1,825 435 144MB
English Pages 9680 Year 2020
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
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
3
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'.)
4
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].
5
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.
6
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].
7
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'.)
9
●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.)
10
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".)
11
●(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.
12
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]:
13
●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.
14
●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.
15
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
16
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
17
●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
18
●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).
19
●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.
20
●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
21
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
22
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
23
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'.)
24
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".)
25
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
26
●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
27
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)
28
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.
29
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'.)
30
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
31
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:
32
●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)
33
●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.
34
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].
35
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,
36
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
37
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
38
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
39
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
40
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
41
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
42
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
43
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
44
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
45
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
46
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
47
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
48
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
49
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
50
Minor dermoscopic patterns seen in acquired melanocytic nevi of palms and soles
(A) Globular pattern. (B) Acral reticular pattern. Graphic 89457 Version 1.0
51
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
52
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
53
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
54
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
55
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
56
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
57
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
58
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
59
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
60
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
61
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
62
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
63
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
64
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
65
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
66
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
67
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
68
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
69
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
70
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
71
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
72
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
73
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
74
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
75
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
76
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
77
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
78
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
79
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
80
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
81
82
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)
83
●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].
84
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]:
86
●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).
114
●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).
115
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
116
(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
117
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
119
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
120
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
150
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
171
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
172
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
173
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
174
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
175
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
176
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
177
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
178
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
179
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
180
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
181
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
182
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
183
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
184
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
185
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
186
Dermatitis herpetiformis
Erythematous papules and vesicles are present on the knee. Graphic 86749 Version 2.0
187
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
188
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
189
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
190
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
191
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
192
Herpes zoster
Courtesy of Vaibhav Parekh, MD, MBA. Graphic 65213 Version 1.0
193
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
194
Herpes zoster
Courtesy of Vaibhav Parekh, MD, MBA. Graphic 52440 Version 1.0
195
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
196
[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
197
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)
198
●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].
199
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.
200
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.
201
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
202
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
203
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.
204
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".)
205
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:
206
●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
207
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".)
208
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.)
209
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".)
210
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')
211
●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)'.)
212
●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
213
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'.)
214
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'.)
215
●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.
216
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".)
217
●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
218
●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
219
●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
220
●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.)
221
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).
222
●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.
223
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.
224
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
225
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.
226
●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].
227
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.
228
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".)
229
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".)
230
●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'.)
231
●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.
232
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.)
233
234
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)
235
●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:
236
●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
237
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
238
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".)
239
●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
240
●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".)
241
●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
242
●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)".)
243
●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.
244
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].
245
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).
246
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
248
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
249
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
250
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
252
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.
253
* 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
254
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
255
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
256
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
257
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
259
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
260
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
262
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
264
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
265
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
266
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
306
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
307
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
308
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
309
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
310
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
311
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
312
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
313
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
314
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
315
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
316
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
317
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
318
Female genital herpes simplex virus Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 58485 Version 4.0
319
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
320
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
321
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
322
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
323
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
324
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
325
Hailey-Hailey disease Typical axillary plaque of Hailey-Hailey disease, showing superficial erosions and crusts. Graphic 61689 Version 3.0
326
Perianal Hailey-Hailey disease Large, erythematous, and crusty perianal plaque in a patient with Hailey-Hailey disease. Graphic 74552 Version 6.0
327
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
328
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
329
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
330
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
331
Stage 3 ocular cicatricial pemphigoid
Note the symblepharon bridging between the eyeball and the eyelid. Graphic 54207 Version 1.0
332
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
333
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
334
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
335
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
336
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
337
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
338
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
339
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
340
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
341
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".)
342
●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".)
343
●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
344
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.
346
●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
347
•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)
348
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).
349
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
350
Rosacea
Centrofacial redness with telangiectasias in rosacea. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 77020 Version 6.0
351
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'.)
465
●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
466
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:
467
●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)
468
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.)
470
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.)
471
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):
472
•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.
473
●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)
474
•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
475
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
476
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.
477
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)
497
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
498
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
499
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):
500
•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
501
management of primary cutaneous melanoma or melanoma at other unusual sites", section on 'Subungual'.)
502
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
503
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].
504
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.
505
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'.)
506
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'.)
507
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).
508
●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.
509
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.
510
●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.
602
●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].
603
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:
1410
●
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
1411
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
1412
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
1413
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
1414
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
1415
GRAPHICS Chronic plaque psoriasis
Clusters of small plaques on the knees. Graphic 113134 Version 1.0
1416
Chronic plaque psoriasis
Thick, well-demarcated plaques of psoriasis on the lower legs of an obese adolescent girl. Graphic 113135 Version 1.0
1417
Inverse psoriasis
Inverse psoriasis involving the axillae in a child. Graphic 113323 Version 1.0
1418
Chronic plaque psoriasis
Thick scale on the temporal scalp. Graphic 113138 Version 1.0
1419
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
1420
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
1421
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
1422
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
1423
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.
1834
• 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".)
1835
●
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].
1836
●
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
1837
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
1838
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
1839
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
1840
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].
1841
●
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'.)
1842
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
1843
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
1844
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
1845
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
1846
GRAPHICS Acute urticaria on the trunk
Graphic 78544 Version 2.0
1847
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
1848
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
1849
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
1850
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
1851
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
1852
Urticarial vasculitis
Urticarial patch with central ecchymosis. Graphic 54877 Version 3.0
1853
Urticarial vasculitis
Annular patch with elevated borders. Graphic 66203 Version 2.0
1854
Urticarial vasculitis
Discrete and confluent urticarial patches with unusual annular and semi-annular features. Graphic 77924 Version 3.0
1855
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
1856
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
1857
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
1858
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
1859
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
1860
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.
