Dermatopathology: A Volume in the Series: Foundations in Diagnostic Pathology [2 ed.] 0323261914, 9780323261913

Table of contents :
Front cover
Inside front cover
Dermatopathology
Copyright page
Dedication
Foreword
Preface
Contributors
Table of Contents
1 Histology of the Skin
Epidermis
Melanocytes
Langerhans Cells
Merkel Cells
Basement Membrane
Dermis
Appendages
Eccrine Glands
Apocrine Glands
Sebaceous Glands
Hair Follicle
Anagen Phase
Catagen Phase
Telogen Phase
Nail
Subcutis
Inflammatory Cells
Suggested Further Reading
2 Non-neoplastic Disorders
1 Inflammatory Diseases of the Dermis and Epidermis
Spongiotic Dermatitis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Allergic Contact Dermatitis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Irritant Contact Dermatitis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Nummular Dermatitis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Atopic Dermatitis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Dyshidrotic Dermatitis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Seborrheic Dermatitis
Clinical Findings
Histologic Features
Prognosis and Treatment
Papular Dermatitis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Urticarial Dermatitis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Pityriasis Rosea
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Psoriasiform Dermatitis
Psoriasis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Lichen Simplex Chronicus and Prurigo Nodularis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Pityriasis Rubra Pilaris
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Necrolytic Migratory Erythema
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Interface Dermatitis
Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Fixed Drug Reaction
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Lichen Planus
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Pityriasis Lichenoides
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Lupus Erythematosus
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Dermatomyositis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Graft Versus Host Disease
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Lichen Sclerosus
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Lichen Nitidus
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Lichen Striatus
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Granulomatous Dermatitis
Sarcoid
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Granuloma Annulare
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Rheumatoid Nodule
Necrobiosis Lipoidica
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Necrobiotic Xanthogranuloma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Foreign Body Granulomas
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Cutaneous Crohn’s Disease
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Sweet’s Syndrome
Sweet’s Syndrome and Sweet’s-Like Reactions
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Neutrophilic Eccrine Hidradenitis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Cellulitis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Pyoderma Gangrenosum
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Perivascular Dermatitis Without Epidermal Changes
Urticaria
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Erythema Annulare Centrifugum
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Erythema Migrans
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Telangiectasia Macularis Eruptiva Perstans
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Plasmacytosis Mucosae
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ Miscellaneous Inflammatory Disorders
Polymorphous Light Eruption
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Arthropod Bite Reactions
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Transient Acantholytic Dyskeratosis (Grover’s Disease)
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Fibrosing Dermatitis
Scar
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Morphea
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Nephrogenic Systemic Fibrosis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Folliculitis
Acne Vulgaris
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Eosinophilic Folliculitis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Infectious Folliculitis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Rosacea
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Drug Reactions
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Suggested Further Reading
2 Panniculitis
■ Vasculitis Involving the Subcutis
■ Panniculitis Without Vasculitis
■ Mostly Septal Panniculitis
Erythema Nodosum
Clinical Features
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Chronic Erythema Nodosum
Clinical Features
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Subcutaneous Involvement by Granulomatous Dermatitis
Subcutaneous Involvement by Sclerosing Disorders
■ Mostly Lobular Panniculitis
Pancreatic Panniculitis
Clinical Features
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
α-1-Antitrypsin Deficiency Panniculitis
Clinical Features
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Lupus Erythematosus Profundus
Clinical Features
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Erythema Induratum (Nodular Vasculitis)
Clinical Features
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Lipodermatosclerosis
Clinical Features
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Traumatic Panniculitis
Clinical Features
Histologic Features
Ancillary Studies
Prognosis and Treatment
Sclerosing Postradiation Panniculitis
Clinical Features
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Subcutaneous Fat Necrosis of the Newborn
Clinical Features
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Calciphylaxis
Clinical Features
Histologic Features
Ancillary Studies
Prognosis and Treatment
Eosinophilic Panniculitis
Neutrophilic Panniculitis
Drug-Induced Panniculitis
Lipoatrophy and Lipodystrophy
Clinical Features
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Acknowledgement
Suggested Reading
3 Infectious Diseases of the Skin
Viral Infections
■ Human Papilloma Virus
Warts (Verrucae)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Condyloma Acuminatum
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Bowenoid Papulosis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Herpesvirus Family
Herpes Simplex
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Varicella and Herpes Zoster
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Cytomegalovirus
Clinical Findings
Histologic Features
Ancillary Studies
Prognosis and Treatment
Infections by Other Members of the Herpesvirus Family
■ Pox Virus Family
Molluscum Contagiosum
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Milker’s Nodule and Orf
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Smallpox, Cowpox, and Monkeypox
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Miscellaneous Viral Exanthems
Hand-Foot-and-Mouth Disease
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Virus-Associated Trichodysplasia Spinulosa
Clinical Findings
Histologic Features
Differential Diagnosis
Ancillary Studies
Prognosis and Treatment
Bacterial Infections
Impetigo—Impetigo Contagiosa, Bullous Impetigo, and Ecthyma
Clinical Findings
Impetigo Contagiosa
Bullous Impetigo
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Staphylococcal Scalded Skin Syndrome
Cellulitis and Erysipelas
Clinical Findings
Histologic Features
Necrotizing Fasciitis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Erythrasma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Bacterial Folliculitis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Pitted Keratolysis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Septic Vasculitis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Cat-Scratch Disease and Bacillary Angiomatosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Rickettsial Infections
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Chancroid
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Granuloma Inguinale
Clinical Findings
Histologic Features
Special Studies
Differential Diagnosis
Prognosis and Treatment
Lymphogranuma Venereum
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Rhinoscleroma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ Mycobacterial Infections
Tuberculosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Nontuberculous Mycobacterial Infections (Excluding Leprosy)
Clinical Findings
Mycobacterium marinum
Mycobacterium ulcerans (Buruli Ulcer)
Mycobacterium avium Complex (M. avium, M. intracellulare, and Others)
Mycobacterium haemophilum
Other Nontuberculous Mycobacterial Infections
Histologic Features
Mycobacterium marinum Infection
Mycobacterium ulcerans Infection
Mycobacterium avium Complex
Mycobacterium haemophilum
Other Nontuberculous Mycobacterial Infections
Differential Diagnosis
Prognosis and Treatment
Leprosy
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Actinomycosis, Nocardiosis, and Botryomycosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ Treponemal Infections
Syphilis
Clinical Findings
Primary Syphilis
Secondary Syphilis
Latent Syphilis
Tertiary Syphilis
Histologic Features
Primary Syphilis
Secondary Syphilis
Tertiary Syphilis
Ancillary Studies
Tissue Tests
Serologic Tests
Differential Diagnosis
Prognosis and Treatment
■ Nonvenereal Treponemal Infections—Yaws, Bejel, and Pinta
Lyme Disease
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Fungal Infections
■ Superficial Fungal Infections
Dermatophytoses
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Candidiasis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Tinea Versicolor and Pityrosporum Folliculitis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ Superficial and Deep Fungal Infections
Phaeohyphomycosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Chromomycosis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Sporotrichosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Alternariosis
Clinical Findings
Histologic Features
Ancillary Studies
Prognosis and Treatment
Blastomycosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Paracoccidioidomycosis
Clinical Findings
Histologic Features
Prognosis and Treatment
Coccidioidomycosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Cryptococcosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Histoplasmosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Mycetoma (Eumycetoma)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Zygomycosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Aspergillosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Lobomycosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Rhinosporidiosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Protozoan Disease, Parasitic Infestations, Algal Infections, and Bites
Amebiasis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Leishmaniasis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Cutaneous Larva Migrans
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Demodicosis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Scabies
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Pediculosis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Cimicosis (Bedbugs)
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Myiasis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Tungiasis
Clinical Findings
Histologic Features
Prognosis and Treatment
Tick Bites
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Spider Bites
Clinical Findings
Histologic Features
Prognosis and Treatment
Protothecosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ Nematodes
Cysticercosis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Onchocerciasis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Dirofilaria
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Schistosomiasis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Suggested Further Reading
General
Viral Infections
Bacterial Infections
Fungal Infections
Arthropod Bites, Infestation
4 Cutaneous Vasculitis
Clinical Findings
Biopsy: Timing and Choice of Lesions
Histologic Findings
Histologic Diagnosis of Vasculitis
Incidental Vasculitis
Other Histologic Findings Associated with Vasculitis
Ancillary Studies
Direct Immunofluorescent Studies
Laboratory Studies
Antineutrophil Cytoplasmic Antibodies
Evaluation of Cutaneous Vasculitis Patients
Differential Diagnosis
Prognosis
Treatment
■ Common Cutaneous Vasculitis Syndromes
Cutaneous Leukocytoclastic Angiitis
Clinical Findings
Histologic Findings
Ancillary Studies
Henoch Schönlein Purpura
Clinical Findings
Histologic Findings
Ancillary Studies
Drug-Induced Vasculitis
Clinical Findings
Histologic Findings
Paraneoplastic (Malignancy-Induced) Vasculitis
Clinical Findings
Urticarial Vasculitis
Clinical Findings
Histologic Findings
Ancillary Studies
Infection-Induced and Septic Vasculitis
Clinical Findings
Histologic Findings
Chronic Localized Fibrosing Leukocytoclastic Vasculitis
Clinical Findings
Histologic Findings
Ancillary Studies
Cryoglobulinemic Vasculitis
Clinical Findings
Histologic Findings
Ancillary Studies
Connective Tissue Disease Vasculitis
Clinical Findings
Histologic Findings
ANCA-Positive Primary Systemic Vasculitis
■ Granulomatosis with Polyangiitis, Eosinophilic Granulomatosis with Polyangiitis, and Microscopic Polyangiitis
Granulomatosis with Polyangiitis
Clinical Findings
Histologic Findings
Eosinophilic Granulomatosis with Polyangiitis
Clinical Findings
Histologic Findings
Microscopic Polyangiitis
Clinical Findings
Histologic Findings
Cutaneous Polyarteritis Nodosa
Clinical Findings
Histologic Findings
Nodular Vasculitis
Clinical Findings
Histologic Findings
Giant Cell Arteritis
Clinical Findings
Histologic Findings
Pseudovasculitis
Suggested Further Reading
5 Blistering Skin Diseases
Approach to the Diagnosis of Blistering Diseases
Clinical Findings
Histologic Features
Ancillary Studies
Intraepidermal Blisters
■ Corneal and Granular Layer Blisters
Miliaria
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Bullous Impetigo
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Staphylococcal Scalded Skin Syndrome
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Acropustulosis of Infancy (Infantile Acropustulosis)
Transient Neonatal Pustular Melanosis
Erythema Toxicum Neonatorum
Subcorneal Pustular Dermatosis (Sneddon-Wilkinson Disease)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Acute Generalized Exanthematous Pustulosis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Intraepidermal Blister with Spongiosis or Edema
Spongiotic Dermatitis
Clinical Findings
Histologic Features
Vesiculobullous Bite Reactions
Clinical Findings
Histologic Features
Polymorphous Light Eruption
Clinical Findings
Histologic Features
Prognosis and Treatment
Incontinentia Pigmenti
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Intraepidermal Blister with Acantholysis
Pemphigus Group
Pemphigus Vulgaris
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Pemphigus Vegetans
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Pemphigus Foliaceus
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Pemphigus Herpetiformis
Drug-Induced Pemphigus
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
IgA Pemphigus
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Paraneoplastic Pemphigus
Clinical Findings
Histologic Features
Ancillary Studies
Immunoprecipitation
Direct Immunofluorescence
Indirect Immunofluorescence
Differential Diagnosis
Prognosis and Treatment
Darier’s Disease
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Hailey-Hailey Disease
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Acantholytic Dermatosis of the Genitocrural Region
Transient Acantholytic Dermatosis (Grover’s Disease)
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Herpetic Dermatitis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Intraepidermal Blister Associated with Epidermolytic Hyperkeratosis
Epidermolytic Hyperkeratosis (Bullous Congenital Ichthyosiform Erythroderma)
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Subepidermal Blisters
■ Subepidermal Blister with Neutrophils or Eosinophils
Bullous Pemphigoid
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Mucous Membrane Pemphigoid (Cicatricial Pemphigoid)
Pemphigoid Gestationis (Herpes Gestationis)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Pruritic Urticarial Papules and Plaques of Pregnancy
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Linear IgA Bullous Dermatosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Dermatitis Herpetiformis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Bullous Sweet’s Syndrome (Neutrophilic Dermatosis)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Bullous Lupus Erythematosus
Arthropod Bites
Subepidermal Vesicular Lichenoid Dermatitis
■ Subepidermal Vesicle with No or Only Minimal Inflammation
Epidermolysis Bullosa Acquisita
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Porphyria Cutanea Tarda
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Pseudoporphyria
Inherited Epidermolysis Bullosa
Clinical Findings
Histologic Features
Ancillary Studies
Prognosis and Treatment
■ Miscellaneous Other Intra- or Subepidermal Blisters
Nutritional Deficiency Syndrome Blisters
Bullous Diabeticorum
Blisters Caused by Friction
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Coma Blisters
Acute Edema Blisters
Blisters Caused by Heat or Cold
Blisters Caused by Topical Medications
Blisters Caused by Vasculitis or Infection
Blisters Associated with a Superficial Dermal Neoplastic Infiltrate
Suggested Further Reading
6 Mucinoses, Deposition Disorders, and Connective Tissue Alterations
Cutaneous Mucinoses
Clinical Findings
Histologic Features
Generalized Myxedema
Pretibial Myxedema
Scleromyxedema
Reticulated Erythematous Mucinosis
Scleredema
Papular and Nodular Mucinosis Associated with Lupus Erythematosus
Cutaneous Mucous Cyst (Myxoid Cyst)
Mucocele
Cutaneous Focal Mucinosis
Follicular Mucinosis
Self-Healing Juvenile Cutaneous Mucinosis
Ancillary Studies
Special Stains
Immunofluorescence Studies
Differential Diagnosis
Prognosis and Treatment
Deposition Disorders
■ Hyaline Deposits
Amyloidosis
Clinical Findings
Systemic Amyloidosis
Localized Cutaneous Amyloidosis
Histologic Features
Systemic Amyloidosis
Localized Cutaneous Amyloidosis
Ancillary Studies
Special Stains
Immunohistochemistry
Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
■ Colloid Milium
Lipoid Proteinosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Gout
Clinical Findings
Macroscopic Features
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Porphyria
Clinical Findings
Histologic Findings
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ Calcium, Osseous, and Cartilaginous Deposits
Calcium Deposits
Clinical Findings
Histologic Features
Ancillary Studies
Prognosis and Treatment
Cutaneous Ossification
