancy.



A timeline of the symptoms. Children with IgA vasculitis (Henoch Schönlein purpura) and Kawasaki disease tend to have acute presentations with characteristic signs and symptoms, whereas children with other systemic vasculitides may present with a longer duration of symptoms that evolve and progress over time. Children with major organ involvement can present with variable durations of symptoms. These children may be extremely unwell, requiring admission to the hospital or the intensive care unit. Systemic inflammation with skin vasculitis

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that presents early in life should raise the suspicion of a monogenic disorder such as ADA2 or SAVI [7-10]. Physical examination — A thorough physical examination may reveal involvement of organs or systems that was not apparent from the medical history. Specific identified abnormalities (below) may support a diagnosis of vasculitis, whereas other findings such as hepatosplenomegaly or widespread lymphadenopathy may be more characteristic of a malignancy or a systemic infection. The physical examination should include: ●

Palpation of all pulses for volume and symmetry (reduced or absent pulses may be seen in Takayasu arteritis).



Measurement of blood pressure (BP). BPs should be measured manually and with the appropriate-sized cuff to optimize accuracy. In addition, BPs should be measured in all four limbs because a significant asymmetry (difference of >10 mmHg between limbs) raises the suspicion of Takayasu arteritis. BP values are compared with normative BP percentiles based upon data on gender, age, height, and BP measurements from the National Health and Nutrition Examination Survey (NHANES) and other population-based studies (table 3 and table 4). Elevated BP may be a marker of renal involvement that can occur in several vasculitides. (See "Definition and diagnosis of hypertension in children and adolescents".)



Auscultation of the neck, abdomen, and extremities to detect the presence of a bruit, which suggests altered blood flow through an affected vessel.



Examination of the respiratory system. Observe for signs of respiratory distress and assess oxygen saturation. Auscultate for stridor or other adventitious sounds.



Examination of the skin for lesions suggestive of vascular insufficiency or inflammation, such as palpable purpura, livedo reticularis (picture 6), nodules, ulcers, and nonblanching rashes.



Examination of the ocular fundi and periungual capillary beds for evidence of vascular abnormalities (picture 7). Referral to an ophthalmologist in cases of suspected vasculitis is warranted, especially in the presence of any ocular symptoms.

Laboratory evaluation — There are no specific laboratory tests to diagnose vasculitis. However, diagnosing active vasculitis in the absence of any evidence of inflammation is difficult. The initial laboratory analysis should include the following: ●

Complete blood count and differential – Elevated white blood cell count may be indicative of inflammation due to vasculitis or infection. Anemia can occur during inflammation or as part of

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a chronic disease. ●

Platelet count – To eliminate thrombocytopenia as the cause of the purpuric or petechial skin lesions. Platelets are also nonspecifically raised during inflammation.



Urinalysis – An abnormal urine sediment (eg, hematuria) may be the only sign of renal involvement in some cases of systemic vasculitis. Examination of a fresh-spun urine sample provides the highest yield for detecting dysmorphic red blood cells or red blood cell casts that are indicative of glomerulonephritis, the more severe manifestation of several types of vasculitis. (See "Glomerular disease: Evaluation in children".)



Liver enzymes – To detect hepatic involvement.



Serum creatinine and blood urea nitrogen – To detect renal involvement and evaluate renal function.



Erythrocyte sedimentation rate and/or C-reactive protein – As indicators of inflammation.

Clinical correlation with vessel size — Once diseases or conditions mimicking vasculitis or causing secondary vasculitis have been excluded and following comprehensive clinical history, physical examination, and basic laboratory evaluation, the next step is to reconcile whether the findings are consistent with one of the known types of primary vasculitis. The primary types of vasculitis are commonly classified and differentiated according to vessel size [13,14]. Nonspecific complaints (ie, fever, fatigue, anorexia, weight loss, and arthralgias) are generally present early in the course of the disease, irrespective of the size of the involved vessels. Clinical manifestations identified by repeat evaluations may become evident over time as the disease evolves, and these findings may correlate with the size of vessels involved. ●

Large- and medium-size vessels – When predominately large- or medium-sized vessels are involved (such as in patients with Takayasu arteritis or polyarteritis nodosa), symptoms and clinical manifestations of arterial insufficiency to the affected organs become apparent. Involvement of large vessels to the extremities, such as the subclavian or femoral arteries, leads to claudication, while involvement of the visceral vessels may lead to hypertension (renal arteries); abdominal pain, especially ischemic bowel pain such as postprandial pain or abdominal pain accompanied by gastrointestinal bleeding (mesenteric arteries); chest pain (aorta or coronary arteries); or neurologic symptoms (cerebral vasculature).



Small vessels – Inflammation of smaller vessels (such as in granulomatosis with polyangiitis, microscopic polyangiitis, IgA vasculitis (Henoch-Schönlein purpura), and eosinophilic granulomatosis with polyangiitis [Churg-Strauss]) leads to symptoms in richly vascularized

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organs including the skin, lungs, kidneys, gastrointestinal tract, and brain [1]. Symptoms and findings might include hemoptysis, abdominal complaints, hematuria, and neurologic dysfunction. Characteristic vasculitic skin lesions include palpable purpura (picture 1), livedo reticularis (picture 6), nonblanching lesions, nodules, ulcers, and palmar/plantar erythema. Further evaluation — If the diagnosis of a specific vasculitis is not clear after the initial assessment, additional investigations are used to confirm the presence of vasculitis and to identify the specific disorder, if possible. These include additional laboratory tests, organ-specific imaging and functional studies, and tissue biopsy. Additional laboratory testing — Other laboratory tests that may be helpful in confirming the presence of vasculitis or in making a specific diagnosis include: ●

Elevation of plasma von Willebrand factor (VWF) – VWF is an acute-phase reactant that is increased 50 to 75 percent in inflammatory conditions [15]. More dramatic elevations (three- to fourfold) occur with vascular endothelium injury due to inflammation of small- and mediumsized vessels. VWF is also elevated in patients with vascular damage due to stroke, trauma, and severe infection. It may be helpful in differentiating vasculitis from malignancy or more selflimited infections and, if abnormal, may be useful as a biomarker to track disease activity.



Antineutrophilic cytoplasmic antibodies (ANCAs) – ANCAs may be present in patients with small-vessel vasculitis. Perinuclear ANCA (pANCA) that is directed against myeloperoxidase (MPO) on immunofluorescence is associated with microscopic polyangiitis, whereas cytoplasmic ANCA (cANCA) that is directed against proteinase 3 (PR3) is associated with granulomatosis with polyangiitis [16-20]. The absence of ANCA in these conditions, however, does not necessarily preclude their diagnosis, as they are not present in all cases. Additionally, ANCA (mainly pANCA) can be detected in other autoimmune conditions, such as SLE, rheumatoid arthritis, and inflammatory bowel disease [18]. Thus, testing for ANCA is not useful, unless the pretest probability of a small-vessel vasculitis is high [21]. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies" and "Vasculitis in children: Incidence and classification".)



Antinuclear antibodies (ANAs) – If SLE is suspected in the differential diagnosis, then testing for ANAs is useful. A negative test result excludes SLE. A positive test is not valuable, because ANA is present both in the normal population and in other conditions. More specific autoantibody tests are required to support a diagnosis of SLE or other related conditions, such as mixed connective tissue disease. In addition, ANAs may interact with some assays of ANCAs, so knowledge of a patient's ANA status is also important for ruling out a false-positive ANCA. (See "Measurement and clinical significance of antinuclear antibodies".)

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Complement – Low serum complement levels may be present in essential mixed cryoglobulinemia, hypocomplementemic urticarial vasculitis, and SLE, but not in most other vasculitic disorders. Among those with cryoglobulins, infection with hepatitis C virus is in the differential. (See "Overview and clinical assessment of the complement system" and "Extrahepatic manifestations of hepatitis C virus infection".)



Anti-glomerular basement membrane (GBM) antibodies – GBM antibodies should be ordered in patients with pulmonary-renal syndrome (diffuse alveolar hemorrhage and glomerulonephritis seen in a variety of diseases including granulomatosis with polyangiitis, microscopic polyangiitis, and SLE) to rule out anti-GBM disease.



Tests for bacterial and viral infections – Evaluation for infectious diseases should include diagnostic studies to detect bacterial (eg, blood and urine cultures) or viral (eg, serology, culture, or rapid diagnostic studies) infections. (See "Fever of unknown origin in children: Evaluation", section on 'Overview of evaluation'.)

Organ-specific imaging and functional studies — Imaging and functional studies are used to evaluate involved organ systems or those that are suspected of being involved based upon the history, physical examination, and laboratory testing. The types of studies chosen will depend upon the particular organ system involved. ●

Pulmonary studies – For suspected pulmonary involvement, chest radiographs, pulmonary function tests (PFT), computed tomography (CT) scans, and sometimes bronchoalveolar lavage may be useful. Chest radiographs are simple and easily accessible. Findings such as infiltrates or nodules may be seen in pulmonary vasculitis (as part of granulomatosis with polyangiitis or microscopic polyangiitis) but can also be seen in infection. Measurement of the diffusing capacity of carbon monoxide (DLCO) may provide a noninvasive tool for identifying a pulmonary hemorrhage since the only condition that elevates the DLCO above 100 percent is blood in the airways [22]. If the patient is too sick to perform PFTs, or if consolidation, granulomata, or lymphadenopathy is suspected, further imaging such as chest CT may be indicated. However, some CT findings are nonspecific, and bronchoalveolar lavage may be needed to determine if an infiltrate seen on chest radiograph or CT is due to hemorrhage or infection, for example. PFT may show an obstructive pattern in eosinophilic granulomatosis with polyangiitis (ChurgStrauss) in keeping with asthma.



Cardiac and vascular studies – Patients with clinical cardiac involvement should have an echocardiogram to evaluate for both structural and functional abnormalities. The presence of coronary aneurysms with some other clinical features may be diagnostic of Kawasaki disease, although other vasculitides (such as polyarteritis nodosa), infections (Epstein-Barr virus), and

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inflammatory disorders (systemic juvenile idiopathic arthritis) also may cause coronary artery dilatation. Large- and medium-sized vessel abnormalities may be detected by Doppler ultrasound, CT angiogram/magnetic resonance arteriography (MRA), and conventional angiography (image 1). Such imaging should be pursued in children suspected of having Takayasu arteritis (large-vessel vasculitis), polyarteritis nodosa (predominantly medium-vessel vasculitis), or Kawasaki disease (when there is suspicion of vessel involvement beyond the coronary arteries). The imaging modality is best guided by the suspected location and size of involved vessels. As an example, Doppler ultrasound of the kidneys may be employed if renal artery involvement is suspected, while mesenteric angiography is indicated if gastrointestinal involvement is suspected, such as in polyarteritis nodosa. When larger vessels are involved, MRA of the aorta and great vessels, including some major branches, such as the coronaries and renal arteries, may be an alternative to contrast arteriography in children. When the two techniques were compared in 10 children with various vascular lesions (age range: 1 month to 16 years), excellent correlation was found between the images (r = 0.99) [23]. For conditions involving smaller vessels, conventional angiography remains the preferred imaging modality and is more likely to demonstrate abnormalities such as small-vessel aneurysms that are characteristic of polyarteritis nodosa. ●

Ear, nose, and throat studies – In children with suspected sinus disease, such as is found in granulomatosis with polyangiitis, sinus radiographs should be ordered and, in some cases, a sinus CT or magnetic resonance imaging (MRI) is required for confirmation. Findings on sinus imaging may include thickening of the sinus mucosa, opacification of the sinuses or paranasal sinuses, or bony thickening and destruction [24]. MRI may be better at demonstrating soft tissue abnormalities, including granulomas, but is less commonly ordered and does not characterize bone lesions well [25]. Bronchoscopy or upper-airway imaging studies may be needed to evaluate upper-airway symptoms suggestive of subglottic stenosis seen in granulomatosis with polyangiitis, particularly in pediatric cases [26]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Ear, nose, and throat' and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Tracheal and pulmonary disease'.)

Tissue biopsy — The gold standard for definitive diagnosis of a vasculitis remains histopathologic evidence of vascular inflammation. A tissue biopsy may be necessary if the diagnosis cannot be made on the basis of syndrome recognition with or without imaging studies. If the affected organ is easily accessible, such as the skin, the procedure is relatively minor and poses minimal risk to the patient. In the case of kidney involvement, there is a higher biopsy-associated risk but also a high

8467

diagnostic yield, and the information obtained about disease activity, extent, severity, and ultimately prognosis is valuable [27]. Some biopsies, such as nasal or transbronchial lung biopsy, have very low diagnostic yields. Other organs are less accessible, such as the brain or the lungs. In this setting, the risk of doing the biopsy plus the potential diagnostic yield is weighed against the risks of administrating a potentially longterm toxic treatment in a patient without diagnostic confirmation of a specific vasculitis. Such cases should be evaluated on their individual merits in consultation with experts.

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)

SUMMARY ●

Vasculitis is defined as the presence of inflammation in a blood vessel, which may occur as a primary process or secondary to an underlying disease. Prompt recognition and treatment of these disorders are important as they can rapidly evolve to being severe and life-threatening conditions without appropriate treatment. (See 'Introduction' above.)



The diagnosis of vasculitis should be considered in children and adolescents who present with persisting systemic symptoms and evidence of multiorgan dysfunction. Clinical symptoms vary widely depending upon the types and location of vessels involved, the extent of inflammation, and the degree to which vascular integrity has been compromised. In some cases, the initial presentation is restricted to a rash and nonspecific constitutional signs and symptoms, including fever, weight loss, weakness, or fatigue, which may be difficult to distinguish from findings seen in children with other disorders (table 1). However, in the majority of cases, a particular combination of findings or pattern of organ involvement (pattern or syndrome recognition) are indicative and sometimes sufficient to diagnosis a specific vasculitis, such as immunoglobulin A (IgA) vasculitis (Henoch-Schönlein purpura) or Kawasaki disease, the two most common causes of primary vasculitis in childhood. (See 'Clinical presentation' above.)



Patients with other disorders, including those associated with secondary vasculitis, can present with symptoms and findings similar to those with a primary vasculitis. A combination of clinical, pathologic, immunologic, and radiologic features will generally distinguish a primary vasculitis

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from other conditions including noninflammatory conditions (table 2). (See 'Differentiating primary vasculitis from other disorders' above.) ●

The initial evaluation of any child suspected of having vasculitis includes a detailed history, comprehensive physical examination, and basic laboratory testing. The goal is to both support a diagnosis of vasculitis and to exclude other, more common conditions that may present similarly. In most cases, the diagnosis of a primary vasculitis is made based upon clinical findings and pattern recognition of the characteristic findings associated with the specific disease. (See 'Initial evaluation' above.)



The primary vasculitides are commonly classified and differentiated according to vessel size. Early in the course of the disease, nonspecific complaints (ie, fever, fatigue, anorexia, weight loss, and arthralgias) are generally present irrespective of the size of the involved vessels, but over time and with further evaluation, some clinical features typically correlate with the size and location of vessel involvement. (See 'Clinical correlation with vessel size' above and "Vasculitis in children: Incidence and classification".)



If the diagnosis of a specific vasculitis is not clear after the initial assessment, additional investigations including imaging and tissue biopsy are used to differentiate vasculitis from other conditions and to determine the specific vasculitic disorder. (See 'Further evaluation' above.) Use of UpToDate is subject to the Subscription and License Agreement.

Topic 6430 Version 22.0

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GRAPHICS Skin manifestations of immunoglobulin A vasculitis (Henoch-Schönlein purpura)

Purpuric papules (palpable purpura) and macules on the lower extremities. Graphic 72094 Version 7.0

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Conjunctivitis in Kawasaki disease

Courtesy of Robert Sundel, MD. Graphic 78898 Version 2.0

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Strawberry tongue

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 68321 Version 4.0

8472

Cracked, red lips seen in Kawasaki disease

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 59319 Version 4.0

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Indurated edema of the dorsum of the hands as seen in Kawasaki disease (acute phase)

The erythema overlying the metacarpophalangeal and proximal interphalangeal joints is indicative of arthritis of the small joints of the hand. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 72040 Version 6.0

8474

Common or specific manifestations of childhood vasculitis at presentation Involved organ or system

Symptom or sign

Constitutional

Fever, weight loss, weakness, fatigue

Musculoskeletal

Arthralgia, myalgia, arthritis

Cutaneous

Palpable purpura, nodules, urticaria, livedoreticularis, superficial phlebitis, ischemic lesions, mucositis, oral/nasal/genital ulcers

Neurologic

Headache, stroke, mononeuritis multiplex

Head and neck

Sinusitis, chondritis, otitis, iritis

Renal

Nephritis, hypertension

Pulmonary

Hemorrhage, cavities, nodules, infiltrates

Cardiovascular

Chest pain, heart failure, limb claudication

Gastrointestinal

Abdominal pain, mesenteric ischemia, gastrointestinal hemorrhage

Laboratory

Anemia, elevated erythrocyte sedimentation rate, abnormal liver function tests, hematuria

Data reproduced with permission from: Churg A, Churg J. Systemic Vasculitides. Igaku-Shoin Medical Publishers. New York 1991. Copyright © 1991 Lippincott Williams & Wilkins.

http://www.lww.com Graphic 71389 Version 7.0

8475

Differential diagnosis for systemic vasculitis in children based upon pathologic process Lesions outside the vessel wall Neurofibromatosis Malignancy (tumors, lymph nodes)

Lesions inside the vessel wall Vessel thrombosis Disseminated intravascular coagulopathy Thrombotic thrombocytopenic purpura Antiphospholipid antibody syndrome Thrombosis secondary to malignancy Embolic disease (endocarditis, atrial myxoma) Thrombocytopenia of any cause Bleeding diatheses

Vessel spasms Raynaud's phenomenon Drug-induced vasospasm (eg, ergot, cocaine, phenylpropanolamine)

Abnormal vessels Coarctation of the aorta Fibromuscular dysplasia Graphic 69111 Version 2.0

8476

Blood pressure levels for boys by age and height percentile BP (percentile)

Systolic BP (mmHg)

Diastolic BP (mmHg)

Height percentile or measured height

Height percentile or measured height

5%

10%

25%

50%

75%

90%

95%

5%

10%

25%

50%

75%

90%

95%

Height (in)

30.4

30.8

31.6

32.4

33.3

34.1

34.6

30.4

30.8

31.6

32.4

33.3

34.1

34.6

Height (cm)

77.2

78.3

80.2

82.4

84.6

86.7

87.9

77.2

78.3

80.2

82.4

84.6

86.7

87.9

50 th

85

85

86

86

87

88

88

40

40

40

41

41

42

42

90 th

98

99

99

100

100

101

101

52

52

53

53

54

54

54

95 th

102

102

103

103

104

105

105

54

54

55

55

56

57

57

95 th + 12 mmHg

114

114

115

115

116

117

117

66

66

67

67

68

69

69

Height (in)

33.9

34.4

35.3

36.3

37.3

38.2

38.8

33.9

34.4

35.3

36.3

37.3

38.2

38.8

Height (cm)

1 year

2 years

86.1

87.4

89.6

92.1

94.7

97.1

98.5

86.1

87.4

89.6

92.1

94.7

97.1

98.5

50 th

87

87

88

89

89

90

91

43

43

44

44

45

46

46

90 th

100

100

101

102

103

103

104

55

55

56

56

57

58

58

95 th

104

105

105

106

107

107

108

57

58

58

59

60

61

61

95 th + 12

116

117

117

118

119

119

120

69

70

70

71

72

73

73

Height (in)

36.4

37.0

37.9

39.0

40.1

41.1

41.7

36.4

37.0

37.9

39.0

40.1

41.1

41.7

Height (cm)

92.5

93.9

96.3

99.0

101.8

104.3

105.8

92.5

93.9

96.3

99.0

101.8

104.3

105.8

50 th

88

89

89

90

91

92

92

45

46

46

47

48

49

49

90 th

101

102

102

103

104

105

105

58

58

59

59

60

61

61

95 th

106

106

107

107

108

109

109

60

61

61

62

63

64

64

95 th + 12 mmHg

118

118

119

119

120

121

121

72

73

73

74

75

76

76

Height (in)

38.8

39.4

40.5

41.7

42.9

43.9

44.5

38.8

39.4

40.5

41.7

42.9

43.9

44.5

Height (cm)

mmHg 3 years

4 years

98.5

100.2

102.9

105.9

108.9

111.5

113.2

98.5

100.2

102.9

105.9

108.9

111.5

113.2

50 th

90

90

91

92

93

94

94

48

49

49

50

51

52

52

90 th

102

103

104

105

105

106

107

60

61

62

62

63

64

64

95 th

107

107

108

108

109

110

110

63

64

65

66

67

67

68

95 th + 12

119

119

120

120

121

122

122

75

76

77

78

79

79

80

Height (in)

41.1

41.8

43.0

44.3

45.5

46.7

47.4

41.1

41.8

43.0

44.3

45.5

46.7

47.4

Height (cm)

104.4

106.2

109.1

112.4

115.7

118.6

120.3

104.4

106.2

109.1

112.4

115.7

118.6

120.3

50 th

91

92

93

94

95

96

96

51

51

52

53

54

55

55

90 th

103

104

105

106

107

108

108

63

64

65

65

66

67

67

95 th

107

108

109

109

110

111

112

66

67

68

69

70

70

71

mmHg 5 years

th

8477

95 th + 12 mmHg

119

120

121

121

122

123

124

78

79

80

81

82

82

83

Height (in)

43.4

44.2

45.4

46.8

48.2

49.4

50.2

43.4

44.2

45.4

46.8

48.2

49.4

50.2

Height (cm)

110.3

112.2

115.3

118.9

122.4

125.6

127.5

110.3

112.2

115.3

118.9

122.4

125.6

127.5

50 th

93

93

94

95

96

97

98

54

54

55

56

57

57

58

90 th

105

105

106

107

109

110

110

66

66

67

68

68

69

69

95 th

108

109

110

111

112

113

114

69

70

70

71

72

72

73

95 th + 12

120

121

122

123

124

125

126

81

82

82

83

84

84

85

Height (in)

45.7

46.5

47.8

49.3

50.8

52.1

52.9

45.7

46.5

47.8

49.3

50.8

52.1

52.9

Height (cm)

116.1

118.0

121.4

125.1

128.9

132.4

134.5

116.1

118.0

121.4

125.1

128.9

132.4

134.5

50 th

94

94

95

97

98

98

99

56

56

57

58

58

59

59

90 th

106

107

108

109

110

111

111

68

68

69

70

70

71

71

95 th

110

110

111

112

114

115

116

71

71

72

73

73

74

74

95 th + 12 mmHg

122

122

123

124

126

127

128

83

83

84

85

85

86

86

Height (in)

47.8

48.6

50.0

51.6

53.2

54.6

55.5

47.8

48.6

50.0

51.6

53.2

54.6

55.5

Height (cm)

6 years

mmHg 7 years

8 years

121.4

123.5

127.0

131.0

135.1

138.8

141.0

121.4

123.5

127.0

131.0

135.1

138.8

141.0

50 th

95

96

97

98

99

99

100

57

57

58

59

59

60

60

90 th

107

108

109

110

111

112

112

69

70

70

71

72

72

73

95 th

111

112

112

114

115

116

117

72

73

73

74

75

75

75

95 th + 12

123

124

124

126

127

128

129

84

85

85

86

87

87

87

Height (in)

49.6

50.5

52.0

53.7

55.4

56.9

57.9

49.6

50.5

52.0

53.7

55.4

56.9

57.9

Height (cm)

126.0

128.3

132.1

136.3

140.7

144.7

147.1

126.0

128.3

132.1

136.3

140.7

144.7

147.1

50 th

96

97

98

99

100

101

101

57

58

59

60

61

62

62

90 th

107

108

109

110

112

113

114

70

71

72

73

74

74

74

95 th

112

112

113

115

116

118

119

74

74

75

76

76

77

77

95 th + 12 mmHg

124

124

125

127

128

130

131

86

86

87

88

88

89

89

Height (in)

51.3

52.2

53.8

55.6

57.4

59.1

60.1

51.3

52.2

53.8

55.6

57.4

59.1

60.1

Height (cm)

130.2

132.7

136.7

141.3

145.9

150.1

152.7

130.2

132.7

136.7

141.3

145.9

150.1

152.7

50 th

97

98

99

100

101

102

103

59

60

61

62

63

63

64

90 th

108

109

111

112

113

115

116

72

73

74

74

75

75

76

95 th

112

113

114

116

118

120

121

76

76

77

77

78

78

78

95 th + 12 mmHg

124

125

126

128

130

132

133

88

88

89

89

90

90

90

53.0

54.0

55.7

57.6

59.6

61.3

62.4

53.0

54.0

55.7

57.6

59.6

61.3

62.4

mmHg 9 years

10 years

11 years Height (in)

8478

Height (cm)

134.7

137.3

141.5

146.4

151.3

155.8

158.6

134.7

137.3

141.5

146.4

151.3

155.8

158.6

50 th

99

99

101

102

103

104

106

61

61

62

63

63

63

63

90 th

110

111

112

114

116

117

118

74

74

75

75

75

76

76

95 th

114

114

116

118

120

123

124

77

78

78

78

78

78

78

95 th + 12

126

126

128

130

132

135

136

89

90

90

90

90

90

90

Height (in)

55.2

56.3

58.1

60.1

62.2

64.0

65.2

55.2

56.3

58.1

60.1

62.2

64.0

65.2

Height (cm)

140.3

143.0

147.5

152.7

157.9

162.6

165.5

140.3

143.0

147.5

152.7

157.9

162.6

165.5

50 th

101

101

102

104

106

108

109

61

62

62

62

62

63

63

90 th

113

114

115

117

119

121

122

75

75

75

75

75

76

76

95 th

116

117

118

121

124

126

128

78

78

78

78

78

79

79

95 th + 12 mmHg

128

129

130

133

136

138

140

90

90

90

90

90

91

91

Height (in)

57.9

59.1

61.0

63.1

65.2

67.1

68.3

57.9

59.1

61.0

63.1

65.2

67.1

68.3

Height (cm)

mmHg 12 years

13 years

147.0

150.0

154.9

160.3

165.7

170.5

173.4

147.0

150.0

154.9

160.3

165.7

170.5

173.4

50 th

103

104

105

108

110

111

112

61

60

61

62

63

64

65

90 th

115

116

118

121

124

126

126

74

74

74

75

76

77

77

95 th

119

120

122

125

128

130

131

78

78

78

78

80

81

81

95 th + 12

131

132

134

137

140

142

143

90

90

90

90

92

93

93

Height (in)

60.6

61.8

63.8

65.9

68.0

69.8

70.9

60.6

61.8

63.8

65.9

68.0

69.8

70.9

Height (cm)

153.8

156.9

162.0

167.5

172.7

177.4

180.1

153.8

156.9

162.0

167.5

172.7

177.4

180.1

50 th

105

106

109

111

112

113

113

60

60

62

64

65

66

67

90 th

119

120

123

126

127

128

129

74

74

75

77

78

79

80

95 th

123

125

127

130

132

133

134

77

78

79

81

82

83

84

95 th + 12

135

137

139

142

144

145

146

89

90

91

93

94

95

96

Height (in)

62.6

63.8

65.7

67.8

69.8

71.5

72.5

62.6

63.8

65.7

67.8

69.8

71.5

72.5

Height (cm)

159.0

162.0

166.9

172.2

177.2

181.6

184.2

159.0

162.0

166.9

172.2

177.2

181.6

184.2

50 th

108

110

112

113

114

114

114

61

62

64

65

66

67

68

90 th

123

124

126

128

129

130

130

75

76

78

79

80

81

81

95 th

127

129

131

132

134

135

135

78

79

81

83

84

85

85

95 th + 12 mmHg

139

141

143

144

146

147

147

90

91

93

95

96

97

97

Height (in)

63.8

64.9

66.8

68.8

70.7

72.4

73.4

63.8

64.9

66.8

68.8

70.7

72.4

73.4

Height (cm)

mmHg 14 years

mmHg 15 years

16 years

162.1

165.0

169.6

174.6

179.5

183.8

186.4

162.1

165.0

169.6

174.6

179.5

183.8

186.4

50 th

111

112

114

115

115

116

116

63

64

66

67

68

69

69

90 th

126

127

128

129

131

131

132

77

78

79

80

81

82

82

95 th

130

131

133

134

135

136

137

80

81

83

84

85

86

86

8479

95 th + 12 mmHg

142

143

145

146

147

148

149

92

93

95

96

97

98

98

Height (in)

64.5

65.5

67.3

69.2

71.1

72.8

73.8

64.5

65.5

67.3

69.2

71.1

72.8

73.8

Height (cm)

163.8

166.5

170.9

175.8

180.7

184.9

187.5

163.8

166.5

170.9

175.8

180.7

184.9

187.5

50 th

114

115

116

117

117

118

118

65

66

67

68

69

70

70

90 th

128

129

130

131

132

133

134

78

79

80

81

82

82

83

95 th

132

133

134

135

137

138

138

81

82

84

85

86

86

87

95 th + 12 mmHg

144

145

146

147

149

150

150

93

94

96

97

98

98

99

17 years

The 50 th, 90 th, and 95 th percentiles were derived by using quantile regression on the basis of normal-weight children (BMI 1 mcg/mL) in 25 percent of patients with VMs, in the absence of other conditions associated with D-dimer increase, such as cancer, inflammatory diseases, or thrombophilia. LIC is considered severe when high D-dimer levels (>1.8

8490

mcg/mL) are associated with low fibrinogen levels (5 cm in diameter

This grading system has a prognostic significance and may predict the response to sclerotherapy. Small and well-defined lesions (grade 1) have a better therapeutic response to sclerotherapy than grade 3 lesions [48]. Other imaging techniques that may be helpful include plain radiographs to detect pathognomonic phleboliths and computed tomography (CT) scans to evaluate bone infiltration. Phlebography (direct percutaneous contrast injection under fluoroscopy) is infrequently performed in the diagnostic setting. However, phlebography is usually performed prior to percutaneous sclerotherapy. (See 'Sclerotherapy' below.) Laboratory tests — In patients with suspected VMs, with or without a history of thrombotic events, the finding of elevated D-dimer blood levels (>0.5 mcg/mL) suggesting localized intravascular coagulopathy (LIC) is pathognomonic of VMs. (See 'Localized intravascular coagulopathy' above.) D-dimer level is a helpful biomarker for the diagnosis of VMs, with high specificity but low sensitivity, as approximately 40 percent of patients with VMs have D-dimer levels >0.5 mcg/mL and up to 25 percent have levels >1 mcg/mL. When D-dimer levels are elevated in a patient with a VM without any concurrent disease that may induce a D-dimer increase, the likelihood that a venous component is present is approximately 96 percent [34,35]. This is true for pure, isolated VMs (unifocal or multifocal), as well as for mixed and syndromic lesions (capillary-venous malformation and Klippel-Trenaunay syndrome). However, normal Ddimer levels cannot rule out a VM because small VMs may have limited intravascular clotting that does not result in elevated D-dimer levels.   D-dimer levels are also helpful in differentiating among variants of VMs as well as in distinguishing VMs from other vascular anomalies. As an example, D-dimer levels are normal in glomuvenous malformations, lymphatic malformations, Maffucci syndrome, and also in fast-flow lesions such as arteriovenous malformations. D-dimer levels are elevated in the majority of patients with KTS but not in those with Parkes

8494

Weber syndrome, which is commonly misdiagnosed as KTS [35]. (See "Klippel-Trenaunay syndrome: Clinical manifestations, diagnosis, and management" and "Klippel-Trenaunay syndrome: Clinical manifestations, diagnosis, and management", section on 'Parkes Weber syndrome'.)

DIFFERENTIAL DIAGNOSIS The differential diagnosis of VMs includes several conditions presenting as "blue lesions": ●

Cutaneous angiosarcoma – Cutaneous angiosarcoma is a rare, aggressive, malignant tumor arising in either blood or lymphatic vessels and characterized by uncontrolled proliferation of vascular endothelial cells. It occurs more frequently in the head and neck areas of older adult males [50]. These tumors present as diffuse and ecchymotic macular, nodular, or plaque-like lesions with rapid expansive growth and tendency to ulcerate. Histopathologic examination clarifies the diagnosis. (See "Head and neck sarcomas", section on 'Angiosarcoma'.)



Collateral venous network – Collateral venous network can result from a severe stenosis or agenesia of a deep venous trunk and may be misdiagnosed as a VM. Such collateral venous networks are asymptomatic and veins are histologically normal.



Lymphatic malformations – Lymphatic malformations (LMs) are often difficult to distinguish from VMs, particularly in case of hemorrhage into the lymphatic cysts, resulting in a blue coloration of the overlying skin. Compared with VMs, LMs are not compressible. Ultrasonography shows hypo- or anechoic cysts with thick septa and fluid levels, although these pathognomonic signs are not always present. D-dimers are usually normal in LMs, unless there is a large associated venous component, such as in KlippelTrenaunay syndrome. Histopathologic examination of LMs show positive D2-40 staining (podoplanin), a specific marker for lymphatic endothelial cells [42]. (See "Vascular lesions in the newborn", section on 'Lymphatic malformations' and "Klippel-Trenaunay syndrome: Clinical manifestations, diagnosis, and management".)



Infantile hemangiomas – Subcutaneous infantile hemangiomas (IHs) can mimic VMs. In contrast to VMs, this vascular tumor usually grows postnatally, between two weeks and two months of life, and regresses spontaneously from 10 to 12 months onwards during several years. Doppler ultrasound is the best examination to differentiate the fast-flow IH from the slow-flow VM. D-dimer levels are normal in IHs [51]. (See "Infantile hemangiomas: Evaluation and diagnosis".)



Dermal melanocytoses – Dermal melanocytoses, including the Mongolian spot, nevus of Ota, and blue nevi, arise from dermal melanocytes that never reached their normal site at the basal layer of the skin. The Mongolian spot is a congenital, large, macular, blue-gray pigmentation present in infants of EastAsian ancestry, but not limited to them, that typically disappears with puberty. It is commonly located in the lumbosacral region (picture 8). Nevi of Ota and Ito are dermal melanocytoses that differ from the Mongolian spot by having a speckled, rather than uniform, appearance. The nevus of Ota manifests as a unilateral discoloration of the face involving the periorbital region, sclera, conjunctiva, temple, forehead,

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malar area, and nose (picture 9). The nevus of Ito is localized in the supraclavicular, scapular, and deltoid region (picture 10). The common blue nevus is a well-circumscribed blue nodule or macular plaque seen on any site of the body. (See "Skin lesions in the newborn and infant", section on 'Dermal melanocytosis' and "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Congenital dermal melanocytosis (Mongolian spots)'.)

MANAGEMENT The management of patients with VMs involves an interdisciplinary team including a dermatologist, an interventional radiologist, a hematologist, a plastic and/or vascular surgeon, and an orthopedic surgeon. Patients with small VMs and mild symptoms may not need treatment. Indications for treatment include esthetic disfigurement, functional impairment, and pain [52]. The approach to management should be tailored for the individual patient, based upon location and extent of the malformation and the patient's preference. The main therapeutic modalities include elastic compression, sclerotherapy, and surgical resection. However, there are no randomized trials comparing the efficacy of these treatment modalities [53]. The choice of one modality over another or a combination of modalities is based upon limited evidence from observational studies, most of which have methodologic limitations, and clinical experience.   Supportive therapies Compression — Tailored compression garments are indicated for symptomatic and extensive VMs of the extremities in order to reduce pain and the risk of thrombosis. Compression is contraindicated in glomuvenous malformations (GVMs), as it increases pain, and is not effective in Maffucci syndrome. Pain control — In patients in whom pain persists despite compression and in those with lesions in anatomic sites that are not amenable to compression, low-dose aspirin and/or anti-inflammatory drugs are a therapeutic option. When pain is associated with localized intravascular coagulopathy (LIC), low molecular weight heparin at a dose of 100 anti-factor Xa units/kg/day is introduced for 20 days, or longer if pain relapses [34,40]. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Low molecular weight heparin'.) Coagulopathy control — Coagulation evaluation with measurement of blood levels of D-dimer and fibrinogen is mandatory before starting any surgical treatment. Patients with evidence of LIC (D-dimer >0.5 mcg/mL) may develop disseminated intravascular coagulation with increased risk of bleeding during surgery. Preventive treatment with low molecular weight heparin at a prophylactic dose of 100 anti-Xa/kg/day should be started 24 hours prior to any surgical procedure for a total of five to seven days [34,35]. Sclerotherapy — Sclerotherapy is the first-line treatment for VMs. Several sessions may be necessary. Sclerotherapy is performed to diminish the volume of the malformation before surgical treatment or may be the sole treatment in patients in whom surgery is technically not feasible. Prior to injecting a sclerosant

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agent, direct percutaneous phlebography should be performed to evaluate the VM architecture, flow rate, rate of venous drainage, and volume of contrast distribution [38].   A variety of sclerosing agents can be used to obliterate vascular channels. They are irritant chemicals that cause damage to the vascular endothelium with subsequent inflammation and fibrosis. (See "Liquid, foam, and glue sclerotherapy techniques for the treatment of lower extremity veins".) Due to the absence of large, randomized trials, it remains unclear which sclerosing agent is superior in terms of efficacy and safety [49,53,54]. Absolute ethanol has been considered to be the most effective sclerosant, but it can cause potential severe side effects [55,56]. Therefore, it should only be used by experienced interventional radiologists in a hospital setting [49]. A systematic review found that ethanol provides an average response rate, defined as improvement in symptoms or reduction in VM size, of approximately 74 percent (range, 27 to 100 percent) [53]. Ethanol is, however, a highly toxic agent with a rate of serious local and systemic complications between 8 and 28 percent [53,54,57]. Local complications, such as skin necrosis, pain, and blistering, are the most common side effects, occurring in approximately 8 percent of patients. Other possible complications include peripheral nerve injury (2 to 10 percent), transient pain, muscle contracture, deep vein thrombosis, pulmonary embolus, and cardiopulmonary collapse [49,55,58]. The quantity of ethanol can be reduced by the addition of ethylcellulose (gelified ethanol), as ethanol is trapped in the malformation by ethylcellulose, resulting in a prolonged contact time of ethanol with the vasculature. Efficacy on pain and functional and esthetic impairment seems to be similar to that reported with ethanol, but in contrast with absolute ethanol, which is administered under general anesthesia, gelified ethanol can be used under local anesthesia for the treatment of superficial lesions [59]. Other sclerosing agents that have been used for the treatment of VMs include detergents, such as polidocanol, sodium tetradecyl sulfate (STS), and microfoams [60-66]. Their superiority in terms of effectiveness compared with absolute ethanol has yet to be demonstrated [49]. Moreover, even if the overall rate of complications seems lower compared with ethanol sclerotherapy, severe adverse events have been reported with foam sclerotherapy [67-70]. In children with extensive head and neck malformations that involve the airways, it is necessary to consider the possibility of performing a tracheostomy prior to sclerotherapy or to have the child in mechanical ventilation for 48 to 72 hours after the procedure. Surgery — Surgery may be a therapeutic option for small VMs amenable to complete excision or for larger VMs with well-defined margins. Surgery alone is often performed for the treatment of GVMs due to their small size and low degree of invasion through adjacent tissues. For large VMs, surgery is rarely performed without prior sclerotherapy, due to difficulty obtaining surgical free margins, elevated risk of relapse, and high surgical morbidity. Surgical techniques may include simple excision and repair, skin graft, local skin expanders, or free fasciocutaneous or muscle flaps, depending upon the size and location of the malformation.

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Patients with high D-dimers and normal or low fibrinogen should receive prophylactic low molecular weight heparin 24 hours prior to surgery and for five to seven days postoperatively to avoid intraoperative and/or postoperative bleeding [34,71]. Targeted agents — The mammalian target of rapamycin (mTOR) inhibitor sirolimus (rapamycin) has emerged as a promising targeted therapy for VMs. The identification of mutation in the TIE2-PI3K-AKT-mTOR pathway led to the development of the first murine model of VMs; mice injected with TIE2-L914F-mutated human umbilical vein endothelial cells developed VMs histologically similar to those of patients with VMs [72]. In these mice, sirolimus decreased the proliferation of endothelial cells and inhibited the excessive activation of AKT, which is responsible for smooth muscle deficiency [72]. The efficacy of sirolimus (2 mg daily continuously) was subsequently evaluated in a pilot study of 6 patients with VMs refractory to standard treatments [72]. All patients experienced pain relief, functional improvement of the affected body part, and improved self-perceived quality of life. Sirolimus had an on/off effect on bleeding and oozing in patients with lymphatic malformations. Biologic markers (D-dimers and fibrinogen) improved, and magnetic resonance imaging (MRI) images showed significant decrease in volume after 12 months of treatment. Sirolimus was well tolerated in all these patients. Minor adverse effects included mucositis (50 percent), fatigue (33 percent), headache (33 percent), cutaneous rash (17 percent), and diarrhea (17 percent), all easily managed with symptomatic treatment. One patient presented a grade 3 stomatitis necessitating cessation of sirolimus, and one patient, with prior history of cutaneous basocellular carcinoma, presented a basocellular carcinoma after one year on treatment. Similar encouraging results have been reported on sirolimus treatment in several case studies on blue rubber bleb nevus syndrome, lymphatic malformations, and mixed malformations [73-76]. A phase II trial evaluated sirolimus in 19 patients with slow-flow malformations, including seven patients with VMs, six with lymphatic malformations, two with generalized lymphatic anomaly, one with capillary-venous malformations, two with Klippel-Trenaunay syndrome, and one with phosphatase and tensin homolog (PTEN) hamartoma syndrome. After one year of treatment, all patients experienced improved mobility or organ function; reduction of pain, bleeding, or oozing; or reduction or cessation of infections. These improvements appeared within three months from the start of sirolimus and were maintained. Although no clinical disappearance of the lesions was observed, the volume reduction induced by sirolimus allowed for the subsequent conventional treatment of two patients (sclerotherapy and surgery). Sirolimus was well tolerated; headache, skin rash, mucositis, fatigue, and diarrhea were the most frequent grade 1 to 2 adverse events. All were easily manageable with symptomatic treatment or temporary arrest. Mucositis was the most common grade 3 adverse event and led to definitive discontinuation of sirolimus in two patients (10.6 percent) despite dose adjustment [77]. Taken together, the results of these preliminary studies indicate that sirolimus is a useful addition to the available treatments for VMs. However, the optimal length of sirolimus treatment, timing of administration (before and/or after surgery or sclerotherapy), and its long-term safety remain to be determined.

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A prospective multicentric phase III trial (VASE, NCT02638389; European Union Drug Regulation Authorities Clinical Trials [EudraCT] Number: 2015-001703-32) is underway in Europe to evaluate the efficacy of sirolimus in pediatric and adult patients with VMs that are refractory to standard treatment.

FOLLOW-UP Regular clinical, imaging, and laboratory follow-up is indicated in all patients with VMs. Lesions often expand around puberty or during pregnancy, due to hormonal changes, and can become symptomatic. Coagulation evaluation is mandatory in all patients with VMs and before any therapeutic intervention or surgical procedure. Patients with evidence of localized intravascular coagulopathy (LIC) are at risk of developing disseminated intravascular coagulopathy with increased risk of bleeding during and after surgery. (See 'Coagulopathy control' above and "Disseminated intravascular coagulation (DIC) in adults: Evaluation and management".) Most patients with Klippel-Trenaunay syndrome have chronic LIC and need careful follow-up to detect venous thrombosis and/or pulmonary embolism. In these patients, however, elevated D-dimer levels cannot be used to screen for recent thrombosis. (See "Klippel-Trenaunay syndrome: Clinical manifestations, diagnosis, and management", section on 'Clotting disorders and thromboembolism'.) Patients with Maffucci syndrome need a close follow-up, due to the high risk of developing malignancies, such as chondrosarcoma, glioma, fibrosarcoma, and angiosarcoma [29,78].

PROGNOSIS Curative treatment of VMs is rarely possible and recurrence is common. Some patients may return 5 to 10 years later with symptoms and evidence of recurrent disease at a previously treated site. Patients with extensive disease may require repeated treatments over time and multimodal therapeutic strategies to control the disease.

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vascular anomalies".)

SUMMARY AND RECOMMENDATIONS ●

Venous malformations (VMs) are slow-flow vascular malformations resulting from inborn errors in the development of the venous network. They consist of dilated and dysfunctional veins that are deficient in smooth muscle cells. In most cases, VMs occur sporadically, but they can rarely be inherited in an autosomal dominant fashion. (See 'Introduction' above and 'Pathogenesis' above.)

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The slow flow through the dilated and ectatic vessels results in blood stagnation and localized intravascular coagulation, reflected by elevated blood levels of D-dimer (>0.5 mcg/mL) and normal or low fibrinogen. (See 'Pathophysiology' above.)



VMs typically manifest as a light to dark blue skin discoloration overlying a soft, compressible, subcutaneous mass (picture 1). However, the clinical presentation may be highly variable, depending upon the size, location, and mass effect of the lesion on the adjacent organs. (See 'Clinical presentation' above.)



The diagnosis of VM is based upon the clinical finding of a solitary blue lesion present since birth that is soft and compressible and not painful on palpation. Typically, there is no thrill or bruit, and the affected area is not warmer than the surrounding areas. Doppler ultrasound and magnetic resonance imaging can confirm the diagnosis and assess the VM extension and infiltration into adjacent organs and structures. (See 'Diagnosis' above.)



The management of patients with VMs involves an interdisciplinary team including a dermatologist, an interventional radiologist, a hematologist, and a plastic and/or vascular surgeon, ideally in a specialized center for vascular anomalies. Treatment should be individualized and may include supportive therapies (compression, medical management of coagulopathy, and pain control), sclerotherapy, and surgery, alone or in combination. (See 'Management' above.)



The mammalian target of rapamycin (mTOR) inhibitor sirolimus has emerged as a promising treatment for complex VMs. Its efficacy and safety is being evaluated in ongoing clinical trials. (See 'Targeted agents' above.) Use of UpToDate is subject to the Subscription and License Agreement.

Topic 110155 Version 7.0

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GRAPHICS Venous malformation

Venous malformation presenting in an infant as a bluish compressible lesion. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 105862 Version 2.0

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Cutaneomucosal venous malformation

Courtesy of Laurence M Boon, MD, PhD. Graphic 113693 Version 1.0

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Multifocal venous malformation

Venous malformation located in the subcutaneous tissue in a patient with sporadic multifocal venous malformations. Courtesy of Laurence M Boon, MD, PhD. Graphic 113717 Version 1.0

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Glomuvenous malformation

Glomuvenous malformation in a plaque-like configuration on the thigh of a 52-year-old male patient. Courtesy of Laurence M Boon, MD, PhD. Graphic 113694 Version 1.0

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Blue rubber bleb nevus syndrome

Venous malformations involving the small bowel in a six-year-old child with blue rubber bleb nevus syndrome.  Courtesy of Laurence M Boon, MD, PhD. Graphic 113695 Version 1.0

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Maffucci syndrome

A) Radiograph demonstrates multiple soft-tissue masses and calcified thrombi in association with expansile bony lesions. B) Late film from an arteriogram shows contrast material filling many cavernous hemangiomas of the soft tissues. Reproduced with permission from: Eisenberg RL. An Atlas of Differential Diagnosis, Fourth Edition. Philadelphia: Lippincott Williams & Wilkins, 2003. Copyright © 2003 Lippincott Williams & Wilkins. Graphic 70081 Version 3.0

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Maffucci syndrome

Large venous malformations and severe deformity of the hand in a patient with Maffucci syndrome. Courtesy of Laurence M Boon, MD, PhD. Graphic 113696 Version 1.0

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Magnetic resonance imaging of a large venous malformation

Coronal T2-weighted MRI of the shoulder showing an extensive venous malformation involving subcutaneous fat and muscles of the shoulder and thoracic wall. MRI: magnetic resonance imaging. Courtesy of Laurence M Boon, MD, PhD. Graphic 113697 Version 1.0

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Venous malformation

Large venous malformation of the shoulder and thoracic wall. Courtesy of Laurence M Boon, MD, PhD. Graphic 113698 Version 1.0

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Congenital dermal melanocytosis (Mongolian spots)

Multiple gray-blue patches on the back and buttocks of an infant. Courtesy of the Yale Dermatology Residents' Slide Collection. Graphic 77805 Version 3.0

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Nevus of Ota (oculodermal melanocytosis, nevus fuscocaeruleus ophthalmomaxillaris)

Mottled blue-black patch in the left periorbital area, with involvement of the conjunctiva and sclera of the left eye. Courtesy of Jean L Bolognia, MD, and Julie V Schaffer, MD. Graphic 77921 Version 1.0

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Nevus of Ito

Nevus of Ito presenting as a blue-gray patch on the scapular area. Note the mottled appearance of the pigmentation. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 94990 Version 2.0

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection Author: Craig A Elmets, MD Section Editors: Robert P Dellavalle, MD, PhD, MSPH, Jeffrey Callen, MD, FACP, FAAD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jul 12, 2017.

INTRODUCTION Photosensitivity is an abnormal cutaneous response to ultraviolet radiation (UVR) and, in some individuals, visible light. Depending upon the type of photosensitivity disease, the abnormal response can manifest as macular erythema, papules, plaques, vesicles, bullae, telangiectasias, or eczematous patches. For some photosensitivity diseases, the rash may result in scarring. One of the key features in establishing the diagnosis of a photosensitive eruption is its distribution. In most instances, it occurs on sun-exposed areas of the skin; the face, ears, dorsal forearms, "V"-area of the neck, and upper chest are commonly affected sites. However, occasionally it can occur on covered areas of the body, especially in individuals who use tanning beds. The principles of photobiology, evaluation of the photosensitive patient, and general recommendations for photoprotection in the photosensitive patient will be reviewed here. The diagnosis and treatment of specific photosensitivity conditions and sunburn are discussed separately. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment" and "Polymorphous light eruption" and "Sunburn".)

PHOTOBIOLOGY Ultraviolet radiation (UVR) emitted from the sun is divided into three wavelength ranges: ultraviolet A (UVA, 320 to 400 nm), ultraviolet B (UVB, 290 to 320 nm), and ultraviolet C (UVC, 200 to 290 nm). UVC is absorbed by the ozone layer in the atmosphere [1]. Because of this, UVC does not reach the earth's surface and usually does not play a role in inducing photosensitivity. However, it is emitted by germicidal lamps and welding arcs and has been rarely reported to provoke photosensitivity in individuals with occupational exposure. UVA and some UVB penetrate the atmosphere and reach the earth's surface. Patients with photosensitivity may react to UVA, UVB, or visible light (400 to 760 nm) (figure 1). Longer wavelengths penetrate deeper into the skin. UVA passes through the epidermis and into the dermis, whereas UVB enters into the epidermis, but little reaches the dermis. UVR has multiple effects on the skin. Notably, UVR causes DNA damage and mutations, which are initiating events in skin carcinogenesis. UV-induced immunosuppression may also contribute to the development of skin cancers by interfering with the ability of the immune system to identify and eliminate neoplastic cells before they become clinically apparent skin cancers. A further effect of UVR is the generation of reactive oxygen species, such as singlet oxygen, superoxide anion and hydrogen peroxide. The generation of reactive oxygen species leads, among other things, to lipid peroxidation, DNA damage, and activation of signal transduction pathways. These effects have been implicated in the pathogenesis of skin cancer, photoaging, and inflammatory responses in photosensitivity disorders.

EVALUATION OF PATIENTS WITH PHOTOSENSITIVITY DISORDERS Photosensitivity disorders of the skin are conditions in which an abnormal cutaneous response occurs after exposure to ultraviolet radiation or visible light. The major categories include idiopathic photodermatoses, photodermatoses due to exogenous or endogenous agents, photoexacerbated dermatoses, and photosensitive genodermatoses. A table describing the clinical and diagnostic findings of many of the disorders is provided (table 1). Detailed discussions of these disorders are available separately.

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(See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment".)



(See "Polymorphous light eruption".)



(See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)



(See "Pseudoporphyria".)

PATIENT EVALUATION The initial evaluation of the photosensitive patient involves taking a thorough history and performing a complete skin examination. Phototesting and photopatch testing, as well as laboratory evaluation, are useful in certain cases. Patient history — A detailed history should include (table 1) [2]: ●

Age of onset



Length of time between exposure and the appearance of the eruption



Duration of the eruption



Location of the eruption



Description of the eruption (useful in patients who present without active lesions)



Symptoms (eg, pruritus, pain, burning, and stinging)



Whether the eruption is induced by sun-exposure through window glass



Seasonal variation



Tanning bed use



Family history of photosensitivity



Medication history (current and past)



History of products applied to skin (exposure to photosensitizers)



Occupational and recreational activities



Prior history of photoexacerbated dermatoses (see "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoexacerbated dermatoses')

These features can be used to narrow the differential diagnosis of photosensitivity (table 1). A report of childhood onset may suggest diagnoses such as hydroa vacciniforme, actinic prurigo, or erythropoietic protoporphyria. In contrast, chronic actinic dermatitis typically occurs in adults and in older adults [3]. A complaint of painful skin with sun exposure may suggest a diagnosis of erythropoietic protoporphyria instead of other photodermatoses that are characteristically pruritic. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment" and "Congenital erythropoietic porphyria".) Transient hive-like lesions appearing within minutes of sun exposure suggest solar urticaria rather than polymorphous light eruption (PMLE). PMLE typically appears hours to days after sun exposure, most commonly as papules and papulovesicles, and persists for days. A history of reaction to sunlight passing through window glass indicates an ultraviolet A (UVA)-sensitive photodermatosis, because ultraviolet B (UVB), unlike UVA, does not penetrate through window glass. Patients often fail to distinguish between sun exposure and exposure to heat. Care must be taken to establish that UV, rather than heat, is responsible for provoking the disease. Review of the patient's past and present medications is important in determining a drug-related cause. Details about outdoor activities, occupation, and recreation are helpful in distinguishing a true photosensitivity eruption from an airborne allergic contact dermatitis, irritant dermatitis, or arthropod bites. Lastly, a history of an underlying disease may bring a photoexacerbated disorder into the differential diagnosis. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoexacerbated dermatoses'.) Physical examination — Skin examination should include both sun-exposed and unexposed areas. Photosensitive eruptions typically occur symmetrically on the face, ears, "V" area on the neck and chest, and extensor forearms. Sparing of the relatively shaded area of the upper lip, submental neck, upper eyelids, nasolabial folds, and post-auricular areas may be clues for a photosensitive eruption. Assessment of the type of lesions (eg, urticaria, papules, or vesicles) is essential. Key features for narrowing the differential diagnosis are often available (table 1).

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Diagnostic studies — The laboratory studies to be ordered are determined by the suspected photosensitivity disorder, based upon the history and physical examination findings. Laboratory evaluation may include ANA, anti-dsDNA, anti-Ro (SSA), anti-La (SSB) titers and porphyrin studies when lupus erythematosus or porphyria is suspected [4]. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Laboratory testing' and "Porphyrias: An overview", section on 'Approaches to diagnosis'.) A skin biopsy may provide helpful information but requires correlation with clinical findings. Even in circumstances in which the skin biopsy is non-diagnostic, histology may be helpful in ruling out other diseases included in the differential diagnosis. Phototesting — Phototesting, if available, can be used to determine a patient's minimal erythema dose (MED). The MED is the lowest dose of ultraviolet radiation delivered to the skin that induces erythema 24 hours after exposure. MED testing is conducted for both UVA and UVB, employing separate light sources. The MED can be helpful as a diagnostic tool. MEDs in patients with certain photodermatoses are lower than those in normal controls. Phototesting can also help to determine the wavelengths causing a photodermatosis (UVA, UVB, or visible light). A summary of the results of phototesting in photosensitivity disorders is provided (table 1). For phototesting, an opaque template with multiple openings and the appropriate light sources are used to irradiate separate areas of skin with progressively increasing doses of UVA, UVB, or, in some instances, visible light [4]. An uninvolved site, typically the back or inner aspect of the forearm, is used as the test area. The lowest dose of radiation that provides uniform erythema over the irradiated site at 24 hours is the MED. In patients with solar urticaria, the minimal urticarial dose (MUD) is evaluated by administering increasing doses of UVA, UVB, or visible light and assessing the occurrence of urticarial lesions at the site of irradiation within the first hour [5]. In addition to basic phototesting to determine the MED, provocation phototesting may be performed in an attempt to induce lesions. Provocation phototesting is primarily used for suspected PMLE [6] and has also been employed to diagnose photosensitive cutaneous lupus and hydroa vacciniforme [7,8]. The best results for PMLE are obtained when the tested site is in a location of previously affected skin [4]. Radiation doses that approximate the MED typically are administered repeatedly over three to five days [4]. The tested area is subsequently examined for occurrence of lesions. Skin biopsy and histologic examination may be required to confirm the diagnosis. Prior to phototesting, patients must discontinue glucocorticoids and other systemic immunosuppressants for at least two weeks and antihistamines for at least one to two days [4]. Topical agents, such as topical corticosteroids, should also be stopped one to two weeks in advance. Photopatch testing — Photopatch testing is useful in patients in whom a topical photoallergen is suspected (photoallergy) [4,9]. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.) Two identical sets of potential photoallergens are placed on the patient's back. After 24 hours, one set is removed and that site is irradiated with UVA at the dose of 5 to 10 J/cm2. The site is covered again, and 24 hours later, both the irradiated and control test sites are examined for reactions. A reaction to a specific photoallergen in the irradiated site, but not the control site, indicates a photoallergy. A similar reaction in both sites suggests a non-photo-induced allergic contact dermatitis. Although phototesting and photopatch testing are relatively simple procedures, they are most often performed in specialized centers.

PHOTOPROTECTION Sun avoidance ●

Avoidance of midday sun (between 10 am and 4 pm)



Protective clothing: long sleeved shirts and pants, broad brim hats



Window films that block ultraviolet radiation (UVR) for cars and homes



Broad spectrum sunscreen (protects against both ultraviolet A [UVA] and ultraviolet B [UVB])

Sun avoidance and protective clothing should be emphasized as important measures of photoprotection for patients with photosensitivity disorders. Sunscreen alone is not sufficient and should be used as an adjunct to other methods of sun protection. (See "Selection of sunscreen and sun-protective measures".) For patients who are sensitive to radiation in the UVA range, it should be noted that substantial amounts of UVA are present in the morning and late afternoon, as well as midday. Because UVA can penetrate window glass, the very photosensitive patient may even have difficulty indoors

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and in a car. Protective clothing such as long sleeves and broad brim hats should be worn while outdoors [10]. Fabrics that are tightly woven, thick, or darkcolored are useful for protection [11]. Clothing developed for photosensitive individuals is commercially available from specialty companies. Clothing treated with broad-spectrum ultraviolet absorbers is also available. Window films that block UVA and some visible light can also be purchased for use in cars or homes [12]. Sunscreen — Sunscreen is important for daily use for patients with photosensitivity, particularly those with photosensitivity in the ultraviolet range. Sunscreens are divided into chemical (organic) and physical (inorganic) products [13]. Chemical sunscreens provide protection in the ultraviolet range. Physical sunscreens have the ability to block both UVR and some visible light. (See "Selection of sunscreen and sunprotective measures", section on 'Types of sunscreens'.) Patients with photosensitivity who have reduced MEDs to UVA should be advised to use a broad spectrum sunscreen with a minimum sun protection factor (SPF) of 30. The effectiveness of sun protection depends on the severity of photosensitivity and how well patients adhere to sun protective guidelines. Patients with more severe cases of photosensitivity may not respond to sun protection alone and will likely require other treatment modalities, depending on their specific diagnosis. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment".) Chemical sunscreens — The active ingredients in chemical sunscreens work by absorbing UVR and possess varying ultraviolet absorption spectra. A specific recommendation of a sunscreen with the most effective ingredients can be made if the action spectrum of the photodermatosis (UVA versus UVB) is known [14]. Sunscreen ingredients and their UVB and UVA range of protection are shown in the table (table 2). Products containing photostabilized avobenzone or ecamsule (Mexoryl SX) have been available in the United States since 2006 and offer improved protection against UVA [15,16]. Tinosorb M is a broad-spectrum sunscreen that has both the absorptive properties of a chemical sunscreen and the light-scattering properties of a physical sunscreen. It is not available in the United States. Chemical sunscreens may rarely cause allergic contact dermatitis or photoallergic reactions in some patients [17]. For patients with allergies to chemical sunscreens, physical sunscreens containing titanium dioxide or zinc oxide are alternatives for protection. (See "Selection of sunscreen and sun-protective measures", section on 'Organic filters'.) Physical sunscreens — Physical blocker (inorganic) sunscreens, such as titanium dioxide and zinc oxide, work by reflecting and scattering ultraviolet and visible radiation (table 2). The large particle size of these ingredients makes them opaque and enables them to block some visible light, but may make them cosmetically unacceptable to patients. As a result, non-opaque, micronized formulations of titanium and zinc oxide have been developed. However, once micronized, the ingredients are less capable of scattering visible light and the longer wavelengths of UVA. Patients with visible light-sensitive photodermatoses utilizing physical blocker sunscreens as an adjunct to sun avoidance and sunprotective clothing should use the opaque, nonmicronized formulations [18]. (See "Selection of sunscreen and sun-protective measures", section on 'Inorganic filters'.)