1861
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.
1862
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'.)
1863
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
1864
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'.)
1865
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
2061
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.
2062
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].
2063
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
2639
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
2755
●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
2756
●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).
2757
●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.
2758
●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
2759
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
2760
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
2761
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'.)
2762
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".)
2763
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].
2764
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".)
2765
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).
2766
•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).
2768
●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.
2769
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".)
2770
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
2771
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].
2772
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.)
2773
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
2774
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
2775
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
2776
Intradermal nevus
A typical skin-colored intradermal nevus is present on the nose. Graphic 96671 Version 1.0
2777
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
2778
Blue nevus
Blue nevus on the face presenting as a small, bluish papule. Graphic 96672 Version 2.0
2779
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
2780
Dermoscopic image of a facial blue nevus
The dermoscopic hallmark of blue nevi is a structureless, blue pigmentation. Graphic 96284 Version 2.0
2781
Spitz nevus
Spitz nevus presenting as a pink, symmetric, dome-shaped papule on the face of a child. Graphic 85817 Version 6.0
2782
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
2783
Pigmented Spitz nevus (Reed nevus)
Pigmented Spitz nevus on the face of a four-year-old child. Graphic 96673 Version 1.0
2784
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
2785
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
2786
Dermoscopic image of lentigo maligna
Asymmetric, pigmented follicular openings appearing as small, gray circles in an early lentigo maligna. Graphic 96312 Version 2.0
2787
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
2788
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
2789
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
2790
Dermoscopic image of lentigo maligna
Annular-granular pattern in a lentigo maligna. Multiple gray dots are seen. Graphic 96316 Version 2.0
2791
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
2792
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
2793
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
2794
Sebaceous hyperplasia A
yellowish papule is present on the forehead of this patient. Graphic 96675 Version 1.0
2795
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
2796
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
2797
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
2798
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
2799
Dermoscopic image of seborrheic keratosis: Milia-like cysts
Graphic 96677 Version 2.0
2800
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
2801
Dermoscopic image of seborrheic keratosis: Comedo-like openings
Graphic 96678 Version 2.0
2802
Dermoscopic image of seborrheic keratosis: Sharp demarcation
Graphic 96681 Version 1.0
2803
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
2804
Dermoscopic image of seborrheic keratosis: Fissures and ridges
Graphic 96682 Version 2.0
2805
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
2806
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
2807
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
2808
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
2809
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
2810
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
2811
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
2812
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
2813
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
2814
Progression model of keratinocyte skin cancer
Graphic 96668 Version 1.0
2815
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
2816
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
2817
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
2818
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
2819
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
2820
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
2821
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
2822
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
2823
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.
2824
Conflict of interest policy
2825
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".)
2826
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
2827
●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
2828
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)
2829
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.
2830
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'.)
2831
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
2832
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:
2833
●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)
2834
●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.
2835
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].
2836
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,
2837
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
2838
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
2839
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
2840
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
2841
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
2842
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
2843
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
2844
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
2845
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
2846
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
2847
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
2848
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
2849
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
2850
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
2851
Minor dermoscopic patterns seen in acquired melanocytic nevi of palms and soles
(A) Globular pattern. (B) Acral reticular pattern. Graphic 89457 Version 1.0
2852
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
2853
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
2854
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
2855
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
2856
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
2857
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
2858
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
2859
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
2860
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
2861
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
2862
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
2863
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
2864
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
2865
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
2866
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
2867
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
2868
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
2869
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
2870
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
2871
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
2872
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
2873
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
2874
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
2875
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
2876
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
2877
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
2878
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
2879
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
2880
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
2881
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".)
2882
●(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.
2883
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.
2884
●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].
2885
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).
2886
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'.)
Benign lesions 2887
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
2888
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.)
3038
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
3039
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'.)
3040
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
3041
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]:
3042
●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'.)
3044
●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.)
3045
●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.
3091
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".)
3092
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
3093
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
3094
●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.
3095
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].
3096
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).
3097
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.)
3098
●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.)
3099
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".)
3100
●(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
3101
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)
3102
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).
3103
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
3104
(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
3105
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:
3106
●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.
3107
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):
3108
●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
3110
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".)
3111
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-
3112
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".)
3113
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).
3114
●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.)
3115
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.
3116
●(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].
3117
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
3118
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].
3119
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
3120
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.
3121
●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.
3122
●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].
3123
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)'.)
3124
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"):
3125
●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'.)
3126
●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.)
3127
●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.)
3128
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".)
3129
●(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.
3130
●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.
3131
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.
3165
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].
3166
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.
3167
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
3168
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).
3169
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.)
3170
●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.)
3171
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.
3172
●(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.
3173
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
3174
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
3175
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?
3176
●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.
3177
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)
3178
●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
3179
●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
3180
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].
3181
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.
3182
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
3183
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].
3184
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).
3185
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")
3186
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
3187
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.)
3188
●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.)
3189
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].
3190
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.
3191
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.
3192
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.
3193
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,
3194
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
3195
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-
3196
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).
3197
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
3198
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
3214
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
3215
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
3216
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.)
3218
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:
3219
●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)
3220
●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'.)
3221
●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.
3222
●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].
3223
●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.)
3224
●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.)
3225
●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'.)
3226
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".)
3227
●(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'.)
3229
Spitz melanoma — Spitz melanomas are predominantly seen in preadolescent children [22,23]. These lesions have histologic features