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Cartilaginous Deposits
■ Pigmentary Deposits
Ochronosis
Clinical Findings
Histologic Features
Prognosis and Treatment
Tattoos
Hemosiderin Pigment Deposition
Mercury Deposits
Argyria
Exogenous (Foreign) Material
Fillers and Implants
Alterations of Dermal Connective Tissue
Solar Elastosis
Clinical Findings
Histologic Features
Prognosis and Treatment
Pseudoxanthoma Elasticum
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Suggested Further Reading
7 Non-neoplastic Disorders of Pigmentation
Café-Au-Lait Macules
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Melasma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Erythema Dyschromicum Perstans
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Drug-Induced Hyperpigmentation
Minocycline-Induced Hyperpigmentation
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Amiodarone-Induced Hyperpigmentation
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Imipramine-Induced Hyperpigmentation
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Postinflammatory Hyperpigmentation
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ Disorders of Decreased Pigmentation
Vitiligo
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Pityriasis Alba
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Ash-Leaf Spots
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Drug-Induced Hypopigmentation
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Postinflammatory Hypopigmentation
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Suggested Further Reading
8 Non-neoplastic Disorders of Hair
Hair Follicle Stem Cells
Nonscarring Alopecias
Androgenetic Alopecia
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Senescent Baldness
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Acute Telogen Effluvium
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Anagen Arrest
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Alopecia Areata
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Trichotillomania
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Traction Alopecia
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Pressure-Induced Alopecia
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Congenital Temporal Alopecia
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Loose Anagen Hair Syndrome
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Syphilitic Alopecia
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Scarring (Permanent) Alopecias
■ Lymphocyte-Associated Primary Scarring Alopecias
Chronic Cutaneous (Discoid) Lupus Erythematosus
Clinical Findings
Histologic Features
Ancillary Studies
Special Stains
Immunofluorescence
Differential Diagnosis
Prognosis and Treatment
Lichen Planopilaris
Clinical Findings
Histologic Features
Ancillary Studies
Special Stains
Immunofluorescence
Differential Diagnosis
Prognosis and Treatment
Classic Pseudopelade (Brocq)
Clinical Findings
Histologic Features
Ancillary Studies
Special Stains
Differential Diagnosis
Prognosis and Treatment
Central Centrifugal Cicatricial Alopecia
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Alopecia Mucinosa
Clinical Findings
Histologic Features
Ancillary Studies
Gene Rearrangement and Immunohistochemical Studies
Differential Diagnosis
Prognosis and Treatment
Keratosis Follicularis Spinulosa Decalvans
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Neutrophil-Associated Primary Scarring Alopecias
Folliculitis Decalvans
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Dissecting Cellulitis and Folliculitis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Mixed Inflammatory Primary Scarring Alopecias
Folliculitis (Acne) Keloidalis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Folliculitis (Acne) Necrotica
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Erosive Pustular Dermatosis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Suggested Further Reading
9 Cysts and Sinuses
Cysts Derived from Appendageal Structures
■ Cysts Arising From the Infundibular Portion of the Hair Follicle
Follicular Cyst of Infundibular Type (Epidermoid Cyst)
Clinical Findings
Histologic Features
Differential Diagnosis
Proliferating Epithelial (Infundibular) Cyst
Clinical Findings
Histologic Features
Differential Diagnosis
Human Papilloma Virus–Related Follicular Cyst
Clinical Findings
Histologic Features
Differential Diagnosis
Pigmented Follicular Cyst
Clinical Findings
Histologic Features
Differential Diagnosis
Milium
Clinical Findings
Histologic Features
Differential Diagnosis
Vellus Hair Cyst
Clinical Findings
Histologic Features
Differential Diagnosis
■ Cysts Arising From the Isthmus Portion of the Hair Follicle
Trichilemmal (Isthmus-Catagen or Pilar) Cyst
Clinical Findings
Histologic Features
Differential Diagnosis
Proliferating Trichilemmal (Pilar) Cyst/Tumor
Clinical Findings
Histologic Features
Differential Diagnosis
■ Cysts Arising From the Sebaceous Duct
Steatocystoma
Clinical Findings
Histologic Features
Differential Diagnosis
Follicular Hybrid Cysts
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Cysts Arising From the Eccrine Duct
Eccrine Hidrocystoma
Clinical Findings
Histologic Features
Differential Diagnosis
■ Cysts Arising From the Apocrine Duct or Gland
Apocrine Hidrocystoma and Cystadenoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Developmental Cysts
Dermoid Cysts
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Cutaneous Ciliated Cysts
Clinical Findings
Histologic Features
Differential Diagnosis
Ciliated Mucinous Cysts of the Vulva
Clinical Findings
Histologic Features
Differential Diagnosis
Median Raphe Cysts
Clinical Findings
Histologic Features
Differential Diagnosis
Omphalomesenteric Duct Cysts
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Pseudocysts
Pseudocysts of the Auricle
Clinical Findings
Histologic Features
Differential Diagnosis
Digital Mucous Cysts
Clinical Findings
Histologic Features
Differential Diagnosis
Ganglion Cyst
Clinical Findings
Histologic Features
Differential Diagnosis
Mucoceles (Mucous Cyst of the Oral Cavity)
Clinical Findings
Histologic Features
Differential Diagnosis
Metaplastic Synovial Cysts
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment of Pseudocysts
■ Pits and Sinuses
Lip Pits
Clinical Findings
Histologic Features
Differential Diagnosis
Sacral Pits
Clinical Findings
Histologic Features
Differential Diagnosis
Pilonidal Sinuses and Cysts
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Suggested Further Reading
3 Tumors and Pseudotumors of the Skin and Subcutis
10 Tumors of the Epidermis
Benign Tumors and Tumorous Proliferations of the Epidermis
Reactive Epidermal Hyperplasia with Emphasis on Pseudoepitheliomatous Hyperplasia
Keratinizing Epidermal Nevus
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Benign Acanthomas and Keratoses
Seborrheic Keratosis
Clinical Findings
Histologic Features
Differential Diagnosis
Seborrheic Keratosis Versus Epidermal Nevus
Seborrheic Keratosis Versus Actinic Keratosis
Seborrheic Keratosis Versus Squamous Cell Carcinoma in Situ
Seborrheic Keratosis Versus Verruca Vulgaris
Seborrheic Keratosis Versus Clear Cell Acanthoma
Seborrheic Keratosis Versus Lichenoid Keratosis
Pigmented Seborrheic Keratosis Versus a Keratotic Melanocytic Lesion
Pedunculated Seborrheic Keratosis Versus Acrochordon
Seborrheic Keratosis Versus Nevoid Hyperkeratosis of the Nipple and Areola
Seborrheic Keratosis Versus Acanthosis Nigricans
Prognosis and Treatment
Verrucous Keratosis
Large Cell Acanthoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Clear Cell Acanthoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Acantholytic Acanthoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Warty Dyskeratoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Benign Lichenoid Keratosis (Lichen Planus–Like Keratosis)
Clinical Findings
Histologic Features
Differential Diagnosis
Lichenoid Keratosis Versus Lichen Planus
Lichenoid Keratosis Versus Inflamed Actinic Keratosis
Lichenoid Keratosis Versus Mycosis Fungoides
Lichenoid Keratosis Versus a Melanocytic Lesion
Lichenoid Keratosis Versus Basal Cell Carcinoma
Prognosis and Treatment
Porokeratosis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Intraepidermal Squamous “Precursor” Lesions: Keratinocytic “Dysplasias” and Squamous Cell Carcinoma in Situ (Noninvasive Carcinoma)
The Spectrum of Actinic Keratosis and Actinic Squamous Cell Carcinoma in Situ
Clinical Findings
Histologic Features
Differential Diagnosis
Actinic Keratosis Versus Benign Keratoses
Digitated Actinic Keratosis Versus Verruca of Sun-Damaged Skin
Pigmented Actinic Keratosis Versus Solar Lentigo or Lentigo Maligna
Acantholytic Actinic Keratosis Versus Acantholytic Squamous Cell Carcinoma or Benign Acantholytic Lesions
Actinic Keratosis Versus Chemotherapy-Induced Atypia
Prognosis and Treatment
Bowenoid Squamous Cell Carcinoma in Situ (Bowen’s Disease and Its Variants)
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Vulvar and Perineal Intraepithelial Neoplasia (Vulvar Intraepithelial Neoplasia and Pain) or Dysplasia
Clinical Findings
Histologic Features
Low-Grade Dysplasia (Low-Grade Squamous Intraepithelial Lesion)
High-Grade Dysplasia (Intraepithelial Lesion Grades II and III)
Differentiated (Simplex Type) of Dysplasia
Differential Diagnosis
Prognosis and Treatment
Arsenical Keratosis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Invasive Squamous Cell Carcinoma
Clinical Findings
Histologic Features
Conventional Squamous Cell Carcinoma
Acantholytic Squamous Cell Carcinoma
Clear Cell Squamous Cell Carcinoma
Basaloid Squamous Cell Carcinoma
Warty Squamous Cell Carcinoma
Verrucous Carcinoma
Lymphoepithelioma-like (Lymphocyte-Rich) Squamous Cell Carcinoma
Spindle Cell Squamous Cell Carcinoma
Desmoplastic or Sclerosing Squamous Cell Carcinoma
Squamous Cell Carcinoma with Single-Cell Infiltrative Pattern
Carcinosarcoma
Adenosquamous Carcinoma
Basosquamous Carcinoma
Merkel Cell (Neuroendocrine) Carcinoma Ex–Squamous Cell Carcinoma
Ancillary Studies
Differential Diagnosis
Invasive Versus in Situ Squamous Cell Carcinoma
Squamous Cell Carcinoma Versus Pseudoepitheliomatous Hyperplasia
Squamous Cell Carcinoma Versus Metatypical Basal Cell Carcinoma
Squamous Cell Carcinoma Versus Adnexal Carcinomas with Squamous Differentiation (Porocarcinoma, Trichilemmal Carcinoma)
Squamous Cell Carcinoma Versus Proliferating Pilar Cystic Tumor
Squamous Cell Carcinoma Versus Melanoma
Squamous Cell Carcinoma Versus Large Cell Lymphoma
Squamous Cell Carcinoma Versus Sarcoma
Prognostic Features of Squamous Cell Carcinoma
Clinical Features
Anatomic Site
Clinical History
Pathologic Features
Histologic Subtype
Tumor Size, Thickness, and Depth of Invasion
Grades of Differentiation
Perineural Invasion
Vascular Invasion
Staging of Squamous Cell Carcinoma
Treatment
Pathologist’s Reporting of SCC
Keratoacanthoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Metastatic Squamous Cell Carcinoma
Suggested Further Reading
11 Adnexal Tumors
Tumorous Proliferations with Follicular Differentiation
■ Follicular Hamartoma (Follicular Nevus)
■ Nevus Comedonicus
■ Benign Follicular Neoplasms
Dilated Pore and Pilar Sheath Acanthoma and Trichofolliculoma
Infundibuloma (Tumor of the Follicular Infundibulum)
Trichoblastoma and Trichoepithelioma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Desmoplastic Trichoepithelioma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Basaloid Follicular Hamartoma
Trichoadenoma
Tricholemmoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Inverted Follicular Keratosis
Pilomatricoma (Calcifying Epithelioma of Malherbe)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Fibrofolliculoma and Trichodiscoma
Clinical Findings
Histologic Features
Treatment of Benign Follicular Tumors
Malignant Neoplasms with Follicular Differentiation: Basal Cell Carcinoma
Clinical Findings
Histologic Features
Superficial Pattern
Nodular Pattern
Morpheaform and Infiltrative Pattern
Fibroepitheliomatous Pattern
Infundibulocystic Basal Cell Carcinoma
Adenoidal Basal Cell Carcinoma
Pigmented Basal Cell Carcinoma
Basal Cell Carcinoma with Squamous Differentiation
Clear Cell Basal Cell Carcinoma
Granular Cell Basal Cell Carcinoma
Basal Cell Carcinoma with Eccrine Differentiation
Basal Cell Carcinoma with Sebaceous Glands
Basal Cell Carcinoma with Matrical Differentiation
Basal Cell Carcinoma with Nuclear Pleomorphism
Collision Scenarios
Biphenotypic Tumors
Ancillary Studies
Differential Diagnosis
Basal Cell Carcinoma versus Trichoblastoma and Trichoepithelioma
Basal Cell Carcinoma versus Squamous Cell Carcinoma
Basal Cell Carcinoma versus Adenoid Cystic Carcinoma
Basal Cell Carcinoma versus Microcystic Adnexal Carcinoma
Basal Cell Carcinoma versus Merkel Cell Carcinoma
Basal Cell Carcinoma versus “No Tumor Seen”
Prognosis and Treatment
Pathologist’s Reporting of Basal Cell Carcinoma
Pilomatrix Carcinoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Trichilemmal Carcinoma
Tumorous Proliferations with Apocrine or Eccrine Features
■ Hamartoma and Nevus
Eccrine Nevus
Apocrine Nevus
■ Benign Neoplasms
Adenoma (Spectrum of Apocrine or Eccrine Adenomas, with Tubular, Cribriform, Papillary, Mixed, or Not Otherwise Specified Patterns)
Clinical Findings
Histologic Features
Differential Diagnosis
Hidradenoma Papilliferum
Clinical Findings
Histologic Features
Differential Diagnosis
Hidradenoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Syringoma
Clinical Findings
Histologic Features
Differential Diagnosis
Syringocystadenoma Papilliferum
Clinical Findings
Histologic Features
Differential Diagnosis
Syringofibroadenoma (of Mascaró)
Acrospiromas—the Spectrum of Hidroacanthoma, Poroma, and Dermal Duct Tumor
Hidroacanthoma Simplex
Clinical Findings
Histologic Features
Differential Diagnosis
Poroma
Clinical Findings
Histologic Features
Differential Diagnosis
Dermal Duct Tumor
Clinical Findings
Histologic Features
Differential Diagnosis
Spiradenoma
Clinical Findings
Histologic Features
Differential Diagnosis
Cylindroma
Clinical Findings
Histologic Features
Differential Diagnosis
Benign Mixed Tumor (Chondroid Syringoma)
Clinical Findings
Histologic Features
Differential Diagnosis
Myoepithelioma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Treatment of Benign Glandular Tumors
Malignant Neoplasms
Microcystic Adnexal Carcinoma (Sclerosing Sweat Duct Adenocarcinoma)
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Porocarcinoma (Malignant Poroma)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Ductal (Eccrine or Apocrine) Adenocarcinoma (De Novo or Arising in Association with an Adenoma)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Aggressive Digital Papillary Adenoma—Adenocarcinoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Hidradenocarcinoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Cribriform Carcinoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Mucinous Adenocarcinoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Endocrine Mucin-Producing Sweat Gland Carcinoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Extramammary Paget’s Disease
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Adenoid Cystic Carcinoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Endocrine Mucin-Producing Sweat Gland Carcinoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Carcinosarcoma
Malignant Mixed Tumor
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Myoepithelial Carcinoma (Malignant Myoepithelioma)
Metastatic Sweat Duct Carcinomas
Tumorous Proliferations with Sebaceous Differentiation
Sebaceous Hyperplasia
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Sebaceous Trichofolliculoma (Folliculosebaceous Cystic Hamartoma)
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Nevus Sebaceus
Clinical Findings
Histologic Features
Prognosis and Treatment
Sebaceous Adenoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Sebaceous Carcinoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ Adnexal Neoplasms Associated with Systemic Syndromes
Gardner’s Syndrome
Xeroderma Pigmentosum
Nevoid Basal Cell Carcinoma Syndrome
Generalized Basaloid Follicular Hamartoma Syndrome
Bazex Syndrome (Bazex-DuprÉ-Christol Syndrome)
Brooke-Spiegler Syndrome, Familial Cylindromatosis, and Multiple Familial Trichoepitheliomas
Cowden Syndrome
Muir-Torre Syndrome
Immunohistochemistry for Mismatch Repair Proteins
Birt-Hogg-Dubé Syndrome
Suggested Further Reading
12 Melanocytic Proliferations
Lentigines and Lentigo-Like Lesions
Solar Lentigo
Clinical Findings
Histologic Features
Differential Diagnosis
Lentigo Simplex
Clinical Findings
Histologic Features
Differential Diagnosis
Miscellaneous Melanotic Macules
Melanocytic Nevi
Common (Typical or Ordinary) Acquired Melanocytic Nevi
Clinical Findings
Histologic Features
Differential Diagnosis
Dysplastic Melanocytic Nevi
Clinical Findings
Histologic Features
Differential Diagnosis
Spindle or Epithelioid Melanocytic (Spitz’s) Nevi
Clinical Findings
Histologic Features
Differential Diagnosis
Congenital Melanocytic Nevi
Clinical Findings
Histologic Features
Differential Diagnosis
Blue Nevi and Dermal Melanocytoses
Clinical Findings
Histologic Features
Differential Diagnosis
Melanocytic Nevi of Special Anatomic Sites
Nevus Spilus or Speckled Nevus
Clinical Findings
Histologic Features
Miscellaneous Unusual Melanocytic Nevi
Deep Penetrating or Plexiform Spindle and Epithelioid Nevus
Desmoplastic (Sclerosing) Melanocytic Nevus
Melanocytic Nevi with Phenotypic Heterogeneity (Combined Nevi)
Recurrent or Persistent Melanocytic Nevi
Primary Melanoma
Clinical Findings
Histologic Features: General Considerations for the Diagnosis of Melanoma
Histologic Features for the Diagnosis of Melanoma in Situ
Differential Diagnosis of Melanoma in Situ
Histologic Features for the Diagnosis of Invasive Melanoma
Differential Diagnosis of Primary Invasive Melanoma
Histologic Parameters Relevant for Prognosis
Tumor Thickness
Ulceration
Microanatomic (Clark) Level
Tumor Mitotic Rate
Lymphatic or Blood Vessel Invasion
Nerve Involvement
Satellites or Locoregional Cutaneous Metastases
Tumor-Infiltrating Lymphocytes
Regression
Common (Conventional) Variants of Melanoma
Uncommon Pathologic Variants of Melanoma
Spindle Cell Melanoma
Desmoplastic Melanoma
Clinical Findings
Histologic Features
Differential Diagnosis
Neurotropic Melanoma
Nevoid Melanoma
Spitzoid Melanoma
Melanoma Arising From or Simulating Blue Nevus (so-Called Malignant Blue Nevus)
Small Cell Melanoma
Balloon Cell Melanoma
Signet Ring Cell Melanoma
Verrucous Melanoma
Melanophage-Rich Melanoma
Melanoma of Soft Parts (Clear Cell Sarcoma)
Clinical Findings
Histologic Features
Differential Diagnosis
Melanocytic Tumors of Uncertain Malignant Potential or Borderline Lesions
Melanocytic Proliferations Associated with Epithelial Tumors
Metastatic Melanoma
Locoregional Metastases (American Joint Committee on Cancer Stage III Disease)
Sentinel Lymph Node Biopsy
Distant Metastases (American Joint Committee on Cancer Stage IV Disease)