SUMMARY AND RECOMMENDATIONS ●

Photosensitivity is an abnormal response to ultraviolet radiation or visible light that underlies many different cutaneous disorders termed "photodermatosis." The action spectra implicated in photodermatoses include ultraviolet and visible light. (See 'Introduction' above and 'Photobiology' above and 'Evaluation of patients with photosensitivity disorders' above.)



The diagnosis of a photosensitivity disorder is primarily based upon obtaining a history and performing a skin examination. The age of onset, timeline of the eruption, family history, medication history, and appearance of the lesions are invaluable for narrowing the differential diagnosis (table 1). (See 'Patient history' above and 'Physical examination' above.)



Laboratory evaluation may include ANA, anti-dsDNA, anti-Ro (SSA), and anti-La (SSB) titers and porphyrin studies based upon a clinical suspicion of lupus erythematosus or porphyria. Skin biopsy can be helpful when correlated with clinical findings. Phototesting to determine the minimal erythema dose (MED) and action spectrum can narrow the differential diagnosis. Photopatch testing is useful in patients in whom a topical photoallergen is suspected. (See 'Diagnostic studies' above.)

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Photoprotection via sun avoidance and sun-protective clothing is essential. Broad-spectrum (ultraviolet A [UVA] and ultraviolet B [UVB]) sunscreens are useful but may not adequately protect patients when used alone. (See 'Sun avoidance' above.)



Patients with photosensitivity in the UV spectrum should apply broad-spectrum (UVA and UVB) sunscreens with a minimum SPF of 30. Products containing photostabilized avobenzone or ecamsule (Mexoryl SX) offer improved protection against UVA; sunscreens that contain nonmicronized zinc oxide and titanium dioxide also provide broad spectrum photoprotection and are another option (table 2). (See 'Sunscreen' above.)



For patients with visible light sensitivity, primary protection is provided by sun avoidance and photoprotective clothing. When skin exposure to sunlight is unavoidable, patients should use a physical blocker sunscreen (titanium dioxide or zinc oxide) in an opaque, nonmicronized formulation, rather than a chemical sunscreen, which has no effect on visible light transmission. (See 'Photoprotection' above.) Use of UpToDate is subject to the Subscription and License Agreement.

Topic 6620 Version 12.0

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GRAPHICS Electromagnetic spectrum

Graphic 70045 Version 4.0

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Photosensitive disorders: Clinical features

 

Sex

Timeline of eruption

Age of onset

Location

Common lesion morphology and symptoms

Family history

Action spectrum

Laboratory findings

Phototesting

Duration/ resolution

Key features

Polymorphous light eruption

F>M

First three decades

Hours after sun exposure, lasts days to weeks; most conspicuous in spring; improves during summer

Sunexposed areas

Pruritic papules, papulovesicles, plaques.

May be present

UVA, UVB, visible

Normal MED; provocative phototesting may induce lesions

 

Recurrent over the course of years, may improve over time

Most common photodermatosis; "hardening" phenomenon may occur

Juvenile spring eruption

M>F

Primarily childhood; also may be seen in young adults

As with PMLE

Classically, helices of ears

Erythematous papules, bullae.

May be present

UVA?

As with PMLE

 

Recurrent over years, may improve with age

 

Actinic prurigo

F>M, M>F reported in adult onset in Asia

Childhood;

Persistent during summer; may also be present year round

Sunexposed areas, may also affect unexposed areas

Pruritic papulonodules, crusts, excoriations, lichenification, cheilitis.

Yes, in up to 50%

UVA>UVB

60% with reduced MED, 60 to 70% with positive provocative phototests

 

Improves in adolescence, but also may persist

More common in American Indians and Mestizos. May have ocular findings.

Hydroa vacciniforme

Slight M>F

Childhood

Hours after sun exposure

Face, dorsal hands

Erythematous macules, papules, vesicles, crusts.

Rarely positive

Likely UVA

May show reduced MED to UVA in some cases

 

Usually resolves by adolescence/young adulthood, but may persist

Lymphoproliferative disease association with severe cases

Chronic actinic dermatitis

M>F

Older, but may be seen in younger patients

Persistent; worsens in summer, may have findings year round

Sunexposed areas

Eczematous patches, lichenification, may see palmoplantar involvement.

 

UVA, UVB, visible light

Decreased MEDs to UVA, UVB, or visible light

May see Sézary cells in severe cases

Persists for years, may resolve

Often coexistent contact dermatitis

Solar urticaria

F>M

Young or midadulthood

Appears within minutes, individual lesions resolve within 24 hours

Sunexposed areas

Urticarial plaques (hives), occasional systemic symptoms.

 

UVA, UVB, visible light

Normal MEDs, urticaria are induced within minutes of phototesting

 

Persists for years, may resolve

"Hardening" phenomenon may occur

Phototoxicity

M=F

Any age

Appears within hours of sun exposure, can occur after first dose of drug

Sunexposed areas

Exacerbated sunburn appearance.

 

UVA

In systemic phototoxicity, MED for UVA decreased, UVB and visible light MEDs normal

 

Resolves when drug discontinued and cleared from body

Can occur in anyone

Photoallergy

M=F

Any age

Appears one to two days after exposure to sun and inciting agent in sensitized individual

Sunexposed areas

Pruritic, eczematous lesions.

 

UVA

In systemic photoallergy, MED for UVA decreased, UVB and visible light MEDs normal

 

Resolves with discontinuation of inciting agent

Usually due to topical agents

Erythropoietic protoporphyria

M = F, versus slight M>F

Onset in early childhood

Symptoms begin within minutes of sun exposure, improves in winter

Nose, cheeks, hands

Burning and stinging, pain, pruritus. Erythema, edema, pupura. Heals with atrophic, wax-like scars; wrinkled knuckles.

Common (siblings), autosomal recessive or pseudodominant

Soret band (400 to 410 nm)

Often normal, some patients may note stinging sensation or lesions

Elevated erythrocyte protoporphyrin level

Chronic

May develop liver disease

Porphyria cutanea tarda

M=F

Middle age, may occur earlier

 

Sunexposed areas

Skin fragility, bullae, crusts, scarring. Hypertrichosis, hyperpigmentation, sclerodermoid changes.

Sporadic in Type I, autosomal dominant in Type II

Soret band (400 to 410 nm)

 

Elevated porphyrins in urine and stool

Chronic, symptoms improve with sun protection, removal of triggers, phlebotomy, antimalarials

Often associated with hepatitis C

Pseudoporphyria

 F>M

Any age; 10% of

 

Sunexposed

Skin fragility, bullae, crusts,

Negative

UVA

 

Normal porphyrin

Symptoms resolve with sun protection,

May be caused by medications, renal

adultonset may occur in Asians

8519

children taking naproxene

 

 

 

 

areas

scarring, milia.

 

 

 

F: female; M: male; UV: ultraviolet; MED: minimal erythema dose; PMLE: polymorphus light eruption. Graphic 57800 Version 12.0

8520

 

 

levels

avoidance of tanning bed use, and discontinuation of the causative medications

failure and hemodialysis, and excessive tanning bed use

 

 

 

Sunscreens Sunscreen

Range of protection

Organic PABA derivatives

PABA (para-aminobenzoic acid)

UVB

Padimate O (octyl dimethyl PABA)

UVB

Cinnamates

Octinoxate (octyl methoxycinnamate)

UVB

Cinoxate

UVB

Salicylates

Octisalate (octyl salicylate)

UVB

Homosalate

UVB

Trolamine salicylate

UVB

Benzophenones

Oxybenzone (benzophenone-3)

UVB, UVA2

Sulisobenzone (benzophenone-4)

UVB, UVA2

Dioxybenzone (benzophenone-8)

UVB, UVA2

Others

Octocrylene

UVB

Ensulizole (phenylbenzimidazole sulfonic acid)

UVB

Avobenzone (butyl methoxydibenzoyl methane, Parsol 1789)

UVA1

Ecamsule (terephthalylidene dicamphor sulfonic acid, Mexoryl SX)*

UVB, UVA2

Drometrizole trisiloxane (Mexoryl XL) ¶

UVB, UVA2

Meradimate (menthyl anthranilate)

UVA2

Bemotrizinol (bis-ethylhexyloxyphenol methoxyphenol triazine, Tinosorb S) ¶

UVB, UVA2

Bisoctrizole (methylene bis-benzotriazolyl tetramethylbutylphenol, Tinosorb M) ¶

UVB, UVA2

Inorganic Titanium dioxide

UVB, UVA2, UVA1

Zinc oxide

UVB, UVA2, UVA1

UVB: ultraviolet B; UVA: ultraviolet A. * Available in the United States since 2006 in combination with avobenzone and octocrylene. ¶ Available in Europe but not in the United States. Adapted with permission from: Sunscreens: An Update. The Medical Letter 2008; 50:70. Copyright © 2008 The Medical Letter. Graphic 73127 Version 8.0

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment Author: Craig A Elmets, MD Section Editors: Robert P Dellavalle, MD, PhD, MSPH, Jeffrey Callen, MD, FACP, FAAD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Nov 25, 2019.

INTRODUCTION Photosensitivity disorders of the skin are conditions in which an abnormal cutaneous response occurs after exposure to ultraviolet (UV) radiation or visible light. The major categories of photosensitivity disorders are idiopathic photodermatoses, photodermatoses due to exogenous or endogenous agents, photoexacerbated dermatoses, and photosensitive genodermatoses and will be reviewed in this topic review (table 1). An overview of photosensitivity, including photobiology, patient evaluation, and photoprotection, is discussed separately. Polymorphous light eruption, which is a type of idiopathic photodermatosis, is also discussed separately. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection" and "Polymorphous light eruption".)

THE IDIOPATHIC PHOTODERMATOSES The idiopathic photodermatoses are a group of photosensitivity disorders whose pathogenesis remains unclear. Many of these disorders have features suggesting that they are immunologically mediated. The idiopathic photodermatoses include polymorphous light eruption, actinic prurigo, hydroa vacciniforme, chronic actinic dermatitis (CAD), and solar urticaria (table 1). Polymorphous light eruption — Polymorphous light eruption (PMLE) is the most common idiopathic photodermatosis and is sometimes colloquially called "sun poisoning" or "sun allergy." PMLE and juvenile spring eruption, a PMLE variant, are reviewed separately. (See "Polymorphous light eruption".) Actinic prurigo — Actinic prurigo, also known as Hutchinson's summer prurigo, familial or hereditary PMLE of American Indians, or hydroa aestivale, is a photo-induced pruritic eruption often considered a variant of PMLE. Actinic prurigo and PMLE may share a common pathophysiologic basis, although actinic prurigo has distinct clinical features [1]. Epidemiology — Onset of actinic prurigo usually occurs in childhood, although it can also first present in adults, especially in Asians [1-6]. Patients with childhood onset may spontaneously improve in adolescence, but the condition can persist into adulthood [2,3]. Actinic prurigo is more common in females [1,2], although studies from Singapore, Thailand, and Taiwan note a greater number of male patients in the adultonset cohort [4-6]. Actinic prurigo is most commonly seen in Mestizos (ie, individuals of mixed American-Indian and European ancestry), although other ethnicities may be affected as well [7]. A family history of actinic prurigo is present in up to 50 percent of patients [8]. Pathogenesis — Lesions of actinic prurigo are induced by exposure to ultraviolet (UV) radiation. Both UVA and UVB have been implicated; UVA wavelengths elicit the disease in most patients [9]. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Phototesting'.) Genetic susceptibility is important. Actinic prurigo is associated with an HLA-DR4 polymorphism [1,10]. The specific locus, HLA-DRB1*0407, has been identified in 60 to 70 percent of patients [1,2]. In affected subjects from Singapore, there is a closer association with HLA-DRB1*0301 [11].

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Clinical manifestations — The onset of actinic prurigo usually occurs in the spring, when more time is spent outdoors and more skin is exposed. The lesions can persist through the summer and, unlike PMLE, may even extend into the winter months. Pruritus is characteristic and significant. Commonly, lesions are symmetrically distributed on sun-exposed skin (eg, forehead, cheeks, chin, ears, forearms), but covered sites such as the back and buttocks may also be affected [9]. Typical lesions are papulonodular and often have a hemorrhagic crust (picture 1A-B). Eczematous changes and lichenification are also seen. Occasionally, mild scarring may be present. Actinic cheilitis is a distinguishing feature of the disease and can be seen with other cutaneous findings or as the sole clinical manifestation. Ocular involvement, which manifests as conjunctivitis or pseudopterygium, can occur, although it is rare in Caucasian patients [12,13]. Actinic cheilitis and ocular manifestations are much less common in patients of Asian descent [6]. Patients who have been evaluated with the Dermatology Life Quality Index (DLQI) report a major impact on their quality of life [14]. Diagnosis — The diagnosis of actinic prurigo is often based upon clinical findings. The differential diagnosis includes prurigo nodularis, arthropod bites, and excoriated eczema. Biopsy findings are not diagnostic, but may help to exclude other diseases. Histopathologic features in early lesions include epidermal spongiosis and a superficial and deep perivascular mononuclear infiltrate. More advanced lesions may also exhibit lichenification, focal papillary dermal fibrosis, and irregular epithelial hyperplasia [15]. Biopsies of cheilitis in actinic prurigo reveal characteristic dense lymphocytic infiltrates with distinctive, well-formed lymphoid follicles [15]. Phototesting can be helpful. A case series of 21 patients with actinic prurigo reported reduced minimal erythema doses (MEDs) in 60 percent [2]. Photoprovocation testing is positive in 60 to 70 percent of patients [12]. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Phototesting'.) Serum immunoglobulin E (IgE) levels have been reported to be elevated in nearly half of patients and are associated with moderate or severe disease [16]. Treatment — The implementation of sun-protective practices is important for the management of actinic prurigo. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Photoprotection'.) Topical corticosteroids can offer additional relief for some patients; in a case series of eight patients with actinic prurigo, intermittent 3- to 14day courses of topical clobetasol led to marked improvement in seven patients [17]. Topical application of the topical calcineurin inhibitor tacrolimus has also been reported to be effective in patients with milder disease [7]. Oral glucocorticoids can temporarily improve symptoms during acute exacerbations [2]. Phototherapy with narrowband UVB [18] or psoralen plus ultraviolet A (PUVA) [19] is a therapeutic option in patients with persistent symptoms. In most situations, a short course of oral corticosteroids is administered at the beginning of phototherapy to prevent a flare of disease. Treatment is initiated in the spring, prior to seasonal recurrence, since the disorder typically worsens during the summer months. In a case series of five patients treated with PUVA twice weekly for 15 weeks, all patients reported increased tolerance to sun exposure after four weeks [19]. By the end of therapy, measurements of MEDs approximated those of normal skin, and the subjects were able to tolerate summer sun exposure without the recurrence of symptoms. In a separate case series, six patients with actinic prurigo treated prophylactically with 10 narrowband UVB treatment sessions delivered over two to five weeks exhibited improved tolerance to sun exposure after completing therapy [18]. During the treatment cycle, pruritus developed in five patients. Pruritus was associated with induction of actinic prurigo in four patients. Phototherapy is not curative, and symptoms of actinic prurigo eventually recur after treatment is discontinued [2]. Thalidomide has been successful in patients with resistant disease in case series and case reports [2,20-24]. In one case series, 32 out of 34 patients with actinic prurigo improved with thalidomide [20]. The potential for side effects such as peripheral neuropathy and teratogenicity must be carefully considered prior to initiating thalidomide therapy. Thalidomide is prescribed at a dose of 50 to 100 mg/day and is subsequently tapered to the lowest dose that sustains improvement [25]. Maintenance doses as low as 50 mg/week have been used, and cases in which patients have been able to discontinue treatment without recurrence have been reported [9]. In one small case series, pentoxifylline 1200 mg per day for six months was an effective treatment [26]. Cyclosporine 2.5 mg/kg per day and azathioprine (50 to 100 mg per day) are other options in resistant cases [5,27].

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Hydroa vacciniforme — Hydroa vacciniforme is a rare photodermatosis of childhood, characterized by vesicular lesions on sun-exposed skin that eventually heal, leaving depressed scars. The prevalence of hydroa vacciniforme has been estimated to be 0.34 per 100,000 [28]. The disease onset typically occurs in childhood, with a mean duration of nine years from symptom onset to resolution [28]. Resolution usually occurs by adolescence or young adulthood, although symptoms may persist throughout life in some patients. Males have been noted to have a more severe disease, with later onset and longer course than in females [28]. Hydroa aestivale, a milder form of hydroa vacciniforme, is more frequent in females. Pathogenesis — The pathogenesis of hydroa vacciniforme is unclear. Photoprovocation testing with UVA produces skin findings that resemble lesions induced by natural sunlight in some patients [28,29]. There are multiple reports of atypical hydroa vacciniforme or hydroa vacciniforme-like eruption associated with chronic or latent Epstein-Barr virus (EBV) infection and lymphoproliferative disorders in children and adults [29-35]. These patients may have associated symptoms of lymphadenopathy, hepatosplenomegaly, fever, and fatigue that are not seen with typical hydroa vacciniforme. Skin lesions are more severe in these patients. Evaluation for a lymphoproliferative disorder should be based upon clinical presentation and suspicion. The presence of latent EBV in typical hydroa vacciniforme in the absence of systemic symptoms or lymphoproliferative disease has also been reported and may be a contributing factor in the etiology [35,36]. Biopsy specimens taken from lesions provoked by repeated exposure to UVA radiation have significantly more EBV-positive cells than adjacent normal skin, and, on electron microscopy, viral particles can be found in keratinocytes from lesional skin but not in normal skin. Moreover, greater amounts of EBV DNA have been found in blood samples from individuals with hydroa vacciniforme compared with individuals with other photosensitivity disorders [29]. Clinical findings — Hydroa vacciniforme occurs primarily in the summer. Sunlight induces the lesions on exposed areas of skin, most commonly the face and dorsal hands, within hours of sun exposure. The eruption is symmetric, exhibiting erythematous macules that progress to tender papules, vesicles, and crusts (picture 2A-B). Lesions are associated with pruritus or a burning sensation. Unlike PMLE, hydroa vacciniforme heals with scarring. In rare cases, patients may also experience malaise, fever, or headaches during flares. Rarely, ocular findings may be present, such as photophobia, lacrimation, conjunctivitis, corneal infiltration with vascularization, keratitis, or uveitis [37-39]. Referral to an ophthalmologist is recommended if eye symptoms are present. Diagnosis — The diagnosis of hydroa vacciniforme is clinical, based upon the morphology of the lesions (picture 2A-B). Photoprovocation tests may be performed to establish the diagnosis in equivocal cases. Skin biopsy may be helpful but requires correlation with clinical findings. Histopathologic examination of active lesions reveals intracellular and intercellular edema, reticular degeneration, vesiculation, and epidermal necrosis. Dermal findings include a perivascular lymphohistiocytic and neutrophilic infiltrate [15]. Photoprovocation tests may be performed to establish the diagnosis. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Phototesting'.) The differential diagnosis includes erythropoietic protoporphyria (EPP), bullous lupus erythematosus, and recurrent facial herpes simplex [40]. Porphyrin studies are helpful in excluding EPP (see "Erythropoietic protoporphyria and X-linked protoporphyria"). Hydroa vacciniforme and bullous lupus erythematosus can be distinguished histologically. In addition, antinuclear antibodies and biopsy specimens for direct immunofluorescence are usually positive in lupus but negative in hydroa vacciniforme. The role of serology for EBV in differentiating hydroa vacciniforme from other photosensitivity disorders has not been systematically evaluated. Treatment — Hydroa vacciniforme is difficult to treat. All patients should be encouraged to engage in strict photoprotection via avoidance of sun exposure and the use of broad-spectrum sunscreens and sun-protective clothing. Individuals with severe disease may need to apply films that block wavelengths within the UV spectrum to automobile and house windows. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Photoprotection'.) In a case series of five patients, three were found to respond to photodesensitization with narrowband UVB [28]. Other treatments include antimalarials, intermittent corticosteroids, azathioprine, cyclosporine, and dietary fish oil [41-44]. There is a single case report of a patient who responded to acyclovir and valacyclovir [45]. There is a report of two adult cases with EBV-associated hydroa vacciniforme-like lymphoproliferative disease treated with minocycline and topical pimecrolimus cream 1%, respectively [46]. Chronic actinic dermatitis — CAD is a rare, persistent, photo-induced eczema affecting the exposed skin. Older men with a history of significant occupational or recreational sun exposure are most commonly affected, although it is becoming more frequent in younger patients and in

8524

women [47,48]. Both light- and dark-skinned individuals can develop CAD [48-50]. Interestingly, in individuals with higher Fitzpatrick skin types (V and VI), CAD has been noted to have earlier onset and to occur more frequently in females [51]. Many patients have a coexisting allergic contact dermatitis, frequently to airborne allergens, but also to carba mix and paraphenylenediamine. Photocontact allergies are also frequent. In the past, these were primarily plant photoallergens. The most common photoallergens associated with CAD are agents found in sunscreens, especially avobenzone and oxybenzone. Among the plant photoallergens, Tanacetum vulgare (common tansy) and Taraxacum officinale (common dandelion) predominate [47,48,52,53]. An association with atopic dermatitis [50,54-56] and with HIV infection has also been reported [57,58]. Pathogenesis — The pathogenesis of CAD is not completely understood, although it is thought to have an immunologic basis. Consistent with this hypothesis is the observation that the dermal infiltrate in lesional skin is predominantly composed of CD8+ cytotoxic suppressor T cells, similar to that seen in allergic contact dermatitis [59], and that the disease is frequently treated with immunosuppressive agents. One theory is that CAD is a delayed-type hypersensitivity reaction against a photo-induced endogenous antigen. An alternative hypothesis is that CAD represents the response to an exogenous photosensitizer, which persists for a prolonged period of time in the skin [60,61]. CAD begins in most cases with an abnormal sensitivity to UVB, UVB and UVA, or, uncommonly, to UVA alone. With time, signs and symptoms can be elicited by a wider spectrum of wavelengths, sometimes extending into the visible spectrum. Prolonged exposure to compact fluorescent lamps, which emit small amounts of UVA and UVB, is thought to be a provocative factor in some CAD patients [62]. Genome-wide analysis of mRNA and long noncoding RNA profiles have been conducted in four patients with chronic actinic dermatitis. Compared with normal controls, differential expression of both annotated and novel long noncoding RNAs were observed, especially in the inflammatory and immune response-related pathways [63]. This included long noncoding RNAs that regulate TNFAIP, a key molecule in the tumor necrosis factor (TNF) pathway. Clinical manifestations — CAD presents with eczematous patches distributed on the face, neck, dorsal hands, scalp, and upper chest, often with sharp demarcations at lines of clothing. Lichenification and erythematous, infiltrated papules and plaques may also be seen (picture 3AB). Although initially present exclusively on sun-exposed skin, the disease can progress over the years to unexposed areas as well. In severe cases, generalized erythroderma may develop [64]. Palmar and plantar eczema are not uncommon. Patients may have abnormal cutaneous findings year round, but the eruption typically worsens in the summertime. Three different clinical pictures, formerly considered distinct entities, are recognized: actinic reticuloid, photosensitive eczema, and persistent light reactivity. Transition from one form to another can occur [65]. Symptoms of CAD often persist for years; approximately 25 percent of patients go into remission within 10 years [47,66]. Diagnosis — The diagnosis of CAD is based upon the clinical finding of a persistent eczematous eruption affecting primarily the sunexposed skin in older individuals and the documentation of increased sensitivity (decreased MED) to UVB, often to UVB and UVA, and occasionally to visible light by phototesting [47,48,54]. Patch testing and photopatch testing are also useful for diagnosis. Patch tests and photopatch tests are used to identify coexisting contact allergens and/or photoallergens that may exacerbate the disorder [50,67]. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Diagnostic studies'.) Skin biopsy may be helpful for diagnosis. Histopathologic findings include epidermal spongiosis, lymphocyte exocytosis, and a superficial and deep perivascular, lymphohistiocytic infiltrate. Lymphocyte exocytosis and small collections of atypical mononuclear cells in the epidermis, resembling the Pautrier microabscesses of mycosis fungoides, may also be seen [15]. Phototesting is helpful to distinguish CAD from cutaneous lymphoma since photosensitivity is not a usual feature of cutaneous T cell lymphoma (CTCL), although occasionally CTCL can exhibit increased photosensitivity [25,68]. Circulating Sézary cells can be found either in CAD or in CTCL [64]. Serologic testing for lupus (ANA, anti-Ro, anti-La) and for HIV is indicated in younger individuals. Overlapping clinical and histologic findings make it difficult to differentiate CAD from photoaggravated atopic or seborrheic dermatitis, contact dermatitis, PMLE, acute and subacute cutaneous lupus erythematosus (SCLE), systemic drug-induced photosensitivity, and CTCL, although age of onset and certain historical features (eg, drug exposure) may be helpful in some cases. Rarely, the two disorders may coexist. Treatment — Treatment of CAD is often difficult. Strict sun protection should be emphasized but often is ineffective as a sole measure. (See "Selection of sunscreen and sun-protective measures".) Avoidance of known contact and photocontact allergens as well as photosensitizing drugs is recommended [54]. Broad-spectrum sunscreens should be used only after patch and photopatch tests rule out a sunscreen allergy [69]. Although no randomized trials have evaluated these

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therapies, topical corticosteroids, topical tacrolimus and pimecrolimus [70-74], and/or emollients may help. For more severe cases, systemic therapy may be prescribed. Azathioprine was effective in one small, randomized trial [75]; cyclosporine [76], mycophenolate mofetil [77], and tofacitinib [78] have led to improvement in anecdotal reports. Low-dose PUVA or narrowband UVB, initially given with oral glucocorticoids to decrease treatment-induced flares, has been effective in small case series [79-81]. In one report, topical tacrolimus 0.1% applied at night under occlusion was successfully used in five patients with CAD resistant to systemic immunosuppressive agents [82]. Solar urticaria — Solar urticaria is a rare variant of urticaria. Pruritic, erythematous wheals appear within 5 to 10 minutes of sun exposure and resolve within 24 hours (picture 4). Symptoms can be induced via exposure to UVA, UVB, or visible light; the precise wavelengths vary from individual to individual. Phototesting is useful to confirm the diagnosis and typically results in the appearance of urticaria within minutes. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Phototesting'.) Pharmacologic therapy or photodesensitization with low-dose PUVA or narrowband UVB initially given with oral glucocorticoids is usually required for management [81]. Omalizumab, a neutralizing antibody to IgE, has been reported to be effective [83,84]. A detailed review of the clinical manifestations, diagnosis, and treatment of solar urticaria is provided separately. (See "Physical (inducible) forms of urticaria", section on 'Solar urticaria'.)

PHOTOSENSITIVITY DUE TO EXOGENOUS AGENTS Photosensitivity induced by exogenous agents refers to a process in which chemicals or drugs that are ingested or applied to the skin promote a photosensitivity reaction when the individual is exposed to sunlight. In one study, photosensitivity was responsible for approximately 20 percent of adverse drug reactions in older adults [85]. This type of photosensitivity is usually divided into phototoxic and photoallergic reactions; phytophotodermatitis is a special form of toxicity elicited by photosensitizing chemicals in plants. Phototoxic and photoallergic reactions differ in their clinical features and causative agents (table 2) [86]. Phototoxicity — Phototoxicity results from direct tissue or cellular damage following ultraviolet (UV) irradiation of a phototoxic agent that has been ingested or applied to the skin. Phototoxicity can occur in any individual in whom the threshold concentration of the chemical or drug has been reached [86-89]. By contrast, photoallergy is a cell-mediated immune response elicited by small amounts of compound in previously sensitized individuals (table 2). Drug-induced — The majority of drug-induced photosensitivity reactions are phototoxic. Common offenders include [86,90]: ●

Tetracyclines (especially doxycycline)



Hydrochlorothiazide



Sulfonamides



Metformin



Fluoroquinolones



Nonsteroidal anti-inflammatory drugs (NSAIDs, especially piroxicam and ketoprofen)



Vemurafenib



Phenothiazines (eg, chlorpromazine)



Psoralens



Griseofulvin



Voriconazole



Amiodarone



Aminolevulinic acid and methyl aminolevulinate



Porfimer sodium



Retinoids



Tar compounds



St. John's wort

Phototoxic reactions appear as an exaggerated sunburn (picture 5A-C). The reaction usually evolves within minutes to hours of sun exposure and is restricted to exposed skin [87]. In severe cases, vesicles or bullae may be seen [60]. Skin biopsy findings are identical to those of

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ordinary sunburn, with vacuolated and apoptotic keratinocytes [15]. Most phototoxic drugs are activated by UVA rather than UVB radiation. Aminolevulinic acid, methyl aminolevulinate, and porfimer sodium are activated by wavelengths in the visible spectrum. A special form of phototoxicity occurs following contact with tar compounds. Tar phototoxicity occurs primarily in road workers and roofers who employ tar in their occupations. Occasionally, it can be seen in individuals who use tar-containing shampoos. A burning and stinging pain, called "tar smarts," occurs within minutes of exposure to sunlight. Phytophotodermatitis — Topical exposure to plant-derived substances may also cause a phototoxic reaction termed phytophotodermatitis. The most common plants that cause phytophotodermatitis are in the Apiaceae (ie, Umbelliferae) and Rutaceae families [91]. Commonly encountered members include celery, wild parsnip, and parsley (Apiaceae), as well as lemons and limes (Rutaceae). The sap of fig trees (Ficus carica) and seeds of Psoralea corylifolia are additional inducers of phytophotodermatitis [92]. A list of plants that may cause phytophotodermatitis is provided (table 3). All of these plants contain furocoumarins, of which psoralens and angelicins are the most notable examples. The furocoumarins alone are inactive, but, following exposure to UVA radiation, they may induce a photosensitivity reaction. Phytophotodermatitis occurs most commonly after exposure to limes, especially in bartenders and others who squeeze limes when making cocktails and other drinks (picture 6A). Other citrus fruits contain furocoumarins and may infrequently cause a phytophotodermatitis. Phytophotodermatitis is also seen in gardeners, children who come in contact with plants and weeds while playing in fields and meadows, chefs, and food-industry workers, especially those who handle celery. Patients with phytophotodermatitis typically present with erythema, edema, and bullae in linear or bizarre configurations on sun-exposed skin that reflect the manner in which they have come in contact with the plant (picture 6A-C). For example, people who develop phytophotodermatitis from exposure to plants in meadows and fields often have a linear distribution to their cutaneous eruption (picture 7). The clinical findings appear approximately 24 hours after sun exposure. Lesions are not pruritic and may be painful. As the acute eruption clears, it is replaced by hyperpigmentation that may take months to years to resolve. It should be noted that often the preceding erythema is inapparent and only the hyperpigmentation is observed. Generalized phototoxic reactions secondary to the ingestion of large quantities of furocoumarins are rare. A few cases of generalized phototoxic reactions have occurred following psoralen plus ultraviolet A (PUVA) therapy or tanning salon use in patients who had consumed large amounts of celery [93-95]. Hypericin, a non-furocoumarin photosensitizing substance found in St. John's wort (Hypericum perforatum), can also lead to a generalized phototoxic reaction on sun-exposed skin after ingestion of high doses of the plant extract. (See "Clinical use of St. John's wort", section on 'Adverse effects'.) Other manifestations — Other manifestations of phototoxicity include pseudoporphyria, usually caused by NSAIDs (most commonly naproxen), tetracycline, voriconazole, or furosemide [87,96]; photo-onycholysis due to tetracyclines, psoralens, and NSAIDs; and slate-gray hyperpigmentation due to amiodarone, chlorpromazine, tricyclic antidepressants, or diltiazem [68,86,87]. Pseudoporphyria presents with the features of skin fragility and subepidermal blisters typically seen in porphyria cutanea tarda. Photoallergy — Photoallergy is a delayed-type hypersensitivity reaction to an allergen whose antigenicity has changed after exposure to UV radiation (UVR; photoallergen). Once the photoallergen has formed, the subsequent steps in the pathogenesis of the reaction are identical to allergic contact dermatitis [68,86-89]. As in other allergic contact dermatitis reactions, affected individuals must have been previously sensitized to the photoallergen. Similar to phototoxic reactions, most photoallergic reactions are initiated by UVA rather than UVB exposure [87]. Photoallergic reactions are typically pruritic, eczematous eruptions in sun-exposed areas of skin that develop 24 to 48 hours after sun exposure [60]. Occasionally, photoallergic contact dermatitis may become persistent and evolve into chronic actinic dermatitis (CAD), even after the offending drug or chemical has been discontinued. (See 'Chronic actinic dermatitis' above.) Photoallergic reactions occur in most instances after exposure to topical rather than systemic agents (picture 8) [87-89]. The most common topical agents responsible for photoallergic reactions are [60,68,86,88,89,97]: ●

Sunscreens (eg, benzophenones, cinnamates, dibenzoylmethanes)



NSAIDs (eg, ketoprofen, diclofenac)



Fragrances (eg, 6-methylcoumarin, musk ambrette, sandalwood oil)



Phenothiazines (eg, promethazine, available in Europe as topical antihistamine)

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Antimicrobial agents (eg, bithionol, chlorhexidine, hexachlorophene, fenticlor)

Systemic medications that can induce photoallergic reactions include [68]: ●

Quinidine



Griseofulvin



Quinine



Quinolones



Sulfonamides



Ketoprofen



Piroxicam

Diagnosis — A thorough history regarding photosensitivity and a full skin examination are essential to accurately diagnose phototoxicity or photoallergy. At times, this can be due to obscure contact. For example, photoallergic contact dermatitis can occur through contact with photoallergens left on swimming goggles or in wristbands [98,99]. If the diagnosis remains uncertain, phototesting and/or photopatch testing are useful. Minimal erythema doses (MEDs) are decreased in patients with phototoxicity or photoallergy secondary to a systemic agent [100]. Photopatch testing identifies patients with photoallergic contact dermatitis. In phototoxic reactions, histopathologic findings include ballooning of keratinocytes with scattered apoptotic keratinocytes (sunburn cells), variable spongiosis, and a mild or moderate superficial inflammatory cell infiltrate in the dermis. In severe reactions, epidermal necrosis may be seen. In photoallergic reactions, histopathologic findings are similar to those of allergic contact dermatitis. Spongiosis, mild acanthosis, and a superficial perivascular lymphocytic infiltrate with eosinophils are usually seen [15]. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Diagnostic studies'.) Treatment — For both phototoxic and photoallergic reactions, the offending drug or chemical causing exogenous photosensitivity should be discontinued whenever possible. Sun-protective measures such as sun avoidance, sun-protective clothing, and sunscreen are essential. Photosensitivity due to exogenous agents is often greatest in the long-wave UVA range. Broad-spectrum sunscreens that offer adequate UVA protection are indicated. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Photoprotection'.) Most phototoxic reactions can be treated as sunburn (see "Sunburn"). Symptomatic treatment with cool compresses, emollients, and oral analgesics usually suffice. Topical anesthetics should be avoided because of the possibility of a contact allergy. Photoallergic reactions should be treated in a manner similar to contact allergy. Specifically, application of topical corticosteroids to the involved areas will reduce pruritus and the inflammatory response. In some instances, a two- to three-week course of systemic corticosteroids may be necessary.

PHOTOSENSITIVITY DUE TO ENDOGENOUS AGENTS Porphyria — Several types of porphyria exhibit photosensitivity as a clinical manifestation. Examples include porphyria cutanea tarda, erythropoietic protoporphyria, variegate porphyria, congenital erythropoietic porphyria, hereditary coproporphyria, and hepatoerythropoietic porphyria. Diagnosis and treatment of the porphyrias are discussed separately. (See "Porphyrias: An overview" and "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis" and "Erythropoietic protoporphyria and X-linked protoporphyria" and "Congenital erythropoietic porphyria" and "Variegate porphyria" and "Hereditary coproporphyria".) Smith-Lemli-Opitz syndrome — Smith-Lemli-Opitz syndrome is a rare, congenital, multiple anomaly syndrome caused by an inborn error of cholesterol metabolism due to deficiency of the enzyme 7-dehydrocholesterol (7-DHC) reductase [101]. There is an associated photosensitivity that appears to be ultraviolet A (UVA)-mediated in more than 50 percent of cases [102,103]. The relationship of abnormal cholesterol metabolism to photosensitivity remains unclear.

PHOTOEXACERBATED DERMATOSES Photoexacerbated dermatoses are disorders that are exacerbated by sun exposure. Two well-known examples are lupus erythematosus and dermatomyositis.

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Lupus erythematosus — Cutaneous manifestations of lupus erythematosus, which may be initiated or exacerbated by ultraviolet radiation (UVR), include acute cutaneous lupus, subacute cutaneous lupus, and discoid lupus. The UV wavelength that provokes the skin lesions in lupus is ultraviolet A (UVA) in some individuals, in others it is ultraviolet B (UVB), and in still others it is both UVA and UVB [104]. Acute cutaneous lupus is seen in patients with systemic lupus erythematosus (SLE) and classically affects the malar area. Subacute cutaneous lupus may be associated with SLE but may occur without systemic involvement. Subacute cutaneous lupus is manifested as photodistributed scaly erythematous psoriasiform papules and plaques, which at times may have an annular appearance. Discoid lupus is sometimes clearly photosensitive. However, the frequent occurrence of discoid lesions on the relatively sun-protected scalp and conchal bowl of the ears is evidence against a strict requirement of sun exposure for discoid lesions to form. However, discoid lupus lesions have been produced experimentally by repeated exposure to UVR [104,105]. A more comprehensive discussion of cutaneous lupus is presented separately. (See "Overview of cutaneous lupus erythematosus".) Drug-induced subacute cutaneous lupus — Drug-induced subacute cutaneous lupus erythematosus (SCLE) presents with a photosensitive cutaneous eruption identical to idiopathic SCLE [106]. Among the medications reported to induce subacute cutaneous lupus, terbinafine, thiazide diuretics, and calcium channel blockers are more frequently involved [107,108]. (See "Drug-induced lupus".) Dermatomyositis — The cutaneous findings associated with dermatomyositis are often induced by UVR and appear on sun-exposed skin. Classic skin findings include a heliotrope rash on the face, erythematous papules overlying dorsal proximal interphalangeal joints (Gottron's papules), and scaly violaceous erythema in a "shawl distribution" (ie, a diffuse violaceous erythema over the back and shoulders) and on the "v"-area of the chest. Approximately 50 percent of dermatomyositis patients have a diminished minimal erythema dose (MED) response to UVB radiation [109]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults" and "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations".) Pellagra — Pellagra is caused by a deficiency of vitamin B3 (niacin) [110]. A dietary basis for niacin deficiency is rarely responsible for pellagra in the United States because it has been incorporated into enriched preparations of flour. However, dietary deficiency of niacin does still occur in other countries, particularly those with a high dietary content of corn. When pellagra is diagnosed in the United States, it is usually a consequence of alcoholism, bariatric surgery, malabsorption syndromes, or certain drugs (isoniazid, ethionamide, chloramphenicol, 6mercaptopurine, 5-fluorouracil, azathioprine, and phenobarbital). Because tryptophan is a precursor of niacin, disorders such as carcinoid syndrome and Hartnup disease may also have clinical features of niacin deficiency. (See "Clinical features of carcinoid syndrome".) Clinical manifestations include a photosensitive dermatitis, diarrhea, and dementia (also called the three Ds). The skin rash presents as an erythema in sun-exposed areas that progresses to hyperpigmentation and scaling. A characteristic feature of the disease is Casal's necklace, which is a ring of erythema and hyperpigmentation extending around the neck onto the chest (picture 9). Based on phototesting of a single patient, UVA wavelengths are thought to provoke the rash [111]. Other — Reports of cases of photoexacerbation exist for a number of other diseases, including [68]: ●

Acne



Atopic dermatitis



Bullous pemphigoid



Carcinoid syndrome



Cutaneous T cell lymphoma



Disseminated superficial actinic porokeratosis



Erythema multiforme



Familial benign chronic pemphigus (Hailey-Hailey disease)



Hartnup disease



HIV infection



Keratosis follicularis (Darier disease)



Lichen planus



Pemphigus, including pemphigus foliaceus (erythematosus)



Pityriasis rubra pilaris



Psoriasis



Reticular erythematous mucinosis



Rosacea



Seborrheic dermatitis

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Transient acantholytic dermatoses (Grover's disease)



Viral infections, including herpes simplex



Viral exanthems

RARE GENODERMATOSES Photosensitivity is a manifestation of several genodermatoses with DNA repair defects or chromosomal instability. These include xeroderma pigmentosum, Bloom syndrome, Cockayne syndrome, trichothiodystrophy, and Rothmund-Thomson syndrome. Skin cancer, cutaneous poikiloderma, short stature, craniofacial defects, intellectual impairment, or skeletal defects present at an early age may suggest one of these syndromes. (See "Xeroderma pigmentosum" and "Bloom syndrome" and "The genodermatoses: An overview", section on 'Disorders with malignant potential'.) Kindler syndrome, another photosensitive genodermatosis, is characterized by acral bullae and skin fragility, among other features. The syndrome is caused by a loss-of-function mutation in FERMT1, which encodes a membrane-associated structural signaling protein [112]. (See "Kindler syndrome".)

SUMMARY AND RECOMMENDATIONS ●

Photosensitivity disorders of the skin are conditions in which an abnormal cutaneous response occurs after exposure to ultraviolet radiation (UVR) or visible light. The major categories of photosensitivity disorders include idiopathic photodermatoses, photodermatoses due to exogenous or endogenous agents, photoexacerbated dermatoses, and photosensitive genodermatoses. A table describing the key features of many of the photosensitive disorders is provided (table 1). (See 'Introduction' above.)



The idiopathic photodermatoses are photosensitive disorders, many of which may be immunologically mediated, although the inciting agents are unknown. Polymorphous light eruption, actinic prurigo, hydroa vacciniforme, chronic actinic dermatitis (CAD), and solar urticaria are included in this category. (See 'The idiopathic photodermatoses' above and "Polymorphous light eruption".)



Actinic prurigo is a childhood-onset pruritic photo-induced eruption most common in Mestizos (ie, individuals of mixed American-Indian and European ancestry). Sun protection is an important component of therapy. For all patients with actinic prurigo, we suggest the use of topical corticosteroids as initial therapy (Grade 2C). For patients with moderate to severe disease who do not improve with sun protection and topical corticosteroids, we suggest treatment with prophylactic phototherapy, given initially with a short course of oral corticosteroids (Grade 2C). For patients with extensive or resistant disease, we suggest treatment with thalidomide (Grade 2C). (See 'Actinic prurigo' above.)



CAD is a persistent photodistributed eczematous eruption often seen in older men. Treatment should include sun-protective measures, emollients, and avoidance of inciting agents, if a contact or photocontact allergy is present. We suggest the use of high-potency topical corticosteroids and/or topical tacrolimus as needed for active dermatitis (Grade 2C). Refractory cases can benefit from treatment with systemic immunosuppressants or psoralen plus ultraviolet A (PUVA) initially given with oral glucocorticosteroids. (See 'Chronic actinic dermatitis' above.)



Phototoxic reactions resemble an exaggerated sunburn and result from direct tissue or cellular damage following exposure to a phototoxic agent and UVR. Most drug-induced photosensitivity reactions are phototoxic. Plant furocoumarins and tar also cause phototoxicity. Phototesting is useful for diagnosis. (See 'Phototoxicity' above and 'Diagnosis' above.)



A photoallergic reaction is a form of allergic contact dermatitis in which a photosensitizing chemical or drug once activated by UVR serves as the allergen and elicits an eczematous reaction in a sensitized individual. Most photoallergic reactions are caused by topical agents, rather than systemic medications. Phototesting and photopatch testing are useful for diagnosis. (See 'Photoallergy' above and 'Diagnosis' above.)



Photosensitive disorders due to endogenous agents include several types of porphyrias. Smith-Lemli-Opitz syndrome may also fit into this category. (See 'Photosensitivity due to endogenous agents' above.)



Photoexacerbated dermatoses are diseases that are exacerbated by sun exposure, such as lupus erythematosus and dermatomyositis. (See 'Photoexacerbated dermatoses' above.)

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Photosensitivity is a manifestation of several genodermatoses. Examples include xeroderma pigmentosa, Bloom syndrome, Cockayne syndrome, trichothiodystrophy, Rothmund-Thomson syndrome, and Kindler syndrome. (See 'Rare genodermatoses' above.) Use of UpToDate is subject to the Subscription and License Agreement.

Topic 6622 Version 24.0

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GRAPHICS Photosensitive disorders: Clinical features

 

Sex

Timeline of eruption

Age of onset

Location

Common lesion morphology and symptoms

Family history

Action spectrum

Laboratory findings

Phototesting

Duration/ resolution

Key features

Polymorphous light eruption

F>M

First three decades

Hours after sun exposure, lasts days to weeks; most conspicuous in spring; improves during summer

Sunexposed areas

Pruritic papules, papulovesicles, plaques.

May be present

UVA, UVB, visible

Normal MED; provocative phototesting may induce lesions

 

Recurrent over the course of years, may improve over time

Most common photodermatosis; "hardening" phenomenon may occur

Juvenile spring eruption

M>F

Primarily childhood; also may be seen in young adults

As with PMLE

Classically, helices of ears

Erythematous papules, bullae.

May be present

UVA?

As with PMLE

 

Recurrent over years, may improve with age

 

Actinic prurigo

F>M, M>F reported in adult onset in Asia

Childhood;

Persistent during summer; may also be present year round

Sunexposed areas, may also affect unexposed areas

Pruritic papulonodules, crusts, excoriations, lichenification, cheilitis.

Yes, in up to 50%

UVA>UVB

60% with reduced MED, 60 to 70% with positive provocative phototests

 

Improves in adolescence, but also may persist

More common in American Indians and Mestizos. May have ocular findings.

Hydroa vacciniforme

Slight M>F

Childhood

Hours after sun exposure

Face, dorsal hands

Erythematous macules, papules, vesicles, crusts.

Rarely positive

Likely UVA

May show reduced MED to UVA in some cases

 

Usually resolves by adolescence/young adulthood, but may persist

Lymphoproliferative disease association with severe cases

Chronic actinic dermatitis

M>F

Older, but may be seen in younger patients

Persistent; worsens in summer, may have findings year round

Sunexposed areas

Eczematous patches, lichenification, may see palmoplantar involvement.

 

UVA, UVB, visible light

Decreased MEDs to UVA, UVB, or visible light

May see Sézary cells in severe cases

Persists for years, may resolve

Often coexistent contact dermatitis

Solar urticaria

F>M

Young or midadulthood

Appears within minutes, individual lesions resolve within 24 hours

Sunexposed areas

Urticarial plaques (hives), occasional systemic symptoms.

 

UVA, UVB, visible light

Normal MEDs, urticaria are induced within minutes of phototesting

 

Persists for years, may resolve

"Hardening" phenomenon may occur

Phototoxicity

M=F

Any age

Appears within hours of sun exposure, can occur after first dose of drug

Sunexposed areas

Exacerbated sunburn appearance.

 

UVA

In systemic phototoxicity, MED for UVA decreased, UVB and visible light MEDs normal

 

Resolves when drug discontinued and cleared from body

Can occur in anyone

Photoallergy

M=F

Any age

Appears one to two days after exposure to sun and inciting agent in sensitized individual

Sunexposed areas

Pruritic, eczematous lesions.

 

UVA

In systemic photoallergy, MED for UVA decreased, UVB and visible light MEDs normal

 

Resolves with discontinuation of inciting agent

Usually due to topical agents

Erythropoietic protoporphyria

M = F, versus slight M>F

Onset in early childhood

Symptoms begin within minutes of sun exposure, improves in winter

Nose, cheeks, hands

Burning and stinging, pain, pruritus. Erythema, edema, pupura. Heals with atrophic, wax-like scars; wrinkled knuckles.

Common (siblings), autosomal recessive or pseudodominant

Soret band (400 to 410 nm)

Often normal, some patients may note stinging sensation or lesions

Elevated erythrocyte protoporphyrin level

Chronic

May develop liver disease

Porphyria cutanea tarda

M=F

Middle age, may occur earlier

 

Sunexposed areas

Skin fragility, bullae, crusts, scarring. Hypertrichosis, hyperpigmentation, sclerodermoid changes.

Sporadic in Type I, autosomal dominant in Type II

Soret band (400 to 410 nm)

 

Elevated porphyrins in urine and stool

Chronic, symptoms improve with sun protection, removal of triggers, phlebotomy, antimalarials

Often associated with hepatitis C

adultonset may occur in Asians

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Pseudoporphyria

 F>M

Any age; 10% of children taking naproxene

 

Sunexposed areas

Skin fragility, bullae, crusts, scarring, milia.

Negative

UVA

 

Normal porphyrin levels

Symptoms resolve with sun protection, avoidance of tanning bed use, and discontinuation of the causative medications

May be caused by medications, renal failure and hemodialysis, and excessive tanning bed use

 

 

 

 

 

 

 

 

 

 

 

 

F: female; M: male; UV: ultraviolet; MED: minimal erythema dose; PMLE: polymorphus light eruption. Graphic 57800 Version 12.0

8533

Actinic prurigo

Excoriated papular lesions on the face of a child with actinic prurigo. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 90422 Version 3.0

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Actinic prurigo

Excoriated papular and nodular lesions on the arms of a child with actinic prurigo. Healed lesions leave hypo- or hyperpigmented scars. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 90424 Version 3.0

8535

Hydroa vacciniforme

Scars and crusted papules are present on the face. This 10-year-old boy had a history of recurrent blisters in sun-exposed areas that healed with depressed vaccination-like scars. Copyright © Shahbaz A Janjua, MD, Dermatlas; http://www.dermatlas.org. Graphic 54500 Version 6.0

8536

Hydroa vacciniforme

Erythematous papules and crusts are seen on the forearm of a 10-year-old boy with hydroa vacciniforme. Copyright © Shahbaz A Janjua, MD, Dermatlas; http://www.dermatlas.org. Graphic 68305 Version 5.0

8537

Chronic actinic dermatitis

Diffuse infiltrated erythema, scaling, and fissures on the face of this patient with chronic actinic dermatitis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 101492 Version 3.0

8538

Chronic actinic dermatitis

The skin on photoexposed areas appears erythematous and lichenified in this patient with chronic actinic dermatitis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 101494 Version 3.0

8539

Solar urticaria induced by ultraviolet A light

(A) Shoulder before sun exposure. (B) Shoulder after 15 minutes of sun exposure through a glass window. The glass window filters out ultraviolet B light. Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd Edition. Philadelphia: Lippincott Williams & Wilkins, 2003. Copyright © 2003 Lippincott Williams & Wilkins. Graphic 57783 Version 3.0

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Differences between phototoxic and photoallergic reactions Feature

Phototoxicity

Photoallergy

Incidence

High

Low

Amount of agent required for photosensitivity

Large

Small

Onset after exposure to photosensitizer and light

Minutes to hours

24 hours or more

Requirement for immunization

No

Yes

Clinical characteristics

Exaggerated sunburn

Acute, subacute, or chronic dermatitis

Distribution

Exposed skin only

Exposed skin; may spread to unexposed skin

Pigmentary changes

Frequent

Unusual

Histopathologic features

Epidermal cell degeneration; dermal edema and vasodilatation; sparse mononuclear infiltrate

Epidermal spongiosis; exocytosis of mononuclear cells; dermal mononuclear cell infiltrate

Development of persistent light reaction

No

Yes

Cross-reactions to related agents

No

Yes

Covalent binding with carrier protein

No

Yes

Reproduced from: Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol 1995; 33:551. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 50323 Version 3.0

8541

Phototoxic eruption

Diffuse, sunburn-like erythema is present on the face and ears. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 69140 Version 9.0

8542

Phototoxic eruption

A bright red, confluent rash on the "V" of the neck of a patient with drug-induced photosensitivity reaction. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 86479 Version 7.0

8543

Phototoxic eruption

Confluent erythema on the dorsum of the hands following sun exposure in a child taking doxycycline. Note initial blistering on the right hand and the sparing of the area covered by a watch. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 90426 Version 5.0

8544

Some potential causes of phytophotodermatitis* Plant family Apiaceae (Umbelliferae)

Common name(s) Angelica Celery Cow parsley, wild chervil Cow parsnip, hogweed Dill Fennel Giant hogweed Parsley Parsnip

Rutaceae

Bergamot orange Bitter orange Burning bush, gas plant Grapefruit Lemon Lime Rue

Moraceae

Fig

Fabaceae (Leguminosae)

Bavachee, scurf-pea (Psoralea corylifolia)

Cruciferae

Mustard

Ranunculaceae

Buttercup

Hypericaceae

St. John's wort (can cause systemic phytophotodermatitis)

* Other plants have also been implicated. Graphic 75581 Version 2.0

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Phytophotodermatitis

Erythematous linear streaks that subsequently became hyperpigmented occurred on the trunk of this 14-year-old male who was exposed to the sun after squeezing limes during a Carribean vacation. Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org. Graphic 77829 Version 6.0

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Phytophotodermatitis

After making lemonade during an outdoor excursion trip, this 38-year-old female presented with erythematous linear and angulated patches and crusts on the face. Copyright © Shahbaz A Janjua, MD, Dermatlas; http://www.dermatlas.org. Graphic 57871 Version 5.0

8547

Severe phytophotodermatitis

Erythema and erosions on the left thigh in a 10-year-old girl with severe phytophotodermatitis caused by exposure to lime juice and sunlight. From: Darracq MA, Heppner J, Lee H, Armenian P. Backyard Pool Party: Not Your Typical Sunburn. Pediatr Emerg Care 2017; 33:440. DOI: 10.1097/PEC.0000000000001204. Copyright © 2017 Wolters Kluwer Health. Reproduced with permission. Unauthorized reproduction of this material is prohibited. Graphic 114275 Version 1.0

8548

Phytophotodermatitis

Meadow grass-induced phytophotodermatitis. The bizarre, linear hyperpigmented lesions on the lower leg correspond to the areas of contact with the grass. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 90428 Version 3.0

8549

Photoallergic eruption

This 45-year-old woman developed an acute, well-demarcated, erythematous plaque with vesicles after topical application of ketoprofen gel followed by sun exposure. The patient wore socks, which protected the foot from the sun, creating the line of demarcation that is visible in the image. Copyright © Eric Ehrsam, MD, Dermatlas; http://www.dermatlas.org. Graphic 63557 Version 8.0

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Pellagra dermatitis

Dermatitis due to niacin deficiency (pellagra). The term "pellagra" derives from the Italian words for "rough skin." The condition is characterized by an erythematous, blistering rash that may be pruritic or painful. The rash occurs in areas of sun exposure and is therefore often seen around the neck ("Casal's necklace"), arms, hands, or malar area. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 69889 Version 8.0

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Polymorphous light eruption Author: Craig A Elmets, MD Section Editors: Robert P Dellavalle, MD, PhD, MSPH, Jeffrey Callen, MD, FACP, FAAD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 03, 2019.

INTRODUCTION Polymorphous light eruption (PMLE) is the most common idiopathic photodermatosis; it is sometimes called "sun poisoning" or "sun allergy." PMLE usually presents as a pruritic rash in sun-exposed areas hours to days after sun exposure and persists for several days before subsiding [1]. Juvenile spring eruption is a variant of PMLE. (See 'Juvenile spring eruption (PMLE variant)' below.) An overview of cutaneous photosensitivity and a review of other photodermatoses are presented separately. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection" and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment".)

EPIDEMIOLOGY The onset of polymorphous light eruption (PMLE) typically occurs within the first three decades of life, and a female preponderance is reported [2,3]. Fair-skinned individuals are the most commonly affected, although PMLE can develop in individuals of all ethnicities and skin types [4]. It occurs more frequently in temperate areas. Several studies have indicated that the prevalence of PMLE is directly related to the latitude, ranging from 1 percent in Singapore to 20 percent in Sweden [2,3,5-7]. However, within Europe, a latitude gradient has not been shown to occur [8].

PATHOGENESIS Both ultraviolet A (UVA) and ultraviolet B (UVB) radiation, and occasionally visible light, have been implicated in the development of polymorphous light eruption (PMLE) [9]. In most studies, a higher proportion of patients develops the disease in response to UVA than UVB [3]. The eruption may be influenced by the dose and frequency of the UV radiation as well as by the extent and site of irradiated skin [10]. PMLE occurring after exposure to ultraviolet C radiation generated from welding arcs has been reported [11]. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Phototesting'.) Patients with PMLE appear to have a genetic susceptibility, as evidenced by increased concordance in monozygotic twins [12]. In addition, a positive family history is present in 15 to 46 percent of cases [5,13]. Genetic modeling of PMLE in families with photosensitivity disorders suggests a dominant mode of inheritance with low penetrance [14]. A case-control study found a negative association with the GSTP1 allele of glutathione-S-transferase [15], but a subsequent study was unable to confirm this finding [16]. Candidate gene analysis of interleukin (IL)-10, Fc fragment of IgG receptor (FCGR2A), selectin-E (SELE), intercellular adhesion molecule-1 (ICAM1), IL1A, IL1B, IL1RN, and tumor necrosis factor (TNF)-alpha has been inconclusive [17]. The higher prevalence and severity of PMLE among younger women suggests that hormonal factors may be involved in its pathogenesis [18]. In animal models, 17-beta-estradiol inhibits UV-induced immunosuppression through a dose-dependent reduction in the release of immunosuppressive IL-10 from UVB-irradiated keratinocytes [19]. PMLE has many features in common with delayed-type hypersensitivity (DTH) responses in the skin, suggesting that it may be a cell-mediated immune response to unknown cutaneous photo-induced antigen(s) [20]. Timed biopsy specimens taken after solar-simulated irradiation displayed perivascular infiltrates of CD4+ T lymphocytes within a few hours and CD8+ T lymphocytes within days [21]. Increased numbers of dermal and epidermal Langerhans cells and dermal macrophages were also noted. In addition, expression of selectin-E (CD62E), vascular cell

8552

adhesion molecule-1 (VCAM-1; CD106), and ICAM-1 (CD54) on endothelial cells and keratinocytes has also been observed, further supporting the relationship between PMLE and DTH reactions [1]. In healthy individuals, exposure to ultraviolet radiation has a suppressive effect on T cell immune responses in the skin. There is evidence to suggest that in patients with PMLE, this immunosuppressive effect of UV does not occur [22-25]. It has been postulated that this abnormal response to UV exposure permits PMLE patients to develop an inflammatory response to an endogenous photo-induced antigen, which does not occur in the general population [1]. The photoantigen responsible for PMLE has not been identified. Regulatory T cells (Tregs) may be involved in the lack of UV-induced immunosuppression seen in patients with PMLE. One study compared the number and function of Tregs in 19 healthy controls and 30 patients with PMLE before and after undergoing photohardening with narrowband (311 nm) UVB phototherapy [26]. Although there was no difference in the number of circulating Tregs between healthy subjects and PMLE patients before phototherapy, Tregs isolated from PMLE patients lacked the capacity to suppress effector T cell proliferation. After receiving photohardening therapy, PMLE patients showed a significant increase in the number of circulating Tregs and expression of FoxP3 mRNA, an indicator of increased suppressive function. Studies have implicated the innate immune system as well. There are increased levels of the antimicrobial peptides psoriasin, HBD2, and LL37 in the UV-irradiated skin of individuals with PMLE compared with healthy controls [27].   Genome-wide analyses have been conducted comparing PMLE patients with healthy controls [28,29]. PMLE subjects were found to have lower levels of genes associated with clearance of apoptotic keratinocytes. It has been proposed that defective clearance of apoptotic keratinocytes may result in the development of an autoantigen eliciting a UV-driven, cell-mediated immune response [29]. This hypothesis is supported by the demonstration of greater amounts of apoptotic keratinocytes in the epidermis of subjects with cutaneous lupus erythematosus or PMLE compared with healthy controls [30].

CLINICAL MANIFESTATIONS The onset of polymorphous light eruption (PMLE) characteristically occurs in the spring and early summer. When it occurs in winter, it usually results from tanning bed exposure [31] or vacationing in a sunny climate [8]. The amount of exposure required to elicit PMLE ranges from several hours to one or two days. Skin lesions typically appear within hours, although they sometimes occur days after sun exposure, and are accompanied by intense pruritus. The eruption lasts one to several days and then resolves if further sun exposure is avoided. Occasionally, PMLE persists for weeks. Lesions heal without scarring. A characteristic feature of PMLE is that it is most severe in the spring and early summer, moderates as the summer progresses, and resolves in the autumn or winter, only to recur the next spring. Sites of predilection for PMLE are sun-exposed areas, including the upper chest, the "V" of the neck, the back of the arms, and occasionally shoulders and lower legs. The disease occurs more frequently in skin that has been covered in the winter [4]. The face and dorsal aspects of the hands are uncommon sites of PMLE, possibly because the hardening phenomenon has occurred from regular sun exposure [1] (see 'Photohardening' below). Lesions often recur in the same anatomic locations. Several different types of skin lesions can occur in PMLE, but in a given individual the morphology is usually monomorphic and when there is a recurrence, lesions are usually identical to those observed during previous eruptions. Most commonly, patients present with pruritic, erythematous, or skin-colored papules or plaques in a symmetric distribution on sun-exposed skin (picture 1A-C). Papulovesicles, vesicles, bullae, or confluent edematous plaques (especially on the face) may also be seen. Less commonly, lesions resemble insect bites or erythema multiforme. In black and Asian patients, PMLE can also present as pinpoint papules (picture 2), which may also involve the face and the perioral area [3234]. In addition, pruritus without a cutaneous eruption has been reported [35]. An eczematous form of PMLE does not exist, although eczematous changes can occur as a secondary response to rubbing and scratching. Another unusual variant presenting with pruritic papules and plaques localized to the elbows also has been reported [36]. Systemic symptoms of fever, chills, headache, and nausea are rare but may accompany PMLE. PMLE has a major impact on patients' lives. Compared with the general population, patients with PMLE are more likely to suffer from depression and anxiety, spend less time in outdoor activities, and take fewer vacations per year [37,38]. Skin hardening effect — Continued sun exposure may lead to increased tolerance to ultraviolet (UV) radiation and even to resolution of PMLE, a process referred to as "hardening." By mid-summer, many patients are clear of the rash due to this phenomenon. The mechanism underlying

8553

hardening is not well understood, but is likely due to the cumulative effect of repeated small amounts of UV radiation resulting in increased melanin production, thickening of the stratum corneum, and, possibly, normalization of cutaneous cell-mediated immune responses [39,40].

DIAGNOSIS A diagnosis of polymorphous light eruption (PMLE) is usually based upon the clinical finding of a pruritic eruption of papules or plaques on exposed skin (picture 1A-C) and the patient's history of a similar eruption occurring in spring or early summer after sun exposure and gradually improving over the summer months. It is important to exclude other photosensitive skin conditions (table 1). (See 'Differential diagnosis' below.) Skin biopsy may be helpful in some cases, particularly to exclude other disorders. Histologic findings for PMLE are nonspecific and require correlation with clinical presentation (picture 3). Focal epidermal spongiosis with focal lymphocyte exocytosis and a perivascular and periadnexal lymphohistiocytic infiltrate with occasional eosinophils and rare neutrophils may be seen. Papillary dermal edema, focal interface changes, and mild hydropic basal cell degeneration are present in more advanced lesions [41]. Direct immunofluorescence of skin biopsies is negative. Phototesting for the assessment of the minimal erythema dose (MED) is usually normal in patients with PMLE. Provocative phototesting, which tests for the appearance of PMLE lesions after repeated UV exposure, may be used to assist with diagnosis. Provocative phototesting is performed by repeatedly exposing the forearms or "V" of the neck to suberythemal doses of either ultraviolet A (UVA) or ultraviolet B (UVB) for four to five days. In over 60 percent of individuals with PMLE, this procedure will elicit clinical and histologic features characteristic of PMLE. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Diagnostic studies'.)

DIFFERENTIAL DIAGNOSIS The differential diagnosis of PMLE includes other photosensitivity disorders, which are summarized in the table (table 1) and discussed in detail separately. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment".) Distinguishing PMLE from actinic prurigo (picture 4), including the photosensitive rash seen in Native Americans and Mestizos, may be particularly difficult because of their overlapping clinical features. However, actinic prurigo occurs mainly in children and, in contrast with PMLE, tends to persist through the summer and may even extend into the winter months. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Actinic prurigo'.) The earliest lesions of subacute cutaneous lupus erythematosus (picture 5) may resemble those of PMLE but are less pruritic. There is controversy as to whether patients with lupus erythematosus have a greater potential to have PMLE or whether the PMLE-like lesions are merely part of the photosensitive phenomenon observed in patients with lupus erythematosus.

MANAGEMENT Preventive measures Sun protection — Sun protection is the first-line preventive measure for patients with PMLE and includes sun avoidance, sun-protective clothing, and sunscreens. Sunscreens should be broad spectrum, with both ultraviolet A (UVA) and ultraviolet B (UVB) protection. A broadspectrum sunscreen with a sun protection factor (SPF) of at least 30 should be regularly and generously applied [42-45]. In one study of 15 patients with a history of PMLE, a broad-spectrum SPF 45 sunscreen applied at a dose of 2 mg/mL prevented PMLE in all subjects after repeated exposure to UVA-UVB radiation [45]. (See "Selection of sunscreen and sun-protective measures".) Products containing photostabilized avobenzone and/or ecamsule (table 2) offer improved protection against UVA, and have been effective in preventing PMLE eruptions [43-46]. Sunscreens that contain the non-micronized form of zinc oxide or titanium dioxide also offer photoprotection that extends throughout the UV and into the visible spectrum. (See "Selection of sunscreen and sun-protective measures", section on 'Spectrum'.) Systemic photoprotection — There is insufficient evidence to suggest oral supplementation with carotenoids or antioxidants for the prevention of PMLE. In a small randomized trial, 12-week oral supplementation with lycopene, beta-carotene, and Lactobacillus johnsonii was not effective in preventing PMLE [47]. In a small uncontrolled study, a two-week oral supplementation with Polypodium leucotomos, a natural

8554

extract of a tropical fern with antiinflammatory and antioxidant properties, prevented the development of a response to UVA and UVB irradiation in approximately one-third of the patients [48]. Afamelanotide, a synthetic analogue of alpha-melanocyte stimulating hormone that promotes skin tanning used for the prevention of phototoxic reactions in patients with erythropoietic protoporphyria, may be a potential prophylactic treatment for patients with PMLE [49,50]. However, data from an industry-sponsored phase III trial have not been published. Photohardening — Prophylactic phototherapy with low-dose PUVA (psoralen plus UVA) or broadband or narrowband UVB in early spring to induce tolerance to sun exposure may be an option for patients who are expected to develop significant symptoms during the spring or summer [51-54]. Treatments are usually given at suberythemal doses two to three times per week over four to six weeks. The use of prophylactic phototherapy for PMLE is supported by a limited number of small randomized trials [52-55]. In one study, treatment was successful in 92 percent of patients treated with PUVA and 62 percent of patients treated with broadband UVB [54]. Other studies have shown narrowband UVB to be as effective as PUVA [52,53]. Because narrowband UVB is easier to administer, it is often preferred to PUVA therapy for patients with PMLE. Narrowband UVB phototherapy can be administered three times per week, starting with a dose equivalent to 50 to 70 percent of the minimal erythema dose (MED). The dose is increased during subsequent treatments as tolerated by the patient. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy" and "UVB therapy (broadband and narrowband)".) Exacerbations may occur early in the course of phototherapy. If these occur, potent topical corticosteroids (groups 1 to 3) (table 3) or a short course of oral glucocorticoid therapy (eg, prednisone 0.5 mg/kg for five to seven days) may be required [51,56]. (See 'Treatment' below.) Other — The 1,25-dihydroxyvitamin D analogue calcipotriol has been investigated as a preventive agent in PMLE. In a randomized placebocontrolled intraindividual half-body trial involving 13 patients, calcipotriol cream significantly inhibited the severity of PMLE lesions on photoprovocation testing, suggesting that it may be of therapeutic benefit [57]. Treatment — Many patients with mild polymorphous light eruption (PMLE) do not seek medical attention, and chronic sun exposure may eventually prevent eruptions via the "hardening" phenomenon. However, some patients may require treatment for symptomatic relief [51]. Patients with mild to moderate eruption — For patients with mild PMLE, we suggest topical corticosteroids for symptomatic treatment of skin inflammation and pruritus. Potent topical corticosteroids (groups 1 to 3) (table 3) are applied once or twice daily on the affected areas for five to seven days. Facial lesions should be treated with lower-potency topical corticosteroids (groups 6 to 7). Oral antihistamines may be useful to control pruritus. (See "Pruritus: Overview of management".) The efficacy of topical corticosteroids for PMLE has not been evaluated in randomized trials. Their use is based upon clinical experience and evidence of efficacy in other inflammatory skin conditions [1]. Patients with severe eruption — Patients with acute episodes of PMLE may require a short course of oral corticosteroids. Prednisolone 25 mg or prednisone 30 mg can be given for four to five days. Slightly longer treatment courses may be required in some cases. However, frequent courses of systemic corticosteroids are not recommended due to associated potential side effects. (See "Major side effects of systemic glucocorticoids".) In one trial, 21 patients with PMLE were given a seven-day supply of both prednisolone 25 mg and placebo tablets prior to a sunny vacation [58]. The order of administration had previously been randomized by a computer-generated sequence. If patients noted improvement, the initial treatment was continued until symptoms resolved or for a maximum of seven days. Patients were instructed to switch to the other therapy if no improvement occurred after 48 hours. Treatment with prednisolone reduced the mean time to resolution of itch (2.8 versus 5.4 days) and rash (4.2 versus 7.8 days). Antimalarials are used for the treatment of some photosensitive disorders, including cutaneous lupus erythematosus, porphyria cutanea tarda, and dermatomyositis. Small randomized trials have demonstrated improvement in PMLE with antimalarials [59,60]. There are isolated reports of successful use of azathioprine and cyclosporine for the treatment of severe, recalcitrant PMLE [61,62].

PROGNOSIS PMLE is a recurrent condition that may persist for years. However, the severity often improves with time. In a follow-up study of 114 patients with PMLE, 57 percent of patients noted decreasing sun sensitivity over the course of seven years, including 12 patients (9 percent) who reported complete resolution [63].

8555

JUVENILE SPRING ERUPTION (PMLE VARIANT) The term "juvenile spring eruption" was first proposed in 1954 for a recurrent springtime eruption on the ears of young boys [64]. This disorder was found to affect approximately 7 percent of school-aged children in New Zealand [65]. A family history may be positive in some cases [66]. Patients often present in childhood or early adolescence, but initial presentation in young adulthood has also been reported [67,68]. The lesions are typically erythematous scaly papules or bullae. They occur on the ears (picture 6A-B), face, and dorsal hands. Onset occurs in the spring, and symptoms resolve within several weeks, not to recur until the following spring. Boys are more commonly affected than girls. It has been postulated that this is related to shorter haircuts that expose their ears. The diagnosis is typically made on a clinical basis. The differential diagnosis includes herpes simplex viral (HSV) infection and hydroa vacciniforme. Viral cultures may be performed to rule out HSV, but the bilateral localization of juvenile spring eruption is uncommon in HSV infection. Predominantly vesicular lesions that heal with scarring and the lack of predilection for the ears are features more characteristic of hydroa vacciniforme. Treatment of juvenile spring eruption is not always necessary due to the transient nature of the disease. Topical corticosteroids may be effective to reduce inflammation. It is important to emphasize sun protection.

SUMMARY AND RECOMMENDATIONS ●

Polymorphous light eruption (PMLE) is the most common idiopathic photodermatosis. Disease onset usually occurs during the first three decades. Individuals with fair skin are more likely to develop the disorder. (See 'Epidemiology' above.)



Ultraviolet A (UVA) is the most common inciting spectrum of light, but ultraviolet B (UVB) and visible light may also provoke PMLE in some patients. (See 'Pathogenesis' above.)



PMLE is characterized by pruritic papules, papulovesicles, or plaques that appear hours or days after sun exposure and persist for days (picture 1A-C). Systemic symptoms are rare. Continued sun exposure characteristically leads to suppression of the condition over time. (See 'Clinical manifestations' above.)



Diagnosis is primarily based upon the patient's history and physical findings. In some cases skin biopsy or provocative phototesting may also be indicated. The differential diagnosis includes lupus erythematosus, erythropoietic protoporphyria, and solar urticaria (table 1). (See 'Diagnosis' above.)



The management of PMLE includes preventive measures such as sun avoidance, sun-protective clothing, sunscreen, and treatment of symptoms. Broad-spectrum sunscreens with an SPF of at least 30 should be regularly used. (See 'Preventive measures' above.)



For patients who develop frequent exacerbations during the spring and summer, we suggest prophylactic phototherapy in early spring (Grade 2B). (See 'Photohardening' above.)



For patients with mild active lesions, we suggest treatment with potent topical corticosteroids (groups 1 to 3 (table 3)) (Grade 2C). Oral antihistamines may be useful to control pruritus. Patients with acute episodes of PMLE may require a short course of oral corticosteroids. (See 'Treatment' above.)



Juvenile spring eruption is a variant of PMLE that is manifested by erythematous papules or bullae typically on ears of children or adolescents after sun exposure. Symptoms are self-limited and resolve within several weeks. (See 'Juvenile spring eruption (PMLE variant)' above.) Use of UpToDate is subject to the Subscription and License Agreement.

Topic 6623 Version 21.0

8556

GRAPHICS Polymorphous light eruption

This photo shows a 35-year-old woman with a symmetrical papulovesicular eruption on the forearms. Lesions were also present on the neck and lower legs. Copyright © Eric Ehrsam, MD, Dermatlas; http://www.dermatlas.org. Graphic 64270 Version 7.0

8557

Polymorphous light eruption

Erythematous papules developed on the dorsal hands (A) and neck (B) of a 40-year-old man following sun exposure. The patient's history and symptoms were consistent with polymorphous light eruption. Copyright © Shahbaz A Janjua, MD, Dermatlas; http://www.dermatlas.org. Graphic 76995 Version 6.0

8558

Polymorphous light eruption

This 12-year-old girl developed a pruritic eruption that consisted of discrete and coalescing erythematous papules on the face. The lesions were photodistributed and appeared within hours after intense sun exposure in the spring. Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org. Graphic 51455 Version 6.0

8559

Polymorphous light eruption

In patients with darker skin tones, PMLE may present as pinpoint papules. PMLE: polymorphous light eruption. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 99549 Version 4.0

8560

Photosensitive disorders: Clinical features

 

Sex

Timeline of eruption

Age of onset

Location

Common lesion morphology and symptoms

Family history

Action spectrum

Laboratory findings

Phototesting

Duration/ resolution

Key features

Polymorphous light eruption

F>M

First three decades

Hours after sun exposure, lasts days to weeks; most conspicuous in spring; improves during summer

Sunexposed areas

Pruritic papules, papulovesicles, plaques.

May be present

UVA, UVB, visible

Normal MED; provocative phototesting may induce lesions

 

Recurrent over the course of years, may improve over time

Most common photodermatosis; "hardening" phenomenon may occur

Juvenile spring eruption

M>F

Primarily childhood; also may be seen in young adults

As with PMLE

Classically, helices of ears

Erythematous papules, bullae.

May be present

UVA?

As with PMLE

 

Recurrent over years, may improve with age

 

Actinic prurigo

F>M, M>F reported in adult onset in Asia

Childhood;

Persistent during summer; may also be present year round

Sunexposed areas, may also affect unexposed areas

Pruritic papulonodules, crusts, excoriations, lichenification, cheilitis.

Yes, in up to 50%

UVA>UVB

60% with reduced MED, 60 to 70% with positive provocative phototests

 

Improves in adolescence, but also may persist

More common in American Indians and Mestizos. May have ocular findings.

Hydroa vacciniforme

Slight M>F

Childhood

Hours after sun exposure

Face, dorsal hands

Erythematous macules, papules, vesicles, crusts.

Rarely positive

Likely UVA

May show reduced MED to UVA in some cases

 

Usually resolves by adolescence/young adulthood, but may persist

Lymphoproliferative disease association with severe cases

Chronic actinic dermatitis

M>F

Older, but may be seen in younger patients

Persistent; worsens in summer, may have findings year round

Sunexposed areas

Eczematous patches, lichenification, may see palmoplantar involvement.

 

UVA, UVB, visible light

Decreased MEDs to UVA, UVB, or visible light

May see Sézary cells in severe cases

Persists for years, may resolve

Often coexistent contact dermatitis

Solar urticaria

F>M

Young or midadulthood

Appears within minutes, individual lesions resolve within 24 hours

Sunexposed areas

Urticarial plaques (hives), occasional systemic symptoms.

 

UVA, UVB, visible light

Normal MEDs, urticaria are induced within minutes of phototesting

 

Persists for years, may resolve

"Hardening" phenomenon may occur

Phototoxicity

M=F

Any age

Appears within hours of sun exposure, can occur after first dose of drug

Sunexposed areas

Exacerbated sunburn appearance.

 

UVA

In systemic phototoxicity, MED for UVA decreased, UVB and visible light MEDs normal

 

Resolves when drug discontinued and cleared from body

Can occur in anyone

Photoallergy

M=F

Any age

Appears one to two days after exposure to sun and inciting agent in sensitized individual

Sunexposed areas

Pruritic, eczematous lesions.

 

UVA

In systemic photoallergy, MED for UVA decreased, UVB and visible light MEDs normal

 

Resolves with discontinuation of inciting agent

Usually due to topical agents

Erythropoietic protoporphyria

M = F, versus slight M>F

Onset in early childhood

Symptoms begin within minutes of sun exposure, improves in winter

Nose, cheeks, hands

Burning and stinging, pain, pruritus. Erythema, edema, pupura. Heals with atrophic, wax-like scars; wrinkled knuckles.

Common (siblings), autosomal recessive or pseudodominant

Soret band (400 to 410 nm)

Often normal, some patients may note stinging sensation or lesions

Elevated erythrocyte protoporphyrin level

Chronic

May develop liver disease

Porphyria cutanea tarda

M=F

Middle age, may occur earlier

 

Sunexposed areas

Skin fragility, bullae, crusts, scarring. Hypertrichosis, hyperpigmentation, sclerodermoid changes.

Sporadic in Type I, autosomal dominant in Type II

Soret band (400 to 410 nm)

 

Elevated porphyrins in urine and stool

Chronic, symptoms improve with sun protection, removal of triggers, phlebotomy, antimalarials

Often associated with hepatitis C

Pseudoporphyria

 F>M

Any age; 10% of

 

Sunexposed

Skin fragility, bullae, crusts,

Negative

UVA

 

Normal porphyrin

Symptoms resolve with sun protection,

May be caused by medications, renal

adultonset may occur in Asians

8561

children taking naproxene

 

 

 

 

areas

scarring, milia.

 

 

 

F: female; M: male; UV: ultraviolet; MED: minimal erythema dose; PMLE: polymorphus light eruption. Graphic 57800 Version 12.0

8562

 

 

levels

avoidance of tanning bed use, and discontinuation of the causative medications

failure and hemodialysis, and excessive tanning bed use

 

 

 

Polymorphous light eruption, histopathology

Marked papillary edema and a superficial and deep lymphocytic infiltrate are visible in this specimen from a patient with polymorphous light eruption. Copyright © Greg Hosler, MD, PhD, Dermatlas; http://www.dermatlas.org. Graphic 65837 Version 6.0

8563

Actinic prurigo

Excoriated papular lesions on the face of a child with actinic prurigo. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 90422 Version 3.0

8564

Subacute cutaneous lupus erythematosus

Multiple erythematous, scaly papules are present on the upper back. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 66580 Version 5.0

8565

Sunscreens Sunscreen

Range of protection

Organic PABA derivatives

PABA (para-aminobenzoic acid)

UVB

Padimate O (octyl dimethyl PABA)

UVB

Cinnamates

Octinoxate (octyl methoxycinnamate)

UVB

Cinoxate

UVB

Salicylates

Octisalate (octyl salicylate)

UVB

Homosalate

UVB

Trolamine salicylate

UVB

Benzophenones

Oxybenzone (benzophenone-3)

UVB, UVA2

Sulisobenzone (benzophenone-4)

UVB, UVA2

Dioxybenzone (benzophenone-8)

UVB, UVA2

Others

Octocrylene

UVB

Ensulizole (phenylbenzimidazole sulfonic acid)

UVB

Avobenzone (butyl methoxydibenzoyl methane, Parsol 1789)

UVA1

Ecamsule (terephthalylidene dicamphor sulfonic acid, Mexoryl SX)*

UVB, UVA2

Drometrizole trisiloxane (Mexoryl XL) ¶

UVB, UVA2

Meradimate (menthyl anthranilate)

UVA2

Bemotrizinol (bis-ethylhexyloxyphenol methoxyphenol triazine, Tinosorb S) ¶

UVB, UVA2

Bisoctrizole (methylene bis-benzotriazolyl tetramethylbutylphenol, Tinosorb M) ¶

UVB, UVA2

Inorganic Titanium dioxide

UVB, UVA2, UVA1

Zinc oxide

UVB, UVA2, UVA1

UVB: ultraviolet B; UVA: ultraviolet A. * Available in the United States since 2006 in combination with avobenzone and octocrylene. ¶ Available in Europe but not in the United States. Adapted with permission from: Sunscreens: An Update. The Medical Letter 2008; 50:70. Copyright © 2008 The Medical Letter. Graphic 73127 Version 8.0

8566

Comparison of representative topical corticosteroid preparations (classified according to the US system) Potency group* Super-high potency (group 1)

High potency (group 2)

Corticosteroid

Gel, lotion, ointment (optimized)

Diprolene

0.05

Clobetasol propionate

Cream, gel, ointment, solution (scalp)

Temovate

0.05

Cream, emollient base

Temovate E

0.05

Lotion, shampoo, spray aerosol

Clobex

0.05

Foam aerosol

Olux-E, Tovet

0.05

Solution (scalp)

Cormax

0.05

Diflucortolone valerate (not available in United States)

Ointment, oily cream

Nerisone Forte (United Kingdom, others)

0.3

Fluocinonide

Cream

Vanos

0.1

Flurandrenolide

Tape (roll)

Cordran

4 mcg/cm 2

Halobetasol propionate

Cream, lotion, ointment

Ultravate

0.05

Amcinonide

Ointment

Cyclocort ¶, Amcort ¶

0.1

Betamethasone dipropionate

Ointment

Diprosone ¶

0.05

Cream, augmented formulation (AF)

Diprolene AF

0.05

Clobetasol propionate

Cream

Impoyz

0.025

Desoximetasone

Cream, ointment, spray

Topicort

0.25

Gel

Topicort

0.05

Ointment

ApexiCon ¶, Florone ¶

0.05

Cream, emollient

ApexiCon E

0.05

Fluocinonide

Cream, gel, ointment, solution

Lidex ¶

0.05

Halcinonide

Cream, ointment

Halog

0.1

Halobetasol propionate

Lotion

Bryhali

0.01

Amcinonide

Cream

Cyclocort ¶, Amcort ¶

0.1

Lotion

Amcort ¶

0.1

Betamethasone dipropionate

Cream, hydrophilic emollient

Diprosone ¶

0.05

Betamethasone valerate

Ointment

Valisone ¶

0.1

Foam

Luxiq

0.12

Cream

Topicort LP ¶

0.05

Diflorasone diacetate

Cream

Florone ¶

0.05

Diflucortolone valerate (not available in United States)

Cream, oily cream, ointment

Nerisone (Canada, United Kingdom, others)

0.1

Fluocinonide

Cream aqueous emollient

Lidex-E ¶

0.05

Fluticasone propionate

Ointment

Cutivate

0.005

Mometasone furoate

Ointment

Elocon

0.1

Triamcinolone acetonide

Cream, ointment

Aristocort HP ¶, Kenalog ¶, Triderm

0.5

Betamethasone dipropionate

Spray

Sernivo

0.05

Clocortolone pivalate

Cream

Cloderm

0.1

Fluocinolone acetonide

Ointment

Synalar ¶

0.025

Flurandrenolide

Ointment

Cordran

0.05

Hydrocortisone valerate

Ointment

Westcort

0.2

Mometasone furoate

Cream, lotion, ointment, solution

Elocon ¶

0.1

Cream

Kenalog ¶, Triderm

0.1

Ointment

Kenalog ¶

0.1

Ointment

Trianex

0.05

Aerosol spray

Kenalog

0.2 mg per 2 second spray

Dental paste

Oralone

0.1

Betamethasone dipropionate

Lotion

Diprosone ¶

0.05

Betamethasone valerate

Cream

Beta-Val, Valisone ¶

0.1

Desonide

Ointment

DesOwen, Tridesilon ¶

0.05

Gel

Desonate

0.05

Fluocinolone acetonide

Cream

Synalar ¶

0.025

Flurandrenolide

Cream, lotion

Cordran

0.05

Fluticasone propionate

Cream, lotion

Cutivate

0.05

Hydrocortisone butyrate

Cream, lotion, ointment, solution

Locoid, Locoid Lipocream

0.1

Hydrocortisone probutate

Cream

Pandel

0.1

Desoximetasone

Medium potency (group 4)

Triamcinolone acetonide

Lower-mid potency (group 5)

Available strength(s), percent (except as noted)

Betamethasone dipropionate, augmented

Diflorasone diacetate

High potency (group 3)

Brand names (United States)

Vehicle type/form

8567



Low potency (group 6)

Hydrocortisone valerate

Cream

Westcort ¶

0.2

Prednicarbate

Cream (emollient), ointment

Dermatop

0.1

Triamcinolone acetonide

Lotion

Kenalog ¶

0.1

Ointment

Kenalog ¶

0.025

Alclometasone dipropionate

Cream, ointment

Aclovate

0.05

Betamethasone valerate

Lotion

Beta-Val ¶, Valisone ¶

0.1

Desonide

Cream

DesOwen, Tridesilon ¶

0.05

Lotion

DesOwen, LoKara

0.05

Foam

Verdeso

0.05

Cream, solution

Synalar ¶

0.01

Shampoo

Capex

0.01

Oil Δ

Derma-Smoothe/FS Body, DermaSmoothe/FS Scalp

0.01

Triamcinolone acetonide

Cream, lotion

Kenalog ¶, Aristocort ¶

0.025

Hydrocortisone (base, ≥2%)

Cream, ointment

Hytone, Nutracort ¶

2.5

Lotion

Hytone, Ala Scalp, Scalacort

2

Solution

Texacort

2.5

Ointment

Cortaid, Cortizone 10, Hytone, Nutracort

1

Cream

Cortaid ¶, Cortizone 10, Hytone, Synacort

1

Gel

Cortizone 10

1

Lotion

Aquanil HC, Sarnol-HC, Cortizone 10

1

Spray

Cortaid

1

Solution

Cortaid, Noble, Scalp Relief

1

Cream, ointment

Cortaid

0.5

Cream

MiCort-HC

2.5

Lotion

Nucort

2

Fluocinolone acetonide

Least potent (group 7)

Hydrocortisone (base, 80 percent of daily heme synthesis; this is because the bone marrow must provide the large amounts of heme needed as the prosthetic group for hemoglobin. The synthesis of heme and globin is closely coordinated in erythroblasts and reticulocytes. The rate of heme synthesis depends on the expression of the erythroid-specific ALAS gene (ALAS2) as well as genes for several other enzymes in the pathway (see 'Enzymes and intermediates' below). Expression of these enzymes is also upregulated by heme and by iron [1,2]. Upregulation by iron is controlled by an iron-responsive element (IRE) in the ALAS2 messenger RNA (mRNA) that is not present in the mRNA for ALAS1, the housekeeping form of ALAS, which is active in other tissues including liver [3]. (See "Structure and function of normal hemoglobins", section on 'Structure'.)



Liver – The liver accounts for most of the rest of overall heme synthesis. In the liver, heme is used primarily as the prosthetic group for various cytochrome P450 (CYP) enzymes, which metabolize toxins and drugs in the endoplasmic reticulum. These are especially abundant and inducible in the liver and have high rates of turnover. (See "Overview of pharmacogenomics", section on 'CYP isoenzymes and drug metabolism'.) In the liver, ALAS1 has a key regulatory role in heme synthesis, and ALAS1 is rate limiting for hepatic heme synthesis [4-6]. A regulatory heme pool controls the expression of the hepatic ALAS1 gene and the transport of ALAS1 into mitochondria. This provides a sensitive feedback mechanism, whereby an increased need for liver heme results in upregulation of ALAS1 expression. Likewise, ALAS1 is downregulated when the regulatory heme pool is augmented with heme and there is no requirement to increase hepatic heme synthesis. This regulatory heme pool has not been specifically defined and may comprise multiple intracellular pools.

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• Since most of the heme synthesized in liver is used for the production of CYPs, induction of CYPs by drugs and other factors leads to induction of ALAS1 through this feedback mechanism [7]. In addition, the ALAS1 gene and certain CYP genes share upstream enhancer elements that respond to inducing chemicals and interact with the pregnane X receptor (PXR); this is an additional mechanism for coordinated induction of hepatic ALAS1 and hepatic CYPs [8].

• Induction of hepatic heme oxygenase, which enzymatically degrades heme, can cause depletion of the regulatory heme pool and consequently cause ALAS1 induction. These hepatic feedback mechanisms are important in the acute hepatic porphyrias (AHP), which are exacerbated when hepatic ALAS1 is induced [4,9]. Accordingly, treatment of AHP with heme, which, when infused intravenously, is taken up primarily in hepatocytes, where it repletes the regulatory heme pool, results in downregulation of ALAS1 and amelioration of the acute attack [10,11]. (See "Acute intermittent porphyria: Management", section on 'Indications and mechanism of action'.) ●

Other tissues – Other important heme-containing proteins are present in all tissues, usually in smaller amounts, and most turn over more slowly than hepatic CYPs [4]. Examples include respiratory cytochromes, catalase, nitric oxide synthase, and myoglobin.

Enzymes and intermediates — The eight enzymes and intermediates that comprise the heme synthetic pathway are shown in the figure (figure 1), and the important features of these enzymes are summarized in the table (table 1). Synthesis of heme begins in mitochondria, where the first enzyme in the pathway, delta-aminolevulinic acid synthase (ALAS, 5-aminolevulinic acid synthase), catalyzes a reaction between two simple molecules, glycine and succinyl-coenzyme A (succinyl-CoA), to form delta-aminolevulinic acid (ALA), an amino acid committed exclusively to the synthesis of heme. ALAS requires pyridoxal-5'-phosphate (a derivative of vitamin B6 [pyridoxine]) as a cofactor. Importantly, ALAS occurs in two forms that are encoded by different genes. The housekeeping (or ubiquitous) enzyme, which is found in all tissues, is termed ALAS1; the ALAS1 gene is found on chromosome 3. No disease-causing ALAS1 mutations are described; however, increased ALAS1 expression is important in the acute hepatic porphyrias. The erythroid-specific form, termed ALAS2, is produced only in bone marrow erythroblasts. The ALAS2 gene is found on the X chromosome (Xp11.21) [12]. ALAS2 mutations cause sex-linked sideroblastic anemia (loss-of-function mutations) or X-linked protoporphyria (gain-of-function mutations). (See 'Classification and clinical categories' below.) The eight pathway enzymes are listed below, with their functions and standard abbreviations. ●

ALA synthase (ALAS) – Converts glycine and succinyl-CoA to ALA (an amino acid).



ALA dehydratase (ALAD) – Converts ALA to porphobilinogen (PBG; a pyrrole). ALA and PBG are commonly referred to as porphyrin precursors.  



PBG deaminase (PBGD) – Converts PBG to hydroxymethylbilane (HMB; a linear tetrapyrrole). This enzyme is also known as HMB synthase (HMBS).



Uroporphyrinogen synthase (UROS) – Converts HMB to uroporphyrinogen III (an octacarboxyl porphyrinogen). The reaction includes cyclization of this linear tetrapyrrole with inversion of one pyrrole to form the first of the asymmetric porphyrins required for heme synthesis. Any remaining HMB cyclizes nonenzymatically to form uroporphyrinogen I, which is a symmetrical molecule.  



Uroporphyrinogen decarboxylase (UROD) – Converts uroporphyrinogen I or III to coproporphyrinogen I or III (tetracarboxyl porphyrinogens).



Coproporphyrinogen oxidase (CPOX) – Converts coproporphyrinogen III (but not coproporphyrinogen I) to protoporphyrinogen IX (a dicarboxyl porphyrinogen). Due to the isomer specificity of this enzyme, isomer III (but not I) porphyrinogens are exclusively metabolized to heme.



Protoporphyrinogen oxidase (PPOX) – Oxidizes protoporphyrinogen IX by removing six protons to form protoporphyrin IX (the only oxidized porphyrin intermediate in the pathway).



Ferrochelatase (FECH) – Inserts iron into protoporphyrin IX to form heme (iron protoporphyrin IX). This enzyme also chelates any remaining protoporphyrin with zinc to form zinc protoporphyrin, which is normally found in small amounts in circulating erythrocytes.

The first and last three enzymes (ALAS, CPOX, PPOX, FECH) are mitochondrial, and the intervening four (ALAD, PBGD, UROS, UROD) are located in the cytoplasm (figure 1). All genes that encode these enzymes are in the cellular genome, and inheritance of the porphyrias follows Mendelian (rather than mitochondrial) genetic transmission patterns.

PATHOPHYSIOLOGY Genes and enzymes affected in specific porphyrias — Each porphyria is due to abnormal (deficient or enhanced) activity of an enzyme in the heme synthesis pathway (table 1). In seven of the eight types of porphyria, mutation of a gene that affects one of the pathway enzymes is responsible. The exception is porphyria cutanea tarda (PCT), which is caused by an acquired inhibitor (uroporphomethene, a uroporphyrinogen molecule that has become partially oxidized) rather than a gene mutation. This inhibitor contributes to reducing activity of the uroporphyrinogen decarboxylase (UROD) enzyme in

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the liver to less than approximately 20 percent of normal. Approximately 20 percent of individuals with PCT are heterozygous for a UROD mutation that acts as a predisposing factor. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'UROD inhibitor'.) In most cases, the causative porphyria mutation affects the gene that encodes the relevant heme synthesis enzyme. In a few cases, the mutation affects a regulatory gene rather than the enzyme itself. Examples include rare cases such as congenital erythropoietic porphyria (CEP) due to a mutation of GATA-1 (a transcription factor that controls expression of the UROS gene) rather than a UROS mutation, and protoporphyria with increased ALAS2 function due to mutation of mitochondrial CLPX, which degrades ALAS2. (See "Congenital erythropoietic porphyria", section on 'Gene mutations' and "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'EPP due to CLPX mutation'.) Heme synthetic enzymes and porphyrias and other diseases resulting from their alterations are as follows: ●

ALAS (delta-aminolevulinic acid [ALA] synthase) – ALAS is the first enzyme in the heme synthetic pathway. There are two forms.

• ALAS1 – Mutations causing porphyria (or other diseases) have not been described for ALAS1. However, upregulation of hepatic ALAS1 is an important feature during exacerbations of the acute hepatic porphyrias. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Enzymatic defect'.)

• ALAS2 – Gain-of-function mutations in ALAS2 have been described in X-linked protoporphyria (XLP) [13]. (See "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'XLP due to ALAS2 gain-of-function mutations'.) Loss-of-function mutations in ALAS2 are present in many cases of X-linked sideroblastic anemia (an inherited anemia with ring sideroblasts in the bone marrow; these individuals do not have porphyria). (See "Causes and pathophysiology of the sideroblastic anemias".) ●

ALAD (ALA dehydratase) – ALAD is the second enzyme in the heme synthetic pathway.

• Mutations in ALAD cause autosomal recessive ALAD porphyria (ADP). (See "ALA dehydratase porphyria".) • Because other causes of ALAD deficiency are associated with the same nonspecific symptoms, DNA studies to identify the responsible mutations are essential for diagnosis of ADP.

• ALAD is inhibited in lead poisoning and hereditary tyrosinemia type 1. Lead displaces zinc from its binding sites on the ALAD enzyme, and succinylacetone (4,6-dioxoheptanoic acid), a metabolite that accumulates in tyrosinemia, is structurally similar to ALA and is a potent inhibitor of ALAD enzymatic activity [14,15]. Accordingly, lead poisoning and tyrosinemia are both associated with accumulation of ALA and other heme pathway intermediates, along with symptoms that resemble acute porphyria. (See "Disorders of tyrosine metabolism", section on 'Hereditary tyrosinemia type 3'.) ●

PBGD (porphobilinogen [PBG] deaminase, also known as hydroxymethylbilane synthase [HMBS]) – PBGD is the third enzyme in the pathway. Mutations in PBGD/HMBS cause acute intermittent porphyria (AIP) in some heterozygotes. Rare homozygous cases have earlier onset and more profound symptoms. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis".)



UROS (uroporphyrinogen synthase) – UROS is the fourth enzyme in the pathway. Mutations in UROS cause CEP, an autosomal recessive disorder. (See "Congenital erythropoietic porphyria".)



UROD (uroporphyrinogen decarboxylase) – UROD is the fifth enzyme in the pathway. As noted above, UROD is inhibited in the liver in all cases of PCT. Mutations in UROD predispose to the development of familial PCT (if monoallelic) or cause hepatoerythropoietic porphyria (HEP; if biallelic). (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)



CPOX (coproporphyrinogen oxidase) – CPOX is the sixth enzyme in the pathway. Mutations in CPOX cause hereditary coproporphyria (HCP) in some heterozygotes. Biallelic mutations cause more severe, early onset symptoms. Some biallelic CPOX mutations cause harderoporphyria, with distinct hematologic features. (See "Hereditary coproporphyria".)



PPOX (protoporphyrinogen oxidase) – PPOX is the seventh enzyme in the pathway. Mutations in PPOX cause variegate porphyria (VP). Homozygous or compound heterozygous PPOX mutation causes earlier and more severe symptoms. (See "Variegate porphyria".)



FECH (ferrochelatase) – FECH is the eighth and final enzyme in the pathway. Mutations in FECH cause erythropoietic protoporphyria (EPP). (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

For each of these enzymes, many different mutations have been described as causes of porphyria, as discussed in the linked topic reviews. The diseasecausing mutation in a particular family is often private or shared with only a few other families. Some are more common geographically due to founder effects. Detection of the responsible mutation is not required for diagnosis but is useful for confirmation and especially for family studies and genetic counseling.

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Role of environmental and metabolic factors — In addition to gene mutations, environmental and metabolic factors are especially important in the development of disease manifestations in the hepatic porphyrias. As noted below, the hepatic porphyrias include those that cause acute neurovisceral symptoms (acute hepatic porphyrias) and PCT. ●

Acute hepatic porphyrias (AHP) – As noted above, mutations that affect specific heme pathway enzymes are essential in these diseases. However, exposure to certain drugs, steroid hormones, and nutritional alterations are important in precipitating attacks. Variants in unidentified modifying genes are also thought to be important. Increases in progesterone may cause attacks during the luteal phase of the menstrual cycle. A table of drugs that commonly exacerbate AHP is provided separately. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Exacerbating factors'.)



PCT – Iron, oxidative stress, and a set of important susceptibility factors act in combination to lead to generation of a hepatic UROD inhibitor in PCT. These are largely different from the factors that exacerbate AHP, and include genetic factors (UROD and HFE mutations), infections (hepatitis C virus [HCV] and HIV), alcohol and estrogen use, and deficiencies of antioxidants. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Susceptibility factors'.)

Accumulation of heme pathway intermediates — The heme biosynthetic pathway intermediates that accumulate in the various porphyrias correlate with (and in some instances, determine) what clinical manifestations will be seen. The heme synthesis intermediates, their chemically altered metabolites, and the primary routes of excretion are listed in the table (table 2). ●

Acute hepatic porphyrias (AHP)

• ALA and PBG are associated with neurovisceral manifestations in AHP. ALA is likely causative of these manifestations, but this has not been thoroughly proven. PBG is not substantially increased in any medical conditions other than AIP, HCP, and VP. ALA and PBG both accumulate in AIP, HCP, and VP; ALA but not PBG accumulates in ADP (as well as in other conditions where ALAD activity is decreased, particularly lead poisoning and hereditary tyrosinemia type 1). ALA and PBG are normal in cutaneous porphyrias, except for slight ALA elevations sometimes seen in PCT.

• Porphyrins are also elevated in all AHPs, sometimes to levels in plasma that cause chronic, blistering photosensitivity, especially in VP, less commonly in HCP, and in AIP only with concurrent end-stage kidney disease. Excess porphyrins in AIP may be explained by two processes:

- Nonenzymatic formation of various uroporphyrin isomers from PBG when concentrated in body fluids - Enzymatic formation of uroporphyrinogen III after tissue accumulation of ALA. The latter mechanism also accounts for excess formation of coproporphyrin III and protoporphyrin in ADP. Urine coproporphyrin III and erythrocyte zinc protoporphyrin are increased in ADP, lead poisoning, and hereditary tyrosinemia. In HCP and VP, porphyrin accumulation occurs because the enzyme deficiencies lead to accumulation of their substrate porphyrinogens, which are then auto-oxidized to the corresponding porphyrins. ●

Cutaneous porphyrias – Porphyrins are substantially elevated in all porphyrias that cause photosensitivity (in plasma, urine, erythrocytes, or a combination). Where porphyrins accumulate and how they are excreted depends on the site of production and on their solubility.

• Substantial elevations of erythrocyte porphyrins are found in erythropoietic porphyrias such as CEP and EPP, which are biallelic, and in XLP. Erythrocyte porphyrin levels are also elevated in very rare biallelic hepatic porphyrias such as HEP and homozygous AIP, HCP, and VP, but they are normal or only slightly elevated in monoallelic hepatic porphyrias, namely AIP, HCP, and VP and familial PCT.

• Highly carboxylated porphyrins (uroporphyrin, hepta-, hexa-, and pentacarboxyl porphyrins) are water soluble and thus are mostly excreted in urine.

• Protoporphyrin and tricarboxyl porphyrin are not water soluble and thus are excreted in bile and feces. • Coproporphyrin (tetracarboxyl porphyrin) is excreted in both urine and bile. Coproporphyrin I is more readily excreted in bile compared with coproporphyrin III.  

• In VP, porphyrin-peptide conjugates produce a diagnostic fluorescence emission peak at approximately 626 nm when diluted plasma is scanned at neutral pH. As discovered by Poh-Fitzpatrick, this allows rapid biochemical distinction of VP from PCT and other blistering cutaneous porphyrias [16-19]. This testing is available in selected specialty laboratories.

• Protoporphyrin accumulates in the protoporphyrias (EPP and XLP) and causes acute nonblistering photosensitivity. Greater solubility of protoporphyrin in nonaqueous cellular components may explain this distinctive type of photosensitivity. As noted above, protoporphyrin is excreted only in bile and feces. All of the heme pathway intermediates are colorless and nonfluorescent, with the exception of protoporphyrin, which, like other oxidized porphyrins, is reddish-colored and fluoresces, especially when illuminated by light near 400 nm (the Soret absorption band for porphyrins). When porphyrinogen

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intermediates accumulate and leave the intracellular environment, they mostly spontaneously oxidize to the corresponding porphyrins, which are reddish and fluorescent. While PBG is colorless, it can degrade in urine to porphobilin, which is brownish. PBG at high concentrations can also spontaneously form porphyrins, which are reddish.

INHERITANCE PATTERNS Patterns of inheritance of the porphyrias are as follows (table 3): ●

Autosomal dominant with low penetrance – Porphyrias with autosomal dominant inheritance have low penetrance (ie, other genetic, environmental, and metabolic factors are necessary for the porphyria to become manifest). This pattern is seen in the following porphyrias:

• Acute intermittent porphyria (AIP) • Hereditary coproporphyria (HCP) • Variegate porphyria (VP) • Familial porphyria cutanea tarda (PCT; applies to the approximately 20 percent of cases of PCT with a heterozygous UROD mutation) Exacerbating factors important in AIP, HCP, and VP (the three most common acute hepatic porphyrias [AHP]) are generally distinct from those in PCT. (See 'Role of environmental and metabolic factors' above.) ●

Autosomal recessive – In porphyrias with autosomal recessive inheritance, the severity of disease appears to be mostly related to the severity of the inherited mutation. This pattern is seen in the following porphyrias:

• Delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria (ADP) • Congenital erythropoietic porphyria (CEP; typically due to UROS mutations) • Hepatoerythropoietic porphyria (HEP; homozygous familial PCT) • Erythropoietic protoporphyria (EPP; due to a FECH mutation [common] or a CLPX mutation [extremely rare, autosomal dominant]) • Homozygous forms of AIP, HCP, and VP are very rare, with a different, more severe, and earlier onset phenotype. Harderoporphyria results from certain CPOX mutations, only when biallelic.   ●

X-linked – In X-linked inheritance, mothers can pass the trait to sons or daughters, but fathers can only pass the trait to daughters. This pattern is seen in the following porphyrias:

• X-linked protoporphyria (XLP) • CEP due to a GATA-1 mutation (rare)

CLASSIFICATION AND CLINICAL CATEGORIES Porphyrias are classified as hepatic or erythropoietic based on whether pathway intermediates first accumulate in the liver or the bone marrow, respectively. This classification reflects pathophysiology but not necessarily other important features of these diseases. It is useful to group porphyrias clinically into three categories, based on acute neurovisceral and either chronic blistering or acute skin manifestations, which do not fully correspond with the hepatic versus erythropoietic designation (table 3). These groups are exemplified by the three most common porphyrias, which differ completely from each other in their clinical manifestations, diagnostic testing, and treatment (table 4) [20]. A framework for categorizing porphyrias is illustrated in the figure (algorithm 1) and discussed below. (See 'Overview and diagnostic framework' below.) Acute hepatic porphyrias (AHP) — These porphyrias cause acute and chronic symptoms due to effects on the nervous system. The most common presenting symptom is neuropathic abdominal pain. The motor, sensory, and autonomic nervous systems are often affected, resulting in autonomic changes (eg, tachycardia, hypertension), muscle weakness, sensory loss, and pain in the back, chest, and extremities. Even severe symptoms may be discounted because they mimic other diseases, and physical findings are often minimal. The prototype and most common of these is acute intermittent porphyria (AIP). Identical systems occur in the other AHPs: delta-aminolevulinic acid (ALA) dehydratase (ALAD) porphyria (ADP), hereditary coproporphyria (HCP), and variegate porphyria (VP). HCP and VP may also present with blistering skin lesions. AIP, HCP, and VP are autosomal dominant inherited disorders with low penetrance and female predominance. Erythrocyte porphyrins are normal or only slightly elevated in these AHPs. Approaches to diagnosing and distinguishing among AHPs are discussed below. (See 'Acute hepatic porphyrias (AHP; exemplified by AIP)' below.)

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ADP is autosomal recessive and extremely rare, with only eight documented cases worldwide, all of whom have been males (which is unexplained), usually with onset of attacks in their early teens. All cases of ADP have elevated erythrocyte zinc protoporphyrin, suggesting an erythropoietic component. Very rare cases of homozygous AIP, HCP, and VP have a completely different phenotype and marked elevations of erythrocyte zinc protoporphyrin. Clinical features include impaired neurologic development and chronic, blistering skin lesions starting in early childhood, with an absence of acute attacks. Blistering cutaneous porphyrias — Blistering cutaneous porphyrias cause chronic blistering cutaneous lesions on sun-exposed areas, often with scarring and pigment changes. The prototype and most common of this type is porphyria cutanea tarda (PCT). Less common are congenital erythropoietic porphyria (CEP), hepatoerythropoietic porphyria (HEP), VP (in which skin manifestations are common), HCP (in which they are uncommon), and AIP (in which they are seen only with advanced renal disease). As noted above, chronic blistering photosensitivity with elevations in erythrocyte porphyrins is also seen in very rare cases of homozygous AIP, HCP, and VP. (See 'Blistering cutaneous porphyrias (exemplified by PCT)' below.) Acute nonblistering cutaneous porphyrias — Acute nonblistering photosensitivity occurs in erythropoietic protoporphyria (EPP) and in two other rare types of protoporphyria, X-linked protoporphyria (XLP) and EPP due to mutation of the CLPX gene, described in a 2017 report [21]. These are erythropoietic porphyrias with elevations of erythrocyte total and metal-free protoporphyrin. (See 'Acute nonblistering photosensitivity (exemplified by EPP)' below.)

APPROACHES TO DIAGNOSIS Overview and diagnostic framework — Porphyrias are rare disorders with nonspecific clinical manifestations similar to those of many other more common diseases. As a result, their diagnosis and appropriate treatment are often delayed. This is unfortunate because biochemical first-line screening tests are sensitive for diagnosis of these disorders, and additional second-line testing readily differentiates the various types of porphyria. Moreover, effective treatment is available but will not be provided unless a diagnosis is made. The three most common porphyrias are acute intermittent porphyria (AIP), porphyria cutanea tarda (PCT), and erythropoietic protoporphyria (EPP). Presenting symptoms and diagnostic testing are very different for these three conditions, and a diagnostic approach is facilitated by focusing on them as prototypical examples of the different porphyria presentations (algorithm 1). With knowledge of diagnostic approaches for these three most common types, the less common porphyrias will also be diagnosed and therefore not neglected.   Guidelines that focus on the porphyrias are not likely to facilitate diagnosis unless a clinician has already thought to consider porphyria as a possible cause for a patient's presenting symptoms. Some guidelines on the evaluation of the presenting symptoms, such as abdominal pain, neglect to mention porphyrias, or they may not provide guidance on how and when testing should be done. Therefore, specific testing for porphyria continues to be seldom considered an important part of the diagnostic workup for the cardinal symptoms of these disorders, and delayed diagnosis continues to be a major problem.   Acute hepatic porphyrias (AHP; exemplified by AIP) Presenting findings — AIP and other AHP should be considered in the evaluation of any patient with unexplained abdominal pain (the most common symptom) or other neurovisceral symptoms after an initial workup for common causes does not provide an answer. Spectrum of neurovisceral manifestations — Abdominal pain with a relatively unremarkable examination is the most common neurovisceral manifestation of AHP. This is often combined with effects on the central nervous system such as insomnia, agitation, hallucinations, seizures, or hyponatremia, which is often attributed to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Rarely, one or more of these manifestations occur in the absence of abdominal pain. Manifestations of peripheral neuropathy (extremity pain, paresis) are often present. These three groups of symptoms (abdominal pain, central nervous system abnormalities, and peripheral neuropathy) are described as a "classic triad" that should suggest acute porphyria, but because they are highly nonspecific, they are often seen as unrelated and not suggestive of a unifying diagnosis. Therefore, screening for AHP (by measuring urine porphobilinogen [PBG] and porphyrins) should be considered even when suspicion is not particularly high. Other common symptoms of AHP include gastrointestinal symptoms (eg, nausea, vomiting, constipation); pain in the limbs, head, neck, or chest; and others listed in the table (table 5). Magnetic resonance imaging (MRI) findings can resemble those in posterior reversible encephalopathy syndrome (PRES), which points to the potentially substantial effects of AHP on the central nervous system. AHP can also mimic Guillain-Barre syndrome [22] and cause reversible cerebral vasoconstriction [23].   Multiple previous hospitalizations and/or visits to the emergency department (ED) with abdominal pain and negative evaluations, especially if accompanied by neurologic or psychiatric symptoms, can be important diagnostic clues [20,24]. Multiple abdominal surgeries without definite diagnoses or benefits should also trigger testing for AHP. In AIP and the other acute porphyrias, attacks are often precipitated by factors such as stress, caloric restriction, medications, or cyclic hormonal changes. Many of these factors act through induction of hepatic ALAS1. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and

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diagnosis", section on 'Exacerbating factors'.) In severe cases of AIP, hereditary coproporphyria (HCP), or variegate porphyria (VP), the urine may develop a red or brown color due to a high concentration of porphobilin, a brownish auto-oxidation product of PBG and porphyrins, which are reddish. Clinical vignette — The typical clinical presentation, disease course, and delay in diagnosis of AHP is illustrated by the following case of AIP: ●

A 30-year-old woman presented to a hospital ED with abdominal pain, nausea, vomiting, and diarrhea. The pain required morphine for relief. She was hospitalized for two weeks for a suspected intestinal infection. The evaluation was negative, including a computed tomography (CT) scan and upper and lower endoscopies. She gradually improved and was discharged. The same symptoms recurred two years later, resulting in multiple ED visits. She reported some increase in alcohol intake to compensate for stressful circumstances. She was admitted to a psychiatric unit with mental status changes and hallucinations and then transferred to an ED for evaluation of abdominal pain. In the ED, she had a grand mal seizure associated with hyponatremia. She was admitted to a medical unit with tachycardia and hypertension (heart rate 120 beats per minute; blood pressure 174/114), along with disorientation; there were no focal neurologic signs. Examination of the cerebrospinal fluid showed no abnormalities; MRI of the brain showed multiple areas of subcortical signal abnormalities. Electroencephalogram (EEG) was abnormal with recurring single and multiple spike and sharp discharge activity appearing to arise from the left anterior temporal region. Laboratory testing revealed increased aminotransferases (ALT 114 international units/L, AST 94 international units/L), which were attributed to alcohol. Phenytoin was started for seizures. Abdominal pain and hyponatremia worsened (serum sodium 116 mEq/L). The syndrome of inappropriate ADH (SIADH) was suspected and attributed to fluoxetine. An abnormal hepatobiliary scan led to laparoscopic removal of a histologically normal gallbladder with no gallstones. She was discharged with diagnoses of alcohol withdrawal and alcoholic liver disease and referred for rehabilitation. Urine porphyrins were ordered and reported as "positive" after discharge, but the ordering physician was unable to contact the patient; she had moved to another part of the country. She had continuing and progressive symptoms, and she was hospitalized after developing muscle weakness. This progressed to quadriparesis and respiratory failure complicated by aspiration pneumonia. Urinary PBG was 44 mg/24 hours (reference range 0 to approximately 4), and a diagnosis of AIP was made. Harmful drugs (including phenytoin) were stopped. She improved gradually with intravenous glucose but was not treated with hemin. Gradual improvement began, and she was discharged for prolonged physical therapy and rehabilitation. Recovery was almost complete, but some objective muscle weakness, painful hyperesthesia of the legs, and impaired short-term memory persisted. She continued to have attacks one to two times yearly, sometimes in the luteal phase of her menstrual cycle.

This case illustrates many of the challenges related to diagnosing and treating AHP, including the delayed recognition of the classic features, the consequences of delay in diagnosis and failure in some cases to provide preferred treatment (hemin) even after diagnosis. Recovery can be complete or nearly complete, but lasting damage may persist. Initial testing (suspected AHP) — Importantly, AHP is readily ruled in or out at the time of symptoms by a simple urine test for porphobilinogen (PBG), which is both highly sensitive and highly specific. Thus, urine PBG is the most important first-line screening test when AHP is suspected (algorithm 2). Urine porphyrins should also be measured, as discussed below.   A timed urine collection is not needed; a spot urine sample is sufficient and generally preferred. Collecting urine for 24 hours can cause unnecessary delays in diagnosis. Highly dilute urine can give falsely negative results [25]; thus, if an initial test result is expressed as PBG per liter of urine, the urine creatinine should also be measured on the same sample and the PBG result expressed per gram (or micromol) of urine creatinine. However, a very high result expressed per liter is diagnostically meaningful. ●

If results are positive (eg, PBG level >10 mg per g creatinine [or >10 mg/L]), treatment with hemin can (and typically should) be initiated without delay if clinical manifestations are severe. (See 'Initial treatment of acute attacks' below.)