Differential Diagnosis of Metastatic Melanoma
Metastatic Melanoma Simulating Other Neoplasms
Metastatic Melanoma of Unknown Primary Tumor
Primary Cutaneous Melanoma versus Metastatic Melanoma to the Skin
Primary Melanoma of Soft Tissue (Clear Cell Sarcoma) versus Metastatic Melanoma to Soft Tissue
Melanocytic Nevus versus Nevoid Metastasis
Nodal Nevus versus Metastatic Melanoma
Melanosis Associated with Metastatic Melanoma
Ancillary Studies
Fontana Masson Stain
Electron Microscopy
Immunohistochemistry
Immunohistochemistry for Melanocyte Differentiation
Immunohistochemistry to Assess Cell Growth
Immunohistochemistry to Document Genetic Changes
Cytogenetic and Molecular Studies
Mutation Analysis
Pathology Reporting of Melanoma
Primary Cutaneous Melanoma
Metastatic Melanoma
prognosis
Clinical Stages I and II
Clinical Stage III
Clinical Stage IV
Surgical Management
Biopsy and Excisions of Melanocytic Nevi
Primary Melanoma
Sentinel Lymph Node Mapping and Biopsy
Management of Metastatic Melanoma
Nonsurgical Treatment Options
Suggested Further Reading
13 Soft Tissue Tumors and Tumor-like Reactions
Fibrous, Myofibroblastic, and Fibrohistiocytic Tumors
■ Benign Tumors and Tumor-Like Reactions
Dermal Scar and Keloid
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Dermatofibroma (Benign Fibrous Histiocytoma)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Dermatofibroma Versus Dermatofibrosarcoma Protuberans
Dermatofibroma Versus Amelanotic Spindle Cell Melanocytic Tumor
Atypical Fibrous Histiocytoma Versus Miscellaneous Pleomorphic Fibrous Tumors
Dermatofibroma Versus Scar
Prognosis and Treatment
Dermatomyofibroma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Fibroblastic Connective Tissue Nevus
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Pleomorphic Fibroma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Sclerotic Fibroma (Storiform Collagenoma)
Clinical Findings
Histologic Features
Prognosis and Treatment
Angiofibroma and Fibrous Papule
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Fasciitis (Nodular Fasciitis and Variants)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Proliferative Fasciitis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Fibroma of the Tendon Sheath
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Tenosynovial Giant Cell Tumor
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Myofibroma and Myofibromatosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Cutaneous Myxoma and Superficial Angiomyxoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Superficial Acral Fibromyxoma (Digital Fibromyxoma)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Fibromatosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Fibrous Hamartoma of Infancy
Clinical Findings
Histologic Features
Prognosis and Treatment
Infantile Digital Fibroma (Fibromatosis)
Clinical Findings
Histologic Features
Prognosis and Treatment
Elastofibroma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Malignant Tumors
■ Malignant Tumors with Propensity for Local Recurrence But Low Risk for Metastasis
Dermatofibrosarcoma Protuberans
Clinical Findings
Histologic Features
Ancillary Studies
Immunohistochemistry
Cytogenetics
Differential Diagnosis
Dermatofibrosarcoma Protuberans Versus Dermatofibroma
Dermatofibrosarcoma Protuberans Versus Diffuse Type of Neurofibroma
Dermatofibrosarcoma Protuberans Versus Perineurioma
Dermatofibrosarcoma Protuberans Versus Fibroblastic Connective Tissue Nevus
Prognosis and Treatment
Giant Cell Fibroblastoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Plexiform Fibrohistiocytic Tumor
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Angiomatoid Fibrous Histiocytoma
Clinical Findings
Histologic Features
Ancillary Studies
Immunohistochemistry
Cytogenetics
Differential Diagnosis
Prognosis and Treatment
Giant Cell Tumor of Soft Tissue
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Atypical Fibroxanthoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Superficial CD34-Positive Fibroblastic Tumor
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Ossifying Fibromyxoid Tumor
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Undifferentiated Pleomorphic Sarcoma (Formerly Malignant Fibrous Histiocytoma)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Myxofibrosarcoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Epithelioid Sarcoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Low-Grade Fibromyxoid Sarcoma
Clinical Findings
Histologic Features
Ancillary Studies
Immunohistochemistry
Cytogenetics
Differential Diagnosis
Prognosis and Treatment
Lipomatous Tumors
■ Benign Tumors and Tumor-Like Conditions
Lipoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Spindle Cell Lipoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Pleomorphic Lipoma
Clinical Findings
Histologic Features
Differential Diagnosis
Angiolipoma
Clinical Findings
Histologic Features
Differential Diagnosis
Chondroid Lipoma
Clinical Findings
Histologic Features
Ancillary Studies
Immunohistochemistry
Cytogenetics
Differential Diagnosis
Lipoblastoma and Lipoblastomatosis
Clinical Findings
Histologic Features
Ancillary Studies
Immunohistochemistry
Cytogenetics
Differential Diagnosis
Prognosis and Treatment
Nevus Lipomatosus Superficialis
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Malignant Tumors (Atypical Lipomatous Tumor and Liposarcoma)
Atypical Lipomatous Tumor
Clinical Findings
Histologic Features
Ancillary Studies
Immunohistochemistry
Cytogenetics
Differential Diagnosis
Prognosis and Treatment
Other Variants of Liposarcoma
Smooth Muscle Tumors
■ Benign Tumors and Tumor-Like Conditions
Leiomyoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Smooth Muscle Hamartoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Malignant Tumors (Leiomyosarcoma)
Clinical Findings
Histologic Features
Ancillary Studies
Prognosis and Treatment
Neural Tumors
■ Benign Tumors and Tumor-Like Conditions
Traumatic Neuroma
Rudimentary Polydactyly
Solitary Circumscribed Neuroma (Palisaded Encapsulated Neuroma)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Schwannoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Neurofibroma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Perineurioma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Granular Cell Tumor
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Dermal Nerve Sheath Myxoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Cellular Neurothekeoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Ectopic (Extracranial) Meningioma
Nasal Glial Heterotopia
Malignant Tumors
Malignant Peripheral Nerve Sheath Tumor
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Malignant Granular Cell Tumor
Cutaneous Ewing Sarcoma
Vascular Tumors
■ Benign Tumors and Tumor-Like Conditions
Hemangiomas
Clinical Findings
Histologic Features
Cherry Angioma
Pyogenic Granuloma (Lobular Capillary Hemangioma)
Arteriovenous Hemangioma (Cirsoid Aneurysm)
Acquired Tufted Hemangioma
Glomeruloid Hemangioma
Spindle Cell Hemangioma
Epithelioid Hemangioma (Angiolymphoid Hyperplasia with Eosinophilia)
Hobnail Hemangioma (Targetoid Hemosiderotic Hemangioma)
Angiokeratoma
Prognosis and Treatment
Papillary Endothelial Hyperplasia
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Acroangiodermatitis (Pseudo-Kaposi sarcoma)
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Reactive Angioendotheliomatosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Venous Lake
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Cutaneous Epithelioid Angiomatous Nodule
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Multinucleate Giant Cell Angiohistiocytoma
Lymphangioma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Radiation-Associated Atypical Vascular Lesion
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Borderline and Low-Grade Malignant Tumors
Epithelioid Hemangioendothelioma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Kaposiform Hemangioendothelioma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Retiform Hemangioendothelioma and Papillary Intralymphatic Angioendothelioma (Dabska Tumor)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Kaposi Sarcoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Epithelioid Sarcoma–Like (Pseudomyogenic) Hemangioendothelioma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ High-Grade Malignant Tumors
Angiosarcoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ Perivascular Tumors
Glomus Tumor and Glomuvenous Malformation
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Myopericytoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Cutaneous Perivascular Epithelioid Tumor
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Cartilaginous Lesions
■ Benign Cartilaginous Tumors
Cutaneous (Soft Tissue) Chondromas
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Malignant Cartilaginous Tumors
Chondrosarcoma
Clinical Findings
Histologic Features
Conventional Chondrosarcoma
Dedifferentiated Chondrosarcoma
Mesenchymal Chondrosarcoma
Extraskeletal Myxoid Chondrosarcoma
Ancillary Studies
Immunohistochemistry
Cytogenetics
Differential Diagnosis
Prognosis and Treatment
Bone-Forming Tumors and Tumor-Like Conditions
■ Benign Osseous Lesions
Osteoma Cutis
Clinical Findings
Histologic Features
Differential Diagnosis
■ Malignant Osseous Tumors
Osteosarcoma
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
■ Notochordal Tumors
Chordoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Suggested Further Reading
14 Hematopoietic Neoplasms
Cutaneous Lymphomas and Pseudolymphomas
■ Cutaneous T-Cell Lymphoma
Mycosis Fungoides
Clinical Findings
Histologic Features
Ancillary Studies
Immunohistochemistry
Molecular Studies
Differential Diagnosis
Mycosis Fungoides Versus Eczema
Mycosis Fungoides Versus Psoriasis
Mycosis Fungoides Versus Drug Reaction
Mycosis Fungoides Versus Tinea
Mycosis Fungoides Versus Pigmented Purpura
Mycosis Fungoides Versus Lichenoid Dermatitis
Mycosis Fungoides Versus Vitiligo
Large Cell Transformation Arising in Mycosis Fungoides Versus Primary Anaplastic Large Cell Lymphoma
Prognosis and Treatment
Follicotropic Mycosis Fungoides with or Without Follicular Mucinosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Syringotropic Mycosis Fungoides
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Pagetoid Reticulosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Granulomatous Slack Skin
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Cutaneous T-Cell Lymphoma: Sézary Syndrome
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Primary Cutaneous CD30-Positive Lymphoproliferative Disorder
Lymphomatoid Papulosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Primary Cutaneous Anaplastic Large Cell Lymphoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
CD30-Negative, Nonmycosis Fungoides Cutaneous T-Cell Lymphoma
Subcutaneous Panniculitis-Like T-Cell Lymphoma
Clinical Findings
Histologic Features
Ancillary Studies
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Primary Cutaneous Peripheral T-Cell Lymphoma, Unspecified
Primary Cutaneous Aggressive Epidermotropic CD8-Positive Cytotoxic Cutaneous T-Cell Lymphoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Primary Cutaneous CD4-Positive Small/Medium Pleomorphic T-Cell Lymphoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
γδ LYMPHOMA
Clinical Findings
Histologic Features
Ancillary Studies
Prognosis and Treatment
■ Secondary Cutaneous Lymphoma (Extracutaneous Lymphoma Commonly Involving Skin)
Adult T-Cell Leukemia/Lymphoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Extranodal Natural Killer T-Cell Lymphoma, Nasal Type
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Hydroa Vacciniforme–Like Cutaneous T-Cell Lymphoma
■ Cutaneous T-Cell Pseudolymphoma
■ Cutaneous B-Cell Lymphoma
■ Indolent Variants of Primary Cutaneous B-Cell Lymphoma
Primary Cutaneous Marginal Zone B-Cell Lymphoma and Immunocytoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Primary Cutaneous Follicle Center Cell Lymphoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ Aggressive Variants of Cutaneous B-Cell Lymphoma
Diffuse Large B-Cell Lymphoma, Leg Type
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Differential Diagnosis
■ Miscellaneous Other B-Cell Lymphomas Affecting the Skin
Cutaneous Epstein-Barr Virus–Positive Diffuse Large B-Cell Lymphoma of the Elderly
Intravascular B-Cell Lymphoma
Cutaneous (Extraosseous) Plasmacytoma
Lymphomatoid Granulomatosis
Mantle Cell Lymphoma
Reactive Lymphoid Infiltrates Simulating B-Cell Lymphomas (B-Cell Pseudolymphoma)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Cutaneous Plasmacytosis
Leukemia Cutis
Chronic Lymphocytic Leukemia
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Myeloid Leukemia
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Plasmacytoid Dendritic Cell Neoplasm
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Mastocytosis
Cutaneous Mastocytosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Suggested Further Reading
15 Histiocytic Proliferative Disorders
Definition of Terms
Langerhans Cell Disease and Langerhans Cell Histiocytosis
Clinical Findings
Letterer-Siwe Disease
Hand-Schüller-Christian Disease
Eosinophilic Granuloma
Congenital Self-Healing Reticulohistiocytosis (Hashimoto-Pritzker)
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Indeterminate Cell Histiocytosis
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ Non–Langerhans Cell Histiocytic Disorders
Xanthogranuloma Family
Juvenile Xanthogranuloma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Benign Cephalic Histiocytosis
Generalized Eruptive Histiocytosis
Xanthoma Disseminatum
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Reticulohistiocytosis (Solitary Giant Cell Reticulohistiocytoma and Multicentric Reticulohistiocytosis)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Cutaneous Destombes-Rosai-Dorfman Disease
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Hyperlipidemia-Associated Xanthoma
Clinical Findings
Histologic Features
Prognosis and Treatment
Xanthoma Not Associated with Hyperlipidemia
Diffuse Normolipemic Plane Xanthoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Erdheim-Chester Disease
Clinical Findings
Histologic Features
Ancillary Studies
Prognosis and Treatment
Necrobiotic Xanthogranuloma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Suggested Further Reading
16 Cutaneous Neuroendocrine (Merkel Cell) Carcinoma
Merkel Cell Carcinoma
Clinical Findings
Histologic Features
Ancillary Studies
Immunohistochemistry
Electron Microscopy
Molecular Studies
Differential Diagnosis
Prognosis and Treatment
Suggested Further Reading
17 Metastatic Tumors Involving the Skin
Prevalence
Pathophysiology
Sites of Origin
Anatomic Localization
Clinical Features
Biopsy Specimens
Histologic Features
General Comments
Ancillary Investigations (Including Immunochemistry and Tumor Profiling)
Specific Metastases
Adenocarcinoma
Squamous Cell Carcinoma
Neuroendocrine Carcinomas
Melanoma
Miscellaneous Tumors
Suggested Further Reading
4 Pathology of Special Sites
18 Neoplastic and Non-neoplastic Disorders of the Nail Apparatus
■ Anatomy of the Nail Unit
Gross Anatomy
Histologic Features
Biopsy Techniques and Nail Biopsy Processing
Nail Plate Samples for Diagnosis
Infectious Disease of the Nail Unit
■ Inflammatory and Keratotic Diseases of the Nail Unit
Psoriasis
Lichen Planus
Trachyonychia
Lupus Erythematosus
Lichen Simplex Chronicus
Pityriasis Rubra Pilaris
Pachyonychia Congenita
Miscellaneous Conditions
■ Neoplasms Affecting the Nail Unit
Melanocytic Neoplasms of the Nail Unit
Clinical Findings
Histologic Findings
Melanocytic Activation (Hypermelanosis)
Lentigo (Melanocytic Hyperplasia)
Melanocytic Nevi
Nail Apparatus Melanoma (Subungual or Ungual Melanoma)
■ Epithelial Neoplasms and Hyperplasia
Verruca Vulgaris
Onychopapilloma
Squamous Cell Carcinoma
Clinical Findings
Histologic Findings
Keratoacanthoma
Painful Subungual Tumors of Incontinentia Pigmenti
Onycholemmal Carcinoma
Subungual Epidermoid Inclusions
Basal Cell Carcinoma
■ Distinctive Tumors of the Nail Unit
Onychomatricoma
Clinical Findings
Histologic Findings
Onychocytic Matricoma
■ Fibrous and Soft Tissue Neoplasms More Common in the Nail Unit
Digital Fibromas
Superficial Acral Fibromyxoma
Clinical Findings
Histologic Findings
Giant Cell Tumor of the Tendon Sheath
■ Vascular Neoplasms
Pyogenic Granuloma (Lobular Capillary Hemangioma)
Glomus Tumor
Miscellaneous Neoplasms Reported in the Nail Unit
Suggested Further Reading
19 Neoplastic and Non-neoplastic Disorders of the Conjunctiva and Eyelid
Non-neoplastic Disorders
■ Inflammatory Lesions
Conjunctivitis (Infectious and Non-Infectious)
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Foreign Body Granuloma or Chalazion
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Connective Tissue Disease (Wegener’s Granulomatosis)
Clinical Findings
Histologic Features
Prognosis and Treatment
■ Noninflammatory Lesions
Degenerative (Solar Elastosis)
Clinical Findings
Histologic Features
Prognosis and Treatment
Pingueculae and Pterygium
Clinical Findings
Histologic Features
Prognosis and Treatment
Amyloid
Clinical Findings
Histologic Features
Ancillary Studies
Prognosis and Treatment
Cysts
Clinical Findings
Histologic Features
Prognosis and Treatment
Neoplasms
■ Squamous Lesions
Squamous Papilloma
Clinical Findings
Histologic Features
Prognosis and Treatment
Ocular Surface Squamous Neoplasia
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
■ Melanocytic Lesions
Complexion-Associated Melanosis
Clinical Findings
Histologic Features
Prognosis and Treatment
Conjunctival Melanocytic Nevus
Clinical Findings
Histologic Features
Differential Diagnosis
Prognosis and Treatment
Primary Acquired Melanosis
Clinical Findings
Histologic Features of Primary Acquired Melanosis without Atypia
Histology of Primary Acquired Melanosis with Atypia or Conjunctival Melanocytic Intraepithelial Neoplasia
Prognosis and Treatment
Conjunctival Melanoma
Clinical Findings
Histologic Features
Ancillary Studies
Prognosis and Treatment
■ Hematolymphoid Neoplasms
Xanthoma and Xanthelasma
Clinical Findings
Histologic Features
Ancillary Studies
Prognosis and Treatment
Lymphoma
Clinical Findings
Histologic Features
Prognosis and Treatment
Leukemia
Clinical Findings
Histologic Features
Prognosis and Treatment
■ Glandular Lesions
Oncocytoma
Clinical Findings
Histologic Features
Prognosis and Treatment
Sebaceous Carcinoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Endocrine Mucin-Producing Sweat Gland Carcinoma
Clinical Findings
Histologic Features
Ancillary Studies
Differential Diagnosis
Prognosis and Treatment
Other Tumors
Suggested Further Reading
5 Frozen Sections and Pathologic Evaluations of Sections from Mohs Surgery
History
Mohs Technique
Advantages
Indications
Limitations/Pitfalls
Role of the Dermatopathologist
Suggested Further Reading
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
R
S
T
U
V
W
X
Y
Z
Inside back cover