If results are negative (eg, PBG level 70 in porphyria cutanea tarda (type 2) and hepatoerythropoietic porphyria

CPO

>40 in hereditary coproporphyria

3q12.1 Protoporphyrinogen oxidase (PPOX)

Mitochondria

PPOX

>120 in variegate porphyria

1q23.3 Ferrochelatase (FECH)

Mitochondria

FECH 18q21.31

Refer to UpToDate for information on diagnostic testing. δ: delta; XLP: X-linked protoporphyria; ALA: delta-aminolevulinic acid; PBG: porphobilinogen. * Standard abbreviations in parentheses. ¶ Gene symbols in italics, by convention. Δ Also known as hydroxymethylbilane synthase (HMBS), and formerly as uroporphyrinogen I synthase. Karl Anderson, MD, FACP. Graphic 54358 Version 8.0

8586

>90 in erythropoietic protoporphyria

Intermediates of the heme biosynthetic pathway, chemical alterations that occur when they accumulate, routes of excretion, and samples collected for their measurement Chemically altered forms ¶

Pathway intermediate*

Primary routes of excretion

Samples for measurement Δ

δ-Aminolevulinic acid

None

Kidney

Urine, plasma

Porphobilinogen

Porphobilin; uroporphyrin

Kidney

Urine, plasma

Uroporphyrinogen (octacarboxyl porphyrin) I & III

Uroporphyrin I & III

Kidney

Urine, plasma

Heptacarboxyl porphyrinogen I & III

Heptacarboxyl porphyrin I & III

Kidney

Urine, plasma

Hexacarboxyl porphyrinogen I & III

Heptacarboxyl porphyrin I & III

Kidney

Urine, plasma

Pentacarboxyl porphyrinogen I & III

Pentacarboxyl porphyrin I & III

Kidney

Urine, plasma

Coproporphyrinogen (tetracarboxyl-porphyrinogen) I & III

Coproporphyrin I & III

Kidney and liver

Urine, feces, plasma

Harderoporphyrinogen (tricarboxyl-porphyrinogen)

Harderoporphyrin

Liver

Feces, erythrocytes

Protoporphyrinogen IX

Protoporphyrin IX

Liver

Feces, plasma

Protoporphyrin IX

None

Liver

Feces, erythrocytes

Refer to UpToDate for an overview of the approach to a patient with suspected porphyria and the details of evaluations for specific porphyrias. δ: delta. * All intermediates are colorless and nonfluorescent, with the exception of protoporphyrin, which is reddish and fluorescent. ¶ The autooxidized porphyrins are reddish and fluorescent; porphobilin is brownish. Δ Urine and fecal porphyrins are fractionated if the total is increased; plasma porphyrins may be fractionated, but for differential diagnosis it is preferred to determine the fluorescence peak at neutral pH. Provided by Karl Anderson, MD, FACP. Graphic 75386 Version 7.0

8587

Classification of porphyrias (hepatic or erythropoietic; acute or cutaneous) Classification Disease Tissue site

Clinical features

Enzyme affected

Major biochemical findings* Inheritance Urine

Plasma

Erythrocytes

Feces

ADP

Hepatic ¶

Acute

ALAD

Autosomal recessive

ALA, coproporphyrin III

 

Zinc protoporphyrin and low ALAD activity

 

AIP

Hepatic

Acute

PBGD

Autosomal dominant

ALA, PBG, uroporphyrin, coproporphyrin

 

Low PBGD activity

 

HCP

Hepatic

Acute and cutaneous

CPOX

Autosomal dominant

ALA, PBG, uroporphyrin, coproporphyrin III

 

 

Coproporphyrin III

VP

Hepatic

Acute and cutaneous

PPOX

Autosomal dominant

ALA, PBG, uroporphyrin, coproporphyrin III

Fluorescence peak at approximately 626 nm

 

Coproporphyrin III and protoporphyrin

PCT

Hepatic

Cutaneous

UROD

Autosomal dominant Δ

Uroporphyrin and heptacarboxyl-porphyrin

Uroporphyrin and heptacarboxyl-porphyrin

 

Isocoproporphyrin

HEP

Hepatic ¶

Cutaneous

UROD

Autosomal recessive

Uroporphyrin and heptacarboxyl-porphyrin

Uroporphyrin and heptacarboxyl-porphyrin

Zinc protoporphyrin and low UROD activity

Isocoproporphyrin

CEP

Erythropoietic

Cutaneous

UROS

Autosomal recessive

Uroporphyrin I and coproporphyrin I

Uroporphyrin I and coproporphyrin I

Uroporphyrin I and coproporphyrin I

Coproporphyrin I

EPP

Erythropoietic

Cutaneous

FECH

Autosomal recessive

 

Protoporphyrin, fluorescence peak at approximately 634 nm

Metal-free protoporphyrin

Protoporphyrin

XLP

Erythropoietic

Cutaneous

ALAS2

X-linked

 

Protoporphyrin

Metal-free and zinc protoporphyrin

Protoporphyrin

The table shows the classification based on tissue site (ie, hepatic or erythropoietic) and on clinical features (ie, acute or cutaneous). The affected enzymes, inheritance patterns, and biochemical findings are listed. Refer to UpToDate for details of initial testing for suspected porphyria and diagnostic evaluations for each specific porphyria. ADP: delta-aminolevulinic acid (ALA) dehydratase porphyria; ALAD: ALA dehydratase; AIP: acute intermittent porphyria; PBGD: porphobilinogen (PBG) deaminase; HCP: hereditary coproporphyria; CPOX: coproporphyrinogen oxidase; VP: variegate porphyria; PPOX: protoporphyrinogen oxidase; PCT: porphyria cutanea tarda; UROD: uroporphyrinogen decarboxylase; HEP: hepatoerythropoietic porphyria; CEP: congenital erythropoietic porphyria; UROS: uroporphyrinogen III synthase; EPP: erythropoietic protoporphyria; FECH: ferrochelatase; XLP: X-linked protoporphyria; ALAS2: ALA synthase 2. * Increases of importance for diagnosis in most cases. ¶ These hepatic porphyrias also have erythropoietic features, including increases in erythrocyte zinc protoporphyrin. Δ UROD inhibition in PCT is mostly acquired, but an inherited deficiency of the enzyme predisposes in familial (type 2) disease. Karl Anderson, MD, FACP. Graphic 80601 Version 11.0

8588

The three most common porphyrias and their contrasting presentations, exacerbating factors, and approaches to diagnosis and treatment Disease

Presenting symptoms

Exacerbating factors

Most important screening tests

Treatment

Porphyria cutanea tarda (PCT)

Chronic, blistering skin lesions*

Iron; alcohol; smoking; estrogens; hepatitis C; HIV; halogenated hydrocarbons

Plasma or urine porphyrins ¶

Phlebotomy; low-dose hydroxychloroquine or chloroquine

Acute intermittent porphyria (AIP)

Neurovisceral Δ

Drugs (mostly cytochrome P450inducers); progesterone; dietary restrictions Δ

Urinary porphobilinogen (PBG) Δ

Hemin; glucose Δ

Erythropoietic protoporphyria (EPP)

Acute, nonblistering skin photosensitivity

 

Erythrocyte protoporphyrin (total and metal-free)

β-carotene; afamelanotide

Porphyria cutanea tarda (PCT) and acute intermittent porphyria (AIP) are distinct, but each shares features with some less common porphyrias (listed in the footnotes and discussed in detail in the overview of porphyrias topic in UpToDate). β: beta. * Also may occur in variegate porphyria (VP), less commonly in hereditary coproporphyria (HCP), and rarely in AIP with concomitant renal failure; much more severe in congenital erythropoietic protoporphyria (CEP) and hepatoerythropoietic porphyria (HEP). ¶ Also useful for diagnosis of variegate porphyria (VP), congenital erythropoietic porphyria (CEP), and hepatoerythropoietic porphyria (HEP). Δ Features shared with hereditary coproporphyria (HCP), variegate porphyria (VP), and delta-aminolevulinic acid (ALA) dehydratase porphyria (ADP). Provided by Karl Anderson, MD, FACP. Graphic 51232 Version 8.0

8589

Algorithm for understanding and categorizing porphyrias according to clinical features

The three most common porphyrias (bold outlines) represent each of the three main categories and are distinct in their clinical features, diagnostic testing, and treatment. Other less common types of porphyria in e should be included in the differential diagnosis. VP and HCP are in the differential diagnosis of acute neurovisceral and chronic blistering cutaneous porphyria; patients may present with either (or both) findings. A information about the responsible genes, enzymes, and exacerbating factors are discussed in UpToDate. Refer to UpToDate for more detailed diagnostic algorithms for each of the three main clinical categories of AIP: acute intermittent porphyria; PCT: porphyria cutanea tarda; EPP: erythropoietic porphyria; ADP: delta-aminolevulinic acid (ALA) dehydratase porphyria; VP: variegate porphyria; HCP: hereditary coproporphyria; HEP: hepatoe porphyria; CEP: congenital erythropoietic porphyria; XLP: X-linked porphyria. Graphic 117978 Version 1.0

8590

Acute intermittent porphyria incidence of signs and symptoms Abdominal pain

85 to 95%

Vomiting

43 to 88%

Constipation

48 to 84%

Muscle weakness

42 to 60%

Psychiatric symptoms

40 to 58%

Limb, head, neck, or chest pain

50 to 52%

Hypertension

36 to 54%

Tachycardia

28 to 80%

Convulsion

10 to 20%

Sensory loss

9 to 38%

Fever

9 to 37%

Respiratory paralysis

9 to 14%

Diarrhea

5 to 12%

AIP: acute intermittent porphyria. From Annals of Internal Medicine, Anderson KE, Bloomer JR, Bonkovsky HL, et al, Recommendations for the diagnosis and treatment of the acute porphyrias, Vol 142, Pg 439. Copyright © 2005 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc. Graphic 56856 Version 10.0

8591

Algorithm for diagnosis of acute porphyria and use of hemin in patients with symptoms suggesting an acute porphyria attack

Urine PBG may be tested by a screening method on-site (semiquantitative result, if available) or measured in a specialized laboratory (quantitative result, available in days to weeks). If available, a rapid method is extremely helpful because treatment can be initiated based on a positive result, and a negative result makes the diagnosis of an acute porphyria very unlikely. However, all symptomatic patients with suspected acute porphyria should have quantitative PBG, total porphyrins, and creatinine measured from the same sample. Because the results of quantitative testing are not known for days to weeks, we also order ALA and total porphyrins on the same urine sample. Urine creatinine is measured to allow normalization (results expressed per gram of creatinine). Refer to UpToDate topics on acute porphyrias for further details of diagnosis and treatment, and patterns of plasma and fecal porphyrin elevation. PBG: porphobilinogen; AIP: acute intermittent porphyria; HCP: hereditary coproporphyria; VP: variegate porphyria; ALA: delta-aminolevulinic acid; ALAD: ALA dehydratase; ADP: ALAD porphyria. * We perform genetic testing for the relevant porphyria following diagnosis; this may be used for further confirmation of the diagnosis and in some cases for counseling of relatives and identification of new mutations. Genetic testing is required to confirm a diagnosis of ADP. Graphic 61709 Version 10.0

8592

Diagnostic testing for active porphyrias Concurrent or recent clinical manifestations Acute neurovisceral

Initial testing Spot urine PBG and total porphyrins (normalized with urine creatinine)

Additional testing (if initial results are positive) Spot urine ALA, PBG, and total porphyrins (quantitative, normalized with urine creatinine) Plasma porphyrins* Erythrocyte porphyrins

Total porphyrins (plasma*, serum, or spot urine), with fractionation if elevated

Erythrocyte total porphyrins

Erythrocyte ALAD

Acute intermittent porphyria (AIP)

Erythrocyte PBGD

Sequence ALAD gene

Sequence PBGD gene Hereditary coproporphyria (HCP)

Sequence CPOX gene

Variegate porphyria (VP)

Sequence PPOX gene

Porphyria cutanea tarda (PCT)

Erythrocyte UROD Sequence UROD gene Δ

Urinary ALA and PBG Fecal total porphyrins

Enzyme and DNA tests

Delta-aminolevulinic acid dehydratase porphyria (ADP)



Fecal porphyrins Blistering photosensitivity

Types of porphyria identified

Hepatoerythropoietic porphyria (HEP)

Erythrocyte UROD Sequence UROD gene

Nonblistering photosensitivity

Total erythrocyte porphyrins ¶

Erythrocyte metal-free and zinc protoporphyrin; plasma total porphyrins and fluorescence scan

HCP

Sequence CPOX gene

VP

Sequence PPOX gene

Congenital erythropoietic porphyria (CEP)

Erythrocyte UROS

Erythropoietic protoporphyria (EPP)

Sequence FECH gene

X-linked protoporphyria (XLP)

Sequence ALAS2 gene

Sequence UROS gene

First-line testing for symptomatic patients is guided by clinical features (ie, neurovisceral, cutaneous chronic blistering, or cutaneous acute nonblistering). All spot urine measurements should be normalized with spot urine creatinine. If initial testing is positive, further comprehensive testing follows to identify the type of acute porphyria. Enzyme measurements may be used but are not available for all porphyrias. DNA testing usually follows establishment of a biochemical diagnosis. Refer to UpToDate topics on overview of porphyria and specific porphyrias for additional details and testing in asymptomatic patients. PBG: porphobilinogen; ALA: delta-aminolevulinic acid; ADP: delta-aminolevulinic acid dehydratase porphyria; ALAD: delta-aminolevulinic acid dehydratase; PBGD: porphobilinogen deaminase; CPOX: coproporphyrinogen oxidase; PPOX: protoporphyrin oxidase; UROD: uroporphyrinogen decarboxylase; UROS: uroporphyrinogen III synthase; FECH: ferrochelatase; ALAS2: delta-aminolevulinate synthase-2. * Plasma porphyrins should include measurement of the total, fractionation if the total is elevated, and determination of the fluorescence peak wavelength at neutral pH. ¶ It is important to verify that the method used by the laboratory measures all erythrocyte porphyrins and not just zinc protoporphyrin. Δ UROD mutations are neither required nor specific for a diagnosis of PCT. UROD mutations are found in approximately 20% of patients with PCT and therefore are helpful if present. The presence of a UROD mutation is a predisposing factor but not sufficient to cause PCT. Graphic 89036 Version 12.0

8593

Excretion patterns for porphyrins, porphyrin precursors, and porphyrin metabolites; and deficient erythrocyte enzymes in the porphyrias Type of porphyria Acute neurovisceral

Specific porphyria ADP

Urine

Stool

ALA, coproporphyrin III

*

Erythrocytes Zinc protoporphyrin

Plasma ALA*

Markedly decreased ALAD activity Acute neurovisceral

AIP

ALA, PBG, uroporphyrin, coproporphyrin

*

ALA, PBG, coproporphyrin III

Coproporphyrin III

Decreased PBGD activity by approximately 50% (most cases)*

ALA, PBG*

*

Δ

[approximately 620 nm] ¶

Acute neurovisceral, rarely blistering cutaneous

HCP

Acute neurovisceral, commonly blistering cutaneous

VP

ALA, PBG, coproporphyrin III

Coproporphyrin III, protoporphyrin

*

Cutaneous, blistering

PCT and HEP

Uroporphyrin, heptacarboxyl porphyrin

Heptacarboxyl porphyrin, isocoproporphyrins

Zinc protoporphyrin (markedly elevated in HEP, normal or mildly elevated in PCT)

Uroporphyrin, heptacarboxyl porphyrin

Uroporphyrin I, coproporphyrin I

[approximately 620 nm] ¶ Porphyrin-peptide conjugate [approximately 626 to 628 nm] ¶

Cutaneous, blistering

CEP

Uroporphyrin I; coproporphyrin I

Coproporphyrin I

Uroporphyrin I; coproporphyrin I

Cutaneous, nonblistering

EPP and XLP



Protoporphyrin*

Metal-free protoporphyrin §

[approximately 620 nm] ¶

[approximately 620 nm] ¶ Protoporphyrin [approximately 634 nm] ¶

Refer to UpToDate topics on individual porphyrias for additional information. ADP: delta-aminolevulinic acid (ALA) dehydratase porphyria; ALAD: ALA dehydratase; AIP: acute intermittent porphyria; PBG: porphobilinogen; PBGD: porphobilinogen deaminase; HCP: hereditary coproporphyria; VP: variegate porphyria; PCT: porphyria cutanea tarda; HEP: hepatoerythropoietic porphyria; CEP: congenital erythropoietic porphyria; EPP: erythropoietic protoporphyria; XLP: X-linked protoporphyria. * Porphyrin levels normal or slightly increased. ¶ Fluorescence emission peak of diluted plasma at neutral pH. Δ Plasma porphyrins usually normal, but increased when blistering skin lesions develop. ◊ Urine porphyrins (especially coproporphyrin) increase only with hepatopathy. § Zinc protoporphyrin ≤15 percent of total in classic EPP, but 15 to 50% in variant form (XLP). Provided by Karl Anderson, MD, FACP. Graphic 60572 Version 13.0

8594

Algorithm for distinguishing chronic blistering cutaneous porphyrias

This algorithm outlines an approach to the patient with suspected cutaneous porphyria and chronic blistering photosensitivity. Increased porphyrins in chronic blistering porphyrias are generally very elevated (eg, 10 times the upper limit of normal). Fractionation of porphyrins is accompanied by determination of the plasma fluorescence peak wavelength at neutral pH. Separate algorithms are available for the patient with suspected cutaneous porphyria with  acute nonblistering photosensitivity and the patient with suspected acute (neurovisceral) porphyria. Refer to UpToDate topics on individual porphyrias for further discussions of the clinical manifestations and diagnostic evaluation. PCT: porphyria cutanea tarda; HCP: hereditary coproporphyria; VP: variegate porphyria; CEP: congenital erythropoietic porphyria; HEP: hepatoerythropoietic porphyria; ALA: delta-aminolevulinic acid; PBG: porphobilinogen; UROD: uroporphyrinogen decarboxylase; CPOX: coproporphyrinogen oxidase; PPOX: protoporphyrin oxidase; UROS: uroporphyrinogen III synthase. * We perform gene sequencing of the relevant gene for all cutaneous porphyrias diagnosed biochemically; this may be used for further confirmation of the diagnosis, identification of new mutations, and genetic counseling. For PCT, UROD gene sequencing often does not reveal a mutation; the presence of a heterozygous UROD mutation is consistent with familial (type 2) PCT. For other biochemically proven cases of porphyria, mutation of the associated gene is expected, and if no mutation is identified, this suggests mutation in a cryptic site, noncoding region, or regulatory gene. Graphic 89035 Version 6.0

8595

Approach to the differential diagnosis of cutaneous blisters

HSV: herpes simplex virus; LCV: leukocytoclastic vasculitis; IgA: immunoglobulin A; VZV: varicella zoster virus. Graphic 103314 Version 3.0

8596

Algorithm for distinguishing non-blistering cutaneous porphyrias

This algorithm outlines an approach to the patient with suspected cutaneous porphyria and non-blistering photosentivity. Separate algorithms are available for the patient with suspected cutanous porphyria with blistering photosentitivity, and the patient with suspected acute (neurovisceral) porphyria. Refer to UpToDate topics on individual porphyrias for further discussions of the clinical manifestations and diagnostic evaluation. Refer to content on photosensitivity disorders for other diagnostic considerations. EPP: erythropoietic protoporphyria; XLP: X-linked protoporphyria; FECH: ferrochelatase; ALAS2: delta-aminolevulinic acid synthase, erythroid form. * We perform gene sequencing of the relevant gene for any patient with protoporphyria (FECH gene in EPP, ALAS2 gene in XLP). This is used for further diagnostic confirmation and especially for genetic testing and counseling of family members. Graphic 89123 Version 6.0

8597

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis Authors: Ashwani K Singal, MD, MS, FACG, FAASLD, Karl E Anderson, MD, FACP Section Editor: Robert T Means, Jr, MD, MACP Deputy Editor: Jennifer S Tirnauer, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jan 17, 2020.

INTRODUCTION The porphyrias are metabolic disorders caused by altered activity of enzymes in the heme biosynthetic pathway. Porphyria cutanea tarda (PCT; previously called symptomatic porphyria, chemical porphyria, toxic porphyria) is the most common of the porphyrias. PCT was named by Waldenström in 1937 to emphasize the predominant cutaneous manifestations and relatively late onset of disease [1]. An earlier name for PCT was chronic hematoporphyria (assigned by Günther in 1911) [2]. This topic review discusses the pathogenesis, clinical manifestations, and diagnostic evaluation for PCT, caused by deficient activity of uroporphyrinogen decarboxylase (UROD) in the liver, with heterozygous UROD mutation sometimes contributing, and hepatoerythropoietic porphyria (HEP), an extremely rare condition caused by biallelic UROD mutation. The management and prognosis of PCT and HEP are discussed in detail separately. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis".) Additional topic reviews discuss the other cutaneous, neurovisceral, and combined cutaneous/neurovisceral porphyrias: ●

Cutaneous – (See "Congenital erythropoietic porphyria" and "Erythropoietic protoporphyria and X-linked protoporphyria".)



Neurovisceral – (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis" and "Acute intermittent porphyria: Management" and "ALA dehydratase porphyria".)



Combined cutaneous and neurovisceral – (See "Variegate porphyria" and "Hereditary coproporphyria".)

An overview of porphyrias is also presented separately. (See "Porphyrias: An overview".)

DISEASE CLASSIFICATION PCT and HEP are cutaneous porphyrias, both due to deficient activity of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD) in the liver [3]. They cause blistering skin lesions as the predominant clinical manifestation; neurovisceral attacks do not occur. ●

PCT – PCT is caused by acquired inhibition of hepatic UROD to less than approximately 20 percent of normal, which occurs in the presence of iron and a variable combination of acquired factors (eg, alcohol, smoking, hepatitis C, estrogens, human immunodeficiency virus [HIV] infection). Genetic factors are present in some patients; these may include heterozygosity for a UROD mutation, which predisposes to the disease by reducing UROD activity to 50 percent of normal in all tissues from birth, and HFE (hemochromatosis) mutations (homozygous or heterozygous), which increase iron absorption.



HEP – HEP is caused by severely deficient UROD activity on a genetic basis due to mutation of both UROD alleles (eg, homozygous mutation, compound heterozygous mutation). Only approximately 40 cases of HEP have been documented worldwide.

PCT can be classified as "sporadic" or "familial" based on the absence or presence of a UROD mutation. Familial cases may present at an earlier age, but in these cases the family history is often negative for PCT. Finding a UROD mutation warrants genetic counseling. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis", section on 'Genetic counseling and asymptomatic carrier management'.) ●

PCT type 1 (sporadic) – Absence of a UROD mutation; accounts for approximately 80 percent of cases [4,5].



PCT type 2 (familial) – Inheritance of a UROD mutation affecting one allele (ie, heterozygous defect); present in approximately 20 percent of cases. Inheritance is autosomal dominant with low penetrance, so there are often no relatives with PCT. Other factors must be present to reduce UROD from 50 percent of normal (due to the mutation) to M, M>F reported in adult onset in Asia

Childhood;

Persistent during summer; may also be present year round

Sunexposed areas, may also affect unexposed areas

Pruritic papulonodules, crusts, excoriations, lichenification, cheilitis.

Yes, in up to 50%

UVA>UVB

60% with reduced MED, 60 to 70% with positive provocative phototests

 

Improves in adolescence, but also may persist

More common in American Indians and Mestizos. May have ocular findings.

Hydroa vacciniforme

Slight M>F

Childhood

Hours after sun exposure

Face, dorsal hands

Erythematous macules, papules, vesicles, crusts.

Rarely positive

Likely UVA

May show reduced MED to UVA in some cases

 

Usually resolves by adolescence/young adulthood, but may persist

Lymphoproliferative disease association with severe cases

Chronic actinic dermatitis

M>F

Older, but may be seen in younger patients

Persistent; worsens in summer, may have findings year round

Sunexposed areas

Eczematous patches, lichenification, may see palmoplantar involvement.

 

UVA, UVB, visible light

Decreased MEDs to UVA, UVB, or visible light

May see Sézary cells in severe cases

Persists for years, may resolve

Often coexistent contact dermatitis

Solar urticaria

F>M

Young or midadulthood

Appears within minutes, individual lesions resolve within 24 hours

Sunexposed areas

Urticarial plaques (hives), occasional systemic symptoms.

 

UVA, UVB, visible light

Normal MEDs, urticaria are induced within minutes of phototesting

 

Persists for years, may resolve

"Hardening" phenomenon may occur

Phototoxicity

M=F

Any age

Appears within hours of sun exposure, can occur after first dose of drug

Sunexposed areas

Exacerbated sunburn appearance.

 

UVA

In systemic phototoxicity, MED for UVA decreased, UVB and visible light MEDs normal

 

Resolves when drug discontinued and cleared from body

Can occur in anyone

Photoallergy

M=F

Any age

Appears one to two days after exposure to sun and inciting agent in sensitized individual

Sunexposed areas

Pruritic, eczematous lesions.

 

UVA

In systemic photoallergy, MED for UVA decreased, UVB and visible light MEDs normal

 

Resolves with discontinuation of inciting agent

Usually due to topical agents

Erythropoietic protoporphyria

M = F, versus slight M>F

Onset in early childhood

Symptoms begin within minutes of sun exposure, improves in winter

Nose, cheeks, hands

Burning and stinging, pain, pruritus. Erythema, edema, pupura. Heals with atrophic, wax-like scars; wrinkled knuckles.

Common (siblings), autosomal recessive or pseudodominant

Soret band (400 to 410 nm)

Often normal, some patients may note stinging sensation or lesions

Elevated erythrocyte protoporphyrin level

Chronic

May develop liver disease

Porphyria cutanea tarda

M=F

Middle age, may occur earlier

 

Sunexposed areas

Skin fragility, bullae, crusts, scarring. Hypertrichosis, hyperpigmentation, sclerodermoid changes.

Sporadic in Type I, autosomal dominant in Type II

Soret band (400 to 410 nm)

 

Elevated porphyrins in urine and stool

Chronic, symptoms improve with sun protection, removal of triggers, phlebotomy, antimalarials

Often associated with hepatitis C

Pseudoporphyria

 F>M

Any age; 10% of children taking naproxene

 

Sunexposed areas

Skin fragility, bullae, crusts, scarring, milia.

Negative

UVA

 

Normal porphyrin levels

Symptoms resolve with sun protection, avoidance of tanning bed use, and discontinuation of the causative medications

May be caused by medications, renal failure and hemodialysis, and excessive tanning bed use

 

 

 

 

 

 

 

 

 

 

 

 

adultonset may occur in Asians

F: female; M: male; UV: ultraviolet; MED: minimal erythema dose; PMLE: polymorphus light eruption. Graphic 57800 Version 12.0

8681

Erythropoietic protoporphyria

Diffuse erythematous infiltration of the nose with edema, petechial hemorrhage, and scattered atrophic scars on the side of the face with telangiectasia. Reproduced with permission from: Fitzpatrick T, Johnson R, Wolff K, et al. Color atlas and synopsis of clinical dermatology: Common and Serious Diseases, Third Edition, McGraw Hill, New York, 1997. Copyright © 1997 McGraw-Hill Companies, Inc. Graphic 68503 Version 15.0

8682

Erythropoietic protoporphyria

Diffuse erythema and confluent petechiae on the face and lips following sun exposure in a child with erythropoietic protoporphyria. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 98729 Version 3.0

8683

Algorithm for distinguishing non-blistering cutaneous porphyrias

This algorithm outlines an approach to the patient with suspected cutaneous porphyria and non-blistering photosentivity. Separate algorithms are available for the patient with suspected cutanous porphyria with blistering photosentitivity, and the patient with suspected acute (neurovisceral) porphyria. Refer to UpToDate topics on individual porphyrias for further discussions of the clinical manifestations and diagnostic evaluation. Refer to content on photosensitivity disorders for other diagnostic considerations. EPP: erythropoietic protoporphyria; XLP: X-linked protoporphyria; FECH: ferrochelatase; ALAS2: delta-aminolevulinic acid synthase, erythroid form. * We perform gene sequencing of the relevant gene for any patient with protoporphyria (FECH gene in EPP, ALAS2 gene in XLP). This is used for further diagnostic confirmation and especially for genetic testing and counseling of family members. Graphic 89123 Version 6.0

8684

Excretion patterns for porphyrins, porphyrin precursors, and porphyrin metabolites; and deficient erythrocyte enzymes in the porphyrias Type of porphyria Acute neurovisceral

Specific porphyria ADP

Urine

Stool

ALA, coproporphyrin III

*

Erythrocytes Zinc protoporphyrin

Plasma ALA*

Markedly decreased ALAD activity Acute neurovisceral

AIP

ALA, PBG, uroporphyrin, coproporphyrin

*

ALA, PBG, coproporphyrin III

Coproporphyrin III

Decreased PBGD activity by approximately 50% (most cases)*

ALA, PBG*

*

Δ

[approximately 620 nm] ¶

Acute neurovisceral, rarely blistering cutaneous

HCP

Acute neurovisceral, commonly blistering cutaneous

VP

ALA, PBG, coproporphyrin III

Coproporphyrin III, protoporphyrin

*

Cutaneous, blistering

PCT and HEP

Uroporphyrin, heptacarboxyl porphyrin

Heptacarboxyl porphyrin, isocoproporphyrins

Zinc protoporphyrin (markedly elevated in HEP, normal or mildly elevated in PCT)

Uroporphyrin, heptacarboxyl porphyrin

Cutaneous, blistering

CEP

Uroporphyrin I; coproporphyrin I

Coproporphyrin I

Uroporphyrin I; coproporphyrin I

Uroporphyrin I, coproporphyrin I

Protoporphyrin*

Metal-free protoporphyrin §

[approximately 620 nm] ¶ Porphyrin-peptide conjugate [approximately 626 to 628 nm] ¶

[approximately 620 nm] ¶

[approximately 620 nm] ¶ Cutaneous, nonblistering

EPP and XLP



Protoporphyrin [approximately 634 nm] ¶

Refer to UpToDate topics on individual porphyrias for additional information. ADP: delta-aminolevulinic acid (ALA) dehydratase porphyria; ALAD: ALA dehydratase; AIP: acute intermittent porphyria; PBG: porphobilinogen; PBGD: porphobilinogen deaminase; HCP: hereditary coproporphyria; VP: variegate porphyria; PCT: porphyria cutanea tarda; HEP: hepatoerythropoietic porphyria; CEP: congenital erythropoietic porphyria; EPP: erythropoietic protoporphyria; XLP: X-linked protoporphyria. * Porphyrin levels normal or slightly increased. ¶ Fluorescence emission peak of diluted plasma at neutral pH. Δ Plasma porphyrins usually normal, but increased when blistering skin lesions develop. ◊ Urine porphyrins (especially coproporphyrin) increase only with hepatopathy. § Zinc protoporphyrin ≤15 percent of total in classic EPP, but 15 to 50% in variant form (XLP). Provided by Karl Anderson, MD, FACP. Graphic 60572 Version 13.0

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Diagnostic testing for active porphyrias Concurrent or recent clinical manifestations Acute neurovisceral

Initial testing Spot urine PBG and total porphyrins (normalized with urine creatinine)

Additional testing (if initial results are positive) Spot urine ALA, PBG, and total porphyrins (quantitative, normalized with urine creatinine) Plasma porphyrins* Erythrocyte porphyrins

Total porphyrins (plasma*, serum, or spot urine), with fractionation if elevated

Erythrocyte total porphyrins

Erythrocyte ALAD

Acute intermittent porphyria (AIP)

Erythrocyte PBGD

Sequence ALAD gene

Sequence PBGD gene Hereditary coproporphyria (HCP)

Sequence CPOX gene

Variegate porphyria (VP)

Sequence PPOX gene

Porphyria cutanea tarda (PCT)

Erythrocyte UROD Sequence UROD gene Δ

Urinary ALA and PBG Fecal total porphyrins

Enzyme and DNA tests

Delta-aminolevulinic acid dehydratase porphyria (ADP)



Fecal porphyrins Blistering photosensitivity

Types of porphyria identified

Hepatoerythropoietic porphyria (HEP)

Erythrocyte UROD Sequence UROD gene

Nonblistering photosensitivity

Total erythrocyte porphyrins ¶

Erythrocyte metal-free and zinc protoporphyrin; plasma total porphyrins and fluorescence scan

HCP

Sequence CPOX gene

VP

Sequence PPOX gene

Congenital erythropoietic porphyria (CEP)

Erythrocyte UROS

Erythropoietic protoporphyria (EPP)

Sequence FECH gene

X-linked protoporphyria (XLP)

Sequence ALAS2 gene

Sequence UROS gene

First-line testing for symptomatic patients is guided by clinical features (ie, neurovisceral, cutaneous chronic blistering, or cutaneous acute nonblistering). All spot urine measurements should be normalized with spot urine creatinine. If initial testing is positive, further comprehensive testing follows to identify the type of acute porphyria. Enzyme measurements may be used but are not available for all porphyrias. DNA testing usually follows establishment of a biochemical diagnosis. Refer to UpToDate topics on overview of porphyria and specific porphyrias for additional details and testing in asymptomatic patients. PBG: porphobilinogen; ALA: delta-aminolevulinic acid; ADP: delta-aminolevulinic acid dehydratase porphyria; ALAD: delta-aminolevulinic acid dehydratase; PBGD: porphobilinogen deaminase; CPOX: coproporphyrinogen oxidase; PPOX: protoporphyrin oxidase; UROD: uroporphyrinogen decarboxylase; UROS: uroporphyrinogen III synthase; FECH: ferrochelatase; ALAS2: delta-aminolevulinate synthase-2. * Plasma porphyrins should include measurement of the total, fractionation if the total is elevated, and determination of the fluorescence peak wavelength at neutral pH. ¶ It is important to verify that the method used by the laboratory measures all erythrocyte porphyrins and not just zinc protoporphyrin. Δ UROD mutations are neither required nor specific for a diagnosis of PCT. UROD mutations are found in approximately 20% of patients with PCT and therefore are helpful if present. The presence of a UROD mutation is a predisposing factor but not sufficient to cause PCT. Graphic 89036 Version 12.0

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Hereditary coproporphyria Authors: Ashwani K Singal, MD, MS, FACG, FAASLD, Karl E Anderson, MD, FACP Section Editor: Robert T Means, Jr, MD, MACP Deputy Editor: Jennifer S Tirnauer, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jan 21, 2020.

INTRODUCTION Hereditary coproporphyria (HCP) is an inherited condition characterized by acute neurovisceral as well as chronic blistering cutaneous manifestations. The neurovisceral manifestations are indistinguishable from those of other acute hepatic porphyrias (acute intermittent porphyria [AIP], variegate porphyria [VP], and delta-aminolevulinic acid [ALA] dehydratase porphyria [ADP]), and the chronic cutaneous manifestations are similar to the other chronic blistering cutaneous porphyrias (porphyria cutanea tarda [PCT], VP, and hepatoerythropoietic porphyria [HEP]). Because it can have both neurovisceral and cutaneous manifestations, HCP has also been called "mixed porphyria," an obsolete term that was also applied to VP. As with AIP and VP, rare homozygous cases with distinct clinical features occur. "Harderoporphyria" is a form of homozygous HCP with prominent hematologic features caused by certain CPOX mutations. The spectrum of HCP disease manifestations is broad, and the condition is rare, making diagnosis challenging. Acute neurovisceral attacks are potentially fatal. Thus, it is especially important to make the diagnosis accurately and in a timely fashion so that appropriate treatment can be administered. This topic review discusses the pathophysiology, epidemiology, clinical features, diagnosis, and treatment of HCP. Separate topic reviews provide an overview of porphyria categories and discuss the individual acute neurovisceral and cutaneous porphyrias: ●

Schematic of categories (algorithm 1) and general overview – (See "Porphyrias: An overview".)



Acute neurovisceral features alone – (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis" and "ALA dehydratase porphyria".)



Acute neurovisceral and chronic blistering cutaneous features – (See "Variegate porphyria".)



Chronic blistering cutaneous features alone – (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis" and "Congenital erythropoietic porphyria" and "Variegate porphyria".)



Acute nonblistering cutaneous features alone – (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

PATHOPHYSIOLOGY CPOX gene mutations — HCP (OMIM #121300) is an autosomal dominant condition with incomplete penetrance caused by heterozygosity for a mutation (also called pathogenic variant) in the coproporphyrinogen oxidase gene (CPOX, previously called CPO; OMIM 612732). The CPOX gene is located on chromosome 3 and consists of seven exons and six introns [1]. The first pathogenic CPOX variant was identified in 1994, approximately 40 years after HCP was first described [2,3]. A variety of pathogenic variants have since been reported in heterozygous and homozygous cases [4-18]. Case reports have described individuals who have a CPOX mutation in combination with mutation of a different enzyme in the heme biosynthetic pathway (so-called "dual porphyria") [19,20]. Pathogenic CPOX variants reduce the activity of the CPOX enzyme, as discussed below. (See 'Enzymatic defect and accumulation of heme metabolites' below.) Genotype-phenotype correlations have not been evident in most individuals who are heterozygous for a CPOX variant. An exception is some CPOX mutations associated with harderoporphyria, an extremely rare form of homozygous HCP with hematologic features [21]. Harderoporphyrinogen III (a tricarboxyl porphyrinogen) is the intermediate in the two-step decarboxylation of coproporphyrinogen III (a tetracarboxyl porphyrinogen) to protoporphyrinogen IX (a porphyrinogen with two carboxyl groups). It was first isolated in its oxidized form (harderoporphyrin) from the rodent Harderian gland, hence its name [21,22]. (See 'More severe phenotypes of HCP' below.)

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Enzymatic defect and accumulation of heme metabolites — Coproporphyrinogen oxidase (CPOX) is the sixth enzyme in the heme biosynthetic pathway (table 1). It is localized to the mitochondrial intermembrane space, where it catalyzes the conversion of coproporphyrinogen III to protoporphyrinogen IX by oxidative decarboxylation (figure 1) [23,24]. CPOX is closely associated in the mitochondrial membrane with protoporphyrinogen oxidase (PPOX), the next enzyme in the heme synthetic pathway, mutations of which cause variegate porphyria (VP). (See "Variegate porphyria", section on 'PPOX gene mutations'.) Because CPOX is a mitochondrial enzyme, it can be measured in many cell types (eg, fibroblasts, lymphocytes) but not in mature red blood cells (RBCs; which do not contain mitochondria) [25]. Most individuals with HCP have approximately half-normal CPOX activity [26]. In rare homozygous cases, the enzyme activity is 4-fold the upper limit of normal is often used as a critical value) is a highly specific finding and confirms that the patient has one of the acute porphyrias and is sufficient to initiate treatment (table 4) (see 'Treatment of acute attacks' below). Total urine porphyrins should be measured on the same sample because PBG is often less elevated and may return to normal more rapidly in HCP (and variegate porphyria [VP]) than in acute intermittent porphyria (AIP), whereas porphyrin elevations, although nonspecific, persist longer.

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Additional samples should be collected and sent at the same time as the urinary PBG (and porphyrins), before treatment is initiated, but the results of this testing is not required for (and should not delay) treatment of an acute attack if the PBG is reported to be substantially elevated. These samples include the following: ●

Urine – The initial spot urine specimen should be sent for total porphyrins, with fractionation of porphyrins if the total porphyrins are elevated. Deltaaminolevulinic acid (ALA) is generally also measured but is usually less elevated than PBG (when both are expressed in milligram rather than millimole). The urine specimen should also be tested for creatinine so that the results of PBG can be expressed per gram of creatinine.



Plasma – A plasma (or serum) sample should be sent for total porphyrins, with fractionation if the total is elevated. Plasma fluorescence scanning is important for excluding variegate porphyria (VP) [51].



Stool – A stool sample should be sent for total porphyrins, with fractionation if the total is elevated.



RBCs – Red blood cell (RBC) total porphyrins should be sent. This is important especially for patients with blistering skin lesions that might be due to congenital erythropoietic porphyria (CEP) or hepatoerythropoietic porphyria (HEP).

Measurement of erythrocyte PBG deaminase (PBGD) activity is also useful in distinguishing among the acute porphyrias; erythrocyte PBGD is decreased in most patients with AIP [21]. There are no specific erythrocyte findings for HCP because the implicated enzyme is mitochondrial, and mature erythrocytes do not contain mitochondria. Results of biochemical testing in HCP (and findings in other porphyrias) are listed in the table (table 5). Key distinguishing points include the following: ●

The most dramatic and distinctive biochemical feature of HCP is a significantly elevated level of fecal and urinary coproporphyrin, especially coproporphyrin III, during an acute attack (table 6).

• Fecal porphyrin elevation is particularly sensitive for the diagnosis of HCP and VP. In rare individuals with harderoporphyria, coproporphyrin III and harderoporphyrin are both elevated, with a predominance of fecal harderoporphyrin (>60 percent harderoporphyrin in one study) [21]. Fecal porphyrins are markedly elevated in active and some inactive cases of HCP and VP, but the fractionation in VP reveals elevations in both coproporphyrin III and protoporphyrin IX, whereas in HCP the fecal porphyrins are almost entirely coproporphyrin III. Fecal porphyrins are normal or only slightly elevated in AIP.

• Urinary ALA, PBG, and uroporphyrin (which forms enzymatically and non-enzymatically from PBG) are elevated in HCP. The typical range for PBG in acute porphyrias is 20 to 200 mg/g creatinine; in HCP and VP the levels are often in the lower part of this range [29]. Urinary porphyrins remain elevated after an attack for longer than urinary ALA and PBG. ●

Plasma porphyrins are generally normal or only modestly elevated in HCP; greater elevations of plasma porphyrins may be seen in individuals with concurrent skin manifestations. (See 'Cutaneous manifestations' above and 'Evaluation of skin findings' below.)



Elevations in urinary porphyrins (especially coproporphyrin) are not specific for HCP or other porphyrias and are seen in many medical conditions other than porphyria, including hepatobiliary and bone marrow disorders. Therefore, an elevation in urinary coproporphyrin is consistent with HCP but insufficient for diagnosis unless there is also a marked elevation in fecal coproporphyrin III. Not uncommonly, HCP is misdiagnosed in patients based solely on nonspecific urinary coproporphyrin elevations.



RBC protoporphyrin levels are normal or only slightly elevated in HCP. Substantial elevation is seen in individuals with homozygous HCP (and in individuals with harderoporphyria, RBC harderoporphyrin levels are also elevated).

Measurement of CPOX activity in mitochondria-containing cells such as lymphocytes helps to confirm a diagnosis of HCP, but such assays are not widely available [52]. This is almost never needed clinically as DNA testing is widely available. Genetic testing (DNA analysis) is used to characterize the genetic defect in an affected individual and then used to screen asymptomatic family members. Sometimes genetic testing is done early in the diagnostic evaluation of a patient with neurovisceral symptoms and demonstrates a pathogenic mutation for one of the acute porphyrias. Biochemical testing then focuses mostly on assessing disease activity as related to symptoms, and less toward exclusion of the other acute porphyrias. However, expertise is needed for interpretation of available molecular and biochemical findings, because some genetic variants are not pathogenic [53]. (See 'Diagnostic confirmation/role of genetic testing' below.) New patient, history of neurovisceral attacks — Evaluation for acute porphyrias is challenging in an individual who gives a history consistent with acute neurovisceral attacks but is currently well. This is because the levels of PBG, ALA, and porphyrins may return to normal between attacks and/or after elimination of exacerbating factors. In such individuals, we test urine ALA, PBG, and porphyrins, as well as plasma and fecal porphyrins. The most sensitive testing for HCP, especially after symptoms have cleared, is fecal porphyrins, and for VP, plasma and fecal porphyrins (algorithm 2). If the results are normal and suspicion for acute porphyrias remains, urine PBG and porphyrins and fecal porphyrin can be measured again in the future if symptoms recur. In testing family members

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with or without a history of symptoms, a high ratio of coproporphyrin III to I in feces is sensitive for detecting those with HCP [54]; however, biochemical testing is not as sensitive as testing for a known CPOX mutation. Genetic testing for a CPOX mutation is widely available and can be used for initial diagnosis in an individual who gives a history consistent with HCP but who does not have active symptoms. However, it would be necessary to screen for AIP, HCP, and VP by sequencing three genes if biochemical findings were normal. Patient with known HCP, confirming an acute attack — Prior laboratory documentation of HCP, including both biochemical and molecular confirmation, should be available to the treating physician from the medical records or from records provided by the patient. In an individual with known HCP who is experiencing neurovisceral symptoms, it is advisable to obtain a spot urine for PBG and creatinine; treatment can typically be started before the result is available. The confirmation of an acute attack, as well as initiation of appropriate treatment, is made on clinical grounds. (See 'Treatment of acute attacks' below.) Importantly, it is not necessary to wait for the results of PBG testing or porphyrin levels before initiating treatment for an acute attack, and such delay may increase the risk of serious adverse outcomes. However, we do obtain this testing because it is helpful in retrospect to confirm the PBG elevation and determine its degree relative to previous attacks (eg, to determine if attacks are escalating or lessening). If PBG is not increased, a more extensive evaluation may be required to determine the cause of the symptoms that were thought to be due to an acute attack. (See 'Differential diagnosis' below.) It is also important to thoroughly evaluate the individual for other potential causes of their symptoms, which may have triggered the acute attack or may have occurred as a result of the acute attack. (See 'Importance of evaluating for associated/triggering conditions' below.) Importance of evaluating for associated/triggering conditions — In any patient with suspected or confirmed HCP who presents with acute neurovisceral symptoms, it is important to evaluate for associated conditions that may have triggered an acute attack, may be masquerading as an acute attack, or may be caused by an acute attack. In some cases, both the HCP and the associated condition may require separate interventions. Examples include [55]: ●

Infections (eg, urinary tract infection, pulmonary infection, intestinal infection)



Liver disease, pancreatitis, or cholecystitis



Major surgeries, injuries, or medical illnesses



Use of a porphyrinogenic medication, hormone, alcohol, or recreational drug



Fasting, dieting, or other metabolic stress

The mechanisms by which these factors cause porphyric attacks are described above. (See 'Precipitating factors' above.) Evaluation of skin findings — Cutaneous porphyria is suspected in individuals who present with chronic blistering cutaneous changes on sun-exposed areas of skin (most commonly, blistering on the dorsal hands and hair growth on the face). (See 'Cutaneous manifestations' above.) The evaluation for suspected cutaneous porphyria begins with testing for plasma or urine porphyrins as a screening test, followed by measurement of porphyrins in plasma and red blood cells (RBCs), in addition to urine and plasma, and measurement of individual porphyrins if totals are elevated (eg, ≥1 mcg/dL in plasma or serum or 300 mcg/g creatinine in urine; typically much higher). Normal results for plasma and/or urine total porphyrins exclude all chronic blistering cutaneous porphyrias. If total porphyrins are increased, the next step is to distinguish among the blistering cutaneous porphyrias (HCP; porphyria cutanea tarda [PCT], the most common blistering cutaneous porphyria; VP; CEP; and HEP). These are distinguished by the porphyrin patterns in urine, plasma, and feces (table 5) [21]. Clinical findings should not be relied upon to differentiate these conditions because neurovisceral symptoms are highly nonspecific; neurovisceral findings are sometimes but not always present in individuals with HCP and VP who have skin manifestations. Such findings are not caused by PCT, CEP, or HEP, but they are very nonspecific and may be present due to a concurrent condition. As noted above, the finding of markedly elevated coproporphyrin III and a high III/I ratio without elevation of other fecal porphyrins is typical of HCP, but is not specific, and is useful mostly for screening family members of a known HCP patient. (See 'New patient, acute attack' above.) This approach is illustrated in the algorithm (algorithm 3) and discussed in more detail separately. (See "Porphyrias: An overview", section on 'Diagnostic testing (blistering cutaneous porphyria suspected)'.) A more general approach to other causes of blistering skin lesions (ie, if testing for porphyria is negative) is also presented separately. (See "Approach to the patient with cutaneous blisters".) Evaluation of asymptomatic relatives — Relatives can be screened in a cascade fashion, with priority given to those with symptoms suggesting porphyria. DNA testing is most reliable once the familial mutation is known. If biochemical testing is used, it should emphasize fecal porphyrin analysis and the fecal coproporphyrin III/I ratio.

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Diagnostic confirmation/role of genetic testing — We consider the diagnosis of HCP to be confirmed if biochemical testing demonstrates elevated urinary or fecal coproporphyrin III and if other porphyrias that can cause PBG elevation (ie, AIP and VP) are excluded biochemically. The diagnosis is also confirmed if genetic testing demonstrates a pathogenic CPOX mutation. However, confirming that symptoms are due to HCP in an individual with a CPOX mutation requires demonstration of substantial elevations of PBG and porphyrins. Also, some identified CPOX variants may not be pathogenic or may have uncertain pathogenicity [53]. Genetic testing is widely available. This testing is helpful and recommended for the following reasons and in the following settings: ●

Making the diagnosis in an individual who is currently asymptomatic and thus may not have substantial elevations of urine and fecal coproporphyrin



Confirming the diagnosis if clinical findings and/or results of biochemical testing are atypical, or if dual enzyme defects are suspected



Sensitive and specific screening of family members, once the familial mutation is identified



Preconception counseling

Several caveats are important to consider with genetic testing: ●

Finding a pathogenic CPOX mutation with normal PBG and porphyrin levels establishes a diagnosis of latent HCP, and can suggest but not prove that past symptoms were due to HCP.



As with other genetic disorders, rare patients with HCP have cryptic mutations that are not detected by sequencing; these can usually (but not always) be demonstrated by other methods such as dose analysis [56].



Expert interpretation of DNA results is required because some identified variants are nonpathogenic or of uncertain pathogenicity, including some mistakenly reported in the past as causing HCP or other acute porphyrias [57]. This caveat applies to other genetic diseases but is especially relevant to porphyria. As an example, one CPOX variant (N272H), which is not found in HCP, causes an unusual urinary porphyrin pattern after mercury exposure and may alter susceptibility to this heavy metal [58]. Individuals with this CPOX variant have been misdiagnosed as having HCP, as are individuals with other CPOX mutations that are nonpathogenic or of uncertain pathogenicity.

Resources for genetic testing are available at the Genetic Testing Registry.

DIFFERENTIAL DIAGNOSIS The major considerations in the differential diagnosis of HCP are other acute porphyrias (and less commonly other cutaneous porphyrias) as well as other causes of abdominal pain, other causes of neuropathic or psychiatric symptoms, and other causes of liver disease. Elevated urinary porphobilinogen (PBG) distinguishes acute hepatic porphyrias from non-porphyria conditions, and excretion patterns of heme pathway intermediates (PBG, delta-aminolevulinic acid [ALA], porphyrins) in urine, plasma, and feces distinguish the acute porphyrias from each other. ●

Other acute porphyrias – Like HCP, other acute porphyrias can cause acute attacks of abdominal and neuropsychiatric symptoms and increases in urinary porphyrin precursors (PBG, ALA) and porphyrins. Other acute porphyrias have different patterns of porphyrin precursors and porphyrins in blood, urine, erythrocytes, and stool (table 5 and table 4); and some (variegate porphyria [VP] and less commonly HCP) have skin manifestations (table 7). Because attacks of all acute porphyrias are treated in the same manner, it is not important to differentiate them before treatment is started if a substantial elevation in PBG has been documented; however, samples needed for differentiating these disorders should be collected before treatment. Genetic testing is best obtained after biochemical diagnosis of one of these acute porphyrias. (See "Porphyrias: An overview".)

• AIP – Acute intermittent porphyria (AIP) is an acute porphyria like HCP. Of the two, AIP is more common. Like HCP, AIP is characterized by elevated urinary PBG, especially during an acute attack; PBG elevations may be higher in AIP than in HCP or VP, and may return to normal more quickly in the latter conditions. HCP may cause blistering photosensitivity, which does not occur in AIP except in cases where concomitant chronic renal failure increases plasma porphyrin levels. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis".)

• VP – Variegate porphyria (VP) is an acute neurovisceral porphyria like HCP. Like HCP, VP can cause either neurovisceral or cutaneous manifestations, which may occur together or at different times. Like HCP, VP is characterized by elevated urinary PBG and urine and fecal porphyrins, especially during an acute attack. Compared with HCP, VP is much more common and more likely to cause blistering photosensitivity, and in VP, the elevated fecal porphyrins include both coproporphyrin III and protoporphyrin (in HCP, coproporphyrin III predominates substantially. The coproporphyrin III/I ratio is elevated in both). Compared with HCP, VP is more likely to have increased plasma porphyrins, with a characteristic peak fluorescence at approximately 626 nm when plasma is diluted at neutral pH; this fluorescence peak distinguishes VP from all other types of porphyria [51]. (See "Variegate porphyria".)

• ADP – ALA dehydratase porphyria (ADP) is an acute neurovisceral porphyria like HCP. ADP is extremely rare. Unlike HCP, ADP is characterized by elevated urinary ALA, increased urinary coproporphyrin III, normal levels of urinary PBG, and markedly increased zinc protoporphyrin in erythrocytes. (See "ALA dehydratase porphyria".)

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Other cutaneous porphyrias – Rarely, other blistering cutaneous porphyrias that can cause elevations in porphyrin levels, such as congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and hepatoerythropoietic porphyria (HEP), may be misdiagnosed as HCP (or VP), especially if a concurrent condition is causing abdominal pain or other symptoms that suggest an acute porphyria. Erythropoietic protoporphyria (and X-linked protoporphyria) cause nonblistering photosensitivity and can cause abdominal pain due to biliary stones or protoporphyric hepatopathy. Unlike HCP, patients with protoporphyrias lack elevations in urinary PBG and porphyrins. Thus, a biochemical evaluation will determine the type of cutaneous porphyria (algorithm 3 and algorithm 4).



Other causes of abdominal pain – Abdominal pain can occur in numerous clinical settings and is often difficult to diagnose. Unlike HCP (and other acute porphyrias), other causes of abdominal pain do not cause elevations of urinary PBG. However, other causes of abdominal pain may be associated with elevations in urinary porphyrins (eg, hepatobiliary disease) or ALA (eg, lead poisoning). (See "Evaluation of the adult with abdominal pain" and "Causes of abdominal pain in adults".) Importantly, an individual known to have porphyria may present with another cause of abdominal pain (eg, appendicitis, diverticulitis, pancreatitis, inflammatory or ischemic bowel disease, renal stones), and these conditions can precipitate an acute porphyria attack. Therefore, an elevated PBG is diagnostic for acute porphyria but does not exclude these other conditions.



Other causes of neuropathy – Neuropathies can have a variety of clinical presentations and etiologies. Unlike HCP, other causes of neuropathy do not cause elevations of urinary PBG. However, lead poisoning causes elevations of urinary ALA and porphyrins. (See "Overview of polyneuropathy" and "Overview of hereditary neuropathies".)



Other causes of neuropsychiatric symptoms – There are a variety of causes of nonspecific neuropsychiatric symptoms (eg, anxiety, agitation, insomnia, hallucinations). Examples include neurodegenerative disease, alcohol and drug use, psychiatric illness, and psychotropic medications. Like HCP, some of these other conditions may be associated with hyponatremia and increased antidiuretic hormone secretion. Unlike HCP, these other causes of neuropsychiatric symptoms do not cause elevations of urinary PBG. (See "Approach to the patient with visual hallucinations".)



Other causes of seizures – Seizures may occur in a setting of acute medical illness including hypoglycemia, hypocalcemia, hyponatremia, uremia, and drug or alcohol intake. Unlike acute porphyria, these other causes of seizures do not cause elevations in PBG. (See "Evaluation and management of the first seizure in adults".)



Liver disease – Like HCP, liver disease of any cause may be associated with elevated urinary porphyrin excretion, especially coproporphyrin. This occurs because coproporphyrin is excreted in both bile and urine, and more appears in the urine when hepatobiliary function is impaired. Unlike HCP, patients with liver disease do not have elevated PBG (although they may have slight elevations in ALA) and slight or substantial elevations in porphyrins (especially coproporphyrin). (See "Approach to the patient with abnormal liver biochemical and function tests".)

MANAGEMENT Treatment of acute attacks — Acute neurovisceral attacks in an individual with porphyria can be potentially life-threatening, and treatment should be initiated as soon as possible: ●

For new patients, treatment for an acute attack, if clinically indicated, is started as soon as the patient is diagnosed as having acute porphyria (based on a substantial increase in urinary porphobilinogen [PBG]) [29,59,60]. Treatment should not be delayed in an individual confirmed to have acute porphyria while first determining which acute porphyria is present or while administering a carbohydrate load.



Ideally, in the absence of prior laboratory evidence of acute porphyria, an elevation in urinary PBG should be documented before initiating treatment with hemin, unless delay would be potentially detrimental. In rare cases with life-threatening neurovisceral manifestations, a high likelihood of porphyria, and an expected long delay in obtaining results of diagnostic testing, we may initiate treatment before urinary PBG results are available. This is justified because hemin is considered highly effective and has few side effects if administered into a large vein and/or after reconstitution with human albumin. The patient and others should understand that without confirmation by a high PBG, the clinical diagnosis of acute porphyria is provisional and may not be confirmed even in a patient with "classic" (but nonspecific) symptoms. However, starting hemin treatment without sending urine for PBG creates a difficult diagnostic situation because PBG and porphyrin levels are lowered by hemin for an unpredictable period of time, so later PBG determinations may be normal even if initial samples would have been elevated.



For established patients who present with symptoms of an acute attack, treatment is started based on the clinical findings and should not be delayed while determining the presence or degree of urinary PBG elevation (unless this information can be obtained within a few hours). However, as noted above, a spot urine should be collected for PBG measurement before starting hemin.

The following summarizes the components of treatment: ●

Give hemin – For any acute attacks that are severe enough to warrant hospitalization, intravenous hydration (eg, due to nausea, vomiting, or ileus), opioid analgesia, or other intravenous medication; or associated with seizures, paresis, agitation, delirium, or hyponatremia, we recommend hemin, consistent with published guidelines [29,60,61]. Hemin is administered intravenously at a dose of 3 to 4 mg/kg of body weight per day and continued

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until the attack abates and/or for at least four days, whichever is longer [29]. Some patients may respond more quickly, especially if treatment is started promptly, and others may require treatment for more than four days. Additional details of hemin dosing, adverse events, different products, and supporting evidence in individuals with acute intermittent porphyria (AIP) are presented separately. (See "Acute intermittent porphyria: Management", section on 'Acute attack: Primary treatment (hemin)'.) The other available treatment for acute porphyric attacks is carbohydrate loading (ie, administration of a 10 percent solution of intravenous glucose or glucose and saline; typical dose, 300 to 400 grams per 24 hours), but observational reports and our experience suggest this is less effective than hemin in aborting the acute attack. Carbohydrate loading should only be used in attacks that are mild (ie, not associated with vomiting, ileus, pain requiring opioid analgesia, need for intravenous medication, seizures, paresis, agitation, delirium, or hyponatremia) and/or as a temporizing measure while awaiting administration of hemin, as long as use of carbohydrate loading does not delay definitive therapy with hemin administration. There are no adequately powered randomized trials comparing hemin with glucose loading or placebo for acute attacks in individuals with HCP or other acute porphyrias. Available evidence includes case series that show a clear benefit of hemin therapy in reducing the severity and duration of acute attacks of other acute porphyrias; this is confirmed by continued experience at many centers. As an example, in a series of 112 patients with an acute attack of AIP or variegate porphyria (VP), hemin resulted in dramatic improvement in symptoms and reduction in the opioid requirement, typically within 24 to 48 hours [62]. These outcomes are similar to our experience and that in published series [63-65]. Details of administration are presented separately. (See "Acute intermittent porphyria: Management", section on 'Carbohydrate loading as a temporizing measure'.) ●

Avoid harmful medications – Medications that are considered unsafe in acute porphyrias should be avoided. If present, their use should be discontinued if at all possible. This includes barbiturates, sulfonamide antibiotics, metoclopramide, griseofulvin, rifampin, anticonvulsants (eg, phenytoin, carbamazepine), ergot alkaloids, and progestins (table 2). (See 'Precipitating factors' above.) It is strongly advised that clinicians consult the websites of the American Porphyria Foundation (www.porphyriafoundation.com) and the European Porphyria Network (EPNET; porphyria.eu), which are frequently updated; list many other drugs, including those that are not classified with certainty; and provide evidence for these classifications. These lists of classified drugs derive from judgments based on the best evidence, which for many drugs is inadequate.



Treat concurrent illnesses – As noted above, treatment for concurrent conditions (eg, infections, dehydration, metabolic abnormalities) should also be provided as soon as possible, both to resolve the condition as well as to optimally treat the acute porphyria attack [29,59]. (See 'Importance of evaluating for associated/triggering conditions' above.)



Provide supportive care – Supportive care may include hydration, analgesia, anticonvulsants (if seizures are present and do not rapidly resolve), and/or correction of metabolic abnormalities such as hyponatremia. Pain during attacks is severe, and opioids are almost always required. Details are identical to patients with AIP and are discussed separately. (See "Acute intermittent porphyria: Management", section on 'Acute attack: Management of symptoms and complications' and "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)

Non-acute management Prevention of acute attacks — Although recurrent attacks are less common in HCP than in AIP, factors that have contributed to past acute attacks or might precipitate future attacks should be identified and addressed [61]: ●

Avoid unsafe drugs – Potentially harmful drugs should be avoided whenever possible. Anesthesia for major surgery should avoid barbiturates and include safe agents such as propofol [66]. Information on safe and harmful drugs based on regularly updated evidence is available at the websites of the American Porphyria Foundation and the European Porphyria Network (web-links are listed above). (See 'Treatment of acute attacks' above.)



Avoid smoking and alcohol – We counsel individuals with acute porphyria to avoid or discontinue smoking, including use of marijuana, and to avoid alcohol intake. These substances can precipitate acute attacks via their stimulatory effects on hepatic heme synthesis. (See 'Precipitating factors' above.)



Hormonal changes – Frequent attacks occur during the luteal phase of the menstrual cycle in some women, and these can be prevented with a gonadotropin-releasing hormone (GnRH) analogue such as leuprolide acetate, which is started during the first few days of a menstrual cycle [67].



Balanced diet – A balanced diet somewhat high in carbohydrates (eg, as 60 to 70 percent of total calories) is recommended. Additional dietary carbohydrates and/or calories are unlikely to be helpful and may lead to excessive weight gain. If used, weight loss diets should provide gradual weight loss and should be used during periods of clinical stability, in consultation with a dietitian. A dietician may also help identify dietary factors responsible for precipitating acute attacks. Precipitation of acute porphyria symptoms after bariatric surgery has been reported, and we prefer other methods of weight loss if possible [68].