Citation preview

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DERMATOPATHOLOGY

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DERMATOPATHOLOGY a volume in the series

FOUNDATIONS IN DIAGNOSTIC PATHOLOGY SECOND EDITION

EDITED BY

Klaus J. Busam, MD Professor of Pathology and Laboratory Medicine Weill Medical College of Cornell University; Director of Dermatopathology Department of Pathology Memorial Sloan Kettering Cancer Center New York, New York S E R I E S E D I TO R

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John R. Goldblum, MD, FACP, FASCP, FACG

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Chairman Department of Pathology, Cleveland Clinic; Professor of Pathology Cleveland Clinic Lerner College of Medicine Cleveland, Ohio

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Tahir99 (Blink99) - UnitedVRG Orignially Release by: tahir99 For more visit: https://kat.cr/user/Blink99/

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1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899



DERMATOPATHOLOGY, SECOND EDITION Copyright © 2016, 2010 by Saunders, an imprint of Elsevier Inc.

ISBN-978-0-323-26191-3

All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  

 

Library of Congress Cataloging-in-Publication Data Dermatopathology (Busam) Dermatopathology / [edited by] Klaus J. Busam.—Second edition. p. ; cm.—(Foundations in diagnostic pathology) Includes bibliographical references and index. ISBN 978-0-323-26191-3 (hardcover) I. Busam, Klaus J., editor. II. Title. III. Series: Foundations in diagnostic pathology. [DNLM: 1. Skin Diseases—pathology. 2. Skin Neoplasms—pathology. WR 140] RL96 616.5′07—dc23 2014026886

Executive Content Strategist: William R. Schmitt Content Development Specialist: Julia Rose Roberts Publishing Services Manager: Hemamalini Rajendrababu Senior Project Manager: Beula Christopher Designer: Louis Forgione/Paula Catalano Illustrations Manager: Amy Naylor Marketing Manager: Abigail Swartz

 

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This book is dedicated to my wife and children. To Vinita—for your tireless love and support. You put up with a lot! To Jonathan and Sophia—for the joy of your company.

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Foreword Surgical pathology, with all of the subspecialties it encompasses, has become increasingly complex and sophisticated. It is simply not possible for any individual to master the skills and knowledge required to perform all of these tasks at the highest level. Providing a correct diagnosis is challenging enough, but the standard of care has far surpassed merely providing an accurate pathologic diagnosis. As pathologists, we are now asked to provide huge amounts of ancillary information, both diagnostic and prognostic, often on minute amounts of tissue, a task that can be daunting even for the most experienced pathologists. General surgical pathology textbooks are useful resources, but by necessity, they cannot possibly cover many of the aspects that pathologists need to know and include in their diagnostic reports. For this reason, Foundations in Diagnostic Pathology was born. This series is designed to cover the major areas of surgical pathology, and each volume is focused on one major topic. The goal of every book in this series is to provide the essential information that any pathologist—whether general or subspecialized, in training or in practice— would find useful in the evaluation of virtually any type of specimen encountered. Dr. Klaus Busam, a world-renowned dermatopathologist, has yet again edited an outstanding tome on dermatopathology that fulfills the goals and philosophy behind Foundations in Diagnostic Pathology. This second edition covers the essentials of what all pathologists want and need to know about neoplastic and nonneoplastic dermatologic conditions. As always, the list of contributors is incredibly impressive and includes nationally and internationally renowned dermatopa-

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thologists who were extremely generous in providing their expertise to this book. By design, there is uniformity in the organization of these chapters, each of which includes practical information and numerous photomicrographs that emphasize the essential diagnostic points. Of course, there is integration of ancillary diagnostic techniques, including immunohistochemistry and molecular genetic techniques, which are essential to the modern practice of dermatopathology. Compared with the prior edition, there are two entirely new chapters, including discussions of nail disorders as well as conjunctival lesions. Throughout the book, there are updates on nomenclature and staging systems when applicable. Moreover, there have been extensive revisions of chapters from the prior edition, including a major update on melanocytic proliferations with incorporation of a discussion of modern cytogenetic and molecular diagnostic techniques as well as major updates on cutaneous mesenchymal neoplasms. I wish to extend my deepest appreciation to Dr. Klaus Busam and all of the authors who have contributed to this outstanding second edition of the Foundations in Diagnostic Pathology series. I strongly believe the second edition improves on what was already an outstanding book, and I am completely confident you will enjoy this second edition of the Foundations in Diagnostic Pathology series.

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John R. Goldblum, MD, FACP, FASCP, FACG Chairman, Department of Pathology, Cleveland Clinic; Professor of Pathology, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio

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Preface The goal of the second edition of this textbook remains the same as for the first: an introductory to midlevel no-nonsense practical guide to the histopathologic diagnosis of skin disorders. We wanted to provide a book for residents in pathology or dermatology as well as fellows in dermatopathology that they can manage to read and use to deal with most daily encountered diagnostic challenges. In an effort to keep the book compact, compromises were necessary, which meant leaving out entities (e.g., rare congenital disorders) or mentioning some only briefly. As before, we minimized references to save space for text and illustrations with the same rationale—that we do not aim to provide an encyclopedic book, and readers can easily query online libraries on the Internet for primary references. We decided to provide a second edition of the book because significant updates were necessary. The field has

advanced, especially in the area of molecular diagnostics, which has affected in particular soft tissue tumor pathology and ancillary testing for diagnostically controversial melanocytic neoplasms. The second edition also provides an opportunity to include chapters that should be part of a midlevel textbook of dermatopathology, such as disorders of the nail and conjunctiva. As editor, I would like to thank all the contributing authors who made this book possible. The book is the result of teamwork. I would also like to thank many colleagues at Memorial Sloan Kettering Cancer Center who provided direct or indirect support. Special thanks go to Allyne Manzo, Lorraine Biedrzycki, and Isla Otap for their assistance with images. Finally, I would like to express my appreciation for the great support I received for this book from the publisher, in particular William Schmitt and Julia Roberts.

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Contributors Rami N. Al-Rohil, MBBS

Anca G. Prundeanu Croitoru, MD

Resident, Department of Pathology, Albany Medical College, Albany, New York

Staff Dermatopathologist, MiracaLS Dermatopathology, Glen Burnie, Maryland

Bijal Amin, MD

Jasmine H. Francis, MD

Assistant Professor, Department of Pathology, Montefiore Medical Center-Albert Einstein College of Medicine, Bronx, New York

Ophthalmic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York

Wilma F. Bergfeld, MD, FAAD

Douglas R. Fullen, MD

Co-Director, Dermatopathology, Departments of Dermatology and Pathology, Senior Staff, Department of Dermatology, Cleveland Clinic, Cleveland, Ohio

Professor of Pathology and Dermatology, Director, Dermatopathology Section, University of Michigan, Ann Arbor, Michigan

Steven D. Billings, MD

Maxwell A. Fung, MD

Professor, Department of Pathology, Cleveland Clinic Lerner College of Medicine; Co-Director, Dermatopathology Section, Anatomic Pathology and Dermatology, Cleveland Clinic, Cleveland, Ohio

Professor of Clinical Dermatology and Pathology, Vice Chair for Academic Personnel, Director, UC Davis Dermatopathology Service, Department of Dermatology, University of California Davis, Sacramento, California

Darya Buehler, MD

Assistant Professor (CHS), Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin

Jacqueline Granese, MD

Klaus J. Busam, MD

Henry Haskell, MD

Professor of Pathology and Laboratory Medicine, Weill Medical College of Cornell University; Director of Dermatopathology, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York

Clinical Assistant Professor, Department of Dermatology, University of Oklahoma, Oklahoma City, Oklahoma; Pathologist, Regional Medical Laboratory; Pathologist, Department of Pathology, St. John’s Medical Center, Tulsa, Oklahoma

J. Andrew Carlson, MD, FRCPC

Stefanie Hu, MD

Professor, Department of Pathology, Albany Medical College, Albany, New York

Dermatopathology Fellow, Section of Dermatopathology, Ronald O. Perelman Department of Dermatology, NYU Langone Medical Center, New York, New York

Julide Tok Celebi, MD

Professor and Vice Chair, Department of Dermatology; Professor, Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York Helen M. Chen, MD

Pathology, Palos Community Hospital, Palos Heights, Illinois Loren E. Clarke, MD

Dermatopathologist; Vice President of Medical Affairs, Dermatology Unit, Myriad Genetic Laboratories, Inc., Salt Lake City, Utah

Departments of Dermatology, Dermatopathology, Pathology Graves Gilbert Clinic, Bowling Green, Kentucky

Jacqueline M. Junkins-Hopkins, MD

Consultant in Dermatopathology and Cutaneous Lymphoma, Ackerman Academy of Dermatopathology, New York, New York Hideko Kamino, MD

Clinical Associate Professor of Dermatology and Pathology, New York University School of Medicine, New York, New York

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CONTRIBUTORS

Annabelle Mahar, MBBS, FRCPA

Luis Requena, MD

Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, New South Wales, Australia

Professor of Dermatology, Department of Dermatology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain

Brian P. Marr, MD

Franco Rongioletti, MD

Associate Attending, Department of Surgery, Memorial Sloan Kettering Cancer Center; Associate Professor of Ophthalmology, Weill-Cornell Medical School; Ophthalmic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York

Professor of Dermatology, DISSAL, Department of Health Science, University of Genoa, Genoa, Italy

Michael E. Ming, MD, MSCE

Director, Pigmented Lesion Clinic; Associate Professor of Dermatology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Rajmohan Murali, MBBS, MD, FRCPA

Department of Pathology and Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York Patricia L. Myskowski, MD

Attending Physician, Dermatology Service, Memorial Sloan Kettering Cancer Center; Professor of Dermatology, Weill Cornell Medical College, New York, New York Kishwer S. Nehal, MD

Member, Memorial Hospital; Memorial Sloan Kettering Cancer Center; Professor of Dermatology, Weill Medical College of Cornell University; Attending Physician, Memorial Hospital for Cancer and Allied Diseases, New York, New York Victor G. Prieto, MD, PhD

Professor, Departments of Pathology and Dermatology and Laboratory Medicine, Ad-interim Chair of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas Melissa P. Pulitzer, MD

Assistant Attending Pathologist, Department of Pathology, Memorial Sloan Kettering Cancer Center; Assistant Professor, Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York

Beth S. Ruben, MD

Professor, Departments of Dermatology and Pathology; Director, Dermatopathology Fellowship Program, University of California, San Francisco, California Richard A. Scolyer, BMedSci, MBBS, MD, FRCPA, FRCPath

Clinical Professor, Discipline of Pathology, Sydney Medical School, The University of Sydney; Senior Staff Specialist, Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia; Co-Director of Research, Melanoma Institute Australia, New South Wales, Australia Klaus Sellheyer, MD

Clinical Professor of Dermatology and Consultant Staff, Department of Dermatology, Cleveland Clinic Foundation, Cleveland, Ohio Christopher R. Shea, MD