Rapid treatment and prevention of infections – We ensure that all age-appropriate vaccinations are updated and rapidly treat infections that may cause metabolic stress. (See "Standard immunizations for nonpregnant adults".)

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We advise patients to wear a medical alert bracelet or to carry a wallet card explaining their condition so that clinicians will be aware of avoiding unsafe medications and of treating neurovisceral manifestations in the event that the patient is unable to provide this information [29]. Unexplained, frequent noncyclic attacks are rare, but such attacks are disabling and markedly affect quality of life. They can sometimes be prevented by prophylactic weekly infusions of a single dose of hemin, as discussed separately. (See "Acute intermittent porphyria: Management", section on 'Prophylactic hemin'.) Givosiran (Givlaari) is an interfering RNA therapeutic that was approved by the US Food and Drug administration in late 2019 for the prevention of frequent recurrent attacks of acute porphyrias; approval was based on promising results in clinical trials [69]. Experience has mostly been with AIP, but the drug is likely to be effective in preventing attacks of other acute hepatic porphyrias including HCP. Givosiran targets hepatocytes. It reduces ALA and PBG for at least a month after administration by downregulating ALAS1 mRNA. Dosing and administration are discussed in detail separately. (See "Acute intermittent porphyria: Management", section on 'Givosiran'.) Prevention and treatment of skin lesions — As in VP and porphyria cutanea tarda (PCT), blistering skin lesions are prevented by advising patients to avoid sunlight exposure. For those prone to developing symptomatic skin lesions, protective clothing and opaque mineral sunscreens containing zinc oxide or titanium oxide that block all wavelengths of light should be used. (See "Selection of sunscreen and sun-protective measures" and "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection".) Most individuals with skin problems from HCP will avoid sunlight and therefore are at risk for vitamin D deficiency. Routine supplementation is used for those who must avoid sunlight. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".) Treatment of skin lesions includes keeping them clean and dry, treating bacterial superinfection with topical (or rarely, systemic) antibiotics, and avoiding medications that appear to exacerbate the disease (eg, hormonal contraceptives in some individuals). Pain may require analgesic therapy, including aspirin, acetaminophen, or opioid analgesics. Topical steroids should be avoided. Beta-carotene may offer some protection against acute nonblistering photosensitivity in erythropoietic protoporphyria, but is not of value in chronic blistering porphyrias such as HCP. Charcoal or cholestyramine, which act by binding porphyrins in the intestine and preventing their reabsorption, have sometimes been helpful [70]. (See "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Beta-carotene'.) Importantly, interventions used to treat acute neurovisceral attacks and/or to treat skin lesions of PCT are not effective in treating the skin lesions of HCP and should not be used for this purpose. Pregnancy — Pregnancy is often well tolerated in individuals with acute porphyria. If acute attacks occur during pregnancy, they should be treated similarly to other acute attacks. There are limited reports on the use of hemin in pregnancy, but hemin appears to be safe and effective [71,72]. Termination of pregnancy is rarely, if ever, indicated for an acute attack of porphyria [61]. Screening and interventions for long-term complications — Long-term management issues include the following: ●

Monitoring of urine and plasma PBG and porphyrin levels at least yearly. Changes over time may reflect susceptibility to attacks.



Some patients with HCP may develop chronic pain, depression, or other psychiatric problems, similar to other acute porphyrias. Because there may be risk for suicide, these manifestations must be recognized and managed appropriately [29,61]. (See "Unipolar depression in adults: Assessment and diagnosis" and "Approach to the management of chronic non-cancer pain in adults".)



The risk of hepatocellular carcinoma (HCC) is increased in HCP, similar to other acute porphyrias [45]. It is generally recommended that patients with acute porphyrias, especially those with persistent increases in porphyrin precursors and porphyrins, be screened for HCC by imaging (eg, hepatic ultrasound) at six-month intervals after age 50. Screening may be initiated at a younger age for those with other risk factors such as cirrhosis, hepatitis C virus infection, or excess alcohol use. Experience indicates that monitoring serum alpha-fetoprotein levels is not useful for surveillance.

Genetic testing and counseling — Identifying a pathogenic CPOX mutation in an affected patient helps confirm the diagnosis of HCP and facilitates reliable identification of family members with latent HCP. These individuals can then be counseled to avoid certain drugs and other factors that may precipitate acute attacks of the disease, and if they develop symptoms, the diagnosis of active HCP will not be delayed. (See 'Evaluation of asymptomatic relatives' above.) The diagnosis of HCP can be made in utero by amniocentesis, but this is seldom indicated because the prognosis in most heterozygotes is favorable and therefore pregnancy interruption is not often considered.

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Porphyria".)

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SUMMARY AND RECOMMENDATIONS ●

Hereditary coproporphyria (HCP) is an acute hepatic porphyria that can cause neurovisceral symptoms (table 3) as well as chronic blistering cutaneous photosensitivity. Variegate porphyria (VP) is the only other porphyria that typically causes both neurovisceral and cutaneous manifestations (algorithm 1). Neurovisceral and cutaneous symptoms may be present together or at different times. (See 'Introduction' above.)



HCP is an autosomal dominant condition with incomplete penetrance caused by mutations in the coproporphyrinogen oxidase (CPOX) gene. The CPOX enzyme, located in mitochondria (figure 1), catalyzes the two-step conversion of coproporphyrinogen III to protoporphyrinogen IX (table 1). Neurotoxic effects are thought to be due to accumulation of early heme precursors such as delta-aminolevulinic acid (ALA) and can be precipitated by a number of medications, steroid hormones, cigarette smoke, alcohol, and metabolic stress (eg, from infection or fasting). These factors lead to induction of ALAS1, which encodes the rate controlling enzyme for hepatic heme biosynthesis. Cutaneous effects are thought to be due to porphyrins in the skin that can be activated by visible and long-wave ultraviolet light. (See 'Pathophysiology' above.)



The prevalence of HCP is approximately two to five per million population. HCP is less common than acute intermittent porphyria (AIP) and VP, but more common than ALA dehydratase porphyria (ADP). (See 'Epidemiology' above.)



HCP typically manifests after puberty in individuals heterozygous for CPOX mutations. Onset in childhood may occur with homozygous forms. Diagnostic delays are common. Features of neurovisceral attacks may include symptoms or findings of central, peripheral, and autonomic nervous system dysfunction (table 3) that are indistinguishable from other acute hepatic porphyrias. Chronic blistering cutaneous manifestations are less common but can occur; these may include blistering, scarring, and pigment changes on sun-exposed areas of skin. Long-term complications may include residual neurologic defects that may cause disability and depression, as well as persistent elevation of liver enzymes and/or hepatocellular carcinoma. (See 'Clinical features' above.)



The appropriate diagnostic evaluation depends on whether the individual is in the midst of an acute attack, has a history of remote attacks and/or positive family history, and/or has chronic skin manifestations (see 'Overview of the evaluation' above):

• For a new patient, acute porphyria is diagnosed based on an elevated urinary porphobilinogen (PBG), after which treatment is started if clinically warranted (algorithm 2). Further testing determines the type of acute porphyria (table 4). HCP is characterized by markedly increased coproporphyrin III in urine and feces with little increase in fecal protoporphyrin (table 6 and table 5). For a patient with known HCP, the presence of an acute attack is diagnosed clinically. In both cases, concomitant infections and other potential triggering conditions should be evaluated. (See 'Evaluation of neurovisceral symptoms' above.)

• Skin findings are evaluated with plasma, urine, and fecal total porphyrins (algorithm 3), followed by fractionation of porphyrins if elevated (table 5). (See 'Evaluation of skin findings' above.)

• Genetic testing is not required for diagnosis but is recommended for confirmation and to evaluate asymptomatic relatives who may have inherited the same mutation. (See 'Evaluation of asymptomatic relatives' above and 'Diagnostic confirmation/role of genetic testing' above.) ●

Major considerations in the differential diagnosis of HCP include other acute and cutaneous porphyrias, other causes of abdominal pain, other causes of neuropsychiatric symptoms and seizures, and other causes of liver disease. (See 'Differential diagnosis' above.)



Acute neurovisceral attacks in an individual with porphyria can be potentially life-threatening, and treatment should be initiated as soon as possible. (See 'Treatment of acute attacks' above.)

• For acute attacks that are severe enough to warrant hospitalization, intravenous hydration (eg, due to nausea, vomiting, or ileus), opioid analgesia, or other intravenous medication; or associated with seizures, paresis, agitation, delirium, or hyponatremia, we recommend hemin rather than carbohydrate loading (Grade 1C). This is given intravenously at a dose of 3 to 4 mg/kg of body weight per day until the attack abates.

• For mild attacks (ie, no intravenous medication or hospitalization required), we also suggest hemin rather than carbohydrate loading (Grade 2C). However, some mild attacks may respond to carbohydrate loading, and carbohydrate loading may be used as a temporizing measure if hemin administration is delayed.

• Other interventions for acute attacks include discontinuing (and avoiding) potentially harmful medications, treating concurrent illnesses (eg, infections), and providing supportive care as needed (eg, analgesics, hydration, anticonvulsants, mechanical ventilation). Potentially harmful medications are listed in the table (table 2); updated information on safe and harmful drugs is available at the websites of the American Porphyria Foundation and the European Porphyria Network. ●

Factors that have contributed to past acute attacks or might precipitate future attacks may include hormonal changes, dietary practices, medications, smoking, and alcohol. These should be identified and addressed, with the aim of hastening recovery and preventing future attacks. GnRH analogues may be used to prevent frequent cyclic attacks. Frequent noncyclic attacks can be prevented by a prophylactic hemin regimen or

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by givosiran, an interfering RNA therapeutic. Pregnancy is generally well tolerated. Sun avoidance and rapid treatment of skin infections is important for the minority of HCP patients who develop skin lesions. During asymptomatic periods, liver function tests and porphyrin levels may be monitored, and patients are screened for depression and hepatocellular cancer. Genetic testing and counseling is appropriate for patients and family members. (See 'Non-acute management' above.)

ACKNOWLEDGMENT We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program. Use of UpToDate is subject to the Subscription and License Agreement. Topic 7100 Version 31.0

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GRAPHICS Algorithm for understanding and categorizing porphyrias according to clinical features

The three most common porphyrias (bold outlines) represent each of the three main categories and are distinct in their clinical features, diagnostic testing, and treatment. Other less common types of porphyria in e should be included in the differential diagnosis. VP and HCP are in the differential diagnosis of acute neurovisceral and chronic blistering cutaneous porphyria; patients may present with either (or both) findings. A information about the responsible genes, enzymes, and exacerbating factors are discussed in UpToDate. Refer to UpToDate for more detailed diagnostic algorithms for each of the three main clinical categories of AIP: acute intermittent porphyria; PCT: porphyria cutanea tarda; EPP: erythropoietic porphyria; ADP: delta-aminolevulinic acid (ALA) dehydratase porphyria; VP: variegate porphyria; HCP: hereditary coproporphyria; HEP: hepatoe porphyria; CEP: congenital erythropoietic porphyria; XLP: X-linked porphyria. Graphic 117978 Version 1.0

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Sequence of enzymes in the heme biosynthetic pathway, subcellular localizations, gene symbols, and chromosomal locations Enzyme*

Gene symbol ¶ and chromosome location

Subcellular localization

δ-Aminolevulinic acid synthase – Housekeeping form (ALAS1)

Mitochondria

δ-Aminolevulinic acid synthase – Erythroid-specific form (ALAS2)

Mitochondria

ALA dehydratase (ALAD)

Cytosol

ALAS1

Number of known disease variants (mutations) None

3p31.2 ALAS2 Xp11.2

>25 in sex-linked sideroblastic anemia; 4 gain-offunction mutations in XLP

ALAD

14 in ALAD porphyria (8 known cases)

9q32 PBG deaminase (PBGD) Δ

Cytosol

PBGD (also called HMBS)

>300 in acute intermittent porphyria

11q23.2 Uroporphyrinogen III synthase (UROS)

Cytosol

UROS

>35 in congenital erythropoietic porphyria

10q26.2 Uroporphyrinogen decarboxylase (UROD)

Coproporphyrinogen oxidase (CPOX)

Cytosol

UROD

Mitochondria

1p34.1

>70 in porphyria cutanea tarda (type 2) and hepatoerythropoietic porphyria

CPO

>40 in hereditary coproporphyria

3q12.1 Protoporphyrinogen oxidase (PPOX)

Mitochondria

PPOX

>120 in variegate porphyria

1q23.3 Ferrochelatase (FECH)

Mitochondria

FECH 18q21.31

Refer to UpToDate for information on diagnostic testing. δ: delta; XLP: X-linked protoporphyria; ALA: delta-aminolevulinic acid; PBG: porphobilinogen. * Standard abbreviations in parentheses. ¶ Gene symbols in italics, by convention. Δ Also known as hydroxymethylbilane synthase (HMBS), and formerly as uroporphyrinogen I synthase. Karl Anderson, MD, FACP. Graphic 54358 Version 8.0

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>90 in erythropoietic protoporphyria

Heme biosynthesis pathway showing chemical intermediates and sites of production (mitochondria versus cytosol)

Heme synthesis begins with the formation of delta-aminolevulinic acid (ALA) from glycine and succinyl-CoA by ALA synthase (ALAS); this step is rate-limiting in the liver. Hepatic ALAS is mainly regulated by heme via feedback repression (dashed arrow at the top of the frame). Refer to UpToDate for a discussion of porphyrias that result from deficiencies of these enzymes. CoA: coenzyme A. Reproduced from: Anderson KE. The porphyrias. In: Zakim and Boyer's Hepatology: A Textbook of Liver Disease, 5th ed, Boyer TD, Wright TL, Manns MP, Zakim D (Eds), Elsevier, Philadelphia 2006. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 117995 Version 1.0

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Examples of drugs known to be safe or unsafe in the acute porphyrias Safe Acetaminophen (paracetamol)

Cephalosporins; refer to note

Local anesthetics ¶ (eg, lidocaine, bupivacaine)

Aminoglycosides

Erythropoietin Δ

Opioid analgesics ¶

Anesthetic (eg, propofol)

Gabapentin

Penicillin and derivatives

Antiemetics* (ondansetron); refer to note

Glucocorticoids

Phenothiazines (eg, chlorpromazine, prochlorperazine, promethazine)

Aspirin

Histamine 2 receptor antagonists Δ (eg, cimetidine, famotidine)

Proton pump inhibitors (eg, lansoprazole, omeprazole, pantoprazole)

Atropine

Insulin

Vigabatrin

Benzodiazepines ¶ (eg, lorazepam, midazolam); refer to note

Levetiracetam

Unsafe Alcohol

Ethosuximide and methsuximide

Primidone Δ

Anesthetics ¶ (eg, etomidate, ketamine, thiopental)

Griseofulvin Δ

Progesterone and synthetic progestins Δ

Antipyrine (phenazone)

Hydralazine

Pyrazinamide Δ

Barbiturates Δ

Hydroxyzine

Rifampin Δ

Carbamazepine Δ

Meprobamate Δ

Spironolactone

Carisoprodol Δ

Nifedipine

Sulfasalazine

Clonazepam (high doses)

Nitrofurantoin

Danazol Δ

Oxcarbazepine

Sulfonamide antibiotics Δ (including trimethoprim-sulfamethoxazole [cotrimoxazole])

Diclofenac Δ and possibly other NSAIDs

Pentazocine

Tamoxifen

Efavirenz

Phenytoin Δ

Ergot derivatives (including dihydroergotamine)

Phenobarbital

Topiramate Valproic acid Δ

Δ

Estrogens Δ

This table includes examples of commonly used drugs known to be safe or unsafe in the acute porphyrias (ie, porphyrias associated with acute neurovisceral attacks). NOTE: This list is incomplete and includes drugs for which there is general agreement among experts. It is recommended that clinicians consult the websites of the American Porphyria Foundation and the European Porphyria Network, which are frequently updated; list many other drugs, including those that are not classified with certainty; and provide evidence for these classifications. Because the evidence base is inadequate, expert assessments of the safety of drugs in porphyria may differ. Refer to the UpToDate topics on individual porphyrias for more information. NSAIDs: nonsteroidal antiinflammatory drugs. * Serotonin 5HT3 antagonists are probably safe. Classification of metoclopramide is controversial but is generally a less effective antiemetic. ¶ Not all agents within the same class will necessarily have the same risk. For example, though opioids are generally considered safe, pentazocine may be unsafe. Benzodiazepines that are rapidly metabolized or administered in low doses are considered safe, but the safety of high doses or prolonged use of long-acting agents is less certain. There are conflicting reports on the safety of cephalosporins. Δ In United States labeling for these drugs, porphyria is listed as a contraindication, warning, precaution, or adverse effect. Erythropoietin is regarded as safe by other sources. Estrogens are unsafe for porphyria cutanea tarda but can be used with caution in the acute porphyrias, especially in low doses or by the transdermal route. Adapted from: Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 2005; 142:439. Graphic 57422 Version 19.0

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Acute intermittent porphyria incidence of signs and symptoms Abdominal pain

85 to 95%

Vomiting

43 to 88%

Constipation

48 to 84%

Muscle weakness

42 to 60%

Psychiatric symptoms

40 to 58%

Limb, head, neck, or chest pain

50 to 52%

Hypertension

36 to 54%

Tachycardia

28 to 80%

Convulsion

10 to 20%

Sensory loss

9 to 38%

Fever

9 to 37%

Respiratory paralysis

9 to 14%

Diarrhea

5 to 12%

AIP: acute intermittent porphyria. From Annals of Internal Medicine, Anderson KE, Bloomer JR, Bonkovsky HL, et al, Recommendations for the diagnosis and treatment of the acute porphyrias, Vol 142, Pg 439. Copyright © 2005 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc. Graphic 56856 Version 10.0

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Algorithm for diagnosis of acute porphyria and use of hemin in patients with symptoms suggesting an acute porphyria attack

Urine PBG may be tested by a screening method on-site (semiquantitative result, if available) or measured in a specialized laboratory (quantitative result, available in days to weeks). If available, a rapid method is extremely helpful because treatment can be initiated based on a positive result, and a negative result makes the diagnosis of an acute porphyria very unlikely. However, all symptomatic patients with suspected acute porphyria should have quantitative PBG, total porphyrins, and creatinine measured from the same sample. Because the results of quantitative testing are not known for days to weeks, we also order ALA and total porphyrins on the same urine sample. Urine creatinine is measured to allow normalization (results expressed per gram of creatinine). Refer to UpToDate topics on acute porphyrias for further details of diagnosis and treatment, and patterns of plasma and fecal porphyrin elevation. PBG: porphobilinogen; AIP: acute intermittent porphyria; HCP: hereditary coproporphyria; VP: variegate porphyria; ALA: delta-aminolevulinic acid; ALAD: ALA dehydratase; ADP: ALAD porphyria. * We perform genetic testing for the relevant porphyria following diagnosis; this may be used for further confirmation of the diagnosis and in some cases for counseling of relatives and identification of new mutations. Genetic testing is required to confirm a diagnosis of ADP. Graphic 61709 Version 10.0

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Diagnostic testing for active porphyrias Concurrent or recent clinical manifestations Acute neurovisceral

Initial testing Spot urine PBG and total porphyrins (normalized with urine creatinine)

Additional testing (if initial results are positive) Spot urine ALA, PBG, and total porphyrins (quantitative, normalized with urine creatinine) Plasma porphyrins* Erythrocyte porphyrins

Total porphyrins (plasma*, serum, or spot urine), with fractionation if elevated

Erythrocyte total porphyrins

Erythrocyte ALAD

Acute intermittent porphyria (AIP)

Erythrocyte PBGD

Sequence ALAD gene

Sequence PBGD gene Hereditary coproporphyria (HCP)

Sequence CPOX gene

Variegate porphyria (VP)

Sequence PPOX gene

Porphyria cutanea tarda (PCT)

Erythrocyte UROD Sequence UROD gene Δ

Urinary ALA and PBG Fecal total porphyrins

Enzyme and DNA tests

Delta-aminolevulinic acid dehydratase porphyria (ADP)



Fecal porphyrins Blistering photosensitivity

Types of porphyria identified

Hepatoerythropoietic porphyria (HEP)

Erythrocyte UROD Sequence UROD gene

Nonblistering photosensitivity

Total erythrocyte porphyrins ¶

Erythrocyte metal-free and zinc protoporphyrin; plasma total porphyrins and fluorescence scan

HCP

Sequence CPOX gene

VP

Sequence PPOX gene

Congenital erythropoietic porphyria (CEP)

Erythrocyte UROS

Erythropoietic protoporphyria (EPP)

Sequence FECH gene

X-linked protoporphyria (XLP)

Sequence ALAS2 gene

Sequence UROS gene

First-line testing for symptomatic patients is guided by clinical features (ie, neurovisceral, cutaneous chronic blistering, or cutaneous acute nonblistering). All spot urine measurements should be normalized with spot urine creatinine. If initial testing is positive, further comprehensive testing follows to identify the type of acute porphyria. Enzyme measurements may be used but are not available for all porphyrias. DNA testing usually follows establishment of a biochemical diagnosis. Refer to UpToDate topics on overview of porphyria and specific porphyrias for additional details and testing in asymptomatic patients. PBG: porphobilinogen; ALA: delta-aminolevulinic acid; ADP: delta-aminolevulinic acid dehydratase porphyria; ALAD: delta-aminolevulinic acid dehydratase; PBGD: porphobilinogen deaminase; CPOX: coproporphyrinogen oxidase; PPOX: protoporphyrin oxidase; UROD: uroporphyrinogen decarboxylase; UROS: uroporphyrinogen III synthase; FECH: ferrochelatase; ALAS2: delta-aminolevulinate synthase-2. * Plasma porphyrins should include measurement of the total, fractionation if the total is elevated, and determination of the fluorescence peak wavelength at neutral pH. ¶ It is important to verify that the method used by the laboratory measures all erythrocyte porphyrins and not just zinc protoporphyrin. Δ UROD mutations are neither required nor specific for a diagnosis of PCT. UROD mutations are found in approximately 20% of patients with PCT and therefore are helpful if present. The presence of a UROD mutation is a predisposing factor but not sufficient to cause PCT. Graphic 89036 Version 12.0

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Algorithm for distinguishing chronic blistering cutaneous porphyrias

This algorithm outlines an approach to the patient with suspected cutaneous porphyria and chronic blistering photosensitivity. Increased porphyrins in chronic blistering porphyrias are generally very elevated (eg, 10 times the upper limit of normal). Fractionation of porphyrins is accompanied by determination of the plasma fluorescence peak wavelength at neutral pH. Separate algorithms are available for the patient with suspected cutaneous porphyria with  acute nonblistering photosensitivity and the patient with suspected acute (neurovisceral) porphyria. Refer to UpToDate topics on individual porphyrias for further discussions of the clinical manifestations and diagnostic evaluation. PCT: porphyria cutanea tarda; HCP: hereditary coproporphyria; VP: variegate porphyria; CEP: congenital erythropoietic porphyria; HEP: hepatoerythropoietic porphyria; ALA: delta-aminolevulinic acid; PBG: porphobilinogen; UROD: uroporphyrinogen decarboxylase; CPOX: coproporphyrinogen oxidase; PPOX: protoporphyrin oxidase; UROS: uroporphyrinogen III synthase. * We perform gene sequencing of the relevant gene for all cutaneous porphyrias diagnosed biochemically; this may be used for further confirmation of the diagnosis, identification of new mutations, and genetic counseling. For PCT, UROD gene sequencing often does not reveal a mutation; the presence of a heterozygous UROD mutation is consistent with familial (type 2) PCT. For other biochemically proven cases of porphyria, mutation of the associated gene is expected, and if no mutation is identified, this suggests mutation in a cryptic site, noncoding region, or regulatory gene. Graphic 89035 Version 6.0

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Excretion patterns for porphyrins, porphyrin precursors, and porphyrin metabolites; and deficient erythrocyte enzymes in the porphyrias Type of porphyria Acute neurovisceral

Specific porphyria ADP

Urine

Stool

ALA, coproporphyrin III

*

Erythrocytes Zinc protoporphyrin

Plasma ALA*

Markedly decreased ALAD activity Acute neurovisceral

AIP

ALA, PBG, uroporphyrin, coproporphyrin

*

ALA, PBG, coproporphyrin III

Coproporphyrin III

Decreased PBGD activity by approximately 50% (most cases)*

ALA, PBG*

*

Δ

[approximately 620 nm] ¶

Acute neurovisceral, rarely blistering cutaneous

HCP

Acute neurovisceral, commonly blistering cutaneous

VP

ALA, PBG, coproporphyrin III

Coproporphyrin III, protoporphyrin

*

Cutaneous, blistering

PCT and HEP

Uroporphyrin, heptacarboxyl porphyrin

Heptacarboxyl porphyrin, isocoproporphyrins

Zinc protoporphyrin (markedly elevated in HEP, normal or mildly elevated in PCT)

Uroporphyrin, heptacarboxyl porphyrin

Uroporphyrin I, coproporphyrin I

[approximately 620 nm] ¶ Porphyrin-peptide conjugate [approximately 626 to 628 nm] ¶

Cutaneous, blistering

CEP

Uroporphyrin I; coproporphyrin I

Coproporphyrin I

Uroporphyrin I; coproporphyrin I

Cutaneous, nonblistering

EPP and XLP



Protoporphyrin*

Metal-free protoporphyrin §

[approximately 620 nm] ¶

[approximately 620 nm] ¶ Protoporphyrin [approximately 634 nm] ¶

Refer to UpToDate topics on individual porphyrias for additional information. ADP: delta-aminolevulinic acid (ALA) dehydratase porphyria; ALAD: ALA dehydratase; AIP: acute intermittent porphyria; PBG: porphobilinogen; PBGD: porphobilinogen deaminase; HCP: hereditary coproporphyria; VP: variegate porphyria; PCT: porphyria cutanea tarda; HEP: hepatoerythropoietic porphyria; CEP: congenital erythropoietic porphyria; EPP: erythropoietic protoporphyria; XLP: X-linked protoporphyria. * Porphyrin levels normal or slightly increased. ¶ Fluorescence emission peak of diluted plasma at neutral pH. Δ Plasma porphyrins usually normal, but increased when blistering skin lesions develop. ◊ Urine porphyrins (especially coproporphyrin) increase only with hepatopathy. § Zinc protoporphyrin ≤15 percent of total in classic EPP, but 15 to 50% in variant form (XLP). Provided by Karl Anderson, MD, FACP. Graphic 60572 Version 13.0

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Classification of porphyrias (hepatic or erythropoietic; acute or cutaneous) Classification Disease Tissue site

Clinical features

Enzyme affected

Major biochemical findings* Inheritance Urine

Plasma

Erythrocytes

Feces

ADP

Hepatic ¶

Acute

ALAD

Autosomal recessive

ALA, coproporphyrin III

 

Zinc protoporphyrin and low ALAD activity

 

AIP

Hepatic

Acute

PBGD

Autosomal dominant

ALA, PBG, uroporphyrin, coproporphyrin

 

Low PBGD activity

 

HCP

Hepatic

Acute and cutaneous

CPOX

Autosomal dominant

ALA, PBG, uroporphyrin, coproporphyrin III

 

 

Coproporphyrin III

VP

Hepatic

Acute and cutaneous

PPOX

Autosomal dominant

ALA, PBG, uroporphyrin, coproporphyrin III

Fluorescence peak at approximately 626 nm

 

Coproporphyrin III and protoporphyrin

PCT

Hepatic

Cutaneous

UROD

Autosomal dominant Δ

Uroporphyrin and heptacarboxyl-porphyrin

Uroporphyrin and heptacarboxyl-porphyrin

 

Isocoproporphyrin

HEP

Hepatic ¶

Cutaneous

UROD

Autosomal recessive

Uroporphyrin and heptacarboxyl-porphyrin

Uroporphyrin and heptacarboxyl-porphyrin

Zinc protoporphyrin and low UROD activity

Isocoproporphyrin

CEP

Erythropoietic

Cutaneous

UROS

Autosomal recessive

Uroporphyrin I and coproporphyrin I

Uroporphyrin I and coproporphyrin I

Uroporphyrin I and coproporphyrin I

Coproporphyrin I

EPP

Erythropoietic

Cutaneous

FECH

Autosomal recessive

 

Protoporphyrin, fluorescence peak at approximately 634 nm

Metal-free protoporphyrin

Protoporphyrin

XLP

Erythropoietic

Cutaneous

ALAS2

X-linked

 

Protoporphyrin

Metal-free and zinc protoporphyrin

Protoporphyrin

The table shows the classification based on tissue site (ie, hepatic or erythropoietic) and on clinical features (ie, acute or cutaneous). The affected enzymes, inheritance patterns, and biochemical findings are listed. Refer to UpToDate for details of initial testing for suspected porphyria and diagnostic evaluations for each specific porphyria. ADP: delta-aminolevulinic acid (ALA) dehydratase porphyria; ALAD: ALA dehydratase; AIP: acute intermittent porphyria; PBGD: porphobilinogen (PBG) deaminase; HCP: hereditary coproporphyria; CPOX: coproporphyrinogen oxidase; VP: variegate porphyria; PPOX: protoporphyrinogen oxidase; PCT: porphyria cutanea tarda; UROD: uroporphyrinogen decarboxylase; HEP: hepatoerythropoietic porphyria; CEP: congenital erythropoietic porphyria; UROS: uroporphyrinogen III synthase; EPP: erythropoietic protoporphyria; FECH: ferrochelatase; XLP: X-linked protoporphyria; ALAS2: ALA synthase 2. * Increases of importance for diagnosis in most cases. ¶ These hepatic porphyrias also have erythropoietic features, including increases in erythrocyte zinc protoporphyrin. Δ UROD inhibition in PCT is mostly acquired, but an inherited deficiency of the enzyme predisposes in familial (type 2) disease. Karl Anderson, MD, FACP. Graphic 80601 Version 11.0

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Comparison of the major features of the four acute porphyrias  

Deficient enzyme (step in heme synthesis)

Inheritance

Neurovisceral manifestations

Blistering skin lesions

ALA dehydratase porphyria (ADP)

ALA dehydratase (2)

Autosomal recessive

Yes

No

Acute intermittent porphyria (AIP)

PBG deaminase (3)

Autosomal dominant, variable penetrance

Yes

No*

Hereditary coproporphyria (HCP)

Coproporphyrinogen oxidase (6)

Autosomal dominant, variable penetrance

Yes

Uncommon

Variegate porphyria (VP)

Protoporphyrinogen oxidase (7)

Autosomal dominant, variable penetrance

Yes

Common

Refer to UpToDate topics on porphyria for details. ALA: 5-aminolevulinic acid (delta-aminolevulinic acid); PBG: porphobilinogen. * A rare exception is patients with advanced renal failure, who may develop elevations in plasma porphyrins that produce blistering skin lesions. Graphic 51032 Version 7.0

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Algorithm for distinguishing non-blistering cutaneous porphyrias

This algorithm outlines an approach to the patient with suspected cutaneous porphyria and non-blistering photosentivity. Separate algorithms are available for the patient with suspected cutanous porphyria with blistering photosentitivity, and the patient with suspected acute (neurovisceral) porphyria. Refer to UpToDate topics on individual porphyrias for further discussions of the clinical manifestations and diagnostic evaluation. Refer to content on photosensitivity disorders for other diagnostic considerations. EPP: erythropoietic protoporphyria; XLP: X-linked protoporphyria; FECH: ferrochelatase; ALAS2: delta-aminolevulinic acid synthase, erythroid form. * We perform gene sequencing of the relevant gene for any patient with protoporphyria (FECH gene in EPP, ALAS2 gene in XLP). This is used for further diagnostic confirmation and especially for genetic testing and counseling of family members. Graphic 89123 Version 6.0

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Pseudoporphyria Author: Craig A Elmets, MD Section Editor: Maja Mockenhaupt, MD, PhD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Aug 26, 2019.

INTRODUCTION Pseudoporphyria is a bullous photodermatosis with the clinical and histologic features of porphyria cutanea tarda (PCT), in the absence of abnormalities in porphyrin metabolism [1]. Pseudoporphyria has been associated with medications, chronic renal failure and hemodialysis, and tanning beds. Patients typically present with skin fragility, bullae, milia, and scarring on the dorsum of the hands and other sun-exposed areas. Histologically, there is a noninflammatory subepidermal blister. This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and treatment of pseudoporphyria. PCT and other types of porphyrias associated with photosensitivity are discussed separately. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis" and "Erythropoietic protoporphyria and X-linked protoporphyria".)

EPIDEMIOLOGY The incidence of pseudoporphyria is unknown. It occurs at any age and more frequently in women than in men. Pseudoporphyria has been reported in approximately 10 percent of children taking naproxen, a nonsteroidal anti-inflammatory drug (NSAID) routinely used in the therapy of juvenile idiopathic arthritis. Among children treated with naproxen, risk factors for the development of pseudoporphyria include skin phototypes I or II (table 1), blue/gray eyes, and the concurrent use of chloroquine [2-4]. Pseudoporphyria has been reported in approximately 1 to 16 percent of hemodialysis patients [5-8].

ETIOLOGY AND PATHOGENESIS Four factors have been implicated in the etiology of pseudoporphyria: ultraviolet (UV) radiation, medications, chronic renal failure and hemodialysis, and tanning beds. Ultraviolet radiation — Although the exact pathogenetic mechanism is unknown, drug-induced pseudoporphyria is considered a photodynamic phototoxic drug reaction. In this type of reaction, the photosensitizing compound, upon absorption of the appropriate wavelength radiation, changes to an excited state and reacts with oxygen to form reactive oxygen species (ROS), such as singlet oxygen, hydrogen peroxide, or superoxide anion. ROS can damage cell components, such as nucleic acids, membranes, lipids, and proteins. Mediators of inflammation and inflammatory cells participate in tissue injury, including products of complement activation, proinflammatory cytokines, arachidonic acid metabolites, proteases, and polymorphonuclear leukocytes. Medications — Pseudoporphyria was first identified among individuals taking the quinolone antibiotic nalidixic acid [9-11]. Subsequently, a variety of other medications have been associated with pseudoporphyria, including nonsteroidal anti-inflammatory drugs (NSAIDs), other types of antibiotics, diuretics, retinoids, and antineoplastic agents (table 2) [1,12-18]. Tyrosine kinase inhibitors imatinib and sunitinib, used in the treatment of several cancers, and voriconazole have also been associated with pseudoporphyria [13,14,19-23]. Naproxen, an NSAID derived from propionic acid, is responsible for most cases of pseudoporphyria [2,3,24-31]. Propionic acid derivative NSAIDs (eg, naproxen, oxaprozin, ketoprofen, and ibuprofen) are more likely to cause pseudoporphyria than other classes of NSAIDs [32-42]. However, several nonpropionic acid NSAIDs (eg, diflunisal, celecoxib, mefenamic acid, and nabumetone) have also been associated with pseudoporphyria [32,33,35,36,42,43].

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It is unknown why pseudoporphyria manifests with vesicles and bullae, whereas drug-induced phototoxic reactions usually appear as exaggerated sunburns [11,30,44]. It is also unknown why pseudoporphyria usually continues for months after the drug has been discontinued. Hemodialysis and peritoneal dialysis — Pseudoporphyria occurs in patients with end-stage kidney disease who are receiving chronic hemodialysis or peritoneal dialysis [45-47]. In case series, 0.6 to 16 percent of patients on hemodialysis developed the disease [5-8]. Aluminum hydroxide in dialysis solutions or chemicals in polyvinyl chloride dialysis tubing are suspected to be the photosensitizing agents in these patients [48,49]. Other theories include an inability to handle oxidative stress due to reduced levels of the endogenous antioxidant glutathione [50]. Patients with end-stage kidney disease may also have elevated plasma porphyrins due to impaired excretion and decreased porphyrin clearance by hemodialysis or peritoneal dialysis [51,52]. Tanning beds — Pseudoporphyria was reported in a small number of women with frequent exposure to high doses of ultraviolet A (UVA) radiation from tanning beds [53-57]. In some cases, the patients were using medications (eg, naproxen, antibiotics, or oral contraceptives) that are known inducers of pseudoporphyria.

HISTOPATHOLOGY The histologic features of pseudoporphyria closely resemble those of porphyria and other types of porphyria that cause blistering. Histologic examination of a bullous lesion typically shows a noninflammatory subepidermal blister with a scant perivascular lymphocytic infiltrate. Festooning (ie, the preservation of the dermal papillae in the floor of the lesion) may be seen (picture 1) [1,44,53,58]. Cytoid or "caterpillar" bodies, which are considered a specific histopathologic finding of porphyrias, are also seen in pseudoporphyria (picture 2) [58,59]. Caterpillar bodies are segmented and elongated structures containing laminin and type IV collagen that are positioned parallel to the epidermis [59,60]. Endothelial wall thickening from periodic acid-Schiff-positive, diastase-resistant material may be seen in the upper dermal microvasculature. Direct immunofluorescence of lesional and perilesional skin reveals changes similar to those seen in porphyria cutanea tarda (PCT). Immunoglobulin G (IgG), immunoglobulin M (IgM), C3, and fibrinogen are frequently found at the dermoepidermal junction and in the vessel walls of lesional and perilesional skin (picture 3) [58]. Deposits of immunoglobulin and complement may be seen in the dermal vasculature in a doughnut-shaped pattern [58,61]. However, the absence of immunoreactants in dermal vessels and at the basement membrane zone does not exclude the diagnosis of pseudoporphyria. Immunofluorescent antigen mapping has been performed to determine the level of skin splitting in pseudoporphyria. Using this technique, type IV collagen, laminin, and bullous pemphigoid antigen have been observed at the base of the blister, with no characteristic cleavage level [62]. However, ultrastructural studies have shown a split in the superficial dermis, with the basal lamina, hemidesmosomes, anchoring fibrils, and collagen fibers in the roof of the blister [30,53].

CLINICAL MANIFESTATIONS Patients with pseudoporphyria present with bullae and vesicles typically localized to the dorsum of the hands, forearms, and face (picture 4AB). Lesions may also occur on the lower legs and feet. Skin fragility and easy bruising after minor trauma are common complaints (picture 5) [27,28,63]. Bullae heal with scarring and milia in most patients [3,24,30,61,64]. In contrast to porphyria cutanea tarda (PCT), hypertrichosis, hyperpigmentation, and sclerodermoid changes are rarely reported in pseudoporphyria (table 3). (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical features'.)

CLINICAL COURSE In most cases, drug-induced pseudoporphyria has a protracted course. Cutaneous lesions continue to develop even after the offending drug has been discontinued. In one series of 16 patients, the symptoms resolved within six months of discontinuation of the medication in 5 patients but persisted for an average of 2.5 years after discontinuation in 11 [61].

DIAGNOSIS

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The diagnosis of pseudoporphyria is based upon the combination of the following: ●

Cutaneous manifestations similar to those found in porphyria cutanea tarda (PCT) (eg, skin fragility, vesicles and bullae involving sunexposed skin, particularly the face and the dorsum of the hands) (picture 4A-B).



Histologic finding of subepidermal blister with scant perivascular lymphocytic infiltrate (picture 1). On direct immunofluorescence, detection of IgG, IgM, C3, and fibrinogen at the dermoepidermal junction and in the vessel walls (picture 3).



Normal porphyrin levels in plasma, erythrocytes, urine, and stool. (See "Porphyrias: An overview", section on 'Diagnostic testing (blistering cutaneous porphyria suspected)'.)



Reported use of potentially phototoxic medications (table 2), history of chronic renal failure and dialysis, or ultraviolet A (UVA) exposure.

The clinical and histologic features of pseudoporphyria closely resemble those of PCT. Pseudoporphyria often is only considered after evaluation for PCT has revealed normal porphyrin levels. This is an essential diagnostic criterion of pseudoporphyria. In some instances, it may be necessary to obtain serology for antinuclear antibodies, antitype VII collagen antibodies, and anti-Ro/SSA and anti-La/SSB antibodies to exclude bullous lupus or epidermolysis bullosa acquisita. (See 'Differential diagnosis' below.) Phototesting is not helpful in the evaluation of patients suspected of having pseudoporphyria. Although some individuals will exhibit a reduced minimal erythema dose (MED) to UVA, neither phototesting nor photoprovocation testing has been successful in reproducing the subepidermal blisters characteristic of the disease.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of pseudoporphyria includes porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), other less common cutaneous porphyrias (ie, variegate porphyria, hereditary coproporphyria, congenital erythropoietic porphyria), and other bullous disorders presenting with similar clinical manifestations, including epidermolysis bullosa acquisita, bullous pemphigoid, bullous lupus erythematosus, and hydroa vacciniforme. Porphyria cutanea tarda — Porphyria cutanea tarda (PCT) is a defect of porphyrin metabolism due to an inherited or acquired deficiency of hepatic uroporphyrinogen decarboxylase (UROD) and precipitated by several cofactors, including alcohol abuse, iron overload, hepatitis C, HIV infection, drugs (table 3), and end-stage kidney disease [65,66]. PCT usually presents in adulthood with blisters, bullae, increased fragility, scarring, and hyper- and hypopigmentation affecting sun-exposed areas of the body, such as the backs of the hands, forearms, face, ears, neck, and feet (picture 6A-C). Measurement of total porphyrins in plasma, serum, or urine can differentiate PCT and the other less common cutaneous porphyrias from pseudoporphyria. However, distinguishing pseudoporphyria from PCT in the setting of end-stage kidney disease may be difficult. In patients on hemodialysis or peritoneal dialysis, plasma porphyrins may be elevated in the absence of UROD deficiency due to impaired excretion and inefficient porphyrin clearance by the renal replacement therapy [51,52,67]. However, in these patients, the plasma porphyrin levels are lower than those seen in patients with PCT, and there is no predominance of the heptacarboxylic fraction typically seen in PCT [51]. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".) Epidermolysis bullosa acquisita — Epidermolysis bullosa acquisita is a rare autoimmune bullous disease caused by autoantibodies against type VII collagen (picture 7A). Serous or hemorrhagic blisters are localized to areas of trauma, especially on the dorsum of the hands and feet and elbows. They heal with scarring, milia, and hyperpigmentation. On direct immunofluorescence, there is a linear deposit of IgG at the basement membrane zone. Circulating autoantibodies against collagen VII can be demonstrated by enzyme-linked immunosorbent assay (ELISA) techniques. (See "Epidermolysis bullosa acquisita".) Bullous pemphigoid — Bullous pemphigoid is an autoimmune bullous disease occurring most commonly in older individuals. Urticarial plaques and tense bullae may occur in all body areas (picture 8). Direct immunofluorescence of perilesional skin shows IgG and C3, or C3 alone along the basement membrane zone. Circulating antibodies against the bullous pemphigoid antigen BP 180 can be detected by ELISA techniques. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".) Pemphigus — Pemphigus is an autoimmune bullous disease caused by the development of autoantibodies to intercellular adhesion molecules desmoglein 1 and 3. Patients develop flaccid blisters and erosions, both on sun-exposed and sun-protected skin (picture 9). There are reports of pemphigus induced or aggravated by exposure to ultraviolet (UV) light [68-71]. Direct immunofluorescence staining showing intercellular

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deposition of IgG as well as the detection of circulating autoantibodies against cell surface antigens in serum are diagnostic. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".) Bullous lupus erythematosus — Bullous lupus erythematosus is an uncommon form of systemic lupus erythematosus caused by autoantibodies against type VII collagen [72]. Vesicles and tense bullae are most often localized to the neck and upper trunk but also may develop on unexposed skin (picture 10). Direct immunofluorescence demonstrates linear deposition of IgG, immunoglobulin A (IgA), IgM, and C3 along the dermoepidermal junction. Salt-split skin is positive for IgG, IgA, and IgM on the floor of the blister. (See "Overview of cutaneous lupus erythematosus", section on 'Bullous cutaneous lupus erythematosus'.) Hydroa vacciniforme — In children with facial blistering, hydroa vacciniforme (picture 11A-B) can mimic pseudoporphyria. Hydroa vacciniforme is a rare photodermatosis of childhood characterized by vesicular lesions on sun-exposed skin that heal leaving depressed scars. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Hydroa vacciniforme'.) Erythropoietic protoporphyria — Erythropoietic protoporphyria (EPP) is an autosomal recessive or pseudodominant disease of porphyrin metabolism due to ferrochelatase deficiency and characterized by painful, nonblistering photosensitivity usually manifesting in early childhood (table 4) [65,66]. Soon after or even during sun exposure, patients develop a severe burning or stinging pain that may be followed by redness, swelling, and petechiae formation (picture 12). Petechiae may last several days. The face and dorsum of the hands are most commonly affected. Repeated exposures may result in shallow vacciniforme scarring, perioral furrows, and waxy skin thickening (picture 13). The diagnosis of EPP is based upon the demonstration of a markedly increased free erythrocyte protoporphyrin. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

TREATMENT ●

For patients with drug-induced pseudoporphyria, discontinuation of the offending agent (if possible) is a crucial aspect of management. The resolution of the clinical manifestations is slow. Patients can expect gradual improvement with a decrease in blistering and skin fragility over a period of months to years [61].



Photoprotection is essential for all patients with pseudoporphyria. Photoprotection should continue at least until resolution of symptoms. Photoprotection measures include sun avoidance, use of protective clothing (long-sleeved shirts, blouses, pants, wide-brimmed hats), and broad-spectrum sunscreens (table 5). (See "Selection of sunscreen and sun-protective measures".)



A beneficial effect of N-acetylcysteine has been reported in a few patients with chronic renal failure and hemodialysis-associated pseudoporphyria [73-78]. N-acetylcysteine is a precursor of glutathione, an endogenous antioxidant, the levels of which are reduced in hemodialysis patients. For patients with pseudoporphyria associated with excessive exposure to artificial ultraviolet A (UVA) sources from tanning beds, discontinuation of the practice is essential for the control of disease.



There is a single report of a patient with hemodialysis-associated pseudoporphyria successfully treated with oral glutathione [77].



There is a single report of hemodialysis-associated pseudoporphyria successfully treated with oral glutamine [79].



There is a report of two pseudoporphyria patients on hemodialysis who responded to photoprotection and vitamin D supplementation [80].

SUMMARY AND RECOMMENDATIONS ●

Pseudoporphyria is a bullous photodermatosis with the clinical and histologic features of porphyria cutanea tarda (PCT), in the absence of abnormalities in porphyrin metabolism. Pseudoporphyria has been reported in approximately 10 percent of children taking naproxen for juvenile idiopathic arthritis. (See 'Introduction' above and 'Epidemiology' above.)



Although the exact pathogenetic mechanism is unknown, pseudoporphyria is considered a photodynamic phototoxic drug reaction. It is most often caused by medications, including nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, diuretics, and antineoplastic agents (table 2). (See 'Etiology and pathogenesis' above.)



The clinical manifestations of pseudoporphyria closely resemble those of PCT and include skin fragility, bullae, and vesicles involving sunexposed areas of the body, such as the face and dorsum of the hands (picture 4A-B). (See 'Clinical manifestations' above.)



The diagnosis of pseudoporphyria is made in a patient with clinical and histologic features of PCT; normal porphyrin levels in red blood cells, plasma, urine, and stool; and reported use of phototoxic medications, hemodialysis, or tanning beds. (See 'Diagnosis' above.)

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Pseudoporphyria should be differentiated from PCT (picture 6A-C), erythropoietic protoporphyria (picture 12), other less common photocutaneous porphyrias, and bullous disorders presenting with similar clinical manifestations, including epidermolysis bullosa acquisita (picture 7A-B), bullous pemphigoid (picture 8), pemphigus (picture 9), bullous lupus erythematosus (picture 10), and hydroa vacciniforme (picture 11A-B). (See 'Differential diagnosis' above.)



Discontinuation of the offending agent and photoprotection are the most important aspects of the management of patients with pseudoporphyria. N-acetylcysteine may be helpful for hemodialysis-associated pseudoporphyria. (See 'Treatment' above.) Use of UpToDate is subject to the Subscription and License Agreement.

Topic 13748 Version 12.0

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GRAPHICS Fitzpatrick skin phototypes Skin type

Unexposed skin color

Reaction to sun exposure*

I

White

Always burns, never tans

II

White

Always burns, minimal tan

III

White to olive

Burns minimally, gradually tans

IV

Light brown

Burns minimally, tans well

V

Brown

Very rarely burns, tans profusely

VI

Dark brown to black

Never burns, tans deeply

Note: Slight variations on the definitions of the phototypes appear in the literature. * After the first one hour of sun exposure on untanned skin on the first day of spring. Graphic 60541 Version 4.0

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Drugs and chemicals inducing pseudoporphyria Antibiotics Nalidixic acid Tetracycline Ciprofloxacin Voriconazole

Nonsteroidal antiinflammatory drugs Naproxen Nabumetone Oxaprozin Ketoprofen Mefenamic acid Diflusinal Celecoxib

Diuretics Furosemide Chlorthalidone Hydrochlorothiazide/triamterene Bumetanide Torsemide

Retinoids Isotretinoin Etretinate

Miscellaneous Imatinib Cyclosporine 5-Fluorouracil (intravenous) Carisoprodol/aspirin Pyridoxine Amiodarone Flutamide Metformin Dapsone Bakers' yeast Oral contraceptives Graphic 83233 Version 3.0

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Histologic features of pseudoporphyria

Subepidermal blister with a scant perivascular lymphocytic infiltrate. Courtesy of Aleodor Andea, MD. Graphic 83260 Version 4.0

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Caterpillar bodies in porphyria cutanea tarda and pseudoporphyria

Linear arrangement of segmented eosinophilic deposits parallel to the epidermal surface above the subepidermal blister. Reproduced with permission from: Raso DS, Greene WB, Maize JC, et al. Caterpillar bodies of porphyria cutanea tarda ultrastructurally represent a unique arrangement of colloid and basement membrane bodies. Am J Dermatopathol 1996; 18:24. Copyright © 1996 Lippincott Williams & Wilkins. Graphic 83388 Version 4.0

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Direct immunofluorescence findings in pseudoporphyria

Direct immunofluorescence shows deposition of IgG at the dermoepidermal junction and in the dermal vessels. Courtesy of Grant Anhalt, MD. Graphic 83261 Version 2.0

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Pseudoporphyria

Vesiculation and crusting are present on the dorsal hand. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 80856 Version 3.0

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Pseudoporphyria

Graphic 83262 Version 1.0

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Pseudoporphyria in a patient with vitiligo

In this patient with vitiligo, bullae developed in areas of pigment loss. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 83391 Version 4.0

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Differential diagnosis of pseudoporphyria and porphyria cutanea tarda   Implicated drugs

Pseudoporphyria

PCT

Naproxen

Alcohol

Voriconazole

Estrogens

Tetracycline

Iron

Furosemide

Tamoxifen

Imatinib

Chloroquine

 

Hydroxychloroquine

Sclerodermoid changes

No

Yes

Hypertrichosis

No

Yes

Hyperpigmentation

No

Yes

Porphyrin abnormalities

No

Yes

PCT: porphyria cutanea tarda. Graphic 83258 Version 3.0

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Porphyria cutanea tarda

Macular erythema, erosions, crusts, and scars are present on the hands of this patient with porphyria cutanea tarda. Reproduced with permission from: Stedman's Medical Dictionary. Copyright © 2008 Lippincott Williams & Wilkins. Graphic 78547 Version 2.0

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Porphyria cutanea tarda

Vesicles and erosions are visible on the dorsum of the hand in a patient with porphyria cutanea tarda related to underlying hepatitis C virus infection. Courtesy of Jean-François Dufour, MD. Graphic 74528 Version 1.0

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Porphyria cutanea tarda: bullous skin lesion

Bullous lesion on the hand of a patient with porphyria cutanea tarda. Erythema, erosions, and crusting are also seen. Courtesy of Karl E Anderson, MD, FACP. Graphic 56810 Version 2.0

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Epidermolysis bullosa acquisita

Tense bullae, erosions, and crusts on skin of a patient with epidermolysis bullosa acquisita. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 62505 Version 6.0

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Bullous pemphigoid

Arm skin with tense bullae arising on urticarial plaques and eroded blister bases. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 79112 Version 6.0

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Pemphigus vulgaris

Flaccid bullae and erosions on the skin of a patient with pemphigus vulgaris. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 53425 Version 7.0

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Bullous lupus

Multiple blisters in a young woman with bullous systemic lupus erythematosus. Courtesy of Samuel L Moschella, MD. Graphic 66048 Version 2.0

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Hydroa vacciniforme

Erythematous papules and crusts are seen on the forearm of a 10-year-old boy with hydroa vacciniforme. Copyright © Shahbaz A Janjua, MD, Dermatlas; http://www.dermatlas.org. Graphic 68305 Version 5.0

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Hydroa vacciniforme

Scars and crusted papules are present on the face. This 10-year-old boy had a history of recurrent blisters in sun-exposed areas that healed with depressed vaccination-like scars. Copyright © Shahbaz A Janjua, MD, Dermatlas; http://www.dermatlas.org. Graphic 54500 Version 6.0

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Photosensitive disorders: Clinical features

 

Sex

Timeline of eruption

Age of onset

Location

Common lesion morphology and symptoms

Family history

Action spectrum

Laboratory findings

Phototesting

Duration/ resolution

Key features

Polymorphous light eruption

F>M

First three decades

Hours after sun exposure, lasts days to weeks; most conspicuous in spring; improves during summer

Sunexposed areas

Pruritic papules, papulovesicles, plaques.

May be present

UVA, UVB, visible

Normal MED; provocative phototesting may induce lesions

 

Recurrent over the course of years, may improve over time

Most common photodermatosis; "hardening" phenomenon may occur

Juvenile spring eruption

M>F

Primarily childhood; also may be seen in young adults

As with PMLE

Classically, helices of ears

Erythematous papules, bullae.

May be present

UVA?

As with PMLE

 

Recurrent over years, may improve with age

 

Actinic prurigo

F>M, M>F reported in adult onset in Asia

Childhood;

Persistent during summer; may also be present year round

Sunexposed areas, may also affect unexposed areas

Pruritic papulonodules, crusts, excoriations, lichenification, cheilitis.

Yes, in up to 50%

UVA>UVB

60% with reduced MED, 60 to 70% with positive provocative phototests

 

Improves in adolescence, but also may persist

More common in American Indians and Mestizos. May have ocular findings.

Hydroa vacciniforme

Slight M>F

Childhood

Hours after sun exposure

Face, dorsal hands

Erythematous macules, papules, vesicles, crusts.

Rarely positive

Likely UVA

May show reduced MED to UVA in some cases

 

Usually resolves by adolescence/young adulthood, but may persist

Lymphoproliferative disease association with severe cases

Chronic actinic dermatitis

M>F

Older, but may be seen in younger patients

Persistent; worsens in summer, may have findings year round

Sunexposed areas

Eczematous patches, lichenification, may see palmoplantar involvement.

 

UVA, UVB, visible light

Decreased MEDs to UVA, UVB, or visible light

May see Sézary cells in severe cases

Persists for years, may resolve

Often coexistent contact dermatitis

Solar urticaria

F>M

Young or midadulthood

Appears within minutes, individual lesions resolve within 24 hours

Sunexposed areas

Urticarial plaques (hives), occasional systemic symptoms.

 

UVA, UVB, visible light

Normal MEDs, urticaria are induced within minutes of phototesting

 

Persists for years, may resolve

"Hardening" phenomenon may occur

Phototoxicity

M=F

Any age

Appears within hours of sun exposure, can occur after first dose of drug

Sunexposed areas

Exacerbated sunburn appearance.

 

UVA

In systemic phototoxicity, MED for UVA decreased, UVB and visible light MEDs normal

 

Resolves when drug discontinued and cleared from body

Can occur in anyone

Photoallergy

M=F

Any age

Appears one to two days after exposure to sun and inciting agent in sensitized individual

Sunexposed areas

Pruritic, eczematous lesions.

 

UVA

In systemic photoallergy, MED for UVA decreased, UVB and visible light MEDs normal

 

Resolves with discontinuation of inciting agent

Usually due to topical agents

Erythropoietic protoporphyria

M = F, versus slight M>F

Onset in early childhood

Symptoms begin within minutes of sun exposure, improves in winter

Nose, cheeks, hands

Burning and stinging, pain, pruritus. Erythema, edema, pupura. Heals with atrophic, wax-like scars; wrinkled knuckles.

Common (siblings), autosomal recessive or pseudodominant

Soret band (400 to 410 nm)

Often normal, some patients may note stinging sensation or lesions

Elevated erythrocyte protoporphyrin level

Chronic

May develop liver disease

Porphyria cutanea tarda

M=F

Middle age, may occur earlier

 

Sunexposed areas

Skin fragility, bullae, crusts, scarring. Hypertrichosis, hyperpigmentation, sclerodermoid changes.

Sporadic in Type I, autosomal dominant in Type II

Soret band (400 to 410 nm)

 

Elevated porphyrins in urine and stool

Chronic, symptoms improve with sun protection, removal of triggers, phlebotomy, antimalarials

Often associated with hepatitis C

Pseudoporphyria

 F>M

Any age; 10% of

 

Sunexposed

Skin fragility, bullae, crusts,

Negative

UVA

 

Normal porphyrin

Symptoms resolve with sun protection,

May be caused by medications, renal

adultonset may occur in Asians

8735

children taking naproxene

 

 

 

 

areas

scarring, milia.

 

 

 

F: female; M: male; UV: ultraviolet; MED: minimal erythema dose; PMLE: polymorphus light eruption. Graphic 57800 Version 12.0

8736

 

 

levels

avoidance of tanning bed use, and discontinuation of the causative medications

failure and hemodialysis, and excessive tanning bed use

 

 

 

Erythropoietic protoporphyria

Diffuse erythema and confluent petechiae on the face and lips following sun exposure in a child with erythropoietic protoporphyria. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 98729 Version 3.0

8737

Erythropoietic protoporphyria

Chronic skin changes in erythropoietic protoporphyria include shallow vacciniform scarring, perioral furrows, and waxy skin thickening. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 98730 Version 4.0

8738

Sunscreens Sunscreen

Range of protection

Organic PABA derivatives

PABA (para-aminobenzoic acid)

UVB

Padimate O (octyl dimethyl PABA)

UVB

Cinnamates

Octinoxate (octyl methoxycinnamate)

UVB

Cinoxate

UVB

Salicylates

Octisalate (octyl salicylate)

UVB

Homosalate

UVB

Trolamine salicylate

UVB

Benzophenones

Oxybenzone (benzophenone-3)

UVB, UVA2

Sulisobenzone (benzophenone-4)

UVB, UVA2

Dioxybenzone (benzophenone-8)

UVB, UVA2

Others

Octocrylene

UVB

Ensulizole (phenylbenzimidazole sulfonic acid)

UVB

Avobenzone (butyl methoxydibenzoyl methane, Parsol 1789)

UVA1

Ecamsule (terephthalylidene dicamphor sulfonic acid, Mexoryl SX)*

UVB, UVA2

Drometrizole trisiloxane (Mexoryl XL) ¶

UVB, UVA2

Meradimate (menthyl anthranilate)

UVA2

Bemotrizinol (bis-ethylhexyloxyphenol methoxyphenol triazine, Tinosorb S) ¶

UVB, UVA2

Bisoctrizole (methylene bis-benzotriazolyl tetramethylbutylphenol, Tinosorb M) ¶

UVB, UVA2

Inorganic Titanium dioxide

UVB, UVA2, UVA1

Zinc oxide

UVB, UVA2, UVA1

UVB: ultraviolet B; UVA: ultraviolet A. * Available in the United States since 2006 in combination with avobenzone and octocrylene. ¶ Available in Europe but not in the United States. Adapted with permission from: Sunscreens: An Update. The Medical Letter 2008; 50:70. Copyright © 2008 The Medical Letter. Graphic 73127 Version 8.0

8739

Epidermolysis bullosa acquisita

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 83259 Version 5.0

8740

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Sunburn Authors: Antony R Young, PhD, Angela Tewari, MBBS, BSc, MRCP, PhD Section Editors: Robert P Dellavalle, MD, PhD, MSPH, Daniel F Danzl, MD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Feb 19, 2019.