Eugene J. Van Scott Professor in Dermatology, Chief, Section of Dermatology, University of Chicago Medicine, Chicago, Illinois John F. Thompson, AO, MD, FRACS, FACS

Executive Director, Melanoma Institute Australia; Professor of Surgery (Melanoma and Surgical Oncology), The University of Sydney; Head of Department, Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, New South Wales, Australia Marie Tudisco, PhD, HT (ASCP)

Histotechnologist, Department of Dermatology, Memorial Sloan Kettering Cancer Center, New York, New York Ravi R. Ubriani, MD, FAAD

Assistant Professor of Clinical Dermatology, Department of Dermatology Education, Columbia University, New York, New York Angela J. Wyatt, MD

Marcia Ramos-e-Silva, MD, PhD

Associate Professor of Dermatology, Head of the Sector of Dermatology, University Hospital of the Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Clinical Assistant Professor, Department of Dermatology, Baylor College of Medicine; Physician, Dermatology, Flagstaff Medical Center, Flagstaff, Arizona

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Contents SECTION 1

Chapter 6

Histology of the Skin  1

Mucinoses, Deposition Disorders, and Connective Tissue Alterations  249

Henry Haskell

SECTION 2 Non-neoplastic Disorders  9

Chapter 1 Inflammatory Diseases of the Dermis and Epidermis  11 Maxwell A. Fung

Chapter 2 Panniculitis  79 Maxwell A. Fung

Chapter 3 Infectious Diseases of the Skin  102 Helen M. Chen, Anca G. Prundeanu Croitoru, Stefanie Hu, Hideko Kamino, Marcia Ramos-e-Silva, and Klaus J. Busam

Chapter 4 Cutaneous Vasculitis  181 Rami N. Al-Rohil and J. Andrew Carlson

Chapter 5 Blistering Skin Diseases  207 Jacqueline M. Junkins-Hopkins and Klaus J. Busam

Franco Rongioletti, Jacqueline Granese, Jacqueline M. Junkins-Hopkins, and Luis Requena

Chapter 7 Non-neoplastic Disorders of Pigmentation  269 Ravi R. Ubriani, Loren E. Clarke, and Michael E. Ming

Chapter 8 Non-neoplastic Disorders of Hair  281 Klaus Sellheyer and Wilma F. Bergfeld

Chapter 9 Cysts and Sinuses  310 Douglas R. Fullen

SECTION 3 Tumors and Pseudotumors of the Skin and Subcutis  337

Chapter 10 Tumors of the Epidermis  339 Angela J. Wyatt and Klaus J. Busam

Chapter 11 Adnexal Tumors  388 Victor G. Prieto, Christopher R. Shea, Julide Tok Celebi, and Klaus J. Busam

xiii

xiv



CONTENTS

447

 

Melanocytic Proliferations

Pathology of Special Sites

 

SECTION 4

Chapter 12

689

Klaus J. Busam

Chapter 18

Chapter 13

Neoplastic and Non-neoplastic Disorders of the Nail Apparatus 691  

Soft Tissue Tumors and Tumor-like Reactions 513  

Beth S. Ruben

Darya Buehler and Steven D. Billings

Chapter 19 Neoplastic and Non-neoplastic Disorders of the Conjunctiva and Eyelid 719

595

 

Hematopoietic Neoplasms

 

Chapter 14 Jacqueline M. Junkins-Hopkins, Klaus J. Busam, Patricia L. Myskowski, and Melissa P. Pulitzer

Jasmine H. Francis, Klaus J. Busam, and Brian P. Marr

SECTION 5

Bijal Amin, Melissa P. Pulitzer, and Klaus J. Busam

Chapter 16

Kishwer S. Nehal, Marie Tudisco, and Klaus J. Busam

INDEX

 

Cutaneous Neuroendocrine (Merkel Cell) Carcinoma 667

Frozen Sections and Pathologic Evaluations of Sections from Mohs Surgery 745  

654

Bijal Amin and Klaus J. Busam

Chapter 17  

Metastatic Tumors Involving the Skin 674 Richard A. Scolyer, John F. Thompson, Annabelle Mahar, and Rajmohan Murali

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Histiocytic Proliferative Disorders

 

Chapter 15

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Histology of the Skin HENRY HASKELL

Skin consists of epidermis and dermis (Fig. I-1). Beneath the dermis lies the subcutis (or hypodermis).

EPIDERMIS The epidermis is a stratified squamous epithelium that consists mainly of keratinocytes, with an admixture of melanocytes, Langerhans cells, and Merkel cells. Of these, keratinocytes are by far the most numerous, making up the bulk of the epidermis and giving it its characteristic microscopic appearance. The epidermis is typically divided into four layers (see Fig. I-1):

Epidermis Papillary Dermis

SC SG SS SB

Reticular Dermis

FIGURE I-1  Normal skin with epidermis, papillary and reticular dermis. The epidermis consists of stratum basale (SB), stratum spinosum (SS), stratum granulosum (SG), and stratum corneum (SC).

1. Stratum 2. Stratum 3. Stratum 4. Stratum

basale (SB) spinosum (SS) granulosum (SG) corneum (SC)

The stratum basale (or stratum germinativum), also known as the basal cell layer, consists of a single layer of cuboidal keratinocytes that lie atop the basement membrane (see the following) and are connected to it by numerous hemidesmosomes. At this depth, keratinocytes have abundant eosinophilic cytoplasm and ovoid nuclei. As its name implies, division of keratinocytes occurs primarily in the stratum germinativum, although mitotic activity is occasionally seen in the lower part of the stratum spinosum, in particular the cell layer immediately above the stratum basale, the parabasal layer. In the process of self-renewal, these cells gradually ascend into the upper layers and are replaced. The stratum spinosum, also known as the spinous cell layer, is named after the spinous processes (or “prickles”), which connect the keratinocytes in this layer and the stratum basale to one another. These spinous processes provide contact points for desmosomes, which are the ultrastructural basis for the tight binding of keratinocytes to one another. These processes may be difficult to visualize in normal skin, but they become more evident by intercellular edema (also known as spongiosis). The stratum granulosum, or granular cell layer, is named for the irregular, darkly basophilic keratohyalin granules that accumulate in the cytoplasm of the cells 1

2

DERMATOPATHOLOGY

FIGURE I-3

Normal acral skin with thick compact stratum corneum and acrosyringeal duct (arrow).

Melanocytes (arrow) are present at the dermoepidermal junction.

in this layer as they flatten and mature. At the superficial edge of the stratum granulosum, programmed cell death occurs. On most parts of the body, the skin possesses a single layer of dead (but functional) cells, the stratum corneum, consisting mostly of keratin. The cells in this layer are sometimes called corneocytes to distinguish them from the living cells in the layers below. The stratum corneum varies widely in thickness according to site: in glabrous skin, it is only a few cell layers thick and forms a characteristic “basket-weave” pattern, but at acral sites, it is both thicker and more compact (Fig. I-2). Where the stratum corneum is particularly thick, another layer, the so-called stratum lucidum, may be present between it and the stratum granulosum. The stratum lucidum differs from the stratum corneum only by a pale eosinophilic appearance and higher lipid content. Although pyknotic nuclei may appear in the stratum corneum or stratum lucidum in pathologic processes, in normal skin, the keratinocytes of both these layers are anucleate. Keratinocytes stain positively for high molecular weight cytokeratins such as 34βE12 but negatively for Cam5.2.

normally visible in their cytoplasms because it is rapidly secreted through their network of dendritic processes and taken up by basal keratinocytes, where it is stored and gradually broken down. Although the amount of melanin produced and stored varies between darker and lighter skinned individuals, the number of melanocytes does not. Normal intraepidermal melanocytes stain immunohistochemically best for tyrosinase, Melan-A/Mart-1, and microphthalmia transcription factor (MITF). Immunostains for Melan-A/Mart-1 may lead to an overestimate of the density of melanocytes, especially if the antibody concentration is high. The cleanest assessment of melanocyte density is by using MITF because it is a nuclear antigen, which does not lead to potential confusion with pigmented keratinocytes. HMB-45 may decorate some normal melanocytes, but it is not a sensitive reagent for visualizing normal resting melanocytes. S100 protein stains normal intraepidermal melanocytes, but it is neither very sensitive nor specific. It also stains Langerhans cells.

 

 

FIGURE I-2

MELANOCYTES Melanocytes are found along the dermal-epidermal junction as well as within hair follicles (Fig. I-3). They are responsible for the production and secretion of melanin pigment. Histologically, the cells are characterized by small, dark, ovoid nuclei and scant, clear cytoplasm. Depending on anatomic site, they number from one per 10 to one per five basal keratinocytes, with higher concentrations on the face and genitalia. Although melanocytes produce melanin, pigment is not

LANGERHANS CELLS The Langerhans cell is a dendritic cell that functions in antigen presentation and travels between the skin and draining lymph nodes. In routine tissue sections of uninflamed skin, these cells are difficult to identify on hematoxylin and eosin (H&E)–stained sections. They are best seen on immunostains for S100 protein, langerin (CD207), or CD1a, which highlight their characteristic location above the stratum basale (Fig. I-4). Historically, the characteristic Birbeck granule, a rod- or tennis-racket–shaped body seen by electron microscopy, identified these cells. Langerhans cells are easily recognized when they aggregate as Langerhans cell abscesses

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SECTION 1  Histology of the Skin

FIGURE I-4 

FIGURE I-6 

Langerhans cells are immunoreactive for CD1a and recognized as dendritic cells within the spinous cell layer.

Meissnerian corpuscle.

BASEMENT MEMBRANE The basal layer of the epidermis is attached to the superficial epidermis by the basement membrane, a complex structure with a deceptively simple appearance under routine light microscopy. By electron microscopy, it consists of a superficial lamina lucida, which binds to the hemidesmosomes of the epidermis, and a deeper lamina densa, consisting mostly of type IV collagen, which binds the collagen fibrils of the superficial dermis. In routine practice, the basement membrane is visible under H&E, but it may be emphasized using the periodic acid-Schiff reaction. Immunohistochemistry for type IV collagen is also available.

DERMIS FIGURE I-5  A Merkel cell is recognized by the immunoreactivity for cytokeratin 20.

(e.g., in allergic contact dermatitis or Langerhans cell proliferative lesions). They are recognized by a reniform nucleus.

MERKEL CELLS Nerve endings from the dermis are frequently associated with Merkel cells in the basal epidermis, which are believed to play a role in tactile sensation. Merkel cells are rarely visible on routine sections. They are best identified by electron microscopy (where they show characteristic features of neuroendocrine differentiation) or by immunohistochemical stains for cytokeratin 20 or chromogranin (Fig. I-5).

The dermis has a deeper and a superficial layer. The papillary dermis lies immediately below the basement membrane. It is highly irregular, possessing an undulating system of dermal papillae, which complement the rete ridge system of the epidermis. It consists mainly of fine, fluffy, pale eosinophilic fibers of collagen (see Fig. I-1). It contains a number of free nerve endings (not visible on routine preparations) as well as Meissnerian corpuscles (Fig. I-6), a specialized mechanoreceptor involved in tactile sensation that is found in greatest concentration on the hands, feet, and lips and is characteristically located in the dermal papillae. The inferior edge of the papillary dermis is bounded by the subpapillary (or superficial vascular) arterial, venous, and lymphatic plexuses. The much thicker reticular dermis lies beneath these plexuses and is easily distinguished at low power by its thick, interlacing bundles of more deeply eosinophilic collagen (see Fig. I-1). It possesses a rich vascular supply, with a system of anastomosing small arteries, veins, and

4



DERMATOPATHOLOGY

smooth muscle actin (SMA) in their cytoplasms. Glomus bodies function in thermoregulation and are most frequently found in distal sites such as the ears and fingertips. Whereas the epidermis is densely cellular, the dermis is paucicellular. It consists mainly of the extracellular matrix. The three main extracellular proteins that make up the dermis are collagen, providing strength; elastin, providing elasticity; and ground substance. In normal skin, elastin is a minor component, consisting of slender, amphophilic fibers that may be difficult to distinguish without the use of various special stains (e.g., van Gieson). Ground substance is also difficult to see in routine preparations because it comprises only a very minor proportion of the overall dermis and is finely intermixed with the more obvious collagen. The basic cellular component of the dermis is the fibroblast,

FIGURE I-7

FIGURE I-9

Smooth muscle bundle with blunt-ended nuclei (pilar erector muscle).

Pacinian corpuscle.

FIGURE I-8

FIGURE I-10

Nerve trunks adjacent to a blood vessel.

Glomus body.

 

 

 

 

lymphatics called the cutaneous (or deep vascular) plexuses at its inferior border. It has adnexal structures embedded and the pilar erector muscle (Fig. I-7). Nerve trunks (Fig. I-8) are also present. They may connect with Pacinian corpuscles (Fig. I-9), a specialized type of nerve ending that participates in the sensation of deep pressure and vibration. These are also found in the subcutis, as well as certain internal organs, and are found in greatest concentrations in the palms, soles, dorsal digits, and genitalia. In addition to the common vascular structures of arteries, veins, and lymphatics, the reticular dermis may also contain a special type of arteriovenous shunt called a glomus body (Fig. I-10). The glomus body consists of arterial and venous limbs surrounded by several layers of glomus cells, modified smooth muscle cells that have round to ovoid nuclei and characteristically express

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SECTION 1  Histology of the Skin

which produces and maintains all three extracellular components—collagen, elastin, and ground substance.

APPENDAGES There are five appendages commonly found in normal skin: eccrine, apocrine, and sebaceous glands; hair; and nail.

ECCRINE GLANDS The most numerous glands in the skin, eccrine glands are present on all skin surfaces but are most concentrated on the palms, soles, forehead, and axillae. They are responsible for thermoregulation and secrete a watery, hypotonic fluid. The glands consist of an unbranched, coiled, secretory component, usually found surrounded by fat in the deep dermis, which feeds into the duct, which is at first coiled and then straight and finally exits through the epidermis in a coiled structure of dermal origin known as the acrosyringium. Whereas the secretory gland consists of a single layer of cuboidal epithelium surrounded by myoepithelial cells, the duct has two layers of epithelium and no myoepithelial cells (Fig. I-11). The cytoplasm of both portions is typically eosinophilic, but in the secretory gland, the cytoplasm may retain significant amounts of glycogen, resulting in clearing or vacuolation. Eccrine glands express cytokeratins (e.g., Cam5.2, CK7), CEA, and epithelial membrane antigen immunohistochemically. Myoepithelial cells can be identified with antibodies to S100 protein, p63 (4A4), calponin, and SMA.

APOCRINE GLANDS Apocrine glands are much less numerous than eccrine glands. They differ from eccrine glands in their distribution (they are found mainly in the axillae, anogenital region, areola, and eyelid) and their mode of secretion. In apocrine glands, the apices of the secretory cells break down during the secretion process and appear to pinch off (“snouts”), leading to a histologic picture of “decapitation secretion” into the glandular lumen (Fig. I-12). The secretory portion of an apocrine gland is a coiled, nonbranching tube lined by a layer of cuboidal to columnar epithelial cells with round nuclei and brightly eosinophilic cytoplasm surrounded by a layer of myoepithelial cells. The apocrine ducts per se are morphologically indistinguishable from eccrine ducts. Apocrine glands develop in association with hair follicles. The apocrine duct opens near the skin surface into the infundibulum of the associated hair follicle. The secretions from apocrine glands are at first odorless but are converted to odorous products by surface bacteria. The scent and musk glands of mammalians are regarded as modified apocrine glands. Specialized apocrine glands in humans are found in the external ear canal (ceruminous glands) and the eyelid (Moll’s glands).

SEBACEOUS GLANDS Unlike eccrine and apocrine glands, sebaceous glands are holocrine glands; that is, they secrete by sloughing of entire cells into the ductal lumen. The result is a thick, oily secretion known as sebum. Sebaceous glands generally have a branched, acinar pattern, with multiple

FIGURE I-11 

FIGURE I-12 

Eccrine glands.

Apocrine glands with snouts (“decapitation secretion”).

6

DERMATOPATHOLOGY

Profile of a terminal anagen hair with upper and lower segment.

lobules, each consisting of an outer rim of cuboidal basophilic germinative cells surrounding multiple inner layers of cells with vacuolated, lipid-filled cytoplasm (Fig. I-13). The cells’ lipid content increases as they approach the sebaceous duct, which is lined by stratified squamous epithelium. Although sebaceous glands in some areas, such as the labia minora, prepuce, or areola (where they are known as Montgomery’s glands) may empty directly onto the surface of the skin, in general, a sebaceous gland exists in continuity with a hair follicle, either terminal or vellus; the combination is known as a pilosebaceous unit. When part of a pilosebaceous unit, the sebaceous duct empties onto the hair shaft; the duct is continuous with the outer root sheath, and the gland as a whole is surrounded by the fibrous root sheath. The gland itself lies above the arrector pili muscle. The meibomian glands of the eyelid are a kind of modified sebaceous gland.

is followed by the brief catagen phase, which marks the transition into the telogen phase, which lasts about 100 days and ends with the hair being shed. The follicle is divided into four zones, which includes (from deep to superficial) the lower transient segment (hair bulb and stem) and the upper permanent segment (isthmus and infundibulum) (Fig. I-14).

 

FIGURE I-14

Sebaceous glands with clear finely vacuolated cytoplasm.

 

FIGURE I-13

HAIR FOLLICLE

 

 

Hairs are typically classified as terminal (thicker than 0.06 mm in diameter), vellus (less than 0.03 mm in diameter), or indeterminate. All follicles, regardless of size, progress through three phases in a repeating cycle. The anagen phase is the longest, lasting up to 7 years, and is the phase in which the hair actively grows. This

ANAGEN PHASE

The anagen hair follicle consists of several layers. Starting with the hair shaft, it is composed of the medulla (center of the shaft), cortex (bulk of the shaft), and the cuticle. The inner root sheath (IRS) also can be subdivided into three layers, the IRS cuticle, Huxley’s layer, and outer Henle’s layer. The last and outermost layers of the follicle include the vitreous, or glassy, layer and, finally, the fibrous root sheath. The hair bulb, located in the subcutis or deep dermis, consists of the dermal papilla surrounded by the basophilic hair matrix, which constitutes the germinative cells of the hair (Fig. I-15). The papilla is of dermal origin and connects via a stalk to the fibrous root sheath. The seven layers of the anagen follicle are not evident in the bulb but come into being just superior to the bulb in the suprabulbar zone. The superficial edge of this zone is marked by the insertion point of the arrector pili muscle, a vestigial organ consisting of a bundle of smooth muscle fibers. Its insertion point also marks the location

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SECTION 1  Histology of the Skin

Infundibulum

Isthmus

FIGURE I-16 

FIGURE I-15 

Upper segment with infundibulum and isthmus. Note the corrugate-surfaced cornified layer of the isthmus and the granular cell layer of the infundibulum.

Lower segment with bulb (thick arrow) and stem. Note the clear cells of the outer root sheath (small thin arrow).

of the bulge, a structure that is now believed to be the site of skin stem cells. Above the bulge is the isthmus, which extends up to the insertion point of the sebaceous duct. It is in the isthmus that the inner root sheath disappears, leaving a gap between the hair shaft and the external root sheath, which begins to cornify without the presence of a granular cell layer (Fig. I-16). Above the sebaceous duct lies the infundibulum, which resembles normal epidermis in that a granular cell layer is present. CATAGEN PHASE

At the end of the anagen phase, the anatomy of the hair shaft undergoes certain changes. The hair matrix disappears and is replaced by a thin rim of epithelial cells with pyknotic nuclei that undergo apoptosis. The hair (although not the papilla) gradually ascends to the level of the bulge, leaving behind it a collapsed fibrous root sheath called the stela or streamer. At this point, the hair is called a club hair, after the shape of its root. TELOGEN PHASE

In telogen, the papilla ascends to the level of the bulge and consists of an asterisk-shaped group of ovoid cells with eosinophilic cytoplasm. The hair continues cornifying and is shed; a new group of cells from the bulge

FIGURE I-17  Nail apparatus with nail fold (*), nail matrix (arrow) and nail bed (arrowhead).

descend into the fibrous root sheath to form a new anagen hair.

NAIL The nail is a specialized skin appendage, which similar to hair, is formed by an invagination of specialized epidermis into dermis (Fig. I-17). The nail apparatus consists of a nail plate, a dense keratinized plate overlying a stratified squamous epithelium called the nail bed.

8

DERMATOPATHOLOGY

At the proximal origin of the nail, the nail root underlies the proximal nail fold, whose distal edge is known as the eponychium, and in this area, the epithelium of the nail bed is known as the nail matrix. The nail matrix has an increased proliferative rate compared with the distal nail plate epithelium and contributes the majority of the thickness of the overall nail plate. The nail matrix is visible grossly as the white, semicircular lunula. At its distal edge, the skin underneath the overhanging nail plate is called the hyponychium.

SUBCUTIS The subcutis (hypodermis, panniculus adiposus) consists of mature adipose tissue, which is divided by fibrous septae into lobules (Fig. I-18). The subcutis also contains small- to medium-sized arteries and veins as well as nerve bundles.

INFLAMMATORY CELLS

FIGURE I-18

 

The skin plays an important role in host defense. In addition to the Langerhans cells mentioned earlier, several other types of inflammatory cells may be recruited to the skin, including lymphocytes (mononuclear cells with dark, angulated nuclei and scant cytoplasm), plasma cells (which have round, eccentrically placed nuclei with clumped [“clock face”] chromatin and an adjacent pale-staining perinuclear hof, all surrounded by basophilic cytoplasm), histiocytes (mononuclear cells with ovoid to reniform nuclei and a moderate amount of cytoplasm, also known as macrophages), neutrophils (polymorphonuclear leukocytes with multilobed nuclei and cytoplasmic granules that are neither basophilic nor eosinophilic), mast cells (mononuclear cells with distinctive basophilic cytoplasmic granules), and eosinophils (cells with bilobed nuclei and brightly eosinophilic intracytoplasmic granules).

Lobules of adipose tissue are separated by fibrous septae.

SUGGESTED FURTHER READING Burkman HG, Young B, Heath JW. Wheater’s functional histology: a text and colour atlas, Edinburgh, 1993, Churchill Livingstone. Conejo-Mir JS, Ortega MN. Nail. In Sternberg S, editor: Histology for pathologists, Philadelphia, 1997, Lippincott-Raven, pp 25–46. Fleckman P. Structure and function of the nail unit. In Scher RK, Daniels CR, editors: Nails: diagnosis therapy surgery, Philadelphia, 2005, Elsevier, pp 13–25. Sperling LC. Normal hair anatomy and architecture. In Sperling LC, editor: An atlas of hair pathology with clinical correlations, Boca Raton, FL, 2003, Parthenon, pp 1–14. Urmacher CD. Normal skin. In Sternberg S, editor: Histology for pathologists, Philadelphia, 1997, Lippincott-Raven, pp 25–46.

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1  Inflammatory Diseases of the Dermis and Epidermis ■ Maxwell A. Fung

Inflammatory disorders of the skin have typically been classified by etiology (suspected or confirmed), clinical features, histologic features (e.g., reaction patterns), location in the skin, or all of the above, as remains the tradition in Foundations in Diagnostic Pathology. As our collective understanding of inflammatory skin disorders continues to evolve, no single uniform classification of disease has been or is likely to be perfect for all uses in the foreseeable future. Instead, as many disorders as possible are classified by etiology, and the remainder are based on distinctive features. Complicating matters, some specific diseases may cause more than one clinical or histopathologic appearance (and multiple names), and some groups of unrelated diseases may have identical clinical or histopathologic manifestations. The subject headings in this chapter represent clinically relevant topics that are biopsied with reasonable frequency and embody a traditional and fairly comprehensive presentation of the material in this field in a way that is designed to be useful as a reference as well as from the standpoint of evaluating new cases. The practicing dermatopathologist is challenged by the fact that one’s interpretations are directly based only on microscopic features of the case in question, sometimes with only minimal additional clinical information of variable quality. Moreover, with the exception of infectious diseases, the instant pattern recognition that is often accomplished when evaluating neoplastic disorders is less frequently the case when examining a biopsy of a rash. An overall assessment of the patient based on both clinical (i.e., gross pathology) and histologic (i.e., microscopic pathology), including a case-by-case judgment of the relative importance of these two components, generally yields the most precise diagnosis or differential diagnosis. The final responsibility for this judgment necessarily falls on the submitting physician. The aim of the dermatopathologist should be to provide the submitting physician with a clinically relevant differential diagnosis (in the standard language of clinical

dermatology) based primarily on the microscopic features, and, when possible, a specific diagnosis. Caveat: Specific diagnoses issued by pathologists whose diagnoses have been clinically disproved (read: wrong per the submitting dermatologist) carry little weight. Keeping an open mind and maintaining communication with submitting physicians are essential to refining one’s diagnostic skills (and reputation) in the area of inflammatory skin disease.

SPONGIOTIC DERMATITIS CLINICAL FINDINGS It is essential to recognize that although spongiotic dermatitis is perhaps the most frequently biopsied inflammatory skin disease, it is not a single clinical disorder (Table 1-1). Rather, spongiotic dermatitis is a descriptive diagnosis that corresponds to a variety of clinical disorders, some of which are completely unrelated. The fact that the most common group of disorders manifesting as spongiotic dermatitis are designated variably and imprecisely by submitting physicians, including dermatologists, is a source of confusion to students and practitioners of medicine. These designations include eczema, dermatitis, and eczematous dermatitis. Unless further specified, these terms are considered synonymous and are referred to herein as eczematous dermatitis. The term eczematous dermatitis still does not correspond to a single clinical disorder, but it does correspond to a more limited number of specific, common clinical disorders, including atopic dermatitis (designated by some as atopic eczema, or simply eczema), allergic contact dermatitis, photoallergic contact dermatitis, nummular dermatitis (or nummular eczema), dyshidrotic dermatitis (or dyshidrotic eczema), and the Id reaction. Stasis dermatitis, xerotic dermatitis (Fig. 1-1), and pityriasis alba may also be added to this list. 11

12 TABLE 1-1

 

DERMATOPATHOLOGY

Basic Differential Diagnosis of Spongiotic Dermatitis

Dyshidrosis

Seborrheic Dermatitis

Allergic Contact Dermatitis

Irritant Contact Dermatitis

Papular Dermatitis

Urticarial Dermatitis

Pityriasis Rosacea

++

++

++

++

++

++

++

++

0

0

0

0

0

0

0

±

0

Epidermal necrosis

0

0

0

0

0

++

±

0

0

Follicular spongiosis

±

0

0

++

0

0

±

0

0

Dermal eosinophils

±

±

±

±

++

±

++

++

±

Lymphocyte exocytosis

±

±

±

±

±

±

0

0

++

Erythrocyte extravasation

0

0

0

0

0

0

0

0

++

Atopic Dermatitis

Nummular Dermatitis

Superficial perivascular lymphocytes

++

Deep perivascular lymphocytes

++, characteristic; ±, variable; 0, unusual.

FIGURE 1-1

 

Site of Involvement (varies from disease to disease) ■ Atopic dermatitis: – Children in acute phase: extensor surfaces and face – Chronic form: flexural sites ■ Seborrheic dermatitis: scalp, ear, face, and central chest ■ Allergic or contact dermatitis: site of exposure

Xerotic (asteatotic) dermatitis, also known as eczema craquelé and winter itch, is very common and is sometimes associated with nummular dermatitis. Exceptionally, it may be associated with systemic lymphoma.

ECZEMATOUS DERMATITIS—DISEASE FACT SHEET Eczema does not represent one disease entity but rather a spectrum of diseases that share the histologic feature of spongiotic dermatitis. Patient Group ■ Children and adults ■ May be associated with personal or family history of asthma (atopic dermatitis)

Clinical Findings (vary from phase to phase) ■ Acute phase – Erythematous or edematous papules and plaques – Vesicles may develop with oozing, serous crusts ■ Subacute phase – Erythematous papules and plaques – Scales and excoriations common ■ Chronic phase – Thickened hyperkeratotic plaques – Lichenification (lichen simplex chronicus) – Nodule formation (prurigo nodularis) – Postinflammatory pigment changes ■ Pruritus ■ Xerosis (dry skin) Prognosis and Treatment ■ Except for contact dermatitis, usually chronic disease ■ Topical steroids for atopic dermatitis ■ Topical azoles and zinc pyrithione shampoos for seborrheic dermatitis ■ Moisturizers ■ Avoidance of exposure to triggers or stimulants

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

A subgroup of these disorders clinically exhibits superimposed urticarial features, designated urticarial dermatitis. To confuse matters further, submitting physicians sometimes refer to any one of these specific disorders simply as eczema or dermatitis. The most common example is eczema as a synonym for atopic dermatitis or atopic eczema. The clinical common denominators of eczematous dermatitis are acutely pruritic, erythematous, and variably edematous papules and papulovesicles that quickly rupture, leaving discrete or coalescent foci of crusts and scale. Often the vesicles are fragile and pruritic enough that intact vesicles are not observed because they are promptly excoriated. As the condition persists, the papules and vesicles may coalesce into relatively poorly demarcated (e.g., compared with psoriasis) erythematous plaques containing crust and scale. As the condition persists further, longstanding lesions become lichenified and may evolve into lichen simplex chronicus (LSC), becoming less erythematous but more thickened, hyperpigmented or hypopigmented, and lichenified, with more prominent skin lines.

A

B

HISTOLOGIC FEATURES The primary feature of spongiotic dermatitis is the presence of epidermal spongiosis. Spongiosis is defined as intercellular edema between epithelial cells, appearing on light microscopy as widened intercellular spaces that allow the intercellular bridges between epithelial cells to be observed more easily. Pronounced spongiosis results in the formation of intraepithelial spongiotic vesicles that correspond to clinically observed papulovesicles when large enough to be appreciated grossly. Spongiotic vesicles exhibit a round or inverted flask shape, usually contain lymphocytes or Langerhans cells, and exhibit spongiosis at their periphery. The underlying dermis usually exhibits a superficial perivascular and variably interstitial predominantly lymphocytic infiltrate. Histiocytes, eosinophils, or neutrophils are variably present. Spongiotic vesicles need to be distinguished from Pautrier microabscesses of mycosis fungoides (MF), which are intraepidermal collections of atypical lymphocytes without significant associated spongiosis or Langerhans cells. In acute spongiotic dermatitis, the stratum corneum exhibits undisturbed basket-weave orthokeratosis (Fig. 1-2, A). The presence of parakeratosis signifies subacute spongiotic dermatitis. In chronic spongiotic dermatitis, there is epidermal hyperplasia characterized by a thickened (acanthotic) epidermis with elongated rete ridges and hypergranulosis, although hypogranulosis may be present in areas exhibiting spongiosis. In chronic spongiotic dermatitis, spongiosis is often minimal (e.g., often lacking spongiotic microvesiculation). With sufficient

FIGURE 1-2  A, Acute spongiotic dermatitis. Spongiotic microvesiculation is the full expression of intercellular edema (spongiosis) that is the hallmark of all forms of spongiotic dermatitis, including allergic contact, nummular, dyshidrotic, and atopic dermatitis. In most cases, the diagnosis is established without biopsy. B, Chronic spongiotic dermatitis is characterized by compact orthokeratosis and irregular psoriasiform epidermal hyperplasia. Compared with psoriasis, the granular layer is retained or thickened in many areas; spongiosis may be less prominent.