INTRODUCTION Sunburn is an acute, delayed, and transient inflammatory response of the skin to excessive exposure to ultraviolet radiation (UVR) from natural sunlight or artificial sources (eg, tanning beds, phototherapy devices) (picture 1A-B). Both ultraviolet B (UVB; 280 to 320 nm) and ultraviolet A (UVA; 320 to 400 nm) can cause sunburn, but the wavelengths that are the most effective at inducing erythema are in the UVB range [1,2]. Sunburn is a self-limited condition. The acute manifestations usually resolve in three to seven days. However, susceptibility to sunburn is a marker of genetic susceptibility to skin cancer and is associated with an increased risk of melanoma at all ages [3,4]. It is very important that clinicians counsel patients with increased susceptibility to sunburn about sun protection. This topic will discuss the pathogenesis, clinical manifestations, and management of sunburn. Photosensitivity, photoprotection, and photosensitivity disorders are discussed separately. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection" and "Selection of sunscreen and sun-protective measures" and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment".)

EPIDEMIOLOGY Sunburn is common. In the United States, the estimated sunburn prevalence (≥1 sunburn in the past 12 months) among all adults was approximately 34 percent in 2005, 37 percent in 2010, and 31

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percent in 2015 [5]. Prevalences ranging from 20 to 70 percent have been reported in cross-sectional studies in Europe and Australia [6-9]. Sunburn occurs more frequently among adolescents and young adults. In nation-wide surveys in the United States, approximately 70 percent of adolescents aged 11 to 18 years and 50 percent of adults aged 18 to 29 years reported at least one sunburn in the previous year [10,11]. The risk of sunburn is inversely related to latitude and is therefore greatest near the equator, where ultraviolet B (UVB) intensity is highest. The time of day is also important and sunburn is more likely to occur at noon than earlier or later in the day. Cloud cover when the sun is high offers some protection, but significant quantities of ultraviolet radiation (UVR) still reach the earth's surface [12]. Additional factors that increase the risk of sunburn include altitude and reflection from snow (approximately 90 percent), sand (15 to 30 percent), and water (5 to 20 percent) [13]. There is also evidence that wet skin is more susceptible to erythema than dry skin [14]. Excessive consumption of alcohol may be a risk factor for sunburn [15,16]. In a study of beachgoers in Texas, participants reporting alcohol drinking on the beach had a greater body surface area with sunburn and blisters than nondrinkers [17].

PATHOGENESIS Individual susceptibility — The susceptibility to sunburn is highly variable among individuals. Phenotypic characteristics that confer high susceptibility to sunburn include fair skin, blue eyes, and red or blond hair [18]. An increased susceptibility to sunburn is also a marker of increased risk of melanoma and nonmelanoma skin cancer [3,19,20]. (See "Risk factors for the development of melanoma", section on 'Ultraviolet radiation' and "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma", section on 'UV radiation'.) An individual's susceptibility to sunburn can be assessed by determining the minimum erythema dose (MED), which is the lowest dose of ultraviolet radiation (UVR) delivered to the skin that produces a clearly marginated erythema in the irradiated site 24 hours after a single exposure (picture 1D). The MED is considered the threshold for sunburn and is widely used as a dose unit in phototherapy, experimental photobiology, and for the determination of a sunscreen's sun protection factor. In clinical practice, the self-reported tendency to develop sunburn or tanning after sun exposure is used to determine an individual's skin phototype (table 1). Darker skin types (IV to VI) typically require higher doses of UVR to develop a visible erythema. On average, the MED of a skin type IV that tans well is about twice the MED of a skin type I that does not tan [21]. However, there is considerable

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overlap of MED values between different skin types. Individuals with skin types I and II may develop a sunburn with daily repeated suberythemal exposures (eg, 0.5 MED) [22]. Action spectra — An action spectrum indicates which wavelengths most effectively produce a skin response and usually corresponds to the absorption spectrum for the chromophore (molecule that absorbs UVR photons) that initiates the response. The action spectrum for erythema indicates that the most effective wavelengths present in sunlight are in the ultraviolet B (UVB) range. Ultraviolet A (UVA) also can cause erythema, but doses nearly 1000 times higher than UVB are required [1,2]. The sun is primarily a UVA source, with UVB representing only a maximum of approximately 5 percent of the UVR reaching the earth's surface [1]; however, this contributes to over 80 percent of the erythemally effective energy [23]. Thus, the risk of sunburn is highest when the UVB to UVA ratio is high, as occurs between 11 AM and 3 PM in the summer months in temperate climates and particularly at latitudes approaching the equator [24]. Mechanism of ultraviolet B-induced inflammation — In the sunburn response, many biochemical and cellular changes occur in the epidermis and dermis before the erythema becomes evident. However, the initiating events are incompletely understood and the nature of the chromophore(s) for erythema is still uncertain. The observation that the action spectrum for erythema is very similar to that for the induction of cyclobutane pyrimidine dimers (CPDs) suggests that DNA photodamage may be the trigger of the inflammatory cascade in sunburn [1]. UVB-mediated pigmentation (delayed tanning) can also be triggered by CPD, suggesting that inflammation and sunburn are also important in the tanning response [25]. Early events include vasodilation and increased blood flow, endothelial cell activation, formation of "sunburn cells" (ie, keratinocytes undergoing p53-dependent apoptosis), and release of inflammatory mediators [26-30]. Vasodilation of dermal small blood vessels and edema of endothelial cells occur within 30 minutes of sun exposure and peak at 24 hours [31]. Dyskeratotic "sunburn cells" may appear in the epidermis within hours of exposure [32]. Erythema becomes clinically apparent 3 to 6 hours after exposure, reaches a peak at 12 to 24 hours, and usually subsides at 72 hours. Neutrophilic infiltration starts approximately three hours after UVB exposure, peaks at 24 hours, and continues up to 48 hours later [33-35]. Prostaglandins and nitric oxide (NO) appear to be the major mediators of UVB-induced inflammation [27,28]. Numerous proinflammatory and anti-inflammatory eicosanoids have been identified in suction blister fluid over a 72-hour period after UVB exposure [27]. Vasodilatory prostaglandins (PG) PGE2, PGF2a, and PGE3 appear in the first 24 to 48 hours and are associated with increased COX-2 expression at 24 hours. Chemoattractant prostaglandins (11-, 12-, and 8-monohydroxy-

8743

eicosatetraenoic acid [HETE]) appear at 4 to 72 hours, whereas the anti-inflammatory 15-HETE is maximally present at 72 hours. Several proinflammatory cytokines, including TNF-alpha, IL-1, IL-6, and IL-8, are elevated after UVB exposure. Cytokines may play several roles in UVB-induced inflammation, including activation of transcription factors, upregulation of endothelial adhesion molecules, and recruitment of neutrophils to the skin [24].

HISTOPATHOLOGY The extent and time course of the histological changes observed after ultraviolet B (UVB) exposure varies with the magnitude of the exposure dose. Epidermal changes include spongiosis, parakeratosis, and "sunburn cells" (apoptotic keratinocytes with condensed nuclear chromatin and eosinophilic cytoplasm). Sunburn cells may be present in the epidermis within hours of exposure and increase in number over the following 24 hours and form a band at the stratum corneum at 72 hours [18]. Dermal changes include endothelial cell swelling, perivenular edema, and presence of degranulated mast cells. A perivascular infiltrate of neutrophils appears shortly after the exposure and peaks at about 14 hours. A later mononuclear infiltrate persists for at least 48 hours.

CLINICAL MANIFESTATIONS Clinical manifestations of sunburn range from mild erythema to highly painful erythema with edema, vesiculation, and blistering (picture 1A-D and table 2). Blistering indicates superficial partial-thickness or, rarely, deep partial-thickness burn. (See "Assessment and classification of burn injury".) Erythema is usually first noted 3 to 5 hours following sunlight exposure, peaks at 12 to 24 hours, and in most cases subsides at 72 hours [24]. The skin areas that were covered or shaded are typically spared (picture 1B). Increased skin sensitivity to heat and mechanical pressure are characteristic and present even in mild cases [36]. In severe cases, systemic symptoms, including headache, fever, nausea, and vomiting, may develop. Clinical course — The erythema typically resolves in three to seven days. Blisters heal without scarring in 7 to 10 days. Scaling, desquamation, and tanning are noted four to seven days after exposure.

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In light-skinned individuals, multiple permanent brown macules, often with irregular borders, may occur after sunburn (sunburn-induced solar lentigines) (picture 2). (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Solar lentigo'.)

DIAGNOSIS The diagnosis of sunburn is usually straightforward, based upon the clinical findings of painful erythema with or without vesiculation and blistering (picture 1A-C, 1E) in exposed areas and a history of exposure to sunlight. Additional elements of history that may be helpful for the diagnosis include: ●

Exposure to photosensitizing drugs (table 3)



Contact with topical photosensitizers (table 4)



Use of indoor tanning equipment



Exposure to ultraviolet B (UVB) phototherapy or ultraviolet A (UVA) photochemotherapy (PUVA)

DIFFERENTIAL DIAGNOSIS Exaggerated sunburn reactions — Exaggerated sunburn reactions may occur as a result of exposure to phototoxic drugs or topical photosensitizer substances and in individuals with genetic disorders conferring an increased sensitivity to ultraviolet radiation (UVR). ●

Drug-induced phototoxic reactions – Phototoxic agents include drugs and other compounds that reduce the dose threshold for UVR-induced erythema when ingested or applied to the skin (table 3). Phototoxic reactions appear as exaggerated sunburns, starting with a stinging or burning sensation associated with redness and swelling in exposed skin within minutes of sun exposure (picture 3A-C). (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)



Phytophotodermatitis – Phototoxic reactions may be induced by topical exposure to plants containing furocoumarins (table 4). Patients with phytophotodermatitis typically present with erythema, edema, and bullae in linear or bizarre configurations that reflect the manner in which they have come in contact with the plant (picture 4A-B). (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phytophotodermatitis'.)



Xeroderma pigmentosum – Xeroderma pigmentosum (XP) is an autosomal recessive disorder resulting from mutations in one of seven genes (XPA to XPG) involved in the nucleotide excision repair of UVR-induced photoproducts in DNA [37,38]. Infants with XP often experience severe

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sunburns after minimal sun exposure. Older children present with premature skin aging, pigmentary changes, and early development of skin cancers. (See "The genodermatoses: An overview", section on 'Xeroderma pigmentosum'.) ●

Erythropoietic protoporphyria – Erythropoietic protoporphyria (EPP) is an inherited autosomal porphyria characterized by acute, painful, nonblistering photosensitivity episodes usually first noted in early childhood. The measurement of total and free erythrocyte protoporphyrin is necessary to confirm the diagnosis. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

Nonsunburn reactions — Several idiopathic photodermatoses may mimic sunburn. However, they can be easily differentiated from sunburn based upon their clinical presentation and time course. ●

Polymorphous light eruption – Polymorphous light eruption (PLE) is an idiopathic photodermatosis characterized by erythematous, itchy papules and vesicles occurring hours to days after sun exposure and persisting for several days (picture 5A-B) [39]. (See "Polymorphous light eruption".)



Solar urticaria – Solar urticaria is a form of physical urticaria that presents with wheals or, less commonly, erythema alone after only minutes of exposure to sunlight and resolves within several hours (picture 6). Phototesting can confirm the diagnosis. (See "Physical (inducible) forms of urticaria", section on 'Solar urticaria'.)



Chronic actinic dermatitis – Chronic actinic dermatitis is a rare, persistent photo-induced eczema that typically affects men over 60 years (picture 7A-B). Many patients have a history of atopic dermatitis or a coexisting allergic contact dermatitis. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Chronic actinic dermatitis'.)



Systemic lupus erythematosus — The classic butterfly rash of systemic lupus erythematosus (picture 8A-B), which usually appears after exposure to sunlight, is frequently mistaken for a sunburn. (See "Overview of cutaneous lupus erythematosus", section on 'Acute cutaneous lupus erythematosus'.)

MANAGEMENT Mild to moderate sunburn — Sunburn is a self-limiting condition that usually resolves in a few days. There are no specific therapies to reverse the skin damage and hasten the healing time. Management involves the symptomatic treatment of skin inflammation and control of pain.

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Cool compresses or soaks, calamine lotion, or aloe vera-based gels provide some relief of pain and discomfort. Bland emollients (eg, liquid paraffin/white soft paraffin 50/50) can be used on intact skin as tolerated. Ruptured blisters should be gently cleaned with mild soap and water and covered with wet dressings (eg, saline or petrolatum impregnated gauzes). For the treatment of skin pain and inflammation, we suggest oral nonsteroidal anti-inflammatory drugs (NSAIDs). We generally use ibuprofen at a dose of 400 to 800 mg per dose three to four times per day in adults and children >12 years and 4 to 10 mg/kg per dose every six to eight hours in children 6 months to 12 years. Treatment should be initiated as soon as the first symptoms become apparent and continued for 24 to 48 hours. The efficacy of oral NSAIDs for the symptomatic treatment of sunburn has not been adequately evaluated in randomized trials. In a few small observational studies of experimentally induced ultraviolet B (UVB) erythema, aspirin, ibuprofen, and indomethacin were reported as effective in reducing UVB-induced erythema if initiated before or immediately after the irradiation [40-42]. In a double-blind crossover study, psoriatic patients receiving UVB phototherapy were given ibuprofen or placebo immediately after irradiation and for the following 24 hours [43]. Ibuprofen was more effective than placebo only in reducing technician-observed erythema, whereas no difference was noted for other endpoints (patient-observed erythema, pruritus, skin pain, general discomfort, and nocturnal restlessness). We do not use topical corticosteroids for the treatment of sunburn. Although they are frequently used in clinical practice, there is little evidence that they are beneficial in reducing the symptoms and healing time of sunburn. In a study of patients with naturally acquired sunburn, participants reported similar pain, redness, and healing time for skin areas treated with topical fluocinolone acetonide or placebo [44]. In a randomized study of patients with experimentally induced UVB erythema, irradiated skin areas were treated with moderate or high potency topical corticosteroids (table 5) 30 minutes before, 6, or 23 hours after exposure [45]. A clinically significant reduction of erythema was noted only in areas treated with high potency corticosteroids before the irradiation. Topical diclofenac gel has been reported as effective in reducing pain and inflammation from sunburn [46]. However, topical diclofenac may induce allergic contact dermatitis and photoallergic contact dermatitis [47-49]. Patients with severe sunburn — Patients with extensive blistering sunburn, severe pain, and systemic symptoms (eg, fever, headache, vomiting, dehydration) may require hospitalization for fluid replacement and parenteral analgesia (table 6). (See "Treatment of superficial burns requiring hospital admission", section on 'Assessment for inpatient care'.)

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Blistered areas should be gently cleaned with mild soap and water and covered with sterile dressings. Topical antimicrobials or antibiotics (eg, silver sulfadiazine or mupirocin 2% ointment) may be used to prevent bacterial superinfection. (See "Treatment of superficial burns requiring hospital admission", section on 'Burn wound dressings and topical therapy' and "Topical agents and dressings for local burn wound care".) There is no evidence that oral corticosteroids are useful in severe sunburn. In a small study, participants received prednisone 80 mg or placebo immediately after UVB irradiation and for the following three days [50]. Prednisone was not more effective than placebo in reducing erythema, edema, and pain of the irradiated sites.

PREVENTION Prevention of sunburn involves sun avoidance, wearing protective clothing, and liberal use of broad spectrum sunscreens. It is important that clinicians counsel patients with sun-sensitive skin types about sun protection, because susceptibility to sunburn is a marker of genetic susceptibility to skin cancer and is associated with an increased risk of melanoma at all ages [3,4]. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Photoprotection'.) ●

Individuals should be advised to seek shade or reduce exposure particularly in the summer months and between 10:00 AM and 4:00 PM, when sunlight intensity is greatest. Infants younger than six months should be kept out of direct sunlight.



Protective clothing such as long sleeves and broad brim hats should be worn while outdoors. Fabrics that are tightly woven, thick, or dark-colored are useful for protection. Clothing developed for photosensitive individuals is commercially available from specialty companies. (See "Selection of sunscreen and sun-protective measures", section on 'Photoprotective clothing'.)



Broad spectrum sunscreens with sun protection factor (SPF) 30 or higher should be regularly used when performing outdoor activities in sunny weather, especially in regions with high levels of insolation. Sunscreens should be applied 15 to 30 minutes before sun exposure to allow the formation of a protective film on the skin and reapplied at least every two hours. Because all sunscreens are washed off upon swimming or sweating, reapplication after swimming is needed even for sunscreen products labeled in Europe as "water resistant" (retains at least 50 percent of the labeled SPF after two 20-minute periods in water) or "very water resistant" (retains 50 percent of the labeled SPF after four 20-minute periods in water) [51]. In the United States, the US Food and Drug Administration (FDA) requires the SPF to remain the same before and after water immersion, with the terms "water resistant" and "very water resistant" meaning that the SPF is

8748

maintained after 40 or 80 minutes of activity in water or sweating, respectively. Sunscreens provide a demonstrated reduction in sun damage, squamous cell carcinomas, melanomas, and photoaging, if used appropriately [51]. (See "Selection of sunscreen and sun-protective measures".) ●

For infants younger than six months, the American Academy of Pediatrics recommends avoidance of sun exposure and the use of clothing (eg, lightweight pants, long-sleeved shirts, brimmed hats). A minimal amount of sunscreen with an SPF of ≥15 may be applied to small areas (eg, face, back of hands) when adequate clothing and shade are not available.



Intentional tanning by using ultraviolet A (UVA) tanning beds does not protect against the risk of sunburn. Although suberythemal repetitive exposures to UVA induce a visible increase in skin pigmentation (immediate tanning, due to oxidation and redistribution of existing melanin), they do not increase melanin production and provide little or no photoprotection against subsequent UV exposures [52].

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Care of the patient with burn injury".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topics (see "Patient education: Sunburn (The Basics)")



Beyond the Basics topics (see "Patient education: Sunburn (Beyond the Basics)")

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SUMMARY AND RECOMMENDATIONS ●

Sunburn is an acute, delayed, and transient inflammatory response of the skin to excessive exposure to ultraviolet radiation (UVR) from natural sunlight or artificial sources. Both ultraviolet B (UVB) and ultraviolet A (UVA) can cause sunburn; however, the wavelengths that are most effective in inducing erythema are in the UVB range (290 to 320 nm). (See 'Introduction' above and 'Action spectra' above.)



Clinical manifestations of sunburn include painful erythema with or without edema, vesiculation, and blistering (picture 1A-D and table 2). Erythema is usually first noted 3 to 5 hours following sunlight exposure, peaks at 12 to 24 hours, and usually subsides at 72 hours. (See 'Clinical manifestations' above.)



The diagnosis of sunburn is usually straightforward, based upon the clinical findings (picture 1AC, 1E) and a history of exposure to sunlight or artificial sources of UV radiation. (See 'Diagnosis' above.)



Sunburn is a self-limiting condition. Cool compresses or soaks, calamine lotion, or aloe verabased gels may be used for the relief of skin discomfort. For the treatment of skin pain and inflammation, we suggest oral nonsteroidal anti-inflammatory drugs (NSAIDs) (Grade 2C). (See 'Management' above.)



Patients with extensive blistering sunburn, severe pain, and systemic symptoms may require hospitalization for fluid replacement and parenteral analgesia (table 6). (See 'Patients with severe sunburn' above and "Treatment of superficial burns requiring hospital admission".) Use of UpToDate is subject to the Subscription and License Agreement.

Topic 6624 Version 18.0

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GRAPHICS Sunburn

Diffuse erythema in sun-exposed areas is present in this patient with a sunburn on the back. Areas covered by clothing are not affected. Reproduced with permission from: Stedman's Medical Dictionary. Copyright © 2008 Lippincott Williams & Wilkins. Graphic 73224 Version 1.0

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Sunburn

Erythema, edema, and bullae are present on this child with a severe sunburn. Reproduced with permission from: Fleisher GR, Ludwig S, Baskin MN. Atlas of Pediatric Emergency Medicine, Lippincott Williams & Wilkins, Philadelphia 2004. Copyright © 2004 Lippincott Williams & Wilkins. Graphic 52112 Version 2.0

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Minimal erythema dose (MED)

The MED is the smallest dose of UVB required to induce a barely perceptible erythema 24 hours after irradiation. The minimal erythema dose (MED) for this patient is shown in the bordered square. Graphic 88081 Version 1.0

8753

Fitzpatrick skin phototypes Skin type

Unexposed skin color

Reaction to sun exposure*

I

White

Always burns, never tans

II

White

Always burns, minimal tan

III

White to olive

Burns minimally, gradually tans

IV

Light brown

Burns minimally, tans well

V

Brown

Very rarely burns, tans profusely

VI

Dark brown to black

Never burns, tans deeply

Note: Slight variations on the definitions of the phototypes appear in the literature. * After the first one hour of sun exposure on untanned skin on the first day of spring. Graphic 60541 Version 4.0

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Sunburn

Erythema and scale are present on the sun exposed areas of the skin. Note the relative sparing in the shadow areas of the nasolabial folds and infranasal skin. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 59991 Version 4.0

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Classification of burns by depth of injury Depth Superficial (epidermal)

Appearance Dry, red

Sensation

Healing time

Painful

3 to 6 days

Painful to temperature and air and touch

7 to 21 days

Painful to pressure only

>21 days, usually requires surgical treatment

Deep pressure only

Rare, unless surgically treated

Deep pressure

Never, unless surgically treated

Blanches with pressure Superficial partialthickness

Blisters Moist, red, weeping Blanches with pressure

Deep partial-thickness

Blisters (easily unroofed) Wet or waxy dry Variable color (patchy to cheesy white to red) Blanching with pressure may be sluggish

Full-thickness

Waxy white to leathery gray to charred and black Dry and inelastic No blanching with pressure

Deeper injury (ie, fourth degree) 

Extends into fascia and/or muscle

Adapted from: 1. Mertens DM, Jenkins ME, Warden GD. Outpatient burn management. Nurs Clin North Am 1997; 32:343. 2. Peate WF. Outpatient management of burns. Am Fam Physician 1992; 45:1321. 3. Clayton MC, Solem LD. No ice, no butter. Advice on management of burns for primary care physicians. Postgrad Med 1995; 97:151. Graphic 61540 Version 7.0

8756

Solar lentigines

Numerous tan macules with irregular borders on the posterior neck and shoulder of an adolescent with a history of several severe sunburns. Courtesy of Jean L Bolognia, MD, and Julie V Schaffer, MD. Graphic 70005 Version 1.0

8757

Sunburn

A severe sunburn in a boy who had been sleeping in the sun. Note the sparing of the chest areas covered by the folded arms. Reproduced from: Lautenschlager S, Wulf HC, Pittelkow MR. Photoprotection. Lancet 2007; 370:528. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 88082 Version 1.0

8758

Some agents that may cause photosensitivity reactions Anticancer drugs

Antipsychotic drugs

Sunscreens

Dacarbazine

Chlorpromazine*

Aminobenzoic acids*

Fluorouracil

Fluphenazine

Avobenzone

Flutamide

Haloperidol

Benzophenonones*

Methotrexate

Perphenazine

Cinnamates

Vinblastine

Prochlorperazine*

Homosalate

Antidepressants

Thioridazine

Menthyl anthranilate

Amitriptyline

Thiothixene

PABA esters*

Amoxapine

Trifluoperazine

Antihistamine

Clomipramine

Triflupromazine

Cyproheptadine

Desipramine

Diuretics

Diphenhydramine

Doxepin

Acetazolamide

Anthypertensives

Imipramine

Amiloride

Captopril

Maprotiline

Bendroflumethiazide

Diltiazem

Phenelzine

Benzthiazide

Methyldopa

Protriptyline

Chlorthiazide*

Minoxidil

Trazodone

Furosemide*

Nifedipine

Trimipramine

Hydrochlorothiazide*

Antimicrobials

Hydroflumethiazide

Ciprofloxacin

Methyclothiazide

Clofazimine

Metolazone

Dapsone

Polythiazide

Demeclocycline*

Trimterene

Doxycycline*

Trichlormethiazide

Enoxacin

Hypoglycemics

Flucytosine

Acetohexamide

Chlordiazepoxide

Griseofulvin

Chlorpropamide

Clofibrate

Lomefloxacin*

Glipizide

Desoximetasone

Minocycline

Glyburide

Disopyramide

Nalidixic acid*

Tolazamide

Etretinate

Norfloxacin

Tolbutamide*

Fluoroscein

Ofloxacin

NSAIDs

Gold salts

Oxytetracycline

Difluisal

Hexachlorophene

Pyrazinamide

Ibuprofen

Isotretinoin

Sulfonamides

Indomethacin

6-methylcoumRIN*

Tetracycline

Ketoprofen

Musk ambrette*

Trimethopterin

Nabumetone

Oral contraceptives

Antiparasitic drugs

Naproxen

Promethazine*

Chloroquine

Phenylbutazone

Quinidine sulfate

Quinine

Piroxicam*

Tretinoin

Others Alpazolam Amantadine Amiodarone* Benzocaine Benzyl peroxide Bergamol oil, oils of citron, lavender, lime, sandalwood, cedar* Carbamazepine

8759

Sulindac

Trimeprazine

* Reactions which occur more frequently Adapted from The Medical Letter 1995; 37:35. Graphic 62152 Version 1.0

8760

Some potential causes of phytophotodermatitis* Plant family Apiaceae (Umbelliferae)

Common name(s) Angelica Celery Cow parsley, wild chervil Cow parsnip, hogweed Dill Fennel Giant hogweed Parsley Parsnip

Rutaceae

Bergamot orange Bitter orange Burning bush, gas plant Grapefruit Lemon Lime Rue

Moraceae

Fig

Fabaceae (Leguminosae)

Bavachee, scurf-pea (Psoralea corylifolia)

Cruciferae

Mustard

Ranunculaceae

Buttercup

Hypericaceae

St. John's wort (can cause systemic phytophotodermatitis)

* Other plants have also been implicated. Graphic 75581 Version 2.0

8761

Phototoxic eruption

A bright red, confluent rash on the "V" of the neck of a patient with drug-induced photosensitivity reaction. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 86479 Version 7.0

8762

Phototoxic eruption

Diffuse, sunburn-like erythema is present on the face and ears. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 69140 Version 9.0

8763

Phototoxic eruption

Confluent erythema on the dorsum of the hands following sun exposure in a child taking doxycycline. Note initial blistering on the right hand and the sparing of the area covered by a watch. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 90426 Version 5.0

8764

Phytophotodermatitis

Erythematous linear streaks that subsequently became hyperpigmented occurred on the trunk of this 14-year-old male who was exposed to the sun after squeezing limes during a Carribean vacation. Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org. Graphic 77829 Version 6.0

8765

Phytophotodermatitis

After making lemonade during an outdoor excursion trip, this 38-year-old female presented with erythematous linear and angulated patches and crusts on the face. Copyright © Shahbaz A Janjua, MD, Dermatlas; http://www.dermatlas.org. Graphic 57871 Version 5.0

8766

Polymorphous light eruption

This photo shows a 35-year-old woman with a symmetrical papulovesicular eruption on the forearms. Lesions were also present on the neck and lower legs. Copyright © Eric Ehrsam, MD, Dermatlas; http://www.dermatlas.org. Graphic 64270 Version 7.0

8767

Polymorphous light eruption

This 12-year-old girl developed a pruritic eruption that consisted of discrete and coalescing erythematous papules on the face. The lesions were photodistributed and appeared within hours after intense sun exposure in the spring. Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org. Graphic 51455 Version 6.0

8768

Solar urticaria induced by ultraviolet A light

(A) Shoulder before sun exposure. (B) Shoulder after 15 minutes of sun exposure through a glass window. The glass window filters out ultraviolet B light. Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd Edition. Philadelphia: Lippincott Williams & Wilkins, 2003. Copyright © 2003 Lippincott Williams & Wilkins. Graphic 57783 Version 3.0

8769

Chronic actinic dermatitis

Diffuse infiltrated erythema, scaling, and fissures on the face of this patient with chronic actinic dermatitis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 101492 Version 3.0

8770

Chronic actinic dermatitis

The skin on photoexposed areas appears erythematous and lichenified in this patient with chronic actinic dermatitis. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 101494 Version 3.0

8771

Acute cutaneous lupus erythematosus

Malar erythema and subtle edema are present in this patient with systemic lupus erythematosus. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 75781 Version 5.0

8772

Acute cutaneous lupus erythematosus

An erythematous, edematous eruption is present on the malar area. Note the sparing of the nasolabial folds. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 55875 Version 4.0

8773

Comparison of representative topical corticosteroid preparations (classified according to the US system)

Potency group* Super-high potency (group 1)

High potency (group 2)

Corticosteroid

Brand names (United States)

Available strength(s), percent (except as noted)

Betamethasone dipropionate, augmented

Gel, lotion, ointment (optimized)

Diprolene

0.05

Clobetasol propionate

Cream, gel, ointment, solution (scalp)

Temovate

0.05

Cream, emollient base

Temovate E

0.05

Lotion, shampoo, spray aerosol

Clobex

0.05

Foam aerosol

Olux-E, Tovet

0.05

Solution (scalp)

Cormax

0.05

Diflucortolone valerate (not available in United States)

Ointment, oily cream

Nerisone Forte (United Kingdom, others)

0.3

Fluocinonide

Cream

Vanos

0.1

Flurandrenolide

Tape (roll)

Cordran

4 mcg/cm 2

Halobetasol propionate

Cream, lotion, ointment

Ultravate

0.05

Amcinonide

Ointment

Cyclocort ¶, Amcort ¶

0.1

Betamethasone dipropionate

Ointment

Diprosone ¶

0.05

Cream, augmented formulation (AF)

Diprolene AF

0.05

Clobetasol propionate

Cream

Impoyz

0.025

Desoximetasone

Cream, ointment, spray

Topicort

0.25

Gel

Topicort

0.05

Ointment

ApexiCon ¶, Florone ¶

0.05

Cream, emollient

ApexiCon E

0.05

Fluocinonide

Cream, gel, ointment, solution

Lidex ¶

0.05

Halcinonide

Cream, ointment

Halog

0.1

Halobetasol propionate

Lotion

Bryhali

0.01

Amcinonide

Cream

Cyclocort ¶, Amcort ¶

0.1

Lotion

Amcort ¶

0.1

Betamethasone dipropionate

Cream, hydrophilic emollient

Diprosone ¶

0.05

Betamethasone valerate

Ointment

Valisone ¶

0.1

Foam

Luxiq

0.12

Desoximetasone

Cream

Topicort LP ¶

0.05

Diflorasone diacetate

Cream

Florone ¶

0.05

Diflucortolone valerate (not available in United States)

Cream, oily cream, ointment

Nerisone (Canada, United Kingdom, others)

0.1

Fluocinonide

Cream aqueous emollient

Lidex-E ¶

0.05

Diflorasone diacetate

High potency (group 3)

Vehicle type/form

8774

Medium potency (group 4)

Lower-mid potency (group 5)

Low potency (group 6)

Fluticasone propionate

Ointment

Cutivate

0.005

Mometasone furoate

Ointment

Elocon

0.1

Triamcinolone acetonide

Cream, ointment

Aristocort HP ¶, Kenalog ¶, Triderm

0.5

Betamethasone dipropionate

Spray

Sernivo

0.05

Clocortolone pivalate

Cream

Cloderm

0.1

Fluocinolone acetonide

Ointment

Synalar ¶

0.025

Flurandrenolide

Ointment

Cordran

0.05

Hydrocortisone valerate

Ointment

Westcort

0.2

Mometasone furoate

Cream, lotion, ointment, solution

Elocon ¶

0.1

Triamcinolone acetonide

Cream

Kenalog ¶, Triderm

0.1

Ointment

Kenalog ¶

0.1

Ointment

Trianex

0.05

Aerosol spray

Kenalog

0.2 mg per 2 second spray

Dental paste

Oralone

0.1

Betamethasone dipropionate

Lotion

Diprosone ¶

0.05

Betamethasone valerate

Cream

Beta-Val, Valisone ¶

0.1

Desonide

Ointment

DesOwen, Tridesilon ¶

0.05

Gel

Desonate

0.05

Fluocinolone acetonide

Cream

Synalar ¶

0.025

Flurandrenolide

Cream, lotion

Cordran

0.05

Fluticasone propionate

Cream, lotion

Cutivate

0.05

Hydrocortisone butyrate

Cream, lotion, ointment, solution

Locoid, Locoid Lipocream

0.1

Hydrocortisone probutate

Cream

Pandel

0.1

Hydrocortisone valerate

Cream

Westcort ¶

0.2

Prednicarbate

Cream (emollient), ointment

Dermatop

0.1

Triamcinolone acetonide

Lotion

Kenalog ¶

0.1

Ointment

Kenalog ¶

0.025

Alclometasone dipropionate

Cream, ointment

Aclovate

0.05

Betamethasone valerate

Lotion

Beta-Val ¶, Valisone ¶

0.1

Cream

DesOwen, Tridesilon ¶

0.05

Lotion

DesOwen, LoKara

0.05

Foam

Verdeso

0.05

Cream, solution

Synalar ¶

0.01

Shampoo

Capex

0.01

Oil Δ

Derma-Smoothe/FS Body, DermaSmoothe/FS Scalp

0.01

Desonide

Fluocinolone acetonide

8775





Triamcinolone acetonide Least potent (group 7)

Hydrocortisone (base, ≥2%)

Hydrocortisone (base, 24 weeks) [37]. However, further studies are needed to confirm the efficacy of this combination therapy and evaluate potential short- and long-term adverse effects.



Several reports suggest that narrowband UVB phototherapy may enhance the therapeutic response to biologics [38-42]. However, long-term safety data on these combinations are not available and there is concern that concurrent treatment with anti-TNF agents and narrowband phototherapy may increase the risk of photocarcinogenesis [40,43-46]. (See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

TARGETED PHOTOTHERAPY WITH 308 NM DEVICES Lasers and lamps emitting monochromatic excimer light at 308 nm wavelength have a clinical use similar to narrowband UVB therapy. Excimer lasers emit a higher amount of radiation over a shorter period of time than conventional narrowband UVB devices and are particularly useful for the treatment resistant psoriasis plaques that are unresponsive to other treatments or located in difficult areas (eg, scalp, palms, soles, knees, and elbows) [47]. A pilot study reports possible useful combinations with topical agents [48]. Excimer lamps may be used to treat large body areas, but have a lower power density than lasers. Targeted phototherapy may also be a treatment modality for stable vitiligo, localized chronic dermatoses (eg, granuloma annulare, lichen planus, lichen simplex chronicus), and alopecia areata [4951].

8809

Targeted phototherapy is discussed in detail separately. (See "Targeted phototherapy".)

SAFETY MEASURES Safety measures for patients undergoing UVB phototherapy include: ●

Wearing UV-blocking goggles to protect the eyes and prevent conjunctivitis and photokeratitis



Protecting the face (if not involved in the disease process) either by using a sunscreen with an SPF of 50+ or a cloth barrier



Protecting the genitalia (if not involved in the disease process) by wearing underwear



Avoiding concurrent natural sun exposure

SHORT- AND LONG-TERM ADVERSE EFFECTS Short-term adverse effects of UVB phototherapy include erythema, skin dryness, pruritus, blistering, and increased frequency of recurrent herpes simplex (table 5). Long-term adverse effects include photoaging and the possibility of photocarcinogenesis. The carcinogenic potential of narrowband phototherapy has not been determined. A systematic review of the carcinogenic risk associated with PUVA and narrowband UVB therapy for psoriasis suggests that narrowband UVB therapy does not increase the risk of skin cancer [52]. However, there is a need for larger studies with longer follow-up time to assess the risk of skin cancer among patients treated with narrowband UVB phototherapy.

CONTRAINDICATIONS Absolute contraindications for UVB phototherapy are: ●

Xeroderma pigmentosum



Lupus erythematosus

Relative contraindications to UVB therapy include: ●

History of photosensitivity diseases (eg, chronic actinic dermatitis, solar urticaria)



History of melanoma



History of nonmelanoma skin cancer



History of treatment with arsenic or ionizing radiation because of the increased risk for skin cancer



Immunosuppression for organ transplant patients

8810

SUMMARY AND RECOMMENDATIONS ●

Narrowband UVB (311 to 313 nm) is the type of phototherapy most frequently used for the treatment of moderate to severe psoriasis and a wide range of skin diseases, including atopic dermatitis, vitiligo, early stages of mycosis fungoides, and pruritic disorders (table 1). (See 'Introduction' above.)



The main cytochemical target of UVB is nuclear DNA. The UVB-induced DNA damage stimulates signal transduction pathways leading to the activation of transcription factors, cytokine secretion, immunosuppression, and a variety of cellular responses, including cell cycle arrest and apoptosis. (See 'Principles and mechanisms' above.)



Devices for broadband UVB therapy utilize fluorescent lamps emitting a wide range of wavelengths, mostly in the UVB range (280 to 320 nm) and, in part, in the UVA range (figure 1). Devices for narrowband UVB therapy use the TL-01 fluorescent lamps that emit UVB in the range of 311 to 313 nm. (See 'Devices for broadband and narrowband UVB' above.)



Treatment is generally started with an initial dose of UVB equal to 50 to 70 percent of the minimal erythema dose (MED) or at a dose determined by the patient’s phototype (table 4). It is important to document the type of lamp used for MED determination, since values obtained with broadband or narrowband sources are markedly different (table 3). (See 'Dosimetry and treatment protocols' above.)



The radiation dose is then gradually increased by 10 to 40 percent of the previous dose. The goal of dose increment is to achieve a minimally perceptible erythema, which is the clinical indicator of optimal dosimetry. Treatment is continued until complete remission is achieved or no further improvement can be obtained with continued phototherapy. The role for maintenance therapy is uncertain. (See 'Treatment initiation, frequency, and dose increments' above.)



The most common indications for UVB therapy, in particular for narrowband UVB, include moderate to severe psoriasis that is unresponsive to topical therapy, severe atopic dermatitis, and vitiligo. (See 'Clinical indications for UVB therapy' above.)



During UVB phototherapy, the eyes must be protected with UV-blocking goggles. The face, genital area, and skin that is not involved must be protected with an SPF 50+ sunscreen or a cloth barrier. (See 'Safety measures' above.)



Short-term adverse effects of UVB phototherapy include erythema, skin dryness, pruritus, blistering, and increased frequency of recurrent herpes simplex (table 5). Long-term adverse effects include photoaging and photocarcinogenesis, although the carcinogenic potential of narrow band UVB is less established. (See 'Short- and long-term adverse effects' above.)

8811

Use of UpToDate is subject to the Subscription and License Agreement. Topic 13745 Version 13.0

8812

GRAPHICS Clinical indications for UVB phototherapy Indication

Broadband

Narrowband

Psoriasis

+

++

Atopic dermatitis

+

++

Pruritus, prurigo

+

+

Parapsoriasis en plaques

+

+

Mycosis fungoides (patch stage)

+

+

Polymorphous light eruption (prophylaxis)

+

++

Vitiligo



++

Pityriasis lichenoides

+

+

Lymphomatoid papulosis

+

+

Seborrheic dermatitis

+

+

HIV-associated pruritic eruptions

+

X

+: recommendable; ++: superior; –: low efficacy; X: no experience. Graphic 87494 Version 1.0

8813

Spectrum of broad band and narrow band UVB lamps

Courtesy of James Ferguson, Dundee, Scotland. Graphic 87492 Version 1.0

8814

Stand-up full body phototherapy unit

Reproduced with permission. Copyright © 2015 Herbert Waldmann GmbH & Co. KG. Graphic 88026 Version 1.0

8815

Partial/full-body phototherapy unit

Reproduced with permission. Copyright © 2015 Herbert Waldmann GmbH & Co. KG. Graphic 88027 Version 1.0

8816

Phototherapy unit for localized treatment

Reproduced with permission. Copyright © 2015 Herbert Waldmann GmbH & Co. KG. Graphic 88028 Version 1.0

8817

Fitzpatrick skin phototypes Skin type

Unexposed skin color

Reaction to sun exposure*

I

White

Always burns, never tans

II

White

Always burns, minimal tan

III

White to olive

Burns minimally, gradually tans

IV

Light brown

Burns minimally, tans well

V

Brown

Very rarely burns, tans profusely

VI

Dark brown to black

Never burns, tans deeply

Note: Slight variations on the definitions of the phototypes appear in the literature. * After the first one hour of sun exposure on untanned skin on the first day of spring. Graphic 60541 Version 4.0

8818

Determination of the minimal erythema dose (MED) with broadband or narrowband UVB sources Exposure doses (mJ/cm 2) Broadband UVB

20

40

60

80

100

120

Narrowband UVB

200

400

600

800

1000

1200

UVB: ultraviolet B. Graphic 87493 Version 2.0

8819

UVB phototherapy: Recommended initial doses according to skin phototype Skin phototype

Initial BB-UVB dose (mJ/cm 2)

Initial NB-UVB dose (mJ/cm 2)

I

20

130

II

25

220

III

30

260

IV

40

330

V

50

350

VI

60

400

Graphic 88228 Version 1.0

8820

Short-term and long-term adverse effects of UVB phototherapy Acute Sunburn or phototoxic reaction if overdosed

++

Phototoxic reaction from accidental intake of a photosensitizer



Conjunctivitis, keratitis (if no eye shielding is used)

++

Provocation of photodermatoses (eg, polymorphous light eruption)

+

Chronic Lentigines

+

Photoaging

++

Actinic keratosis, nonmelanoma skin cancer

+/±

Melanoma

?

–: no risk; ++: high risk; +: medium risk; ±: low risk; ?: possible, insufficient data. Most photosensitizing substances absorb in the UVA range. Thus, exposure to UVB after the accidental ingestion of a photosensitizer does not induce a phototoxic reaction. Graphic 87496 Version 2.0

8821

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

UVA1 phototherapy Authors: Jean Krutmann, MD, Akimichi Morita, MD, PhD Section Editor: Craig A Elmets, MD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 01, 2019.

INTRODUCTION Ultraviolet A1 (UVA1) is a newer form of phototherapy that uses only the longer, non-erythemogenic UV wavelengths (340 to 400 nm), thus reducing the risk of sunburn reactions associated with the shorter-wavelength UVA2 (320 to 340 nm) and UVB (290 to 320 nm). It is important to note that the UVA1 light sources are not equivalent to the light sources used for cosmetic purposes in tanning parlors and home units, which emit UVA2 wavelengths and often some UVB as well in addition to UVA1. The therapeutic effect of UVA1 is due to its ability to penetrate into the dermis deeper than UVB and target cells that reside in or infiltrate the dermis, including dendritic cells, fibroblasts, mast cells, and T and B lymphocytes [1]. This topic reviews the mechanism of action, clinical indications, and adverse effects of UVA1 phototherapy. PUVA therapy and broadband and narrowband UVB phototherapy are discussed separately. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy" and "UVB therapy (broadband and narrowband)".)

MECHANISM OF ACTION AND BIOLOGIC EFFECTS The long-wavelength ultraviolet A1 (UVA1) radiation (340 to 400 nm) is able to penetrate into the dermis deeper than short-wavelength UVA2 (320 to 340 nm) and UVB (290 to 320 nm). UVA1 exerts its biologic effects on a variety of cells, including T and B lymphocytes, fibroblasts, dendritic cells, and immature mast cells [2-4].

8822

UVA1-induced apoptosis — The ability of UVA1 to induce apoptosis of infiltrating T cells is thought to underlie its therapeutic efficacy for the treatment of T cell-mediated inflammatory and neoplastic skin diseases, such as atopic dermatitis and mycosis fungoides. Malignant CD4+ T cells appear to be more sensitive to UVA1 radiation-induced apoptosis than normal CD4+ T cells [5]. In vitro, UVA1 has been shown to induce immediate and delayed cell apoptosis through at least two different mechanisms. In the first, UVA1 induces the generation of singlet oxygen species, which depolarize mitochondrial membranes and trigger immediate cell apoptosis through the activation of the FAS/FAS ligand system [2]. This mechanism is termed preprogrammed cell death and appears to be specific of UVA1 phototherapy, since it is not observed with UVB or PUVA phototherapy. The second mechanism involves the production of superoxide anions, which damage the mitochondrial membrane resulting in the release of cytochrome C and activation of a caspase-dependent apoptotic pathway [3]. Cytokine modulation — UVA1 radiation has been shown to suppress proinflammatory cytokines, such as IL-12 and tumor necrosis factor (TNF)-alpha, and downregulate transforming growth factor (TGF)-beta in human skin [6]. In addition, UVA1 decreases the levels of interferon-gamma and ICAM1, which are involved in lymphocyte activation and trafficking. Effects on fibroblasts — UVA1-induced singlet oxygen species and hydrogen peroxide upregulate matrix metalloproteinases such as collagenase-1 produced by dermal fibroblasts [7,8]. The resulting increased collagen breakdown is thought to be the mechanism underlying the efficacy of UVA1 in the treatment of morphea and other sclerotic skin diseases [9,10]. (See "Treatment of morphea (localized scleroderma) in adults", section on 'Phototherapy'.)

LIGHT SOURCES Ultraviolet A1 (UVA1) is generated by fluorescent tubes or filtered metal halide lamps that filter out the erythemogenic UVA2. Treatment units equipped with fluorescent lamps deliver mean patient irradiance of 20 mW⁄cm2 and are suitable for low-dose UVA1 [11]. The delivery of medium and high doses of UVA1 requires the higher irradiance (approximately 60 mW⁄cm2) of metal-halide units [11]. Because of the high amount of heat generated, metal-halide lamp units require the installation of large fans or other heat-removal systems.

DOSIMETRY Ultraviolet A1 (UVA1) dosimetry is categorized into low (10 to 29 J/cm2), medium (30 to 59 J/cm2), and high (>60 J/cm2) dose regimens. Low-dose UVA1 is generated by fluorescent lamps, whereas

8823

medium and high doses require high-intensity emitting metal-halide lamps. (See 'Light sources' above.) Before initiating treatment, a half-dose of UVA1 is used as a provocation challenge to assess the patient's sensitivity to UVA1. If erythema does not develop, treatment with the required dose of UVA1 can be administered. Treatment times can range from 10 minutes to one hour per treatment session, depending upon the irradiance of the UVA1 phototherapy unit; sessions are typically repeated three to five times per week. In contrast with UVB or PUVA therapy, which uses incremental radiation doses, the dose of UVA1 is held constant throughout the treatment. The therapeutic efficacy of UVA1 therapy is dose-dependent. In studies of patients with atopic dermatitis, a medium UVA1 dose (50 J/cm2) was superior to a low-dose UVA1 regimen (10 J/cm2), but no significant difference was noted between medium- and high-dose regimens [12,13]. Moreover, low-dose UVA1 (30 J/cm2) was less effective than UVA/UVB therapy, whereas high-dose UVA1 therapy (130 J/cm2) was superior to UVA/UVB phototherapy [14,15].

INDICATIONS Ultraviolet A1 (UVA1) phototherapy was first used for the treatment of atopic dermatitis. In an open study of patients with acute severe exacerbation of atopic dermatitis, high-dose UVA1 (130 J/cm2) given daily for 15 consecutive days rapidly induced clinical improvement and reduced the levels of serum eosinophil cationic protein [15]. Subsequently, the indications for UVA1 phototherapy have extended to several other skin diseases, including mycosis fungoides, urticaria pigmentosa, and localized and systemic scleroderma [16]. Atopic dermatitis — The role of UVA1 phototherapy in the treatment of severe atopic dermatitis is well established. A systematic review of nine randomized trials found that in adult patients with acute, severe atopic dermatitis phototherapy with UVA1 was faster than conventional UVA/UVB in inducing clinical improvement, with a peak response after 10 treatments [17]. A subsequent systematic review of 19 randomized trials including 905 adult patients with atopic dermatitis, showed that medium-dose UVA1 phototherapy was as effective as narrowband UVB phototherapy in improving the clinical signs and symptoms of dermatitis, as measured with several scoring systems [18]. The use of UVA1 and other forms of phototherapy for the treatment of severe atopic dermatitis is discussed in greater detail separately. (See "Evaluation and management of severe refractory atopic dermatitis (eczema) in adults", section on 'Phototherapy' and "Management of severe atopic dermatitis (eczema) in children", section on 'Phototherapy'.)

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Localized scleroderma (morphea) — UVA1 has been used for the treatment of morphea (localized scleroderma) and other sclerotic skin diseases [19]. Morphea is characterized by the presence of an inflammatory infiltrate predominantly composed of T helper cells and dysregulated matrix metabolism leading to excessive collagen deposition [20]. Patients with morphea have increased levels of circulating intercellular adhesion molecule (ICAM)-1 and fibrogenic T-helper 2 cytokines, such as interleukin-4 and transforming growth factor (TGF)-beta. These cytokines recruit eosinophils and other inflammatory cells, and induce fibroblasts to synthesize excessive collagen and connective-tissue growth factor. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults".) UVA1 irradiation disturbs the cellular responsiveness to TGF-beta-1 through the induction of nonfunctional latent TGF-beta binding protein and the downregulation of TGF-beta receptors. In addition, UVA1 depletes skin-infiltrating T cells by inducing T cell apoptosis; inhibits T cell activation and cytokine production; and upregulates the expression of matrix metalloproteinase-1 (collagenase-1) in dermal fibroblasts [8]. The ultrastructural changes observed in clinically softened skin of scleroderma patients treated with UVA1 include a decrease in the diameter of the broad collagen fibrils in the reticular dermis and de novo synthesis of type I collagen and new thin fibrils [21]. Phototherapy for localized scleroderma is discussed in detail separately. (See "Treatment of morphea (localized scleroderma) in adults", section on 'Phototherapy'.) Systemic sclerosis — UVA1 may be helpful for the treatment of acral cutaneous sclerosis in patients with systemic sclerosis [22-24]. In a small study of four patients with systemic sclerosis, UVA1 phototherapy induced marked softening of the forearm skin after 9 to 29 exposures, with increase in joint passive range of motion and skin temperature and elasticity [22]. Histologic examination of skin specimens obtained before and after UVA1 phototherapy revealed loosening of collagen bundles and the appearance of small collagen fibers. Urticaria pigmentosa — Several studies have suggested that UVA1 phototherapy reduces pruritus and urtication in patients with urticaria pigmentosa. (See "Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations", section on 'Urticaria pigmentosa' and "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in children".) In an open study, four adult patients with severe generalized urticaria pigmentosa were treated with high-dose UVA1 phototherapy administered as monotherapy once daily five times per week for two consecutive weeks [25]. The initial dose of 60 J/cm2 UVA1 was subsequently increased to 130 J/cm2 UVA1. High-dose UVA1 therapy reduced pruritus and urtication from stroking (Darier's sign) after three exposures, but little or no effect was noted on the hyperpigmented skin lesions. In two patients with systemic manifestations of urticaria pigmentosa, relief from systemic symptoms (eg,

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migraine, diarrhea) and reduction of elevated serum serotonin to normal levels was observed after 10 exposures. No relapses occurred more than two years after cessation of high-dose UVA1 therapy. Another study including 12 patients with urticaria pigmentosa found that high-dose (130 J/cm2) and medium-dose (60 J/cm2) UVA1 given for 15 days were equally effective in reducing pruritus for six months after the completion of treatment [26]. Although the number of lesions was not reduced after treatment, the number of mast cells in the lesions decreased after treatment and remained low after a follow-up of six months. (See "Treatment and prognosis of cutaneous mastocytosis".) Cutaneous T cell lymphoma — In a few small studies, UVA1 phototherapy has been successfully used for the treatment of patients with cutaneous T cell lymphoma [27-30]. In one study, three patients with early-stage mycosis fungoides were treated with high- or medium-dose UVA1 regimen [27]. Complete clinical and histologic clearance of lesions was observed after 16 to 20 exposures. In another study, 11 of 13 patients with widespread plaque-type, nodular, and erythrodermic mycosis fungoides showed complete clinical and histologic response with a high-dose UVA1 regimen [28]. Although PUVA is a widely accepted therapeutic option for early-stage mycosis fungoides, UVA1 phototherapy may be a valuable alternative to PUVA, without the undesirable side effects of oral psoralens (eg, nausea, long-lasting skin photosensitivity, requirement for eye protection). Along the same lines, narrowband UVB phototherapy has been proposed for the treatment of early stages of mycosis fungoides [31]. (See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Phototherapy'.) Dyshidrotic eczema — Localized UVA1 phototherapy appears to be effective for the management of chronic dyshidrotic hand eczema [32-34]. In a small study, 10 of 12 patients with acute exacerbation of dyshidrotic eczema reported a marked improvement after 15 treatments with 40 J/cm2 per day administered over a period of three weeks [32]. In a small randomized trial involving 28 patients, medium dose UVA1 (40 J/cm2) was more effective than placebo in improving the symptoms of dyshidrotic eczema, as measured by the dyshidrotic eczema area and severity index (DASI) score [33]. In a right-left comparison study involving 27 patients, localized high-dose UVA1 (maximum dose 130 J/cm2) was as effective as cream PUVA in reducing the DASI score by nearly 50 percent after 15 treatments administered over three weeks [34]. (See "Acute palmoplantar eczema (dyshidrotic eczema)".) Other diseases — UVA1 phototherapy has also been used for the treatment of a variety of skin conditions, including: ●

Pityriasis rubra pilaris [35] (see "Pityriasis rubra pilaris", section on 'Phototherapy')



Hypereosinophilic syndromes with cutaneous involvement [36] (see "Hypereosinophilic syndromes: Treatment")

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Pityriasis rosea [37] (see "Pityriasis rosea", section on 'Phototherapy')



Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica [38] (see "Pityriasis lichenoides et varioliformis acuta (PLEVA)", section on 'Phototherapy' and "Pityriasis lichenoides chronica", section on 'Phototherapy')



Scleredema [39] (see "Scleredema", section on 'Phototherapy')

CONTRAINDICATIONS Ultraviolet A1 (UVA1) phototherapy is contraindicated in patients with xeroderma pigmentosum, porphyria, melanoma and nonmelanoma skin cancer, and in patients on long-term immunosuppressive therapy (eg, after organ transplantation). UVA1 phototherapy should not be used for patients with UVA-sensitive photodermatoses or photosensitive atopic dermatitis or patients taking photosensitizing drugs. The efficacy and long-term safety of UVA1 therapy has not been evaluated and therefore should be used with caution in patients younger than 18 years [40]. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment".)

ADVERSE EFFECTS Severe acute adverse effects of ultraviolet A1 (UVA1) phototherapy have not been reported. Mild adverse effects are common and include hyperpigmentation, erythema, xerosis, and pruritus. Skin darkening may occur after a single high-dose UVA1 treatment and may limit the efficacy of subsequent UVA1 phototherapy [41]. Although UVA1 is not highly erythemogenic, episodes of phototoxicity may occur, especially among light-skinned individuals [42,43]. Long-term adverse effects of UVA1 phototherapy include photoaging and photocarcinogenesis. Although the carcinogenic potential of UVA1 has not been determined in humans, it is now accepted that UVA1 causes DNA damage with formation of cyclobutane pyrimidine dimers, which are the most relevant lesions for UV-induced mutagenesis [44,45]. The actual contribution of UVA radiation to the development of malignant melanoma in humans is still under debate but cannot be excluded. There is a single case report of melanoma in a patient with mastocytosis who received long-term UVA1 and bath PUVA therapy [46]. Two cases of Merkel cell carcinoma have been reported in immunocompromised patients receiving high-dose UVA1 therapy [47].

MONITORING

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Patients receiving ultraviolet A1 (UVA1) phototherapy should be monitored with lifelong regular skin examinations [40]. A complete skin examination for skin cancer, premalignant lesions, and actinic damage should be performed before starting treatment and annually thereafter.

SUMMARY AND RECOMMENDATIONS ●

Ultraviolet A1 (UVA1) is a newer form of phototherapy that uses only the longer UV wavelengths (340 to 400 nm). The UVA1 therapeutic effect is due to its ability to penetrate into the dermis and target a variety of cells, including T and B lymphocytes, fibroblasts, mast cells, and dendritic cells. (See 'Introduction' above and 'Mechanism of action and biologic effects' above.)



UVA1 dosimetry is categorized into low (10 to 29 J/cm2), medium (30 to 59 J/cm2), and high (>60 J/cm2) dose regimens. Low-dose UVA1 is generated by fluorescent lamps, whereas medium and high doses require high-intensity emitting metal-halide lamps. (See 'Light sources' above and 'Dosimetry' above.)



Indications for UVA1 phototherapy include severe atopic dermatitis, localized scleroderma, urticaria pigmentosa, and early stage mycosis fungoides. (See 'Indications' above.)



Short-term adverse effects of UVA1 phototherapy include hyperpigmentation, erythema, xerosis, and pruritus. Long-term adverse effects include photoaging and photocarcinogenesis, although the carcinogenic potential of UVA1 has not been determined. (See 'Adverse effects' above.) Use of UpToDate is subject to the Subscription and License Agreement.

Topic 91676 Version 6.0

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Psoralen plus ultraviolet A (PUVA) photochemotherapy Author: Elisabeth G Richard, MD Section Editor: Craig A Elmets, MD Deputy Editor: Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Mar 12, 2019.

INTRODUCTION Psoralen plus ultraviolet A (PUVA) photochemotherapy combines the administration of psoralens, a class of phototoxic plant-derived compounds, with an exposure to ultraviolet A radiation (UVA). PUVA is used for the treatment of a variety of skin diseases, including psoriasis, mycosis fungoides, eczema, vitiligo, and graft-versus-host disease [1-3]. This topic will discuss the mechanism of action, treatment protocols, contraindications, adverse effects, and clinical indications of PUVA therapy. The use of PUVA for the treatment of specific skin conditions is discussed separately. UVB phototherapy and UVA1 phototherapy are discussed separately. ●

(See "Treatment of psoriasis in adults", section on 'Ultraviolet light'.)



(See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'PUVA'.)



(See "Vitiligo: Management and prognosis".)



(See "Treatment of chronic graft-versus-host disease", section on 'Psoralen ultraviolet irradiation'.)



(See "UVB therapy (broadband and narrowband)".)



(See "UVA1 phototherapy".)

PSORALENS Psoralens are naturally occurring phototoxic compounds that are able to enter the cell, absorb light photons, and produce a photochemical reaction that alters the function of DNA and other cell

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constituents. As part of psoralen plus ultraviolet A (PUVA) therapy, psoralens may be applied topically or taken orally. Psoralens are produced by a variety of plants of the Apiaceae and Rutaceae families, including fig, lime, celery, and parsnip. The medicinal properties of psoralens have been known for centuries and their use in treating vitiligo was recorded as long ago as 1550 BC [4]. Three psoralens are used for PUVA therapy (table 1). Methoxsalen or 8-methoxypsoralen (8-MOP) is the most widely used and the only psoralen available in the United States. Trioxsalen or 4,5',8trimethylpsoralen and bergapten or 5-methoxypsoralen are available in Europe and elsewhere (figure 1). Pharmacokinetics — The intestinal absorption rate of psoralens depends upon the physical characteristics of the preparation, concomitant food intake, and individual factors [5-8]. Variable absorption can impact the effect of psoralen on UVA exposure. Dissolved preparations (eg, soft gelatin capsules) are better absorbed than micronized, crystalline formulations (eg, hard gelatin capsules) and yield peak serum levels in a relatively reproducible time in all subjects (table 1). Food intake retards and decreases the absorption of psoralens. A first-pass effect (eg, the amount of drug that is metabolized by the liver after intestinal absorption, before entering the general circulation) may be the cause of the high interindividual variability in the plasma levels achieved after a fixed dose of methoxsalen. In the blood, 75 to 80 percent of methoxsalen is reversibly bound to serum albumin and is distributed to all organs. In the absence of UVA exposure, the binding is short lived and the drug is rapidly metabolized in the liver and excreted with urine as inactive metabolites. Drugs that induce cytochrome P-450 enzymes accelerate the metabolism of methoxsalen and may decrease the biologic effect of PUVA [7,9-11]. The pharmacokinetics of methoxsalen after transepidermal absorption depends upon the method of application [12]. Methoxsalen 0.15% emulsion or solution applied topically to large body areas leads to plasma levels comparable to those achieved with oral administration. In contrast, plasma levels after whole body bath PUVA treatment are very low. Bathwater-delivered psoralens are readily absorbed in the skin but are promptly eliminated without cutaneous accumulation. Photochemistry — Psoralens penetrate into the cells and intercalate between DNA base pairs in the absence of UV exposure. Upon exposure to UVA radiation, the psoralen molecules absorb photons, become chemically activated and covalently bond with DNA base pairs, producing interstrand crosslinks of the double helix (figure 2).