ECZEMATOUS DERMATITIS—PATHOLOGIC FEATURES Histologic Features ■ Spongiotic dermatitis – Acute: spongiosis with or without intraepidermal vesicle – Subacute: spongiosis and parakeratosis – Chronic: psoriasiform epidermal hyperplasia ■ Superficial dermal lymphocytic infiltrate with or without eosinophils Ancillary Studies ■ PAS, PAS-D, or GMS stain to exclude fungal infection Differential Diagnosis ■ Spongiotic drug reaction ■ Mycosis fungoides ■ Tinea GMS, Gomori methenamine; PAS, periodic acid-Schiff; PAS-D, periodic acid-Schiff with diastase digestion.

DERMATOPATHOLOGY



chronicity, the histopathologic picture evolves to LSC, with compact orthokeratosis and papillary dermal fibrosis (Fig. 1-2, B). Superimposed excoriation is frequent, with variable erosion or ulceration, junctional fibrin, extravasated erythrocytes, and superficial fibrovascular granulation tissue.

ANCILLARY STUDIES Histochemical stains (periodic acid-Schiff [PAS], PAS with diastase digestion [PAS-D], or Gomori methenamine silver [GMS]) are routinely used in spongiotic dermatitis to exclude dermatophytosis. Direct immunofluorescence (DIF) may be required if immunobullous disorders such as pemphigoid or pemphigus are clinical concerns.

DIFFERENTIAL DIAGNOSIS The pathologist may narrow the differential diagnosis based on the biopsy site and submitted clinical information but should not attempt to unequivocally distinguish different forms of spongiotic dermatitis based on histopathologic features alone. The clinician determines the final clinical-pathologic diagnosis based on clinical pathologic correlation. Histopathologic features that may suggest a specific disorder are discussed in the sections below. Failure to identify dermatophytosis is a common diagnostic pitfall. These should be most strongly considered for cases with a clinical suspicion for tinea or in which central clearing or annular lesions or disorders (e.g., granuloma annulare [GA]) are described. Histologically, a parakeratotic neutrophilic crust or prominent dermal eosinophils are typical of dermatophytosis. Drug reactions may be suspected when eosinophils are prominent or when a mixed pattern is present (e.g., combined spongiotic and interface). Ultimately, drug reactions require clinical correlation and may not be excluded based on histology alone. The early, prebullous phase of immunobullous disorders such as pemphigus and pemphigoid typically require DIF testing. Early pemphigus and pemphigoid usually exhibit eosinophilic spongiosis or neutrophilic spongiosis and may exhibit subtle acantholysis (pemphigus) or focal subepidermal clefting (pemphigoid). Distinction among spongiotic dermatitis, parapsoriasis, and patch or plaque (stages Ia–Ib) mycosis fungoid can be difficult because of overlapping clinical, histologic, and immunophenotypic features. This differential diagnosis is discussed in detail in Chapter 14 (Hematopoietic Neoplasms). Briefly, classic lesions of MF are

characterized by increased numbers of atypical lymphocytes in the basilar epidermis and minimal or absent spongiosis compared with conventional spongiotic dermatitis. Spongiosis (usually mild) may also occur as a nonspecific, secondary feature in other inflammatory processes, including interface dermatitis, vasculitis, diffuse dermal infiltrates (e.g., Sweet’s syndrome), or cases with marked papillary dermal edema. In chronic spongiotic dermatitis exhibiting psoriasiform hyperplasia but only minimal spongiosis, it is sometimes impossible to exclude psoriasis. Moreover, contact dermatitis may be superimposed upon psoriasis. Typically, psoriasis exhibits more prominent or con sistent loss or diminution of the granular layer (hypogranulosis), chronic spongiotic dermatitis exhibits hypergranulosis except in areas of active spongiosis, where hypogranulosis may be present. The presence of non-neutrophilic spongiotic microvesiculation is not typical of psoriasis. Other typical features of psoriasis are described in the following section. ­

14

PROGNOSIS AND TREATMENT Because spongiotic dermatitis is not a disease sui generis, the prognosis, natural history, and management of spongiotic dermatitis depend on the specific clinicalpathologic diagnosis, the major forms of which are discussed in the sections that immediately follow. Nevertheless, most cases of spongiotic dermatitis respond to topical corticosteroids. Mid- to super-high (class 1) potency may be required on the hands and feet. Occlusion of topical steroids, intralesional injection of corticosteroid, and short courses of systemic corticosteroids (intramuscular or oral) may be helpful in refractory areas. Nonsteroidal topical agents include tacrolimus ointment and pimecrolimus cream. Oral antihistamines help to suppress pruritus, and their sedative effects are sometimes beneficial. Phototherapy may be helpful in severe or refractory cases.

ALLERGIC CONTACT DERMATITIS CLINICAL FINDINGS Acute allergic contact dermatitis frequently manifests as papules, vesicles, or plaques in linear array at the sites where the offending agent (commonly poison ivy and poison oak) brushed the skin (Fig. 1-3, A). In these cases, the diagnosis is usually obvious, and patients are rarely biopsied. Subacute or chronic allergic contact dermatitis may be clinically indistinguishable from atopic, nummular, or dyshidrotic dermatitis or LSC. In some

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of allergic contact dermatitis include urticarial (e.g., latex), systemic, pustular (e.g., cement), purpuric (e.g., textile dyes), granulomatous (e.g., gold), lymphomatoid (e.g., nickel), and contact dermatitis with prominent postinflammatory hypopigmentation (leukodermic variant).

A

ANCILLARY STUDIES B

If the culprit is not revealed by a detailed exposure history, diagnostic patch testing may reveal the etiology. However, not all patch test results are clinically relevant, and interpretation of test results may be confounded by false-negative or false-positive (irritant) reactions.

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DIFFERENTIAL DIAGNOSIS

FIGURE 1-3

 

Photocontact dermatitis, particularly chronic cases, may exhibit deep perivascular extension of the dermal inflammatory cells (see Spongiotic Dermatitis).

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Allergic contact dermatitis. A, Vesicles in linear array secondary to poison oak exposure. B, Secondary to nickel in jewelry.

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cases, the diagnosis may be established based on the suggestive shape or distribution of lesions, the clinical history, or patch testing. Common allergen sources include plants, metals (Fig. 1-3, B), and skin care products (fragrances, antibiotics, preservatives). Allergic contact dermatitis on the face or groin may present as diffuse edema resembling cellulitis.

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HISTOLOGIC FEATURES

For general features, see Spongiotic Dermatitis. Allergic contact dermatitis cannot be reliably or consistently distinguished from other forms of eczematous dermatitis based on assessment of histopathologic features alone. The presence of eosinophils has traditionally been regarded as characteristic. Dermal eosinophils, eosinophilic spongiosis, and papillary dermal edema are often present, but their absence does not preclude the possibility of this diagnosis. Likewise, the presence of dermal neutrophils is variable and not required. Chronic photoallergic contact dermatitis may exhibit deep perivascular extension of the dermal infiltrates. Rare variants

PROGNOSIS AND TREATMENT

Allergic contact dermatitis subsides if the allergen is withdrawn. The challenges in most cases are the identification and effective removal of the allergen from the patient’s environment (see Spongiotic Dermatitis).

IRRITANT CONTACT DERMATITIS CLINICAL FINDINGS Irritant contact dermatitis is often clinically obvious, suggested by the pattern of inflammation corresponding to the site of contact with the irritant. The severity of the reaction is proportional to the severity of the exposure or the nature of the irritant in dose-dependent fashion. In contrast to allergic contact dermatitis, prior sensitization is not required. Compared with allergic contact dermatitis, atopic dermatitis, nummular dermatitis, and dyshidrotic dermatitis, pruritus is less characteristic. Mild reactions resemble allergic contact dermatitis. Severe irritants (e.g., chemical burn) may cause large blisters (bullae), may cause erosion or ulceration, and may leave scars. Dermatitis associated with dry skin (xerotic dermatitis, asteatotic dermatitis, eczema craquelé) may be regarded as a variant of irritant dermatitis.

DERMATOPATHOLOGY



16

HISTOLOGIC FEATURES

ANCILLARY STUDIES

For general features, see Spongiotic Dermatitis. The histopathologic features of irritant contact dermatitis depend on the severity of the irritant and extent of exposure. Severe irritants cause confluent epidermal necrosis with “ghost” nuclei caused by a loss of nuclear basophilia, either within the superficial epidermis or full thickness. Mild irritants or lesser exposure may result in single necrotic keratinocytes within the suprabasal epidermis associated with spongiosis. Dermal eosinophils and neutrophils are variable.

DIFFERENTIAL DIAGNOSIS Single necrotic keratinocytes are usually located above the basal layer in irritant dermatitis, but in interface dermatitis, they are found mostly along the dermalepidermal junction. Single necrotic keratinocytes at the junction may also reflect wound healing from secondary excoriation by the patient (see Spongiotic Dermatitis).

Nummular dermatitis is usually diagnosed based on clinical features alone, without biopsy. It is essential for the pathologist to exclude dermatophytosis.

DIFFERENTIAL DIAGNOSIS Clinically, nummular dermatitis may resemble other forms of spongiotic dermatitis, as well as dermatophytosis, psoriasis, parapsoriasis, patches or plaques MF, as well as Bowen’s disease or superficial basal cell carcinoma. If lesions are located on the legs, the differential diagnosis may include xerotic dermatitis and stasis dermatitis. Xerotic dermatitis is primarily a clinical diagnosis. Stasis dermatitis should exhibit concomitant changes of venous stasis, including clusters of small thick-walled vessels in the upper dermis or full thickness of the dermis, associated with extravasated erythrocytes and hemosiderin. If venous stasis change is minimal or inactive (e.g., vascular changes, but no hemorrhage), the possibility of nummular or other spongiotic dermatitis superimposed on a background of venous insufficiency cannot be excluded.

PROGNOSIS AND TREATMENT Removal of the offending agent is curative. Otherwise the condition persists depending on the frequency and severity of exposure (see Spongiotic Dermatitis).

NUMMULAR DERMATITIS

PROGNOSIS AND TREATMENT There is a chronic waxing and waning course (see Spongiotic Dermatitis).

ATOPIC DERMATITIS

CLINICAL FINDINGS

CLINICAL FINDINGS

Round erythematous plaques that typically manifest in the shape and approximate size of coins characterize nummular dermatitis. There is a predilection for the extremities. Plaques may be crusted (wet) or dry and scaly. Outbreaks are often seasonal, associated with the onset of hot and humid, or more often, cold and dry winter weather. Emotional stress may also play a role in some cases.

HISTOLOGIC FEATURES For general features, see Spongiotic Dermatitis. Nummular dermatitis cannot be reliably or consistently distinguished from other forms of eczematous dermatitis based on the assessment of histopathologic features alone.

Atopic dermatitis (commonly designated eczema) is associated with a personal or family history of atopy, including asthma, allergic rhinitis, and allergic conjunctivitis. Atopic dermatitis is most common in infancy and childhood. Atopic dermatitis is known as the “itch that scratches” because pruritus often appears before a significant visible skin lesion. The earliest lesions are believed to be papulovesicles, akin to those that may be observed in acute spongiotic dermatitis. However, in atopic dermatitis, intact vesicles are rarely observed because papulovesicles are promptly excoriated, resulting in crusted papules that coalesce into ill-defined plaques. Atopic dermatitis is most common in childhood, and plaques involve the antecubital and popliteal fossae. Chronically manipulated lesions become scaly, lichenified, and dyspigmented (Fig. 1-4, A). Secondary impetiginization with Staphylococcus aureus or

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larly susceptible to secondary bacterial impetiginization by S. aureus or HSV superinfection. Impetiginized lesions are characterized by clusters of gram-positive cocci within the crust areas of the stratum corneum. HSV infections are characterized by intraepidermal vesiculation with ballooning and multinucleation of keratinocytes and a steel gray appearance of infected keratinocytes nuclei with peripheral margination of nuclear chromatin.

A

DIFFERENTIAL DIAGNOSIS

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Atopic dermatitis. A, Ill-defined plaques composed of pruritic focally crusted papules (in many instances ruptured papulovesicles) that become lichenified secondary to chronic rubbing. B, Papular or follicular atopic dermatitis is more common in dark-skinned children and clinically resembles lichen nitidus.

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secondary herpes simplex virus (HSV) infection (eczema herpeticum) may occur. Papular or follicular atopic dermatitis is most common in dark-complected children (Fig. 1-4, B).

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HISTOLOGIC FEATURES

For general features, see Spongiotic Dermatitis. Atopic dermatitis cannot be reliably or consistently distinguished from other forms of eczematous dermatitis based on the assessment of histopathologic features alone, but biopsy is rarely required for diagnosis. Biopsies of atopic dermatitis are usually taken from subacute or chronic lesions, so parakeratosis, epidermal hyperplasia with hypergranulosis, and superimposed LSC (see section following) are typical, and spongiosis itself is often mild. Papular or follicular atopic dermatitis is characterized by spongiosis involving the infundibula of hair follicles. Lesions of atopic dermatitis are particu-

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The diagnosis of atopy is determined by the patient’s personal and family history and clinical findings. Atopic dermatitis is invariably pruritic and characteristically involves the antecubital and popliteal fossae. Atopic dermatitis may exhibit prominent lichenification and postinflammatory hyperpigmentation or hypo pigmentation. Most cases do not require biopsy for diagnosis. However, atypical cases may be biopsied to evaluate for MF, psoriasis, pityriasis rubra pilaris (PRP), or other disorders. Follicular atopic dermatitis is clinically and histologically indistinguishable from a rare disorder, recurrent and disseminate infundibulofolliculitis, which has been reported in individuals without history of atopy. Miliaria rubra and Fox-Fordyce disease (apocrine miliaria) are clinically distinctive disorders charac terized by spongiosis of acrosyringium and apocrine duct, respectively. However, depending on the plane of section, it may be difficult to determine whether focal spongiosis is associated with follicular, eccrine ductal, or apocrine ductal epithelium. Pityriasis alba is characterized by hypopigmented patches with fine pityriasiform scale, most commonly on the face of dark-complected children, on whom it is generally not biopsied. The process may be generalized and involve the trunk and extremities. It is widely believed to represent postinflammatory hypopigmentation secondary to atopic dermatitis. ­

FIGURE 1-4

 

B

PROGNOSIS AND TREATMENT See Spongiotic Dermatitis. Atopic dermatitis is common in infancy and childhood and typically resolves or diminishes in severity with advancing age. Atopic individuals are particularly susceptible to S. aureus superinfection, and a 2-week course of dicloxacillin or cephalexin will often improve refractory cases, especially if there is significant crusting of lesions. New-onset, unexplained, generalized eczema or atopic dermatitis in older adults without satisfactory explanation should evoke consideration of a drug reaction or, rarely, occult malignancy.

DERMATOPATHOLOGY



18

DYSHIDROTIC DERMATITIS CLINICAL FINDINGS Dyshidrotic dermatitis (also designated pompholyx) is characterized by small “tapioca pearl”–like vesicles bilaterally on the fingers or toes. There is a tendency to involve the lateral aspects of the digits (Fig. 1-5). Vesicles may coalesce or extend onto the palms or soles but generally not beyond the wrist or ankle. In milder cases that do not exhibit visible vesicles, the more general term hand dermatitis is sometimes used. In severe acute cases, there may be extension to the distal extremities.

from dyshidrotic dermatitis. Dyshidrotic dermatitis may also be clinically indistinguishable from contact dermatitis limited to acral skin. Patients with tinea pedis may develop an Id reaction with dyshidrotic dermatitis on the hands and sometimes a generalized eczematous dermatitis. Id reactions may occur during initiation of systemic antifungal therapy for tinea pedis or onychomycosis.