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DNA crosslinking suppresses DNA synthesis and mitosis and may cause cell apoptosis through the activation of the p53 pathway. Cells with sublethal damage repair the DNA through an error-prone repair process, resulting in mutagenesis and photocarcinogenesis. Psoralens also interact with other cell components, including mitochondria, RNA, and proteins. In keratinocyte cultures, psoralens induce mitochondrial depolarization, cytochrome c release, production of reactive oxygen species, and activation of proteases such as caspase-3 and -9 that are implicated in cell apoptosis [13]

UVA SOURCES The wavelengths of ultraviolet A (UVA) lie between 320 and 400 nm in the electromagnetic spectrum (figure 3). The most common sources of UVA radiation are fluorescent phototherapy light bulbs with maximum emission at 352 nm. UVA doses are measured in joules/cm2 (J/cm2), most often using a photometer with a maximum sensitivity at 350 to 360 nm. Although in vivo wavelengths most efficient at activating psoralens peak at 320 to 340 nm (UVA2 spectrum (figure 3)), the longer wavelength emitted by the available lamps is equally effective in clinical practice [14,15]. Psoralen activation also occurs in the UVB spectrum. Although a convenient source of UVA, natural sunlight is not safe for use with psoralens because of inherent difficulties in defining the therapeutic dose and increased risk of severe phototoxic reactions [16]. Similarly, the use of tanning beds, which have emission peaks in the range of 320 to 340 nm, may unpredictably activate psoralens with increased risk of severe erythema.

MECHANISMS OF ACTION OF PUVA Psoralen plus ultraviolet A (PUVA) exerts its therapeutic effect through multiple mechanisms, some of which are not completely understood. Initially, the mechanism in psoriasis was believed to be the inhibition of keratinocyte proliferation. However, it is now well established that the efficacy of PUVA in the treatment of psoriasis is based upon its immunomodulatory properties. Proposed mechanisms include the following: ●

Inhibition of cell proliferation – The mammalian target of rapamycin (mTOR) signaling, implicated in the regulation of cell growth and proliferation, appears to have a role in the pathogenesis of psoriasis [17]. PUVA may reduce cell proliferation in psoriasis through downregulation of the mTOR signaling pathway [18].

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Immunosuppression – The effect of PUVA in inflammatory diseases (with or without a hyperproliferative component) is mediated by its immunomodulatory properties, including alteration of cytokine and cytokine receptor expression, lymphocyte apoptosis, functional perturbation in the types and function of antigen presenting cells, and reduced expression of adhesion molecules [19-23]. The effect of PUVA in the early stages of mycosis fungoides is likely related to the ability of PUVA to induce lymphocyte apoptosis in dermal infiltrates.



Melanogenesis – PUVA stimulates melanocyte proliferation, melanogenesis, and transfer of melanosomes to keratinocytes [24]. This mechanism of action, while therapeutic in vitiligo, leads to hyperpigmentation as an adverse effect of PUVA in the treatment of other conditions.

PHOTOSENSITIVITY EFFECTS Delayed phototoxic erythema and pigmentation are the main photosensitivity effects of psoralen plus ultraviolet A (PUVA) treatment. The erythema intensity is proportional to the dose of psoralen and ultraviolet A (UVA) radiation, although there is variability in the photosensitivity response among individuals. PUVA-induced erythema usually appears 36 to 48 hours after exposure to UVA radiation and peaks at 48 to 96 hours or even up to 120 hours [25]. Erythema occurs in 10 percent of patients. PUVA treatments are usually given 48 hours apart because daily exposure may result in severe delayed cumulative phototoxicity. Excessive doses of PUVA may induce severe erythema with blistering, intense pruritus, or skin pain. (See 'Short-term adverse effects' below.) PUVA-induced pigmentation may occur in the absence of erythema, particularly with trimethylpsoralen or 5-methoxypsoralen, and is more intense and longer lasting than that produced by sunlight. The efficacy of PUVA is reduced in the presence of intense pigmentation. Therefore, for skin diseases other than vitiligo, higher doses of UVA radiation may be required as treatment proceeds.

TREATMENT PROTOCOLS Protocols for psoralen plus ultraviolet A (PUVA) treatment were initially developed for the treatment of psoriasis, but may be applied to its use in other conditions. Oral PUVA — Methoxsalen capsules are taken orally at doses of 0.4 to 0.6 mg/kg actual body weight one to two hours before exposure to ultraviolet A (UVA) radiation (table 2). Soft gelatin formulations

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of methoxsalen are absorbed faster and provide higher and more reproducible plasma levels than microcrystalline preparations. (See 'Pharmacokinetics' above.) Methoxsalen ideally should be taken with water on an empty stomach, or at least one hour after eating. However, nausea develops in about 30 percent of patients and is more common with soft gelatin preparations because of rapid absorption and increased blood levels. Nausea can be prevented by taking the drug with a small amount of food with high fat content (eg, cheese) or milk. Initial treatment (clearance phase) — The initial dose of UVA radiation is based upon one of two factors: the patient's skin type (table 3A-B); or the minimal phototoxic dose (MPD) [12,26,27]. The latter is more commonly used in a few specialized centers in Europe. The MPD is defined as the minimal dose of UVA that produces a barely perceptible but well-defined erythema when template areas of the skin are exposed to increasing doses of UVA after psoralen ingestion. Erythema readings are performed 48 or 72 hours after testing, at which time the psoralen phototoxicity reaction usually reaches its peak. The MPD test should be performed on previously nonexposed skin (eg, buttocks). Treatment is started using 50 to 70 percent of the MPD. Treatments are delivered two or three times per week, at least 48 hours apart. If no erythema is noted, the UVA dose is increased by 0.5 to 1 J/cm2 in the subsequent treatments until satisfactory control of the disease has been obtained. The dose is then held at that level. If faint erythema is present, the dose of radiation is held constant. If skin tenderness or definite erythema is present, treatment is stopped until erythema and pain have diminished. Treatment is then resumed at a lower dose. If localized erythema develops in previously unexposed parts of the body (eg, the breasts or buttocks), shielding may be employed using clothing or sunscreens that protect against UVA radiation and treatment may be continued. Repeated exposures are usually required to clear PUVA-responsive diseases, with gradual increment in the UVA dose as pigmentation develops. As an example, improvement of moderate plaque psoriasis is generally noted after 8 to 10 treatments. On average, 25 to 30 treatments are needed for complete clearance [28-32]. Since arms and legs generally respond to treatment more slowly than the trunk, the extremities may require additional doses of UVA. After the whole body dose, the patient puts on a gown or shorts and t-shirt, and covers his or her head. In patients with skin type I or II, an additional dose of one J/cm2 is delivered to the limbs and increased by 0.5 J/cm2 at each subsequent treatment. In patients with skin type ≥III, additional doses of 2 to 4 J/cm2 are delivered to the limbs and increased by 0.5 to 1 J/cm2 at each treatment.

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Adherence to the schedule is critical for treatment success. Decreased frequency of PUVA (eg, once weekly) can result in treatment failure. Maintenance treatment — After satisfactory clearing of disease, the final dose of UVA is held constant and the frequency of treatments is gradually reduced to as low as once per month [32]. Ultimately, PUVA therapy can be discontinued for patients in stable remission to avoid overtreatment and the long-term adverse effects of high cumulative doses of PUVA. Schedules for maintenance treatment and when to discontinue therapy vary between institutions. The optimal interval between treatments and the duration of the maintenance treatment should be determined for the individual patient, based upon the type of disease and the time to relapse. Treatment of relapses — If a significant relapse of the disease occurs after treatment discontinuation or during the maintenance phase, it is appropriate to resume a clearance schedule. For minor recurrences occurring during the maintenance phase, the frequency of treatments may be increased until disease control is achieved. Alternative psoralen administration — To avoid the gastrointestinal side effects of oral psoralen, protocols have been developed for psoralen to be applied topically (for localized disease) or by bath immersion. Topical PUVA — Topical PUVA may be used as an alternative to oral PUVA in patients with localized diseases, including limited plaque or palmoplantar psoriasis, hand eczema, or localized vitiligo. Topical PUVA consists of direct application to the skin of psoralens in creams, ointments, or lotions followed by exposure to UVA radiation. As an example, Methoxsalen 1% lotion can be diluted 1:10 with ethanol to yield a 0.1% solution that is applied to affected skin 15 minutes before exposure to UVA radiation. For vitiligo, the initial exposure is 0.5 J/cm2. Incremental increases of 0.25 J/cm2 are given at each treatment thereafter, until a light pink erythema is achieved in the depigmented skin. UVA dose is either held at this level or adjusted with the goal of maintaining a faint erythema in affected skin until repigmentation occurs. Treatment is given two or three times per week. A frequent complication of topical PUVA is an unexpected, usually bullous phototoxic reaction, typically caused by inadvertent exposure to natural sunlight after treatment [33]. Bath PUVA — Bath PUVA consists of whole body immersion or localized skin soaking (eg, of hands or feet) in a 0.5 to 3 mg/L solution of methoxsalen for 15 to 30 minutes. UVA irradiation is

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performed immediately after, since the photosensitivity decreases rapidly over two hours following immersion. The main advantage of bath PUVA is the absence of systemic adverse effects associated with oral psoralens [34]. However, eye protection is still required after bath PUVA since methoxsalen is detectable in the blood after topical application [35]. Bath PUVA is not widely available and there is no consensus on the optimal treatment protocol [35]. Bath PUVA is not FDA approved. In addition, the long-term adverse effects of bath PUVA, including skin carcinogenesis, are unknown.

SAFETY MEASURES It is important to protect skin that is not involved in the disease process from both topical psoralen and ultraviolet A (UVA) exposure during topical psoralen plus ultraviolet A (PUVA). When systemic psoralen is taken, the patient must be protected from additional UV exposure after the treatment. The following measures are recommended: ●

In PUVA units, small UV-blocking goggles are used to protect the eyes. If treatment is not required for facial involvement, the face is protected either by use of a broad spectrum sunscreen with an SPF of 50+ or a cloth barrier. Male genitalia are protected with the use of underwear or an athletic supporter.



Patients must protect their eyes after ingesting psoralen (or after bath exposure). Wraparound UV-blocking glasses should be worn when the patient is exposed to sunlight, from the time methoxsalen is ingested until sunset that same day.



Sun avoidance is advised to minimize pigmentation from natural sunlight. Excessive pigmentation may ultimately limit the effectiveness of PUVA therapy and require higher doses of UVA. The skin should be protected from natural sunlight through appropriate clothing and avoidance.



The amount of UVA emitted by common fluorescent lights is insufficient to activate psoralens. Thus, photoprotection is not required in home or office settings.

DRUG INTERACTIONS Phototoxic drugs (eg, thiazides, tetracyclines, fluoroquinolones, phenothiazines, or sulfonamides), and topical preparations (eg, anthralin or coal tar) may augment the action of psoralen plus

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ultraviolet A (PUVA) and increase the risk of acute phototoxic erythema. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)

CONTRAINDICATIONS Contraindications to psoralen plus ultraviolet A (PUVA) treatment are listed in the table (table 4). Absolute contraindications include: ●

Xeroderma pigmentosa



Pregnancy and lactation (methoxsalen is a pregnancy category C drug)



Lupus erythematosus with a history of photosensitivity or a positive Ro antibody

PUVA is not contraindicated in patients with cataract or aphakia because most lens implants are UV blocking. The cataracts are protective of the retina. However, patients with cataracts or aphakia should remain particularly vigilant with adequate eye protection measures. (See 'Safety measures' above.)

ADVERSE EFFECTS Short-term adverse effects — Short-term adverse effects of psoralen plus ultraviolet A (PUVA) therapy include: ●

Nausea – Nausea is the most common adverse reaction induced by oral PUVA. Taking methoxsalen with a small amount of food with high fat content or milk may prevent or reduce nausea. If nausea persists, the dose of methoxsalen can be decreased by 10 mg. In some patients, antiemetics may be needed. Ginger (ginger ale, ginger snaps) has also been used to reduce the nausea.



Erythema – Excessive phototoxicity ranging from intense delayed erythema to blistering occurs in about 10 percent of patients during the clearance phase [36]. Treatment is symptomatic and includes cool baths and liberal use of emollients and antipruritics. (See "Sunburn", section on 'Management'.)



Pruritus and skin pain – Mild pruritus is common and usually associated with skin dryness. Emollients are generally sufficient to relieve this symptom. Intense pruritus ("PUVA-itch") is often associated with erythema and is described as a deep, burning itch. PUVA-itch can also occur without erythema. It generally begins on the outer aspect of arms, thighs, buttocks, and, in women, on the breasts. Persistent skin pain is an uncommon complication of PUVA therapy [37-

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39]. Pruritus and pain are thought to be caused by phototoxic damage of the dermal nerve endings [40]. The treatment of pruritus is symptomatic. In severe cases, PUVA should be discontinued until the symptoms resolve (one to three weeks) and resumed using an ultraviolet A (UVA) dose reduced by 10 to 20 percent. There is no definite treatment for PUVA-induced skin pain. A single case report found benefit for gabapentin use [37]. ●

Subacute phototoxicity – Subacute phototoxicity manifests as a widespread scaly erythema accompanied by intense pruritus and may occur at any point during treatment, even if the UVA dose has been stable for some time [36]. An important feature is sparing of areas not exposed to UVA light during treatment (eg, axilla and/or inner thigh). Management includes cessation of PUVA therapy, and use of emollients, cool baths, and antipruritic medications until the symptoms subside. PUVA can then be resumed with a UVA dose 30 to 40 percent lower than the last used dose, with gradual increases as tolerated.



Excessive pigmentation – Excessive pigmentation is common, especially in patients with skin types ≥III and may decrease the efficacy of treatment [2].



Other adverse effects – Other short-term adverse effects include reactivation of herpes simplex, bronchoconstriction, drug fever, heart rate increase, photo-onycholysis and melanonychia, friction blisters, and ankle edema [41-43]. Central nervous system disturbances reported with PUVA therapy include headache, dizziness, depression, insomnia, and hyperactivity [36].

Long-term adverse effects Photoaging — Photoaging occurs in all patients with Fitzpatrick skin types I to IV after long-term PUVA therapy. These changes are partially reversible upon early discontinuation of therapy. Skin types I and II have more marked changes than types III and IV. The photoaging changes are similar to those produced by natural sunlight and include hyper- or hypopigmentation, telangiectasia, wrinkles, lentigines, and actinic keratosis. Hypertrichosis has been reported to occur in both men and women treated with long-term PUVA [44]. The lentigines seen with long-term PUVA therapy are composed of melanocytes of larger size and with some cellular atypia. Despite the histologic changes, there is no evidence that PUVA lentigines are precursors of melanoma [45-47]. Skin cancer — Long-term studies have demonstrated a dose-related increase in the incidence of nonmelanoma skin cancers among patients exposed to high cumulative doses of oral PUVA [48-50]. In a 30-year follow-up study of 1330 patients with psoriasis treated with PUVA, the risk of developing one or more squamous or basal cell carcinomas was greatly increased for those exposed to more

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than 350 treatments (incidence rate ratio 20.9, 95% CI 14.1-31.1) [50]. In patients previously exposed to PUVA, treatment with cyclosporin further increases the risk of developing skin cancer [51]. Men exposed to PUVA have an increased risk of genital skin cancer. In a cohort of 892 men treated with PUVA, the incidence of invasive scrotal or penile squamous cell carcinoma was 53-fold higher than that expected in the general white population [52]. Controversy surrounds the issue of long-term PUVA and melanoma. In a 25-year follow-up study, melanoma incidence in patients treated with more than 200 PUVA treatments was eightfold higher than that expected in the general population [53]. In contrast, other data (primarily from Europe) do not show an increased risk of melanoma [54]. Adding to the controversy, a retrospective study published in 2017 found that psoriasis patients had 1.53 times the risk of developing melanoma and hematologic cancers compared with patients without psoriasis. This risk was not impacted by psoriasis therapies including phototherapy [55]. Prior studies have also identified increased risk of lymphoproliferative cancers and nonmelanoma skin cancers in patients with psoriasis [56]. Based on these findings, monitoring for skin cancers remains important in patients undergoing phototherapy, including PUVA. Cataracts — Long-term PUVA carries a potential risk for cataract formation. However, a 25-year follow-up study did not show an increased risk of visual impairment or cataract formation in patients treated with PUVA [57].

MONITORING Monitoring of patients undergoing psoralen plus ultraviolet A (PUVA) treatment includes [2,58]: ●

Skin examination – Complete skin examination for skin cancer, premalignant lesions, and actinic damage is performed before starting treatment and annually thereafter [58]. It is also important to educate patients to recognize the signs of skin cancer and perform skin selfexamination.



Eye examination – Eye examination, including slit-lamp exam of lens and cornea and funduscopic examination of the retina, is performed before starting treatment and annually thereafter. (See 'Safety measures' above.)



Laboratory tests – Laboratory tests are not routinely performed before or during PUVA treatment, unless suggested by history (eg, lupus or photosensitivity).

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Outcome evaluation – The evaluation of disease activity and treatment efficacy is performed by the treating clinician at three to four month intervals.

Ongoing monitoring is indicated in patients who have received prolonged PUVA treatment, since an increased risk of skin cancer may persist after discontinuation of treatment [52].

CLINICAL INDICATIONS FOR PUVA The potential benefits of psoralen plus ultraviolet A (PUVA) must be weighed against the doserelated risks of long-term therapy in the individual patient. Most common indications for PUVA include moderate to severe psoriasis that is unresponsive to topical therapy and mycosis fungoides. Recognition of the immunosuppressive and antiproliferative effects of PUVA has led to a role for PUVA in the treatment of many other skin diseases, including eczema, vitiligo, and chronic and acute graft-versus-host disease. Additional indications for PUVA therapy are summarized in the table (table 5) [59]. The use of PUVA for the treatment of specific skin conditions is discussed separately. ●

(See "Treatment of psoriasis in adults", section on 'Ultraviolet light'.)



(See "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'PUVA'.)



(See "Vitiligo: Management and prognosis".)



(See "Treatment of chronic graft-versus-host disease", section on 'Psoralen ultraviolet irradiation'.)

SUMMARY AND RECOMMENDATIONS ●

Psoralen plus ultraviolet A (PUVA) photochemotherapy combines the administration of psoralens (table 1) with an exposure to ultraviolet A radiation. PUVA is used for the treatment of a variety of skin diseases, including psoriasis, mycosis fungoides, eczema, vitiligo, and graftversus-host disease. (See 'Introduction' above and 'Psoralens' above and 'UVA sources' above.)



The mechanisms of action of PUVA include: suppression of DNA synthesis and cell proliferation; lymphocyte apoptosis and perturbation in the type and function of antigen presenting cells; changes in cytokine and cytokine receptor expression; melanocyte proliferation and increased melanogenesis. (See 'Mechanisms of action of PUVA' above.)



The main photosensitivity effects of PUVA include a delayed phototoxic erythema that appears 36 to 48 hours after exposure, and peaks at 48 to 96 hours, and pigmentation. (See 'Photosensitivity effects' above.)

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Protocols for PUVA treatment initially developed for the treatment of psoriasis may be applied to the treatment of other conditions. For oral PUVA, which is the most common type of ultraviolet A (UVA) therapy, methoxsalen capsules are taken orally at doses of 0.4 to 0.6 mg/kg one to two hours before exposure to UVA radiation (table 2). (See 'Oral PUVA' above.)



The eyes and the skin that is not involved must be protected during PUVA. Additionally, the eyes must be protected from natural sunlight by wearing UV-blocking sunglasses after ingesting psoralens until sunset that same day. (See 'Safety measures' above.)



Short-term adverse effects of PUVA include nausea, erythema, pruritus, and excessive pigmentation. (See 'Short-term adverse effects' above.)



Long-term adverse effects of PUVA include photoaging and increased risk of nonmelanoma skin cancer. Skin examination for skin cancer should be performed annually in patients on PUVA therapy. Ongoing monitoring is indicated in patients who have received prolonged PUVA treatment, since an increased risk of skin cancer may persist after discontinuation of treatment. (See 'Long-term adverse effects' above.)

ACKNOWLEDGMENT The editorial staff at UpToDate would like to acknowledge Warwick Morison, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Subscription and License Agreement. Topic 13749 Version 11.0

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GRAPHICS Psoralens used with ultraviolet A light therapy (PUVA) for psoriasis and vitiligo Brand or generic

Drug Methoxsalen (8methoxypsoralen, 8-MOP)

Trioxsalen (4,5',8trimethylpsoralen, trioxysalen, TMP)

Trade name(s)

Manufacturer

Preparation

Suggested initial dose* (adult)

Brand

Oxsoralen-Ultra

Valeant Pharmaceuticals

10 mg liquid filled soft-gelatin capsule

0.4 mg/kg orally 1 hour prior to UVA ¶

Generic

N/A

Oceanside Pharmaceuticals (a division of Valeant Pharmaceuticals)

10 mg liquid filled soft-gelatin capsule

0.4 mg/kg orally 1 hour prior to UVA ¶

Generic

N/A

Strides Pharmaceuticals

10 mg liquid filled soft-gelatin capsule

0.4 mg/kg orally 1 hour prior to UVA ¶

Brand Δ

8-MOP

Valeant Pharmaceuticals

10 mg hard-gelatin capsule

0.6 mg/kg orally 2 hours prior to UVA ¶

Brand

Oxsoralen (lotion)

Valeant Pharmaceuticals

10 mg/mL lotion (in 71% ethanol)

Diluted 1:10 with ethanol to deliver 0.1% strength; applied to affected area according to PUVA protocol (refer to text)

Brand

Trisoralen (inactive trade name)

ICN pharmaceuticals; Valeant (former United States manufacturer)

5 mg

0.6 mg/kg orally 2 hours prior to UVA

Brand

Pentaderm, Psoraderm 5, Geralen

May be available in some countries as an unlicensed product

20 mg tablet ◊

1.2 mg/kg orally 2 hours prior to UVA

Not available in the United States Bergapten ◊ (5methoxypsoralen, 5-MOP) [1] Not available in the United States * Doses must be given at least 48 hours apart. ¶ Weight-based doses are rounded to nearest 10 mg increment. Δ Older formulation having lower oral bioavailability and longer time to onset than newer Oxsoralen-Ultra. ◊ Micronized preparations appear to provide greater cutaneous absorption than unmicronized. Reference: 1. McNeely W. 5-Methoxypsoralen: A review of its effects in psoriasis and vitiligo. Drugs 1998; 56:4. Graphic 83021 Version 5.0

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Psoralens

Graphic 83609 Version 2.0

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Mechanisms of action of psoralens

Graphic 83232 Version 4.0

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Electromagnetic spectrum

Graphic 70045 Version 4.0

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Dose schedule for methoxsalen Patient weight

Methoxsalen dose (mg)

(lb)

(kg)

90

40

Reproduced with permission of: Informa Healthcare, from Phototherapy and Photochemotherapy of Skin Disease, Morison WL, 3rd ed, New York 2005; permission conveyed through Copyright Clearance Center, Inc. Graphic 83191 Version 4.0

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PUVA treatment schedule by skin type during the clearance phase UVA radiation dose (J/cm 2)

Skin type Initial

Increments

Maximum dose

I

1.5

0.5

5

II

2.5

0.5

8

III

3.5

0.5-1.0

12

IV

4.5

1.0

14

V

5.5

1.0

16

VI

6.5

1.0-1.5

20

Reproduced with permission of: Informa Healthcare, from Phototherapy and Photochemotherapy of Skin Disease, Morison WL, 3rd ed, New York 2005; permission conveyed through Copyright Clearance Center, Inc. Graphic 83193 Version 4.0

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Fitzpatrick skin phototypes Skin type

Unexposed skin color

Reaction to sun exposure*

I

White

Always burns, never tans

II

White

Always burns, minimal tan

III

White to olive

Burns minimally, gradually tans

IV

Light brown

Burns minimally, tans well

V

Brown

Very rarely burns, tans profusely

VI

Dark brown to black

Never burns, tans deeply

Note: Slight variations on the definitions of the phototypes appear in the literature. * After the first one hour of sun exposure on untanned skin on the first day of spring. Graphic 60541 Version 4.0

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Contraindications to PUVA phototherapy Absolute Xeroderma pigmentosum Lupus erythematosus with photosensitivity or positive Ro antibody Pregnancy (category C) Lactation

Relative Photosensitivity and/photosensitizing medications History or family history of melanoma History of nonmelanoma skin cancer and/or extensive solar damage Previous treatment with ionizing radiation or arsenic Severe liver, renal, or cardiac disease Young age PUVA: psoralen plus ultraviolet A. References: 1. Morison WL. Phototherapy and Photochemotherapy of Skin Disease, 3rd ed, Taylor and Francis, New York 2005. 2. Morison WL. PUVA Photochemotherapy. In: Comprehensive Dermatologic Drug Therapy, 2nd ed, Wolverton SE (Ed), Elsevier, Philadelphia 2007. Graphic 83207 Version 3.0

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PUVA indications FDA approved indications Psoriasis* Vitiligo ¶

Off label dermatologic uses Neoplastic Mycosis fungoides/Sezary syndrome Histiocytosis X (Langerhans cell histiocytosis)

Papulosquamous/dermatitis Atopic dermatitis Seborrheic dermatitis Chronic hand dermatitis Palmoplantar pustulosis Lichen planus Parapsoriasis Pityriasis lichenoides Lymphomatoid papulosis

Photosensitivity dermatoses Polymorphous light eruption Erythropoietic protoporphyria Solar urticaria Chronic actinic dermatitis

Other pruritic dermatoses Dermographism Aquagenic urticaria/pruritus Chronic urticaria Polycythemia vera Idiopathic pruritus Urticaria pigmentosa Prurigo nodularis

Other immunologic dermatoses Alopecia areata Graft-versus-host disease Morphea Linear scleroderma

Miscellaneous dermatoses Transient acantholytic dermatosis (Grover's disease) Pigmented purpuric dermatoses Ichthyosis linearis circumflexa Scleromyxedema Generalized granuloma annulare

* Methoxsalen capsules approved for this indication. ¶ Methoxsalen solution and trioxsalen are approved for this indication. Reproduced from: Morison WL. PUVA Photochemotherapy. In: Comprehensive Dermatologic Drug Therapy, 2nd ed, Wolverton SE (Ed), Saunders Elsevier, Philadelphia 2007. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 83200 Version 3.0

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The genodermatoses: An overview - UpToDate uptodate.com/contents/the-genodermatoses-an-overview/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Nov 15, 2018.

INTRODUCTION

The genodermatoses are a large group of inherited

disorders with skin manifestations. Many of these disorders are rare. However, the recognition of their skin findings is important not only for the initiation of appropriate therapy but also for the detection of other associated abnormalities, including malignancy, in these frequently multisystem disorders [1-3]. An overview of the genodermatoses is presented here. Online resources that provide general information about these disorders include Orphanet and Online Mendelian Inheritance in Man (OMIM).

DISORDERS WITH MALIGNANT POTENTIAL

This group of genodermatoses is of particular importance because

of the association of skin findings with the development of malignancies, both cutaneous and noncutaneous (table 1). Examples include basal cell nevus syndrome, Gardner syndrome, PeutzJeghers syndrome (PJS), and xeroderma pigmentosum (XP).

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Basal cell nevus syndrome — The basal cell nevus syndrome (nevoid basal cell carcinoma syndrome, Gorlin syndrome, MIM #109400) is a rare disorder of autosomal dominant inheritance that results from germline mutations of the human patched gene (PTCH). (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".) Affected patients have both developmental anomalies and postnatal tumors, especially multiple basal cell carcinomas (BCCs), usually by age 35 years. Most have the following clinical features: ●Macrocephaly, frontal bossing, and hypertelorism. ●Bifid ribs. ●Palmar and plantar pitting (picture 1). ●Odontogenic keratocysts, especially in the mandible, which usually develop in adolescence and typically are the presenting sign of the disorder. ●Medulloblastoma in 3 to 5 percent; meningioma occurs infrequently. (See "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma".) The histologic appearance of the BCCs in basal cell nevus syndrome does not differ from those seen in sporadic cases. The diagnosis should be suspected in patients who present with multiple BCCs, especially at an early age. These patients require careful sun protection from infancy and regular skin surveillance by a dermatologist. Radiotherapy should be avoided due to the risk of inducing BCCs in the treatment fields.

Gardner syndrome — Gardner syndrome consists of familial adenomatous polyposis (FAP, MIM #175100) with associated extraintestinal manifestations [4]. It is inherited as an autosomal dominant disorder caused by mutations in the tumor suppressor gene, adenomatous polyposis coli (APC). (See "Gardner syndrome".) The most characteristic skin feature is multiple epidermoid cysts. Other findings include desmoid tumors, lipomas, osteomas (especially of the mandible), supernumerary teeth, gastric polyps, and juvenile nasopharyngeal angiofibromas. Congenital hypertrophy of the retinal pigmented epithelium is a reliable and early marker of the disease when it is present. Prophylactic colectomy is recommended because of the nearly universal development of colorectal cancer in affected patients. In addition to colorectal adenocarcinoma, patients with FAP are at risk for several extracolonic malignancies, including: ●Duodenal ampullary carcinoma

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●Follicular or papillary thyroid cancer ●Childhood hepatoblastoma ●Gastric carcinoma ●Central nervous system (CNS) tumors (mostly medulloblastomas)

Peutz-Jeghers syndrome — Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant condition characterized by distinctive mucocutaneous pigmentations and multiple hamartomatous polyps in the gastrointestinal tract [5]. Most cases are associated with mutations in the tumor suppressor gene STK11 (serine/threonine kinase 11)/LKB1 [6]. (See "PeutzJeghers syndrome: Clinical manifestations, diagnosis, and management".) The characteristic mucocutaneous pigmentations (lentigines) of PJS are present in more than 95 percent of patients and are caused by pigment-laden macrophages in the dermis. They are typically flat, blue-gray to brown spots 1 to 5 mm in size that look like freckles. However, the onset and location of PJS spots are different from those of freckles. Lentigines occur most commonly on the lips and perioral region (94 percent), hands (74 percent), buccal mucosa (66 percent), and feet (62 percent) (picture 2) [7]. They also occur on the nose, perianal area, and genitals and are rarely found in the intestines. They usually occur during the first one to two years of life, increase in size and number over the ensuing years, and finally fade after puberty, with the exception of those on the buccal mucosa. Gastrointestinal hamartomatous polyps are present in most patients with PJS, and patients may develop gastrointestinal malignancy. The risk of nongastrointestinal cancers, including adenocarcinomas of the breast, cervix, pancreas, uterus, and ovaries, is also increased.

Xeroderma pigmentosum — Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder caused by mutations in any of eight genes involved in the recognition and repair of ultraviolet radiation (UVR)-induced DNA damage [8]. XP is characterized by increased sensitivity to UVR, early development of pigmentary changes and UVR-induced skin and mucous membrane cancers (beginning in early childhood), and, in some patients, progressive neurodegeneration. The pathogenesis, clinical manifestations, diagnosis, and management of XP are discussed in detail separately. (See "Xeroderma pigmentosum".)

Epidermolysis bullosa — Patients with particular subtypes of epidermolysis bullosa are at increased risk for cutaneous malignancy. (See "Epidemiology, pathogenesis, classification, and clinical features of epidermolysis bullosa", section on 'Skin cancer'.)

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DISORDERS OF KERATINIZATION

Keratins

are intermediate filament proteins that form the cytoskeleton in all epithelial cells, including the stratified epithelium of the epidermis [9]. Keratins represent the major proteins produced by the keratinocyte, which is the primary cell type of the epidermis. The maturation of basal epidermal cells to the flattened cells that constitute the superficial stratum corneum is known as keratinization [10]. Over 50 genes that encode keratins have been identified in humans [11]. The phenotype resulting from a particular mutation depends upon the tissue-specific expression pattern of that keratin.

Ichthyoses — The ichthyoses are a diverse group of hereditary skin disorders characterized by the accumulation of "fish-like" scales resulting from abnormal epidermal cell kinetics or differentiation (table 2) [12]. The severity of the individual disorders ranges from asymptomatic to life threatening. The cornerstone of therapy for all types is aggressive hydration of the skin with emollients. When tolerated, keratolytics also may be used. Severe or extensive involvement may require systemic retinoids. Referral to a dermatologist is indicated when basic treatment measures, such as emollients, are not working, when there are complications related to the skin condition, or if the diagnosis is not clear. Biopsy is useful for certain types of ichthyoses or disorders of cornification. The major types of inherited ichthyoses are reviewed separately. Information for patients and families is available on the website of the Foundation for Ichthyosis and Related Skin Types. ●(See "Overview and classification of the inherited ichthyoses".) ●(See "Autosomal recessive congenital ichthyosis".) ●(See "Recessive X-linked ichthyosis".) ●(See "Keratinopathic ichthyoses".) ●(See "Netherton syndrome".) ●(See "Sjögren-Larsson syndrome".)

Palmoplantar keratodermas — These disorders share the common feature of palmar and plantar hyperkeratosis that manifests as thickening and scaling of the palms and soles. The general underlying defect in the majority of the palmoplantar keratodermas is overproduction of a normal or an abnormal keratin in the palms and soles. The majority of cases are mild to moderate, without systemic problems and with autosomal dominant inheritance.

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The keratodermas differ in their mode of inheritance, severity, and extent of involvement and associated features [13,14]. This is illustrated by the following examples of these disorders: ●Howel-Evans syndrome is a rare, autosomal dominant diffuse form with onset between 5 and 15 years of age [15]. It has been associated with the early development of esophageal cancer. ●Vohwinkel syndrome is a rare, autosomal dominant disorder in which patients may have autoamputation of the digits (pseudoainhum) and high-frequency hearing loss. ●Papillon-Lefèvre syndrome is an autosomal recessive condition that presents in the first six months of life. Patients often have severe periodontitis, leading to early dental loss. Dermatologic management of these disorders includes regular application of emollients and keratolytic agents and physical removal of excess scale. Oral retinoids also have been beneficial in some cases. Secondary bacterial, viral, or fungal infections are a frequent complicating feature, necessitating appropriate treatment with antibiotics.

Pachyonychia congenita — Pachyonychia congenita (PC) is an autosomal dominant disorder caused by mutations in the genes that encode keratins (KRT6A, KRT6B, KRT6C, KRT16, and KRT17), the type I and II intermediate filament proteins that form a cytoskeletal network in all epithelial cells [16]. Affected patients present with thickened, discolored nails of the fingers and toes (picture 3). These changes are present at birth in approximately 50 percent of the affected children [17]. Palmar and plantar hyperkeratoses and hyperhidrosis, follicular keratoses of the knees and elbows, and oral leukoplakia may develop within the first decade of life. Thickened nails and plantar hyperkeratoses may be extremely painful [18]. The pathogenesis, clinical manifestations, diagnosis, and management of PC are discussed in detail separately. (See "Pachyonychia congenita".)

Darier disease — Darier disease, also known as Darier-White disease or keratosis follicularis (MIM #124200), is an autosomal dominant disorder caused by mutations in the gene encoding the sarco/endoplasmic reticulum Ca(+2)-ATPase [19]. This results in loss of adhesion between epidermal cells and abnormal keratinization. The disorder is a relatively common genodermatosis with a frequency of up to 1 in 36,000 individuals [20]. The disorder typically presents in the second decade of life with hyperkeratotic, yellow-brown, greasy-appearing papules that coalesce into verrucous-like plaques (picture 4A-B) [21,22]. The lesions are often pruritic and frequently become purulent and malodorous, especially if infected. Typical sites of involvement are in a seborrheic distribution: trunk, face, scalp, and groin. Nails may demonstrate red/white vertical stripes, subungual hyperkeratosis, and notching of the distal nail margins (picture 5). Palmar keratosis and pits often are present. The course of the illness is chronic and persistent, with characteristic worsening in summer months. Darier disease is discussed in detail separately. (See "Darier disease".)

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GENETIC BLISTERING DISORDERS

These disorders result from abnormalities in the cohesion of the

layers of the epidermis. They result in separation of the layers in response to minimal injury.

Epidermolysis bullosa — Epidermolysis bullosa (EB) constitutes a clinically and genetically heterogeneous group of rare inherited disorders characterized by marked skin and mucosal fragility caused by mutations in skin structural proteins. There are four major types of EB, based upon the ultrastructural level of tissue cleavage in the skin: EB simplex, junctional EB, dystrophic EB, and Kindler syndrome (table 3) [23,24]. Many subtypes have been identified based upon clinical, pathophysiologic, and molecular criteria (table 4A-D). The clinical features, diagnosis, and management of EB are discussed in detail separately. (See "Epidemiology, pathogenesis, classification, and clinical features of epidermolysis bullosa" and "Diagnosis of epidermolysis bullosa" and "Overview of the management of epidermolysis bullosa".)

PIGMENTATION DISORDERS

Melanin, a black or

brown pigment formed from tyrosine, is responsible for the color of skin and hair [25]. Melanin is synthesized in melanocytes, which are specialized, dendritic secretory cells derived from the neural crest. These cells migrate to the basal layer of the epidermis during embryogenesis. The presence of melanin in the epidermis helps provide protection from ultraviolet radiation. Disorders include decreased and excessive pigmentation. Diagnosis is based on the clinical features in most cases, although some may be clarified with molecular testing. (See "Congenital and inherited hyperpigmentation disorders".)

Oculocutaneous albinism — Oculocutaneous albinism (OCA) is a group of rare genetic disorders of melanin biosynthesis inherited in an autosomal recessive pattern [26,27]. There are seven types of OCA caused by mutations in different genes (table 5). Although all types share absent or reduced pigmentation of the hair, skin, and eyes, the clinical phenotypes vary along a broad spectrum of disease severity. The pathogenesis, clinical manifestations, diagnosis, and management of OCA are discussed in detail separately. (See "Oculocutaneous albinism".)

Ocular albinism — Ocular albinism is albinism in which the hypopigmentation is primarily limited to the eyes [28,29]. It is less common than oculocutaneous albinism.

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Ocular albinism type 1 (OA1, MIM #300500), also known as Nettleship-Falls ocular albinism, is the most common form of ocular albinism and has X-linked recessive inheritance. It has an estimated prevalence of 1 in 50,000 to 150,000 live births [30,31]. The clinical manifestations of OA1 are variable. In affected males, clinical features may include mild cutaneous hypopigmentation, hypopigmentation of the iris and retina, foveal hypoplasia, prominent choroidal vessels, nystagmus, strabismus, head nodding, photophobia, impaired vision, and abnormal crossing of the optic fibers resulting in deficient stereoscopic vision [29,32,33]. Female carriers may have a patchy distribution of retinal pigmentation resulting from X-inactivation [29,34]. OA1 is diagnosed by careful analysis of the family pedigree for X-linked inheritance and/or molecular analysis of the OA1 gene [34]. The severity of OA1 appears to be related to ethnic background, with individuals from lightly pigmented racial groups more severely affected than those from darkly pigmented groups [35-37]. Life expectancy is normal [28]. OA1 has been associated with late-onset sensorineural deafness. This form (OASD, MIM 300650) is probably a contiguous gene defect that includes the OA1 gene [38,39]. Another form of ocular albinism with sensorineural deafness has been linked to chromosome 11 and has autosomal recessive inheritance; this form is also known as Waardenburg syndrome type 2 (MIM 103470) [40]. (See 'Waardenburg syndrome' below.) Ocular albinism type 2 (OA2, MIM #300600), also known as Forsius-Eriksson type ocular albinism and Aland Island eye disease, is a rare, X-linked disorder with clinical manifestations that include nystagmus, myopia, astigmatism, foveal hypoplasia, reduced visual acuity, pigmentary changes in the retina, and changes in color vision; the optic nerves are normal [28].

Piebaldism — Piebaldism (piebald trait) is a rare, autosomal dominant disorder in which cell proliferation and migration of neural crest-derived melanoblasts are defective. This leads to an abnormal distribution of melanocytes during embryogenesis and results in patchy areas of depigmentation [41]. The disorder is caused by mutations in the cell-surface receptor tyrosine kinase gene (KIT) [42]. Affected patients have patches of depigmented skin, with hyperpigmented borders occurring principally on the midforehead, neck, anterior trunk, and midextremities (picture 6A-C). Normal pigmentation occurs on the hands, feet, back, shoulders, and hips. A white forelock is a common finding. The depigmentation is stable and permanent. Patients with piebaldism are generally otherwise healthy and have normal life spans. The pathogenesis, clinical manifestations, diagnosis, and management of piebaldism are discussed in detail separately. (See "Piebaldism".)

Waardenburg syndrome — Waardenburg syndrome is another autosomal dominant inherited pigmentary disorder in which abnormal distribution of melanocytes during embryogenesis results in patchy areas of depigmentation [41,43,44]. Several forms of

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Waardenburg syndrome are described. All have the clinical features of type 1, which is characterized by a piebald-like distribution of patchy depigmentation of the hair and skin. Other distinctive noncutaneous features include pigmentary abnormalities of the iris (heterochromia irides) and a broad nasal root, secondary to lateral displacement of the inner canthi of the eyes (picture 7). Congenital deafness occurs in one in five patients with Waardenburg syndrome, and, conversely, an estimated 2 to 7 percent of cases of congenital deafness result from the disorder [45,46]. Occasional findings in Waardenburg syndrome type 1 include cleft lip and palate and neural tube defects (eg, spina bifida, myelomeningocele) [47]. Waardenburg syndrome type 1 (MIM #193500) and type 3 (MIM #148820) are caused by mutations in the gene for one of three transcription factors (PAX3), whereas type 2 (MIM #193510) is caused by mutations in the transcription factor MITF [48,49]. Waardenburg syndrome type 4 (MIM #277580) also has features of Hirschsprung disease. This type is a result of biallelic mutation in the genes for the endothelin-B receptor (EDNRB) or its ligand endothelin-B (EDN3) [50,51] or heterozygous mutation in the SOX10 gene [52]. (See "Congenital aganglionic megacolon (Hirschsprung disease)".)

NEUROCUTANEOUS SYNDROMES

Neurocutaneous genetic disorders, also called phakomatoses,

may present with a variety of neurologic and cutaneous findings. Examples include the neurofibromatoses and tuberous sclerosis complex.

Neurofibromatosis type 1 — Neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease, is an autosomal dominant neurocutaneous disorder with nervous system, skeletal, and dermatologic manifestations [53]. It is caused by mutations in the NF1 gene, encoding the protein neurofibromin. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".) The characteristic skin findings that contribute to establishing the diagnosis are: ●Six or more café-au-lait macules of greatest diameter >5 mm in prepubertal and >15 mm in postpubertal individuals (picture 8A) ●Two or more neurofibromas of any type or one plexiform neurofibroma (picture 8B) ●Freckling in the axillary or inguinal regions (Crowe sign) (picture 8C)

Neurofibromatosis type 2 — Neurofibromatosis type 2 (NF2) is the central form of neurofibromatosis and is characterized by bilateral vestibular schwannomas (acoustic neuromas), meningiomas of the brain, and schwannomas/neurilemmomas of the dorsal roots of the spinal cord. The disorder typically presents in the teens or soon after puberty with unilateral hearing loss. In contrast to NF1, café-au-lait spots in NF2 are typically few, large, and

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relatively light in color [54]. NF2 is caused by mutations in the gene encoding the intracellular membrane-associated protein neurofibromin-2 (NF-2), a tumor suppressor, which is also known as merlin [55]. (See "Neurofibromatosis type 2".)

Tuberous sclerosis complex — Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder that's skin findings are often the first clues to its diagnosis [56,57]. TSC is caused by mutations in one of two genes: TSC1, which encodes hamartin, and TSC2, which encodes tuberin. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis".) It is estimated that more than 95 percent of patients with TSC have one of the characteristic skin lesions [57]. The most common lesions are: ●Hypopigmented macules, also known as ash-leaf spots, which are usually elliptical in shape (picture 9A). These are often present at birth, although a Wood's lamp examination may be required to visualize them. ●Angiofibromas, previously called adenoma sebaceum, which typically involve the malar regions of the face (picture 9B) and usually become apparent by late childhood or early adolescence. ●Shagreen patches (connective tissue nevi), seen most commonly over the lower trunk. ●A distinctive brown, fibrous plaque on the forehead, which may be the first and most readily recognized feature of TSC to appear on physical examination of affected neonates and infants (picture 10) [57].

Ataxia-telangiectasia — Ataxia-telangiectasia (AT, also known as Louis-Bar syndrome) is an autosomal recessive disorder caused by mutations in the gene designated ATM (AT mutated). The ATM gene, which is expressed in all tissues in the body, is involved in the detection of DNA damage and plays an important role in cell cycle progression. The pathogenesis of AT is thought to be a defect in DNA repair resulting in increased sensitivity to ionizing radiation, immunodeficiency, and progressive cerebellar Purkinje cell death. Patients with AT suffer from progressive cerebellar ataxia and other neurologic abnormalities, oculocutaneous telangiectasias, and immune deficiency. Associated features are an increased incidence of malignancy, radiation sensitivity, and diabetes mellitus caused by insulin resistance. (See "Ataxia-telangiectasia".)

VASCULAR DISORDERS

Inherited syndromes associated

with cutaneous vascular abnormalities include ataxia-telangiectasia (AT) and hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome. These disorders are discussed separately. (See "Ataxia-telangiectasia" and "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

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DISORDERS OF CONNECTIVE TISSUE

Abnormalities of connective tissue are frequently expressed in the skin. Thus,

multisystem inherited connective tissue disorders, such as Ehlers-Danlos syndrome, Marfan syndrome, and osteogenesis imperfecta, can be classified as genodermatoses. Pseudoxanthoma elasticum (PXE) and focal dermal hypoplasia are less common connective tissue disorders with prominent skin abnormalities. ●(See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes".) ●(See "Overview of the management of Ehlers-Danlos syndromes".) ●(See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".) ●(See "Management of Marfan syndrome and related disorders".) ●(See "Osteogenesis imperfecta: Clinical features and diagnosis".) ●(See "Osteogenesis imperfecta: Management and prognosis".)

Pseudoxanthoma elasticum — Pseudoxanthoma elasticum (PXE, also called Grönblad-Strandberg syndrome, MIM #264800 and #177850) is a genetic disorder of abnormal elastic tissue (fragmentation of elastic fibers) and calcification. Inherited forms are autosomal recessive, but sporadic forms have been observed [58]. The underlying defect is a mutation in the ABCC6 gene on chromosome 16 that encodes an ATP-binding cassette transporter [59-61]. The onset of the disorder varies from childhood to early adulthood, although the characteristic skin findings may be subtle in children. The primary organ systems involved include the skin, eyes, and cardiovascular systems; gastrointestinal bleeding also can occur [62-64]. Progressive skin lesions develop in 80 percent of individuals before age 20 years. The characteristic skin findings are 2 to 5 mm yellow to orange papules, which may coalesce into irregularly shaped plaques surrounded by normal skin. Because such lesions have a pebbly appearance and are yellow, they are named pseudoxanthomas. The texture of the skin has been likened to plucked-chicken skin. Lesions occur most commonly in flexural areas, such as the neck and axillary folds, periumbilical region, and on the inner lower lip (picture 11A-D). The involved skin may eventually become lax and redundant. The primary ocular finding is that of angioid streaks, representing tears in Bruch's membrane, but this finding is seen in other disorders as well (picture 11E). Macular degeneration and retinal deformities contribute to loss of central vision. Severe vision loss occurs in 3 to 8 percent of patients.

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Common cardiovascular manifestations include accelerated atherosclerosis, which is thought to result from calcification of the internal elastic laminae. These changes can result in myocardial infarction, cerebrovascular disease, and renovascular hypertension at a young age and result in a shortened life expectancy. The diagnosis of PXE is based upon the clinical appearance and findings on histologic examination of lesional skin. Treatment consists of close ophthalmologic management, monitoring and treatment of any cardiovascular symptoms, and dietary consultation. Because of the risk of ocular disease, patients should be educated to avoid contact sports and straining (eg, weight lifting) [64]. They should be referred for genetic counseling.

X-LINKED DOMINANT DISORDERS

Incontinentia pigmenti (IP), focal dermal hypoplasia, congenital

hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome, MIM #308050), and chondrodysplasia punctata (Conradi-Hünermann-Happle syndrome, MIM #302960) are examples of X-linked dominant disorders with cutaneous manifestations [65,66]. ●(See "Overview and classification of the inherited ichthyoses", section on 'X-linked dominant disorders'.) ●(See "Focal dermal hypoplasia (Goltz syndrome)".) ●(See "Incontinentia pigmenti".)

ECTODERMAL DYSPLASIAS

The ectodermal

dysplasias are a large group of inherited disorders that manifest as developmental anomalies in at least two of the structures derived from the embryonic ectoderm, with at least one involving the skin appendages (hair, nails, sweat glands) or teeth (table 6) [67]. The classic ectodermal dysplasias, including hypohidrotic ectodermal dysplasia, hypohidrotic ectodermal dysplasia with immune deficiency, and hidrotic ectodermal dysplasia; tumor protein p63-related disorders; and focal dermal hypoplasias are discussed separately. ●(See "Ectodermal dysplasias".) ●(See "Tumor protein p63-related disorders".) ●(See "Focal dermal hypoplasia (Goltz syndrome)".)

SUMMARY 8861

●The genodermatoses are a heterogeneous group of rare inherited single-gene disorders with skin manifestations. Recognition is important for the initiation of appropriate dermatologic therapy and detection of other associated abnormalities, including malignancy. (See 'Introduction' above.) ●Genodermatoses associated with the development of cutaneous and noncutaneous malignancies include basal cell nevus syndrome (picture 1), Gardner syndrome, Peutz-Jeghers syndrome (PJS) (picture 2), and xeroderma pigmentosum (XP) (table 1). (See 'Disorders with malignant potential' above.) ●Keratins form the cytoskeleton in epithelial cells. Disorders of keratinization include the ichthyosiform dermatoses (table 2 and picture 12A-C), palmoplantar keratodermas, pachyonychia congenita (picture 3), and Darier disease (picture 4A-B). (See 'Disorders of keratinization' above.) ●Abnormalities in the cohesion of the layers of the epidermis underlie the congenital blistering disorders (ie, the epidermolysis bullosa syndromes), in which blister formation occurs with little or no trauma (picture 13A-B). (See 'Epidermolysis bullosa' above.) ●Congenital defects in melanin synthesis lead to pigmentation disorders. These include oculocutaneous albinism, a group of autosomal recessive disorders resulting in hypopigmentation of the hair, skin, and eyes (table 5); piebaldism; and Waardenburg syndrome (picture 7). (See 'Pigmentation disorders' above.) ●Cutaneous findings are often a key to the diagnosis of the most common neurocutaneous syndromes: neurofibromatosis (picture 8A-C), tuberous sclerosis complex (TSC) (picture 9A-B), and ataxia-telangiectasia (AT). (See 'Neurocutaneous syndromes' above.) ●Multisystem inherited connective tissue disorders include Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum (picture 11A-B, 11E). (See 'Disorders of connective tissue' above.) ●X-linked disorders with cutaneous manifestations include incontinentia pigmenti (picture 14) and focal dermal hypoplasia (picture 15). (See 'X-linked dominant disorders' above.) ●The ectodermal dysplasias are a large group of inherited disorders that manifest as developmental anomalies in at least two of the structures derived from the embryonic ectoderm, with at least one involving the skin appendages (hair, nails, sweat glands) or teeth (table 6). (See 'Ectodermal dysplasias' above.)

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Epidemiology, pathogenesis, classification, and clinical features of epidermolysis bullosa uptodate.com/contents/epidemiology-pathogenesis-classification-and-clinical-features-of-epidermolysis-bullosa/print

Epidemiology, pathogenesis, classification, and clinical features of epidermolysis bullosa All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Aug 17, 2018.

INTRODUCTION

Epidermolysis bullosa (EB) encompasses a clinically

and genetically heterogeneous group of rare inherited disorders characterized by marked mechanical fragility of epithelial tissues with blistering, erosions, and nonhealing ulcers following minor trauma. EB is caused by mutations involving at least 20 genes encoding structural proteins within keratin intermediate filaments, focal adhesions, desmosome cell junctions, and hemidesmosome attachment complexes, which form the intraepidermal adhesion and dermoepidermal anchoring complex within the basement membrane zone (BMZ) of the skin and mucosae (figure 1) [1-4]. The molecular aberrations interfere with the functional and structural integrity of the BMZ (which is a highly specialized interface between epithelial cells and the underlying matrix) that is crucial for cell adhesion, proliferation, and differentiation; tissue repair; and barrier function [3] and leads to cell and tissue dehiscence. Type (homozygosity versus heterozygosity), number (monogenic, digenic inheritance), and location of mutation(s) within the gene or gene segment, as well as the spectrum of subsequent quantitative (absence, reduction) or qualitative (gradual loss of function) alteration of protein expression, results in considerable genetic heterogeneity with complex genotype-phenotype correlations. Apart from the primary structural-functional defect, secondary epigenetic factors (eg, differentially regulated

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expression of a host of other genes involved in the maintenance and function of this microenvironment, induction of inflammatory cascades) and environmental factors further contribute to the highly variable phenotype of EB [5,6]. Against this background, advanced molecular profiling techniques/methodologies (next-generation sequencing panels encompassing EB-related genes, whole exome/genome sequencing, homozygosity mapping) have been established to allow confirmation of diagnosis, precise subcategorization, and more accurate prognostication [7-11]. The epidemiology, pathogenesis, and clinical features of EB are discussed in this topic. The diagnosis and management of EB and Kindler syndrome are discussed separately. ●(See "Diagnosis of epidermolysis bullosa".) ●(See "Overview of the management of epidermolysis bullosa".) ●(See "Kindler syndrome".)

EPIDEMIOLOGY

The most reliable figures on prevalence and incidence of

epidermolysis bullosa (EB) are derived from the National EB Registry (NEBR), which collected crosssectional and longitudinal data on about 3300 EB patients in the United States from 1986 through 2002 [12-14]. Over a 16-year period (1986 through 2002), the prevalence of EB was estimated to be approximately 11 per million and the incidence approximately 20 per million live births [14]. Over the same period, the incidence rates of EB by subtype were approximately eight per million live births for EB simplex, three per million live births for junctional EB, two per million live births for dominant dystrophic EB, and three per million live births for recessive dystrophic EB. Data from the Dystrophic Epidermolysis Bullosa Research Association of America (DebRA) report an incidence rate of 3.6 per million per year for junctional EB over the period 2007 to 2011 [15]. Data from the Australasian EB Registry provided a prevalence estimate of 10 cases per million live births [16]. Prevalence rates ranging from 15 to 32 cases per million have been estimated in the UK [17-19].

NOMENCLATURE AND CLASSIFICATION OF EB

In 2013, a revised nomenclature

and classification system of EB have been proposed [20]. The new classification includes the new clinical phenotypes and gene mutations that have been described since the 2008 consensus classification [1].

The "onion skin approach" — The first diagnostic step in the classification of the patient with EB involves the determination of the level of blister formation, usually by immunofluorescence antigen mapping and/or transmission electron microscopy (figure 1) [1].

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Based upon the level of skin cleavage, EB is classified into four major groups: ●Epidermolysis bullosa simplex (EBS) – Intraepidermal cleavage plane, within the basal keratinocytes (basal EBS) or above the level of basal keratinocytes (suprabasal EBS) ●Junctional epidermolysis bullosa (JEB) – Cleavage plane within the lamina lucida of the dermoepidermal junction ●Dystrophic epidermolysis bullosa (DEB) – Cleavage plane below the lamina densa, within the upper papillary dermis at level of anchoring fibrils ●Kindler syndrome – Multiple cleavage planes (intraepidermal, intralamina lucida, or sublamina densa) In the next step, EB is classified based upon phenotypic features, such as distribution (eg, localized or generalized), severity, and presence of extracutaneous involvement. The patient's family history may suggest the mode of inheritance. The final classification of EB into specific subtypes involves the identification of the defective protein by immunofluorescence staining with panels of specific monoclonal antibodies directed against epidermal antigens/structural proteins and components of the dermoepidermal junction and, whenever possible, the identification of the gene involved and specific mutation by mutational analysis. (See "Diagnosis of epidermolysis bullosa".)

EPIDERMOLYSIS BULLOSA SIMPLEX Overview — Epidermolysis bullosa simplex (EBS) is the most common type of EB, accounting for 75 to 85 percent of all cases of EB in Western countries [21]. In the vast majority of cases, EBS is caused by mutations in the keratin genes, resulting in the formation of a cleavage plane at the level of the basal keratinocytes. Rare variants are associated with mutations in genes encoding other structural proteins of the basal membrane zone, including desmoplakin, plakophilin1, plakoglobin, integrins A6 and B4, type XVII collagen, plectin, transglutaminase 5, and dystonin (figure 1) [22]. EBS is almost always inherited in an autosomal dominant fashion, but rare autosomal recessive forms have been reported [21,23-26]. EBS is characterized by trauma- or friction-induced skin blistering with localized or disseminated anatomic distribution. The most common subtypes of EBS are: ●EBS, localized (formerly known as EBS Weber-Cockayne) ●EBS, generalized severe (formerly known as EBS Dowling-Meara)

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●EBS, generalized intermediate (includes the type formerly known as EBS Koebner) Rare variants include suprabasal EBS, recessive EBS, EBS associated with pyloric atresia, EBS with mottled pigmentation, EBS associated with muscular dystrophy, and EBS of Ogna. The pattern of inheritance, gene mutations, and clinical features of EBS variants are summarized in the table (table 1).

Pathogenesis — In most cases, EBS is caused by dominant negative missense mutations in KRT5 and KRT14 genes (table 1), encoding keratins that are mainly expressed in the basal keratinocytes [27]. Rarely, EBS may be caused by autosomal recessive inheritance of either one of these genes (more often KRT14) [28,29]. Three cases of digenic inheritance (ie, combined mutations in KRT5 and KRT14-) have also been reported [30-32]. Large intragenic KRT5 mutations have additionally been implicated in some unsolved cases of EBS [33]. Genotype-phenotype analyses revealed that mutations affecting conserved areas at the beginning (N-terminal end-domain) or end (C-terminal end-domain) of the central alpha-helical rod segment of keratin molecules inhibit the end-to-end aggregation of keratin filaments [3,34-37] and are associated with a severe disruption of the cytoskeleton, epidermal fragility to friction forces, and phenotype. Mutations affecting less conserved areas, such as the head or tail domain, result in an impaired but still possible partial filament formation and are associated with a milder phenotype [21,23]. Some keratin mutations may affect cytoskeletal dynamics or interfere with normal post-translational keratin modifications [38]. The disease severity is also influenced by homozygosity (severe phenotype) or heterozygosity (milder phenotype) of the genetic defect and by the type of point mutation [39,40]. Mutations in the PLEC1 gene that encodes plectin (a hemidesmosomal protein expressed in various tissues, including gastrointestinal epithelia and striated muscle) are associated with autosomal recessive EBS with muscular dystrophy and EBS with pyloric atresia (table 1) [41,42]. Many plectin mutations cluster in exon 31 that encodes the rod domain. Plectin mutations are also associated with the autosomal dominant EBS of Ogna [43], a lethal form of EBS [44], and an autosomal recessive EBS form (with acral, later generalized blistering) without extracutaneous involvement [45]. Mutations affecting structural components of desmosomes, adhesion contacts, or proteins involved in the terminal differentiation within the upper epidermis are associated with suprabasal EBS (table 1): ●Acantholytic EBS (includes variants formerly termed lethal acantholytic EBS and lethal congenital EBS) is associated with loss-of-function mutations in the DSP and JUP genes, encoding the desmosomal proteins desmoplakin and plakoglobin [46]. DSP mutations lead to the truncation of the keratin-binding tail domain of desmoplakin, resulting in impaired attachment or connection between the keratin intermediate filaments and the desmosomal inner dense plaque in all layers of the epidermis.

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●Skin fragility syndromes are autosomal recessive disorders caused by loss-of-function or compound heterozygous mutations in the PKP1, DSP, or JUP genes, encoding the desmosomal proteins plakophilin-1, desmoplakin, and plakoglobin, respectively [47-54]. Plakoglobin and desmoplakin are desmosomal proteins that are pan-epidermal, whereas plakophilin-1 is expressed mainly in the suprabasal epidermis. ●Mutations in the translation initiation codon of KLHL24, encoding kelch-like protein 24, have been found in individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes [55-57]. Mutant KLHL24 was associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts due to keratin 14 excessive ubiquitination and degradation.

Clinical presentation EBS, localized — Localized EBS, formerly known as Weber-Cockayne EBS, is the mildest and most common form of EB. Localized EBS presents between infancy and the third decade with trauma- or friction-induced blistering mainly limited to the palms and soles (picture 1A-D) [58]. An associated palmoplantar hyperhidrosis is common. Blistering or ulceration of the oral mucosa may develop in infants, sometimes triggered by trauma from bottle feeding, and usually resolves with increasing age. Hair and teeth are normal; nail dystrophy is rare and generally mild. Blisters heal without scarring or milia. Discrete or focal calluses are common, especially in adults.

EBS, generalized severe — Generalized severe EBS, formerly known as Dowling-Meara EBS, is the most severe form of EBS. It presents at birth with disseminated trauma or friction-induced blistering. Grouped blisters with an arcuate, "herpetiform" arrangement may appear spontaneously on the trunk, upper limbs, or neck (picture 1C-D). Involvement of the oral mucosa is common. Hyperkeratosis of the palms and soles appears during infancy and can progress over time to confluent keratoderma. Additional clinical features include nail dystrophy, nail shedding, and hair loss (telogen effluvium). Erosions usually heal without scarring, but postinflammatory hypo- or hyperpigmentation are common; milia and atrophy may occur, mainly in infancy rather than later in life. Generalized severe EBS tends to improve with age. High ambient temperatures or sweating (eg, during summer) are exacerbating factors. Extracutaneous manifestations may be severe (eg, laryngeal stenosis) and result in increased mortality [59].

EBS, generalized intermediate — Generalized intermediate EBS, formerly known as Koebner EBS, includes all forms of generalized EBS other than the severe (Dowling-Meara) subtype [1]. Blistering starts at birth or during early infancy, is generally mild, and particularly involves the hands, feet, and extremities. Development of hair, teeth and nails is normal. Lesions often heal with postinflammatory dyspigmentation; atrophy and milia may occur, although less frequently than in the generalized severe form.

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Unusual variants Suprabasal EBS — In suprabasal EBS, intact blisters are hardly observed, due to the thin, and therefore fragile, blister roofs. Erosions or impaired keratinization with increased desquamation and palmoplantar keratoderma are usually seen (table 1). The severity of the clinical manifestations and extracutaneous involvement varies among subtypes.  

Other variants — Other unusual variants of EBS include EBS with mottled pigmentation, EBS with muscular dystrophy, EBS with pyloric atresia, autosomal recessive EBS, and EBS Ogna and are summarized in the table (table 1) [60,61].

JUNCTIONAL EPIDERMOLYSIS BULLOSA Overview — Junctional epidermolysis bullosa (JEB) encompasses a group of autosomal recessive disorders characterized by blistering of the skin and mucosae that heal with scarring. In most cases, JEB is caused by autosomal recessive mutations in the laminin-332 genes, which result in a structural defect of the anchoring filaments located in the lamina lucida and superior lamina densa of the basal membrane zone. Rare variants of JEB are associated with mutations in the genes encoding the hemidesmosomal proteins collagen XVII, integrin alpha-6, and integrin beta-4. Genotypic and phenotypic variants of JEB include (table 2) [20]: Generalized JEB subtypes: ●JEB, generalized severe (formerly known as JEB, Herlitz) ●JEB, generalized intermediate (formerly known as generalized non-Herlitz or generalized, other) ●JEB with pyloric atresia Localized JEB subtypes: ●JEB, localized (hands, feet, elbows, knees) ●JEB inversa ●JEB, laryngo-onycho-cutaneous syndrome

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Pathogenesis — Most cases of generalized severe JEB (formerly Herlitz) and generalized intermediate JEB (formerly non-Herlitz) are caused by autosomal recessive mutations in the LAMA3, LAMB3, or LAMC2 genes encoding the alpha-3, beta-3, and gamma-2 subunits of laminin332, respectively (table 2). The absence of any of the three laminin subunits prevents the assembly and secretion of functional trimeric laminin-332. Laminin-332 is expressed in embryonal and adult tissues, including amnion; embryonic cartilage; enamel forming matrix; cornea; dermoepidermal junction; and the basement membrane zone of kidney (glomeruli and tubuli), lung (alveoli, bronchioli, and bronchi), and small intestine epithelium [62-65]. Approximately 80 percent of mutations occur in the LAMB3 gene, which harbors a number of recurrent mutations, such as R635X [66]. In generalized severe JEB, homozygous or compound heterozygous null mutations within the LAM genes generate premature termination codons that lead to accelerated nonsense mediated mRNA decay or truncated, unstable, nonfunctional proteins sensitive to proteolytic degradation. Any of these pathways results in biallelic complete loss of laminin-332 and a severe phenotype. The majority of generalized intermediate JEB cases is caused by missense mutations or in-frame deletions in the laminin 332 genes leading to a reduced expression of aberrant laminin-332, due to defective triple helix formation, decreased thermal stability, and intracellular accumulation. The abnormal laminin-332 retains a residual biological activity that results in mild or moderate generalized intermediate phenotypes. The remaining generalized intermediate JEB cases are caused by mutations in the COL17A1 gene, encoding the hemidesmosomal protein collagen XVII, also known as bullous pemphigoid antigen 180 (BP180) or BPAG2 [1,66,67]. Most mutations are nonsense or insertion/deletion mutations causing premature chain termination. Type XVII collagen is mainly expressed in hemidesmosomes but is also present in extracutaneous tissues such as the eye and the central nervous system [68,69]. However, in these JEB cases the clinical manifestations are mainly limited to the skin, hair, and mucous membranes and generally do not involve other organs as in other forms of JEB. Up to 30 percent of patients with generalized intermediate JEB due to mutations in COL17A1 or LAMB3 present with the "revertant mosaicism" phenomenon, also called "natural gene therapy" [70,71]. This phenomenon occurs when a causative germline mutation is locally corrected by a spontaneous genetic event in a somatic cell, including intragenic crossover, second-site mutation, mitotic gene conversion, or true back mutation [72,73]. Revertant mosaicism may explain milder than expected phenotypes in some patients with generalized intermediate JEB. These patients present at birth or later in life with skin areas that are typically darker than affected areas and do not blister. The JEB variant with pyloric atresia is caused by mutations in the genes ITGB4 and ITGA6 encoding the hemidesmosomal protein alpha-6 beta-4 integrin. The level of tissue separation in JEB-PA is just above the plasma membrane. A total lack of functional alpha-6 beta-4 integrin, due to mutations

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generating premature termination codons in both alleles, is associated with severe skin fragility and early mortality. However, more subtle missense mutations have been identified in association with milder disease [74,75]. Homozygous mutations in the ITGA3 gene encoding the transmembrane integrin receptor subunit integrin alpha-3 have been reported in three patients with a new form of epidermolysis bullosa, JEB with respiratory and renal involvement, characterized by mild skin fragility but fatal multiorgan involvement with congenital nephrotic syndrome and interstitial lung disease [22]. The structural abnormalities detected in these patients (eg, subepidermal multi-layer blistering with lamina densa located in the blister floor with intact hemidesmosomes and cell fragments) are similar to those described in integrin alpha-3 knockout mice [76]. These observations indicate that integrin alpha-3 is indispensable for epidermal cell adhesion and basement-membrane organization. Mutations of the LAMA3A gene, encoding the laminin alpha-3a polypeptide, a component of the laminin-332 heterotrimer, are associated with the laryngo-onycho-cutaneous (LOC) syndrome, a distinct variant of localized JEB, seen in families from the Punjab region of Pakistan and India. The affected individuals are generally homozygous for the recessive frameshift mutation 151insG in LAMA3A on chromosome 18q11.2. However, LOC syndrome can be caused by other mutations in exon 39 [77-79]. In addition, homozygous LAMB3 mutations have been determined by autozygosity mapping to underlie LOC syndrome in a patient initially diagnosed with LAMA3A aberration [10]. Mutations causing JEB are generally inherited in an autosomal recessive pattern. However, unusual inheritance patterns have been described in some JEB patients, including autosomal dominant traits and uniparental isodisomy (inheritance of two identical copies of one parental chromosome) of chromosome 1 with reduction to homozygosity or compound heterozygosity (two different pathogenic mutations in the same gene that together are sufficient to manifest a recessive phenotype) [80-83]. This phenomenon has to be taken into account for accurate genetic counseling. (See "Genetics: Glossary of terms".)

Clinical presentation JEB, generalized severe — Generalized severe JEB (former JEB, Herlitz) presents with generalized, often extensive mucocutaneous blistering at birth (picture 2A-E) and is associated with early lethality despite aggressive therapeutic interventions. Secondary lesions following repeated tissue trauma include atrophic scarring, webbing (scar formation between fingers or toes), contractures (typically in the axillary vaults), and milia. Pigmentary abnormalities include hypo- or mottled pigmentation and, rarely, EB nevi. (See 'Epidermolysis bullosa nevi' below.) Exuberant granulation tissue presenting as moist, red, friable plaques (picture 3) around the mouth, central face, or nose is pathognomonic of severe generalized JEB [84]. Other areas involved include the upper back, axillary vaults, and nail folds. Periorificial vegetations can cause luminal occlusion and may mimic squamous cell carcinoma clinically.

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Onychodystrophy with onychogryphosis (thickened, yellowish, longitudinally grooved, markedly curved nail plates), or absence of nails (anonychia) due to atrophy and scarring of the nail bed and matrix are common findings (picture 2E). Uncommon cutaneous features include localized or diffuse scarring alopecia, palmoplantar keratoderma, and areas of congenital absence of the skin (aplasia cutis congenita) presenting as smooth, red, well-demarcated, depressed patches on hands, feet, wrists, or ankles. Blisters and erosions may occur in all stratified squamous epithelial tissues, including the conjunctival, oral, gastrointestinal, respiratory, and genitourinary mucosae. Strictures and obstructions resulting from healing of mucosal lesions are associated with significant morbidity and mortality (table 3). (See 'Extracutaneous manifestations' below.) Enamel hypoplasia, due to mutated structural proteins interfering with dental histomorphogenesis, is a characteristic feature of intraoral disease in all JEB subtypes [85]. Excessive pitting and furrowing of the tooth surfaces create areas that are difficult to clean and are ideal for microbial growth and substrate retention, which cause dental caries. In addition, the thin enamel provides decreased resistance to the development and progression of caries. Upper airway injury may occur spontaneously or follow episodes of coughing, crying, or upper respiratory tract infection [86]. Symptoms associated with laryngotracheal stenosis, such as chronic hoarseness, weak cry, or inspiratory stridor, are seen in up to 50 percent of patients with generalized severe JEB and are ominous signs [87]. Partial or complete occlusion of the upper airways may occur in the generalized subtypes of JEB within the first year of life [86]. The risk of upper airway obstruction decreases in later childhood, probably because of the age-related increase in the luminal diameter of airways. Urologic complications may occur in patients with generalized severe JEB [88]. Urethral meatal stenosis and urinary retention have been reported in approximately 10 percent of patients; less frequent complications include hydronephrosis and bladder hypertrophy. The risk of death among children with generalized severe JEB is estimated to be approximately 45 percent by age 1 and 60 percent by age 15. These estimates are based upon data from the United States national epidermolysis bullosa registry (NEBR), which included cases diagnosed by nonmolecular tests from 1986 through 2002 [89,90]. In contrast, mortality rates of up to 100 percent, with most deaths occurring in the first two years of life, have been reported among children with severe generalized JEB in whom the diagnosis was based upon the complete absence of functional laminin-332 in immunofluorescence antigen mapping and DNA analyses [16,91]. Sepsis, failure to thrive, and respiratory failure are the major causes of death.

JEB, generalized intermediate — Generalized intermediate JEB (former JEB, non-Herlitz) encompasses a group of rare, less severe forms of JEB, initially described in patients presenting with a generalized severe JEB phenotype who survived to adulthood [92,93]. The disease was formerly termed "generalized atrophic benign epidermolysis bullosa" (GABEB) [94,95]. Several variants of generalized intermediate JEB have been recognized (table 2) [20].

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In infants and children, generalized intermediate JEB may be clinically indistinguishable from other forms of generalized EB (picture 4) [94]. In adults, it is characterized by serous or hemorrhagic blisters predominantly located in sites exposed to friction, trauma, or heat (picture 5A-B) [96]. Lesions may progress to form superficial or deep ulcers, crusted lesions, and fissures. Recurrent blistering and healing results in skin atrophy with poikilodermatous appearance, pigmentary disturbances, and faint stellate scars [1,94,95]. Sometimes, a mild disease early in life may evolve to a severe phenotype in adults or vice versa. Additional clinical features include a permanent, diffuse, but incomplete alopecia that becomes apparent by the end of the first or second decade, dystrophic or absent nails (picture 6), dental enamel hypoplasia and caries, and EB nevi. Involvement of mucous membranes may occur in infancy and early childhood and, in contrast to generalized severe JEB, is usually moderate and without scarring. However, tracheolaryngeal stenosis, esophageal webs and strictures, and urogenital complications have been reported [97,98]. Generalized intermediate JEB is associated with a substantial risk of death during infancy [89]. Patients surviving into adulthood have an increased risk of developing squamous cell carcinoma [99,100].

DYSTROPHIC EPIDERMOLYSIS BULLOSA Overview — Dystrophic epidermolysis bullosa (DEB) is characterized by blistering of the skin and mucosal membranes that heal with scarring. DEB is caused by mutations in the COL7A1 gene encoding the alpha-1 chain of type VII collagen. Collagen VII is the main constituent of the anchoring fibrils located below the lamina densa of the epidermal basement membrane zone. DEB can be inherited in an autosomal dominant or recessive fashion. (See 'Pathogenesis' below.) The 2013 consensus classification [20] recognizes one major dominant (DDEB) and two major recessive (RDEB) subtypes of DEB and several rare dominant or recessive subtypes (table 4).

Pathogenesis — All DEB subtypes are caused by mutations in the COL7A1 gene on chromosome 3p21.31, coding for the alpha-1 chain of type VII collagen. Collagen VII is the main constituent of the anchoring fibrils, which are located below the basal lamina at the dermoepidermal basement membrane zone and anchor the epidermal basement membrane to the dermis. More than 600 distinct mutations in the COL7A1 gene have been identified in DEB [101-106]. Although a few mutations are recurrent in some populations due to the founder effect, most families carry unique mutations ("private mutations") [7].

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In autosomal dominant DEB (DDEB), the predominant type of mutation is a missense mutation resulting in a glycine substitution within the triple helical domain of the pro-alpha-chain of type VII collagen [101]. Less frequently, deletions and splice-junction mutations have been identified [107]. Both the mutated and the wild-type allele are expressed in DDEB, so some anchoring fibrils are functionally intact, accounting for the relatively mild phenotype. In rare cases, the skin symptoms may be transient with improvement in the first years of life. In generalized severe recessive DEB (RDEB, formerly called Hallopeau-Siemens type) nonsense mutations, deletions, insertions, or splice site mutations with frame shift of translation typically result in premature termination codons [108]. Homozygosity or compound heterozygosity for premature termination codon mutations in COL7A1 result in null alleles and complete absence of anchoring fibrils, as visualized by transmission electron microscopy and by negative or severely reduced immunofluorescence for type VII collagen epitopes. Complete absence of anchoring fibrils is associated with extreme skin fragility, extensive scarring, joint contractures and deformity, severe mucosal involvement, malnutrition, and growth retardation. In milder forms of RDEB, different types of mutations (eg, missense or splice site mutations) and allelic combinations (eg, a premature termination codon mutation on one allele and a missense mutation or in-frame deletion on the other) result in defective collagen VII synthesis and structurally abnormal anchoring fibrils [109]. In these patients, electron microscopy reveals anchoring fibrils morphologically altered or reduced in number, and immunofluorescence for collagen VII is positive but attenuated. Genotype-phenotype correlation studies have helped in the understanding of the phenotype diversity in RDEB. As an example, specific recessive arginine and glycine substitutions in the triple helix domain of type VII collagen were demonstrated to cause RDEB inversa, which predominantly involves the intertriginous areas [110,111].

Clinical presentation — Clinical hallmarks of DEB are skin fragility, blistering, scarring, nail changes, and milia formation (picture 7A-E). Since collagen VII is expressed also in noncutaneous stratified epithelia, blistering also occurs in the mucous membranes and upper third of the esophagus. The phenotypic spectrum of DEB ranges from the mildest "nail-only" dominant DEB, in which patients have only dystrophic toe nails, to the most severe RDEB, in which there is generalized blistering and scarring leading to fusion of fingers and toes (ie, pseudosyndactyly or "mitten" deformity). The three major clinical subtypes of DEB are: ●DDEB, generalized ●RDEB, generalized severe (formerly named RDEB, Hallopeau–Siemens type) ●RDEB, generalized intermediate (formerly named RDEB, other) Uncommon variants of dominant and recessive DEB are summarized in the table (table 4).

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DDEB, generalized — In generalized dominant DEB (DDEB), blistering starts at birth or soon after, predominantly in the skin overlying bony prominences, such as the knees, ankles, and dorsa of the hands and feet. Mucosal involvement is rare and teeth are normal. Blisters heal with scarring and milia. Nail dystrophy is probably the most important diagnostic feature, especially in adults, because most patients have only limited scarring that becomes less noticeable with age.

RDEB, generalized severe — Generalized severe recessive DEB (RDEB), formerly known as Hallopeau-Siemens type, is the most severe form of DEB. Blistering starts at birth, spontaneously or after the mildest trauma, particularly in skin areas exposed to repeated friction or mechanical trauma (eg, knees, elbows, hands, feet, back of the neck, shoulders, and over the spine). Occasionally, there is extensive denudation of a body area due to congenital absence of the skin. Healing occurs with scarring and milia [112]. Pseudosyndactyly due to repeated blistering and scarring on hands and feet is a clinical hallmark of recessive dystrophic EB. Pseudosyndactyly initially presents as partial fusion of the interdigital spaces due to proximal webbing and synechiae and is followed by progressive bridging and complete fusion of all of the individual digits in a cocoon-like, scarred mass ("mitten" deformity) (picture 8). Contractures of hands and feet begin to develop as early as in the first year of life [113]. Proximal contractures may also occur, especially within the popliteal and antecubital fossae and axillary vaults. Scarring alopecia is common. Oral, esophageal, anal, and ocular mucosae are also affected with erosions and mutilating scarring (table 3). Dystrophic teeth, restricted mouth opening and tongue mobility due to scarring promote severe caries, and, together with esophageal strictures, lead to reduced food intake and nutritional deficiencies. Severe generalized RDEB patients have an extremely high risk of developing squamous cell carcinomas, which is the leading cause of death in this group [114]. (See 'Skin cancer' below.)

RDEB, generalized intermediate — In generalized intermediate RDEB, blistering is less severe and mutilating deformities are generally missing. The clinical picture is variable. Some patients have widespread disease whereas others present with blistering limited to the extremities. Skin lesions heal invariably with scars and milia. Oral, dental, nail, and hair manifestations are similar to those seen in recessive DEB, severe generalized, but are less extensive. The risk of squamous cell carcinomas is elevated [114].

Rare subtypes — Rare, localized subtypes of both dominant and recessive DEB include inverse, pretibial, pruriginosa, and nail-only forms (table 4). Pretibial DEB presents in adolescence or adulthood with fragile blisters and erosions that are often overshadowed by pruritic, lichenified plaques [115]. DEB pruriginosa is also a late-onset variant of dominant, or occasionally recessive, dystrophic EB. Intense pruritus on a background of inherited skin fragility leads to skin signs resembling hypertrophic lichen planus or prurigo nodularis [116].

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KINDLER SYNDROME Overview — Kindler syndrome (KS) is a distinct type of autosomal recessive epidermolysis bullosa characterized by skin blistering, photosensitivity, progressive poikiloderma (a combination of skin atrophy, telangiectasia, and dyspigmentation), and extensive skin atrophy [1,117]. KS is caused by loss-of-function mutations in the FERMT1 gene, encoding the focal adhesion protein fermitin family homolog 1, also called kindlin-1. (See "Kindler syndrome".)

Pathogenesis — KS is caused by mutations in the FERMT1 gene, encoding the fermitin family homolog 1 protein (FFH1), also referred to as kindlin-1, a focal adhesion protein predominantly expressed in skin basal keratinocytes, periodontal tissues, and colon. Kindlin-1 has a critical regulatory role in linking the actin cytoskeleton with the underlying extracellular matrix anchorage network and is implicated in the control of integrin activation (figure 1) [118-121]. About 40 different pathogenic mutations have been identified in KS, including frameshift, splice site, large deletion mutations, and gene rearrangements following homologous unequal crossing over [122-125]. Loss-of-function mutations in FERMT1 lead to the disruption of the attachment of the actin cytoskeleton to focal adhesion junctions at the dermoepidermal junction and impaired epithelialmesenchymal signaling via these complexes [117,126-130]. KS ultrastructural key features of thickening and reduplication of lamina densa may be related to repeated episodes of keratinocyte disadhesion and overcompensation by excessive matrix production and remodeling beneath the basement membrane [131,132]. Long-term FFH1 deficiency is also associated with an increased mucocutaneous cancer risk, suggesting that focal adhesions may have an important role in cell cycle control and cell survival, growth, signaling, and invasion [129,133,134]. In addition, a homozygous splicing mutation in CD151, which encodes a tetraspanin expressed in the basement membrane zone interacting and stabilizing alpha-3 beta-1 as well as alpha-6 beta-4 integrins, was found in a patient with Kindler syndrome-like phenotype presenting with early blistering subsiding with age and nephropathy [135].

Clinical presentation — Kindler syndrome (KS) presents at birth or in early infancy with trauma-induced skin blistering that predominantly involves acral sites and heals with atrophic changes [117]. In late childhood, blistering generally subsides and gives way to progressive poikiloderma and skin atrophy localized to sun-exposed areas such as the dorsal aspect of the hands and feet. Most patients with KS develop variable degrees of photosensitivity. Mucosal involvement tends to increase with age. Gingivitis and periodontitis are common findings. Esophageal or genitourinary stenoses, gastrointestinal symptoms, including constipation and colitis, have also been reported. Patients with KS have an increased risk of nonmelanoma skin cancer during adulthood [136]. (See "Kindler syndrome", section on 'Clinical manifestations and natural history'.)

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EXTRACUTANEOUS MANIFESTATIONS

Index genes involved in the pathogenesis of

epidermolysis bullosa (EB) are also partly expressed in other epithelial tissues and mesenchymal organs, resulting in the occurrence of primary extracutaneous manifestations and relevant complications, especially in the severe forms of EB [86]. Complications may also involve other organs and systems, such as the heart and musculoskeletal system [113]. EB should thus be considered a multisystem disease associated with significant morbidity and mortality. The extracutaneous manifestations and complications of EB are summarized in the table (table 3).

Nail and hair — Nail abnormalities are a feature of most EB subtypes (table 3), since antigenic expression of basement membrane zone (BMZ) components in the normal matrix, nail bed, proximal nail fold, and hyponychium is similar to that of normal skin [137]. Nail involvement ranges from a mild cosmetic problem to a disabling condition. Early nail dystrophy and loss correlate with disease severity and progression, particularly in junctional epidermolysis bullosa (JEB) and recessive dystrophic epidermolysis bullosa (RDEB) [138]. Nail abnormalities may precede skin blistering as in late-onset JEB and pretibial dystrophic epidermolysis bullosa (DEB) or be an isolated finding as in "nails-only" dominant dystrophic epidermolysis bullosa (DDEB) [139]. In the nails-only DDEB variant, the involvement is often limited to the toenails and can be mild and easily overlooked. Moreover, nail involvement without blistering may be present for generations before a DEB family member develops blisters in the skin [139-142]. The expression of BMZ components in the anagen hair follicles of the human scalp is similar to that of the interfollicular epidermis [143]. Blistering of the scalp involving the lamina lucida and below, as in JEB and DEB, usually leads to cicatricial alopecia secondary to inflammation of the interfollicular epidermis and upper portion of the hair follicle. In addition, absence of or abnormal BMZ proteins in the hair follicle may increase hair fragility. The hair abnormalities and alopecia patterns associated with EB subtypes are summarized in the table (table 3).

Eye — Ocular involvement is frequent in patients with JEB or recessive DEB [144,145]. Symptoms range from mild conjunctival irritation to severe cicatrization of eyelids, cornea, or conjunctiva and progressive visual impairment (table 3). Corneal blisters and erosions are the most common ocular findings and have been reported in approximately 50 percent of patients with generalized severe JEB and 70 percent of patients with severe generalized DEB [145].

Oral cavity — The oral manifestations of EB include soft tissue and dental abnormalities (table 3) [113]. Intraoral blisters and superficial erosions are common in all EB patients, although they are usually minimal in those with EBS. Scarring and loss of normal architecture of intraoral soft

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tissues occur in most patients with JEB or DEB. Enamel hypoplasia with pitting and furrowing is a pathognomonic feature of all subtypes of JEB and predisposes to dental caries and tooth loss. Additional factors contributing to dental caries and premature tooth loss include: ●Poor oral hygiene due to painful peri- and intraoral blisters or erosions and impaired manual dexterity ●Altered soft tissue architecture with contractures (microstomia, ankyloglossia), abnormal tongue mobility, and obliteration of oral vestibules resulting in decreased food clearance ●Frequent feeding with high-calorie, cariogenic soft diets ●Malnutrition

Gastrointestinal tract — In patients with JEB, recessive DEB, or Kindler syndrome, any portion of the gastrointestinal tract may be injured [86]. Gastrointestinal manifestations include esophageal strictures, gastroesophageal reflux, rectal tears, anal fissures and stenosis, and constipation (table 3). Esophageal strictures, resulting from recurrent mucosal blistering and scarring, are the most frequent and often the most disabling complication. The majority of strictures occur in the upper third of the esophagus, but they may arise anywhere, leading to progressive dysphagia initially with hard or bulky foods, then with softer foods, and eventually with liquids. In recessive DEB, esophageal strictures develop in early childhood and more than 50 percent of patients report symptoms by the age of 10.

Genitourinary tract — Complications of the genitourinary tract are reported in approximately 30 percent of patients with JEB or recessive DEB (table 3) [146]. Urethral meatal stenosis and recurrent vesiculation within the mucosa of the urethra, ureterovesical junction and ureters may cause dysuria and urinary retention. Subsequently, bladder distention and hypertrophy, vesicoureteral reflux, hydroureter and hydronephrosis may develop and ultimately lead to chronic renal failure, if not treated [147].

COMPLICATIONS Malnutrition and anemia — In patients with epidermolysis bullosa (EB), several factors contribute to severe nutritional compromise, including: ●Feeding difficulties due to oropharyngeal involvement, esophageal narrowing, dysphagia, and poor swallowing coordination ●Moderate to severe malabsorption due to recurrent mucosal lesions of the small intestine ●High energy consumption from accelerated skin turnover, wound healing, and natural growth

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●Hypercatabolic state from chronic inflammation and infection ●Transcutaneous loss of nutrients Malnutrition may result in refractory anemia, hypoalbuminemia, failure to thrive, and delayed puberty with secondary hypogonadism [148]. Anemia is largely caused by iron deficiency resulting from reduced intake and absorption, blood loss from chronic skin and mucosal wounds, and loss of skin cells. A chronic inflammatory state additionally suppresses erythropoiesis [149]. Anemia has a significant impact on the general well-being, causing fatigue, breathlessness, reduced exercise tolerance, poor wound healing, and anorexia. Many patients with severe forms of EB maintain hemoglobin levels of 70 percent) improvement in the appearance of striae rubra in eight patients and good (30 to 70 percent) improvement in an additional eight patients [26]. Treatment was well tolerated, complicated only by mild, transient erythema and edema. (See "Nonablative skin resurfacing for skin rejuvenation", section on 'Infrared lasers and light devices'.) Treatment with other nonablative infrared lasers has been attempted, such as the 1320 nm Nd:YAG and 1450 nm diode lasers. However, these devices yielded poor clinical outcomes and an unacceptably high incidence of postinflammatory pigmentation [102].

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Other — Limited data suggest that regimens incorporating 20% glycolic acid [89], topical silicone or nonsilicone gels applied with massage [103], sand abrasion and trichloroacetic acid [90], succinylated atelocollagen [104], or a product containing onion extract and Centella asiatica [105] may be beneficial for the treatment of striae distensae. Further study is necessary to clarify the role of these treatments. Our clinical experience suggests that the 532 nm potassium titanyl phosphate (KTP) laser may also be of benefit for the treatment of striae rubra.

PREVENTION

Interventions for the prevention of striae distensae are usually

discussed in the context of pregnancy given the common and expected occurrence of striae distensae in pregnant women. Although many women use a wide variety of creams, lotions, and ointments in attempts to reduce risk for striae development, strong evidence to confirm efficacy of any of these interventions is lacking [106,107]. A 2012 systematic review of randomized trials that included trials assessing olive oil; cocoa butter; a product containing hyaluronic acid, vitamins A and E, allantoin, and calcium pantothenate; a product containing C. asiatica extract, alpha-tocopherol, and collagen-elastin hydrolysates; and a product containing vitamin E, essential free fatty acids, panthenol, hyaluronic acid, elastin, and menthol found no high-quality evidence to support the use of these topical preparations to prevent striae distensae during pregnancy [106]. In addition, a subsequent randomized trial (n = 360) comparing use of olive oil or a cream containing lanolin, stearin, triethanolamine, almond oil, and other ingredients with no treatment found that neither intervention was effective for prevention [108]. Many "belly band" garments to support the abdomen are marketed to pregnant women. However, efficacy of peripartum or postpartum use for preventing or treating striae distensae is unproven. Topical retinoids may be beneficial for the treatment of early striae distensae but, due to fetal safety concerns, should not be used for prevention or treatment during pregnancy. (See 'Topical retinoids' above.)

SUMMARY AND RECOMMENDATIONS ●Striae distensae (stretch marks) are a common form of dermal scarring that usually appear as linear erythematous, violaceous, or hypopigmented striations. Predisposing factors include pregnancy, adolescence, drug exposure (eg, topical or systemic corticosteroids), underlying disease (eg, Cushing's syndrome or Marfan syndrome), and surgery (eg, breast augmentation). (See 'Epidemiology and risk factors' above.) ●The pathogenesis of striae distensae is not well understood. Mechanical forces on the skin, intrinsic alterations in skin structure or function, and hormonal factors may play a role. (See 'Pathogenesis' above.)

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●The two main clinical presentations of striae distensae are striae rubra and striae alba. Striae rubra precede striae alba and are characterized by an erythematous to violaceous color (picture 1A-C). Striae rubra eventually evolve into the hypopigmented, scar-like, and atrophic plaques known as striae alba (picture 2A-B). Common sites for striae distensae are the abdomen, breasts, medial upper arms, hips, lower back, buttocks, and thighs. (See 'Clinical manifestations' above.) ●The diagnosis of striae distensae can usually be made easily during the physical examination. A biopsy usually is not necessary. The major disorder in the differential diagnosis is linear focal elastosis. (See 'Diagnosis' above and 'Differential diagnosis' above.) ●Treatment of striae distensae is optional. A paucity of high-quality trials has led to uncertainty about the best approach to therapy (algorithm 1). (See 'Treatment' above.) ●For patients with striae rubra who desire treatment, we suggest pulsed dye laser therapy as initial treatment (Grade 2C). For patients who prefer to avoid laser therapy, we recommend topical tretinoin as initial therapy (Grade 2B). Disadvantages of tretinoin include the need to adhere to at least several months of daily therapy and the potential for skin irritation. (See 'Pulsed dye lasers' above and 'Topical retinoids' above.) ●For patients with striae alba, we suggest fractional laser therapy or microneedling as initial treatment (Grade 2B). We suggest use of microneedling with radiofrequency (RF microneedling), rather than other modalities of microneedling, when RF microneedling is available (Grade 2C). Microneedling is preferred over fractional laser therapy for patients with skin phototypes IV to VI because of increased risk for laser-induced hyperpigmentation in this population. Nonablative fractional lasers are often preferred over ablative fractional lasers due to lower risk of complications and shorter recovery times.

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Tattoo removal - UpToDate uptodate.com/contents/tattoo-removal/print

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: Jan 29, 2020.

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INTRODUCTION

Tattoo removal is an increasingly common office

procedure often performed by dermatologists with special training in tattoo removal. A variety of procedures have been used to remove tattoos, such as laser therapy, surgical excision, and dermabrasion. Quality-switched (Q-switched, QS) lasers are the standard of care for tattoo removal based upon demonstrated efficacy and safety and an extensive history of use for this indication. QS laser treatment can result in good cosmetic outcomes and complete or near-complete removal of many unwanted tattoos. The approach to tattoo removal will be reviewed here. The epidemiology of tattoos, tattoo placement process, and health risks of tattooing are reviewed separately. (See "Tattooing in adolescents and young adults".)

TATTOO PRINCIPLES

A tattoo is visible and permanent

pigmentation of the skin secondary to the deliberate or accidental deposition of exogenous pigment within the dermis. There are five major subtypes of tattoo [1]: ●Professional tattoos – Professional tattoos are decorative tattoos placed by professional tattoo artists and are typically placed with a vibrating needle. Pigment is deposited more deeply and extensively in the dermis than most amateur tattoos, which can make professional tattoos more difficult to remove. ●Amateur tattoos – Amateur tattoos are decorative tattoos performed by nonprofessionals. Amateur tattoos are often placed by hand with a needle or other improvised devices. Amateur tattoos are most often black and may contain ingredients such as charcoal, soot, or pen ink. ●Traumatic tattoos – Traumatic tattoos result from the entry of pigmented substances, such as gunpowder or road residue (eg, dirt, asphalt, gravel), into the skin in sites of cutaneous injury (picture 1). The pigment remains following re-epithelialization, causing permanent discoloration of the skin. ●Medical tattoos – Tattoos may be placed following reconstructive surgery (eg, areolar tattoo in breast construction) or to facilitate patient positioning for radiation therapy. ●Cosmetic tattoos – Cosmetic tattoos are tattoos placed for the purpose of permanent makeup. The lips and eyebrows are common sites. Tattoo pigments are composed of a wide variety of ingredients. Common ingredients used to create specific colors in professional tattoos include: ●Black: carbon and iron oxide ●Blue: cobaltic aluminate ●Green: chrome oxide

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●Red: mercury sulfide or cadmium selenide ●Yellow: cadmium sulfide or ochre ●White: titanium dioxide and zinc oxide Tattoo pigment particles deposited in the skin are subsequently taken up by phagocytic cells. Histopathologic examination will reveal pigment particles within large phagosomes in the cytoplasm of epidermal keratinocytes and dermal phagocytic cells (ie, fibroblasts, macrophages, or mast cells).

TREATMENT PRINCIPLES

Although most individuals

with decorative tattoos are satisfied with their tattoos, a desire to remove tattoos is not uncommon [2,3]. Among 120 patients who reported having a tattoo in an American telephone survey, 20 (17 percent) had considered tattoo removal [2]. Reasons for desiring removal may include embarrassment, a negative impact on body image, occupational concerns or requirements, concern for stigmatization, and life status changes [3]. In the past, methods for tattoo removal were limited to excisional and destructive procedures (eg, surgical excision, dermabrasion, traditional ablative lasers). The discovery of the theory of selective photothermolysis, which describes how light can be manipulated to achieve a desired clinical effect while limiting collateral tissue damage, has contributed to advances in laser therapy for tattoos. (See 'Surgical excision and destructive therapies' below and "Principles of laser and intense pulsed light for cutaneous lesions", section on 'Selective photothermolysis'.) The theory of selective photothermolysis includes the following principles: ●The wavelength of light delivered should be preferentially absorbed by the target molecule (also known as a chromophore). ●Light must be delivered within a period of time that limits damage to adjacent tissue. ●The light energy transferred to the target chromophore must be sufficient to exert the desired therapeutic effect while minimizing damage to adjacent tissue. In tattoo removal, the target chromophore is the deposited pigment. The laser selected should emit light in a wavelength that is preferentially absorbed by the targeted pigment, should have a pulse duration that is sufficiently short to heat pigment particles while minimizing damage to adjacent tissues, and should be utilized at an energy (fluence) setting that is sufficient to destroy tattoo pigment. Tattoo pigment particles of different colors preferentially absorb different wavelengths of light; therefore, attention to the colors within a tattoo is critical, and more than one laser is often required to remove a multicolored tattoo. Laser wavelengths preferentially absorbed by specific tattoo pigments are reviewed in a table (table 1). (See "Principles of laser and intense pulsed light for cutaneous lesions", section on 'Wavelength'.)

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The selection of the correct pulse duration is based upon knowledge of the thermal relaxation time of tattoo particles (the time required for a target to lose heat). Heating the target for periods shorter than the thermal relaxation time prevents damage to surrounding tissue. Tattoo pigment particles are small and have a short thermal relaxation time (30 cm2, tattoos older than 36 months, high color density, location on the feet or the legs, and treatment interval shorter than eight weeks [8].

Patient counseling — Patients should be thoroughly counseled about risks and expectations for treatment. In particular, we inform patients that although QS lasers are effective, complete removal is not guaranteed and multiple treatments are typically required. Often, eight or more treatment sessions are required to achieve maximum improvement. Potential side effects (eg, blistering, dyspigmentation, scarring) should also be reviewed. It is particularly important to discuss risk for scarring with patients who have a history of hypertrophic or keloidal scars since scars are more likely to be disfiguring in these patients. Treatment of tanned skin is generally not recommended to minimize risk for complications (eg, dyspigmentation, blistering, scarring) related to the absorption of laser light by melanin in the epidermis. Patients should protect the tattoo area from sun exposure with sunscreens and sunprotective clothing prior to treatment and existing tans should fade prior to treatment. Prophylactic antibiotic or antiviral therapy generally is not necessary; however, prophylactic therapy for the prevention of herpes simplex virus reactivation is reasonable for patients receiving treatment of perioral tattoos. For these patients, antiviral therapy (eg, 500 mg of valacyclovir or famciclovir given twice daily or 400 mg of acyclovir given twice daily) can begin one day prior to treatment and is continued until healing.  

Photography — Photographs are helpful for assessing the response to treatment. Photographs are typically taken prior to initial and subsequent treatment sessions.

Administration — Treatment of a test spot (a small inconspicuous area of the tattoo) is suggested prior to treatment of the entire tattoo. Performance of a test spot can identify unexpected adverse effects, such as paradoxical darkening or scarring. Skin should be thoroughly cleansed and dry prior to the start of treatment. Anesthesia is usually necessary; topical or intralesional anaesthesia or regional blocks are commonly used. Once the appropriate laser wavelength is selected based upon tattoo color, the clinician should select the most appropriate fluence (energy) setting. For the first few treatment sessions, relatively low fluence settings should be used to minimize adverse effects. The lowest fluence setting sufficient to induce slight whitening of the tattooed skin immediately after the laser pulse is delivered (immediate whitening reaction) should be used.   A single laser pass is typically performed during each treatment session, though multiple pass protocols have been utilized by some authors to reduce the number of required treatment sessions. Multiple pass protocols involve subsequent laser passes performed after the resolution of the

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immediate whitening reaction. This has been accomplished through a waiting period of 20 minutes between laser passes (R20 method) or facilitated through use of topical perfluorodecalin to resolve immediate whitening reactions more quickly (P0 method) [14-16]. However, these multipass protocols have not gained favor in clinical practice due to the time-consuming nature of multiple same-day treatments and unclear superiority to standard treatment. Additional treatment sessions are usually separated by four to six weeks. Subsequent treatments may need higher laser energy settings to remove residual tattoo pigment. In general, QS laser therapy is not considered ineffective until the fluence dose has been optimized and patients have failed to achieve an adequate response to multiple treatments (eg, >10 treatments).

Post-treatment care — Our preferred post-treatment care of the laser site consists of daily application of a bland, occlusive ointment such as petrolatum to maintain wound moisture. Moisture promotes wound healing, and application should continue until the treatment site is fully healed. Crusting and scabbing are normal occurrences that typically persist for one to two weeks after treatment [17]. Some patients find cool packs helpful for minimizing discomfort after treatment. Patients should protect treated skin from sun exposure through use of sun-protective clothing and sunscreen to minimize risk of postinflammatory hyperpigmentation. Strict sun protection should be continued for at least several weeks after treatment.

Adverse effects — The most common adverse effects of QS laser treatment include blister formation, bleeding, infection (if the skin barrier is compromised), and scarring. Scarring typically occurs if the laser energy settings are too high or due to abnormal healing after treatment. Infrequent adverse events include local or widespread allergic reactions [13,18,19].

Alternative therapy — Picosecond lasers are an additional treatment option for tattoo removal. However, picosecond laser therapy has not been proven superior to quality-switched (Q-switched, QS) laser therapy, and QS lasers remain the gold standard for tattoo removal.

Picosecond lasers — Picosecond lasers have pulse durations in the picosecond range. It is proposed that the very short pulse duration facilitates treatment of small targets with short thermal relaxation times, such as tattoo particles. Picosecond laser treatments cause significant photomechanical effects and are thought to lead to mechanical breakup of pigment particles with minimal collateral tissue heating [20,21]. Compared with QS lasers, lower fluence settings are required for tattoo removal. Whether picosecond lasers are more effective than QS lasers is uncertain. Although successful treatment of black and colored tattoos with picosecond alexandrite and neodymium-doped:yttrium aluminum garnet (Nd:YAG) lasers is documented in uncontrolled studies [22-26], data from randomized trials conflict. A single-blind randomized trial in which 30 black professional tattoos in 21 patients were treated with a picosecond 1064 nm Nd:YAG laser (fluence 0.2 to 12.5 J/cm2, spot

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size 3 to 8 mm) on one-half of a tattoo and a QS 1064 nm Nd:YAG laser (fluence 2 to 12 J/cm2, spot size 2 to 10 mm) on the contralateral half did not find a significant difference in efficacy after two treatments [27]. A separate single-blind randomized trial in which 49 patients with tattoos (primarily professional and black or blue tattoos) received treatment with one of two picosecond 1064/532 nm lasers (fluence ranges 2 to 8.4 and 2 to 5.5 J/cm2) on one-half of a tattoo and treatment with a QS 1064/532 nm nanosecond laser (fluence 2 to 8.4 J/cm2) on the other half found the picosecond laser more effective for reducing at least 75 percent of the color intensity of the tattoos (33 versus 14 percent achieved this endpoint) [28]. Both trials found picosecond laser treatments less painful.

OTHER THERAPIES

Less common methods for tattoo removal

include surgical excision, destructive therapies, and fractionated ablative lasers. Topical imiquimod does not appear to be a useful therapy.

Surgical excision and destructive therapies — The use of surgical excision and destructive therapies such as traditional ablative lasers and dermabrasion declined significantly following the discovery of the efficacy and safety of qualityswitched (Q-switched, QS) laser therapy. The major disadvantage of these therapies is risk for scarring. Patients who are poor candidates for QS laser therapy (eg, patients with allergic tattoo reactions [surgical excision preferred] or paradoxical pigment darkening in response to QS laser treatment) and patients who lack access to QS laser therapy can be successfully treated with these modalities [29,30]. In addition, punch biopsy excision is an effective method for removing very small tattoos, such as iatrogenic radiation tattoos; in a trial in which two radiation tattoos in 10 patients were randomly assigned to either punch biopsy excision or three QS yttrium aluminum garnet (YAG) laser treatments, a 75 to 100 percent reduction in tattoo appearance was achieved for all tattoos except one tattoo in the laser group [31]. However, scarring and hypopigmentation were more frequent in the punch biopsy excision group, and most patients preferred laser therapy. The protocol for traditional ablative laser therapy mimics the protocols utilized for skin rejuvenation. Traditional ablative laser therapy is reviewed in detail separately. (See "Ablative laser resurfacing for skin rejuvenation", section on 'Traditional ablative lasers'.) Dermabrasion involves superficial abrasion of the skin with an abrading device. Adequate depth of abrasion is indicated by brightening of the tattoo color and a glistening aspect to the skin surface. Several sessions may be required for tattoo removal [29].

Fractionated lasers — Fractionated ablative lasers function by pixelated vaporization of skin tissue, leaving primarily unaffected skin in between zones of ablation to serve as reservoirs for healing (figure 1). The proposed mechanisms for tattoo removal include physical removal of a portion of the tattoo, transepidermal elimination of pigment through the microscopic channels created by the laser, and additional removal of tattoo pigment during the wound-healing

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process [32]. Transepidermal elimination of tattoo pigment following nonablative and ablative fractional laser therapy has been demonstrated in animal studies [33,34]. (See "Principles of laser and intense pulsed light for cutaneous lesions", section on 'Fractionated lasers'.) Data on the clinical use of ablative fractionated lasers for tattoo removal are limited. Better responses to combination treatment with a fractioned carbon dioxide laser and QS ruby laser compared with the QS laser alone is documented in case reports [35]. Significant removal of tattoo pigment and improvement of symptoms of tattoo allergy after treatment with a 2940 nm erbium:yttrium aluminum garnet (Er:YAG) fractionated laser alone or in combination with a QS neodymium-doped:yttrium aluminum garnet (Nd:YAG) laser has also been described in individual patients [32]; however, a generalized hypersensitivity reaction has also occurred after such treatment [36]. Combination treatment with a picosecond 755 nm alexandrite laser and fractionated carbon dioxide laser may reduce risk for bulla formation, a common side effect of treatment with the picosecond 755 nm alexandrite laser. In a retrospective study, 26 of 81 patients (32 percent) treated with the picosecond 755 nm alexandrite laser alone developed blistering compared with none of 20 patients treated with both modalities [37].

Imiquimod — Topical imiquimod was proposed as a method to augment the efficacy of laser tattoo treatment based upon observed benefit for tattoo removal in an animal model [38]. However, in a small, randomized trial, the addition of imiquimod to QS laser therapy did not increase treatment efficacy [39].

SUMMARY AND RECOMMENDATIONS ●Tattoos are visible and permanent deposits of exogenous pigment in the skin. Although most individuals with decorative tattoos are satisfied with their tattoos, a subset desire removal. (See 'Tattoo principles' above and 'Treatment principles' above.) ●Lasers are the primary treatment modality for tattoo removal. Discovery of the theory of selective photothermolysis, which describes how light can be manipulated to achieve a desired clinical effect while limiting collateral tissue damage, has facilitated effective and safe laser therapy for tattoos. (See 'Treatment principles' above.) ●Tattoo pigment particles have short thermal relaxation times; therefore, lasers with short pulse durations, such as quality-switched (Q-switched, QS) lasers, are necessary to minimize damage to adjacent tissues. We suggest QS laser therapy as the first-line intervention for tattoo removal (Grade 2B). QS lasers have a long history of use for tattoo removal and have demonstrated efficacy and safety for this indication. QS laser therapy may exacerbate tattoo allergic reactions and is not advised for tattoos with allergic reactions. (See 'Quality-switched lasers' above.)

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●Candidates for QS laser therapy should be carefully evaluated to assist with selection of the appropriate laser and minimize side effects. QS lasers are available in a variety of wavelengths. Selection of the appropriate laser wavelength is guided by the colors in the tattoo. Treatment of a test spot is prudent prior to full treatment of a tattoo. (See 'Pretreatment measures' above.) ●Patients should be thoroughly informed of the risks of QS laser therapy prior to treatment. Patients should also be informed that multiple treatment sessions are typically necessary for optimal results and that complete removal is not guaranteed. (See 'Patient counseling' above.) ●Picosecond laser therapy is an alternative treatment modality that appears effective for tattoo removal, though relative efficacy to QS lasers is unclear. (See 'Alternative therapy' above.) ●Limited data suggest that fractionated lasers may also be useful for tattoo removal. Further study is necessary to clarify the role of picosecond lasers and fractionated lasers in the treatment algorithm for tattoo removal. (See 'Picosecond lasers' above and 'Fractionated lasers' above.)

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

What's new in dermatology Authors: Abena O Ofori, MD, Rosamaria Corona, MD, DSc All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2020. | This topic last updated: May 11, 2020.

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

ACNE AND ROSACEA Topical clascoterone for acne vulgaris (April 2020) Systemic hormonal therapy is effective for acne vulgaris but is typically limited to female patients and has an associated risk for systemic adverse effects. In two phase 3 randomized trials that enrolled approximately 1400 males and females (ages nine years and older) with acne vulgaris, clascoterone 1% cream, an investigational topical androgen receptor inhibitor, was more effective than a vehicle cream for reducing acne severity [1]. Clascoterone exhibited a safety profile similar to the vehicle cream. These findings support further evaluation of topical hormonal agents as a new approach to acne therapy. (See "Treatment of acne vulgaris", section on 'Emerging therapy'.) Topical minocycline for rosacea (February 2020) Oral tetracyclines are a mainstay of treatment for papulopustular manifestations of rosacea but are associated with a variety of adverse effects, supporting a desire for an alternative mode of drug delivery. In two blinded, multicenter, phase 3 trials that used the same protocol and enrolled over 1500 patients with moderate to severe rosacea, topical minocycline 1.5% foam, an investigational drug, was more effective than vehicle alone for reducing the number of cutaneous inflammatory lesions and achieving clinical improvement based upon the investigators’ assessment [2]. There were no serious treatment-related adverse effects. The findings support topical minocycline as a novel mode of treatment for rosacea. However, the efficacy and safety of minocycline 4% foam, a

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commercially available formulation, for rosacea has not been established. (See "Management of rosacea", section on 'Topical minocycline'.) Minocycline foam for acne vulgaris (November 2019) Oral and topical antibiotics are frequently prescribed for the treatment of acne vulgaris. Three randomized, placebo-controlled trials support efficacy of minocycline 4% foam, a new topical drug, for moderate to severe acne vulgaris [3,4]. Minocycline foam appears to be a generally well-tolerated treatment option, but its efficacy has not been compared with other topical and oral antibiotics. (See "Treatment of acne vulgaris", section on 'Minocycline'.)

ATOPIC DERMATITIS AND OTHER DERMATITIS Nemolizumab for prurigo nodularis (May 2020) In a phase II, randomized trial of 70 patients with moderate to severe prurigo nodularis (PN), an uncommon, chronic skin disorder characterized by symmetrically distributed, multiple, firm skin nodules and disabling pruritus (picture 1A-B), nemolizumab, an investigational anti-interleukin (IL) 31 monoclonal antibody, was more effective than placebo in reducing pruritus at four weeks and the number of skin lesions at 12 weeks [5]. Adverse events associated with nemolizumab included abdominal pain, diarrhea, and musculoskeletal pain. Larger and longer-duration studies are needed to confirm the long-term efficacy and safety of nemolizumab for recalcitrant PN. The interleukin 4 receptor inhibitor dupilumab remains our preferred treatment. (See "Prurigo nodularis", section on 'Experimental therapies'.) Frequency of bathing for atopic dermatitis (March 2020) There is controversy regarding the frequency of bathing for patients with atopic dermatitis, with some clinicians considering bathing or showering an additional skin irritant. In a two-week randomized, crossover trial that included 42 children with moderate to severe atopic dermatitis, frequent bathing (twice-daily bath for 15 to 20 minutes followed by emollient application) was associated with a greater decrease in the severity score of atopic dermatitis, compared with infrequent bathing (twiceweekly for 10 minutes or less) [6]. We suggest daily bathing to most patients. Whether bath or shower is preferred, rapid application of emollients and/or prescribed topical preparations immediately after ("soak-and-seal") is essential. (See "Treatment of atopic dermatitis (eczema)", section on 'Frequency of bathing'.) Dupilumab for prurigo nodularis (March 2020)

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Multiple recent studies have documented the efficacy of dupilumab, an interleukin (IL) 4 receptor inhibitor, for the treatment of recalcitrant prurigo nodularis (PN), an uncommon, chronic skin disorder that is frequently associated with a history of atopic dermatitis, primarily affects older adults, and is characterized by symmetrically distributed, multiple, firm, pruritic nodules (picture 1A-B). In the largest case series, a French multicentric cohort of 16 adult patients with chronic PN refractory to multimodal treatment regimens, dupilumab induced a complete or partial response of skin lesions and pruritus in 15 of 16 patients at three months [7]. We suggest dupilumab for patients with recalcitrant PN, especially those with a history of atopic dermatitis, because of its demonstrated efficacy in reducing pruritus in patients with atopic dermatitis. (See "Prurigo nodularis", section on 'Dupilumab'.)

PSORIASIS AND OTHER PAPULOSQUAMOUS DISORDERS New guidelines for the management of psoriasis in pediatric patients (February 2020) The American Academy of Dermatology and National Psoriasis Foundation have released guidelines on the management of children and adolescents with psoriasis [8]. The guidelines include recommendations for screening for comorbidities, such as obesity, cardiovascular disease, insulin resistance, hypertension, psoriatic arthritis, mental health, and inflammatory bowel disease; assessment of disease severity; and the use of topical therapies, systemic therapies, and phototherapy. We agree with the screening, assessment, and treatment recommendations reviewed in the guidelines. (See "Psoriasis in children: Epidemiology, clinical manifestations, and diagnosis" and "Psoriasis in children: Management of chronic plaque psoriasis".) Guselkumab for palmoplantar pustulosis (November 2019) Palmoplantar pustulosis (PPP), a potentially disabling, chronic inflammatory skin condition characterized by chronic and recurring pustules, erythema, and scale on the palms or soles, is often challenging to treat, supporting investigations for new, effective treatments (picture 2A-B). The first phase 3 trial to evaluate guselkumab, a systemic anti-IL-23p19 drug, for PPP found guselkumab improved disease severity scores for PPP refractory to conventional treatment [9]. Guselkumab was generally well tolerated, with infrequent serious treatment-emergent adverse effects. These findings support guselkumab as an additional treatment option for refractory PPP. (See "Palmoplantar pustulosis: Treatment", section on 'Severe recalcitrant disease'.) Serum ustekinumab levels and clinical response in psoriasis (November 2019) Therapeutic drug monitoring has been proposed as a method to optimize treatment with ustekinumab, a weight-based biologic therapy for psoriasis; however, data on this approach are

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limited. A prospective cohort study of approximately 500 adults receiving ustekinumab for psoriasis found that higher serum levels of ustekinumab in the first three months of treatment were correlated with better clinical response rates after approximately six months [10]. However, additional study is necessary to confirm the value of monitoring drug levels in patients receiving ustekinumab for psoriasis. (See "Treatment of psoriasis in adults", section on 'Ustekinumab'.) Expert guidelines for the use of phototherapy for psoriasis (November 2019) The American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) released joint guidelines for the management and treatment of psoriasis with phototherapy [11]. The guidelines review recommendations for the effective and safe use of ultraviolet light-emitting devices for psoriasis. Examples of key points include regimens for phototherapy, home narrowband UVB phototherapy as an acceptable alternative to in-office phototherapy, and the use of maintenance phototherapy regimens to maintain the response to phototherapy. We agree with the principles outlined in the guidelines. (See "Treatment of psoriasis in adults", section on 'Ultraviolet light'.)

SKIN CANCER Decreasing melanoma incidence among adolescents and young adults in the United States (November 2019) Results from the combined National Program of Cancer Registries-Surveillance Epidemiology and End Results (NPCR-SEER) database show that the incidence of invasive melanoma among adolescents and young adults declined between 2006 and 2015, with an annual decrease of approximately 4 percent [12]. A change in the sun-protection behavior among young people is a possible explanation for this trend. We continue to counsel all individuals, including adolescents and young adults, regarding the importance of sun protection to limit their risk of melanoma. (See "Risk factors for the development of melanoma", section on 'Incidence'.) Complete lymph node dissection versus observation for positive sentinel lymph node biopsy in melanoma (November 2019) For patients with cutaneous melanoma of the trunk or extremities and a positive sentinel lymph node biopsy (pSLNB), two randomized trials with intermediate follow-up found that routine immediate completion lymph node dissection (CLND) did not improve prognosis. In the final analysis of one of these trials (DeCOG-SLT), survival rates (distant metastasis-free survival, relapse-free survival, and overall survival) remained similar for the CLND and observation groups at five years, although CLND resulted in a trend toward fewer regional lymph node recurrences (11 versus 16 percent) [13]. These long-term data support current recommendations for observation with serial ultrasound

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examinations following pSLNB. Delayed CLND is performed in patients with confirmed lymph node recurrence. (See "Evaluation and treatment of regional lymph nodes in melanoma", section on 'DeCOG-SLT trial'.)

OTHER DERMATOLOGY Systemic absorption of chemical sunscreens (January 2020) Systemic absorption after maximal use of avobenzone, oxybenzone, octocrylene, and ecamsule chemical sunscreens has been previously documented. In a new randomized trial of 48 healthy volunteers who applied four sunscreen products containing three of these four chemicals in a manner mimicking real-life usage, systemic absorption of avobenzone, oxybenzone, and octocrylene with plasma concentration >0.5 ng/mL was confirmed, and absorption of three additional active ingredients (homosalate, octisalate, and octinoxate) beyond this limit was identified [14]. Pending further data, we continue to advise that patients use sunscreen along with other sun-protection measures (eg, seeking shade and wearing sun-protective clothing, hats, and sunglasses). Those who wish to avoid systemic absorption of chemical sunscreen ingredients may use sunscreens that contain mineral ingredients (eg, zinc oxide, titanium dioxide). (See "Selection of sunscreen and sunprotective measures", section on 'Organic (chemical) filters'.) Proposed diagnostic criteria for necrobiotic xanthogranuloma (January 2020) The first diagnostic criteria have been proposed for necrobiotic xanthogranuloma (NXG), a rare nonLangerhans cell histiocytic disorder, based on analysis of demographic and clinical data from over 200 patients [15]. The criteria require characteristic cutaneous and histopathologic findings, in addition to at least one minor criteria (an associated lymphoproliferative disorder or periorbital distribution of cutaneous lesions). If validated, these diagnostic criteria may be useful for standardizing the diagnosis of NXG and promoting consistency among future clinical studies. (See "Necrobiotic xanthogranuloma", section on 'Diagnosis'.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 87552 Version 9505.0

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GRAPHICS Prurigo nodularis

Multiple dome-shaped nodules with central erosion are symmetrically distributed on the lower limbs. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 116912 Version 2.0

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Prurigo nodularis

Numerous dome-shaped nodules are symmetrically distributed on the trunk and arms. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 116913 Version 2.0

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Palmoplantar pustulosis

Pustules within an erythematous, scaly plaque on the lateral heel. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 62582 Version 5.0

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Palmoplantar pustulosis

In palmoplantar pustulosis, pustules become old over several days, become brown in color and dry, and desquamate. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 82842 Version 4.0

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