PROGNOSIS AND TREATMENT See Spongiotic Dermatitis. Unless a cause can be identified and removed (see Id reaction), dyshidrotic dermatitis usually exhibits a chronic, waxing and waning course. Emotional stress has been implicated as a cause.

HISTOLOGIC FEATURES

SEBORRHEIC DERMATITIS For general histologic features, see Spongiotic Dermatitis. Dyshidrotic dermatitis cannot be reliably or consistently distinguished from other forms of eczematous dermatitis based on assessment of histopathologic features alone. However, the diagnosis may only be considered when the hands or feet are involved, usually symmetrically.

CLINICAL FINDINGS Seborrheic dermatitis is common in adulthood, exhibiting a soft, greasy scale and erythema, with a predilection for the scalp, eyebrows, nasolabial and retroauricular skin folds (Fig. 1-6), and upper trunk. Inguinal skin folds are less commonly involved. Seborrheic dermatitis is also common in newborns.

DIFFERENTIAL DIAGNOSIS HISTOLOGIC FEATURES

FIGURE 1-5

FIGURE 1-6

 

Dyshidrotic dermatitis consists of pruritic vesicles that tend to arise on the lateral fingers and hands. In contrast to spongiotic vesicles at other sites, they often remain intact in dyshidrosis.

 

Seborrheic dermatitis cannot be reliably or consistently distinguished from other forms of eczematous

­

Dyshidrotic dermatitis is usually diagnosed based on clinical features alone, without biopsy. The pathologist should exclude vesiculobullous lesions caused by der matophytes, which may be clinically indistinguishable

Seborrheic dermatitis is rarely biopsied. There is usually ill-defined, greasy, soft scale involving the scalp, and nasolabial and retroauricular skin folds.

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dermatitis based on assessment of histopathologic features alone. However, classic examples of seborrheic dermatitis exhibit spongiosis localized to the ostia or upper infundibula of hair follicles. A neutrophilic crust is commonly present. Colonizing Pityrosporum (Malassezia) yeast spores may be present in the stratum corneum or superficial follicular orifice. See Spongiotic Dermatitis. Seborrheic dermatitis is usually clinically sufficiently diagnostic. Occasionally, chronic seborrheic dermatitis is clinically or histologically indistinguishable from psoriasis.

PROGNOSIS AND TREATMENT See Spongiotic Dermatitis. Seborrheic dermatitis usually exhibits a chronic, waxing and waning course. In addition to topical corticosteroids, topical ketoconazole, medicated (e.g., coal tar, selenium sulfide, zinc

A

sulfate) shampoos, and topical tacrolimus are also often helpful.

PAPULAR DERMATITIS CLINICAL FINDINGS Papular dermatitis describes adults with refractory pruritic papules of unknown etiology with a predilection for the trunk, pelvis, and proximal extremities (Fig. 1-7, A). Papular dermatitis has been equated to what other observers have previously designated subacute prurigo and itchy red bump disease. Individuals with papular dermatitis may have some atopic features but not enough to warrant a diagnosis of atopic dermatitis. The incidence of papular dermatitis is unknown but is believed to be underrecognized, with cases likely being “lumped” into established diagnostic categories (e.g., atopic dermatitis, arthropod bite reactions).

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D

 

C

FIGURE 1-7

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Papular dermatitis (subacute prurigo, itchy red bump disease). A, Numerous edematous red pruritic papules with variable crusting (from excoriation) on the trunk and proximal extremities. B, Scanning magnification reveals superficial and mid perivascular and interstitial lymphocytes. C, D, Closer inspection reveals focal spongiosis and dermal eosinophils. Urticarial dermatitis is histologically identical to papular dermatitis.

DERMATOPATHOLOGY



HISTOLOGIC FEATURES Papular dermatitis is characterized by minimal spongiosis and dermal perivascular lymphocytes with eosinophils (Fig. 1-7, B–D). These nonspecific changes have historically been classified under various headings, particularly dermal hypersensitivity reaction (DHR) pattern, by many pathologists and, subsequently, some clinicians. In contrast to urticaria, lesions may be excoriated. In subacute prurigo the spongiosis has been reported to be localized to follicular infundibula.

DIFFERENTIAL DIAGNOSIS

akin to papular dermatitis, may be underrecognized; case series from the United States and Australia have been reported to date.

HISTOLOGIC FEATURES Urticarial dermatitis is characterized by minimal spongiosis with normal stratum corneum (e.g., no para keratosis) and upper dermal perivascular lymphocytes with eosinophils (i.e., identical to papular dermatitis) (Fig. 1-7, B–D). ­

20

DIFFERENTIAL DIAGNOSIS

As with most forms of spongiotic dermatitis, the diagnosis of papular dermatitis is primarily based on clinical features. Cases entirely devoid of spongiosis exhibiting otherwise identical dermal changes may represent nondiagnostic samplings of papular dermatitis. Papular presentations of other forms of spongiotic dermatitis, most commonly follicular atopic dermatitis, cannot be reliably distinguished from papular dermatitis without clinical correlation. Likewise, the diagnosis of pruritic urticarial papules and plaques of pregnancy (PUPPP) requires clinical correlation. Arthropod bite reactions typically exhibit denser and deeper dermal perivascular involvement and more prominent eosinophils. Scabies typically exhibits very prominent eosinophils and crust. The urticarial stage of bullous pemphigoid can be confirmed by DIF analysis. Papular acrodermatitis (GianottiCrosti disease) exhibits variable histopathologic features that may include spongiotic or lichenoid features.

As with most forms of spongiotic or eczematous dermatitis, the diagnosis of urticarial dermatitis is primarily based on clinical features and does not designate a specific disease entity. Most cases appear to be idiopathic, but some cases can be classified more specifically, including drug reactions, urticarial pemphigoid, atopic dermatitis, or contact dermatitis. In contrast to papular dermatitis, the differential diagnosis for urticarial dermatitis does not include arthropod bite reactions, but scabies, PUPPP, dermatitis herpetiformis, viral exanthems, and cutaneous T-cell lymphoma have rarely been documented.

PROGNOSIS AND TREATMENT Urticarial dermatitis may be managed with topical corticosteroids and oral antihistamines. Phototherapy and dapsone may be beneficial in selected cases.

PROGNOSIS AND TREATMENT Papular dermatitis typically exhibits a chronic, waxing and waning course. Topical corticosteroids, oral antihistamines, and phototherapy may be beneficial. Systemic immunosuppressive therapy (mycophenolate mofetil) has been reported.

URTICARIAL DERMATITIS CLINICAL FINDINGS Urticarial dermatitis designates a subset of the DHR pattern. The term urticarial dermatitis includes many patients with DHR who present clinically with pruritic urticarial eczematous plaques rather than only papules. The incidence of urticarial dermatitis is unknown, but

PITYRIASIS ROSEA CLINICAL FINDINGS Pityriasis rosea (PR) is a common, seasonal (spring, fall), self-limited eruption usually affecting children and young adults, manifesting as multiple round or oval erythematous papules, patches, or plaques with a collarette of pityriasiform (branlike) scale (Fig. 1-8, A) distributed in a “Christmas tree” pattern on the trunk (following relaxed skin tension lines on either side of the midline). The inguinal and axillary skin folds may be involved in inverse PR. A single lesion preceding by 1 to 2 weeks the onset of the generalized eruption is often identified (herald patch or mother patch) and is often larger than all subsequent lesions. Many

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B

C

D

FIGURE 1-8

 

A

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Pityriasis rosea. A, Characteristic oval plaque with collarette of pityriasiform (branlike) scale oriented along relaxed skin tension lines. B, C, Focal “caps” of parakeratosis and spongiosis are typically focal. D, Extravasated erythrocytes in the papillary dermis.

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individuals experience flulike symptoms before the onset of the herald patch or during the early stages of the eruption. PR is widely suspected of being virus induced, but no specific etiology has been consistently identified.

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HISTOLOGIC FEATURES

Pityriasis rosea cannot always be reliably or consistently distinguished from other forms of spongiotic dermatitis based on assessment of histopathologic features alone. Classic examples of PR exhibit periodic foci of spongiosis with overlying focal parakeratosis (Fig. 1-8, B, C), relatively prominent exocytosis of small lymphocytes, and extravasated erythrocytes in the papillary dermis or epidermis (Fig. 1-8, D). Scattered single dyskeratotic keratinocytes may be identified and may be more prominent in the herald patch. However, the pattern of inflammation is predominantly spongiotic rather than primary interface dermatitis. Inflammation within the dermis is

usually confined to the upper dermis and is predominantly lymphocytic. Eosinophils are variable.

DIFFERENTIAL DIAGNOSIS See Spongiotic Dermatitis. PR is usually diagnosed based on clinical features alone, without biopsy. If the epidermal changes are focal, the findings in PR may be indistinguishable from the superficial variant of erythema annulare centrifugum (EAC). Because biopsies from acute lesions of EAC may sometimes exhibit multiple foci of parakeratosis with spongiosis, including spongiotic vesiculation, clinical correlation is required to distinguish EAC from PR. Lymphocyte exocytosis, scattered single necrotic keratinocytes, and extravasation of erythrocytes are also features of pityriasis lichenoides and morbilliform viral exanthems. Pityriasis lichenoides is primarily an interface dermatitis with more keratinocyte necrosis and junctional vacuolar alteration than spongiosis. Morbilliform viral exanthems

DERMATOPATHOLOGY



22

are characterized by sparse lymphocytes with extravasated erythrocytes, mild vacuolar alteration, minimal spongiosis with lymphocyte exocytosis, or no epidermal alteration at all. PR-like drug reactions have been associated with captopril, gold, barbiturates, clonidine, isotretinoin, metronidazole, and penicillamine and require clinical correlation to establish.

PSORIASIS—DISEASE FACT SHEET





Patient Group ■ May occur at any age (bimodal onset between 20 to 30 and 50 to 60 years) ■ Familial predisposition; eruption often triggered by events (e.g., trauma, infection, medication) Site of Involvement ■ Scalp, elbow, knees—most common ■ Nails, hand, feet, and trunk may also be affected



PROGNOSIS AND TREATMENT

Clinical Findings (variable) Chronic plaque disease (most common): ■ Erythematous plaques with silvery scale; sharply demarcated

Pityriasis rosea invariably resolves within 2 weeks to 3 months. Recurrence is unusual. Most patients are managed symptomatically with such agents as low- to midpotency topical corticosteroids or oral antihistamines. Ultraviolet B phototherapy may shorten the disease course, especially if initiated early.



Guttate (eruptive) psoriasis (rare): ■ Discrete papules and plaques Pustular psoriasis (rare): ■ Pustules

PSORIASIFORM DERMATITIS

Erythrodermic psoriasis (rare): ■ Generalized erythroderma and scaling: associated arthritis found in a subset of patients (5% to 30%)

Similar to spongiotic dermatitis, psoriasiform dermatitis is a descriptive “diagnosis” used by pathologists in dermatopathology reports that does not correspond to a single clinical disorder. Rather, it describes a specific feature, psoriasiform epidermal hyperplasia, that is characteristic of a variety of inflammatory disorders, the prototype being psoriasis (Table 1-2).



Prognosis ■ Chronic disorder





Treatment ■ Topical vitamin D analogs ■ Topical corticosteroids ■ Topical retinoids or acitretin ■ Phototherapy ■ Systemic immunosuppressive therapy (methotrexate, cyclosporine) ■ Systemic biologic therapies against tumor necrosis factor-α, interleukin-12, interleukin-23



PSORIASIS





CLINICAL FINDINGS

TABLE 1-2

 

Classic plaque type psoriasis (psoriasis vulgaris) is characterized by well-circumscribed erythematous plaques

Basic Differential Diagnosis of Psoriasiform Dermatitis Psoriasis

Chronic Spongiotic Dermatitis

Lichen Simplex Chronicus or Prurigo Nodularis

Pityriasis Rubra Pilaris ++

Superficial perivascular lymphocytes

++

++

±

Deep perivascular lymphocytes

0

0

0

0

Hypogranulosis

++

±

0

0

Hypergranulosis

0

±

++

±

Dermal eosinophils

0

±

±

0

“Checkerboard” parakeratosis pattern

±

±

±

++

Parakeratosis with neutrophils

++

±

±

0

Papillary dermal fibrosis

±

±

++

±

++, characteristic; ±, variable; 0, unusual.

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with a thick, silvery scale with a predilection for the elbows, knees, scalp, and gluteal fold (Fig. 1-9, A, B). Fingernail plate involvement includes pitting and distal onycholysis. Lesions often arise at sites of trauma (Koebner phenomenon). Involvement of the face is uncommon. Flexural skin folds are involved in inverse psoriasis. Guttate psoriasis is characterized by the acute onset of innumerate papules or small plaques, classically

A

in association with streptococcal pharyngitis. Pustular psoriasis may be generalized or localized to the distal extremities (Fig. 1-9, C). Psoriasis is one of the more common etiologies underlying diffuse erythroderma, or exfoliative dermatitis (Fig. 1-9, D). Individuals with psoriasis often have concomitant psoriatic arthritis. Approximately one third of patients have a family history of psoriasis.

B

C

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FIGURE 1-9

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Psoriasis. A, B, Classic well-demarcated plaques with a thick scale. C, Pustular psoriasis. A few intact pustules are present at the base of the great toe. D, Erythrodermic psoriasis. E, At scanning magnification, there is regular elongation of the rete ridges. F, Parakeratotic crust, hypogranulosis, and a thinned suprapapillary plate. Continued

DERMATOPATHOLOGY



24

G H

I

J

K

L

FIGURE 1-9, cont’d G, Neutrophilic spongiosis. H, Layered neutrophils within parakeratosis. I, Collections of neutrophils in the stratum corneum (Munro microabscess) and in the stratum malpighii (spongiform pustule of Kogoj). J, Spongiform pustule at higher magnification. K, L, Pustular psoriasis may be generalized or localized to acral skin (whereupon the clinician has no choice but to biopsy at this site, as shown in the figure).

HISTOLOGIC FEATURES Psoriatic plaques exhibit parakeratosis with horizontally flattened layers of neutrophils, psoriasiform hyperplasia with strikingly regular elongation of slender rete ridges, hypogranulosis, thinned suprapapillary plates, prominent blood vessels within edematous papillary

dermal tips, and superficial perivascular predominantly lymphocytic dermal infiltrates (Fig. 1-9, E–H). Acute, guttate, or pustular lesions exhibit neutrophilic spongiosis, spongiform pustules (of Kogoj), and Munro microabscesses (Fig. 1-9, I–L). Spongiform pustules are intraepidermal collections of neutrophils situated in the stratum malpighii. Munro microabscesses describe neutrophil aggregates in the stratum corneum. Despite the

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

PSORIASIS—PATHOLOGIC FEATURES Histologic Features ■ Chronic plaque lesions – Psoriasiform epidermal hyperplasia – Multilayered mounds of parakeratosis and orthohyperkeratosis – Neutrophils cluster in a parakeratotic stratum corneum (microabscess of Munro) – Neutrophil cluster in stratum malpighii (spongiform pustule of Kogoj) – Diminished or absent granular cell layer (hypogranulosis) – Thinning of suprapapillary plate – Hypervascular edematous dermal papillae ■ Guttate psoriasis – Less hyperplasia, more inflammation and spongiosis ■ Pustular psoriasis – Dense accumulation of neutrophils Ancillary Studies ■ Consider PAS stain to exclude fungal infection Differential Diagnosis ■ Chronic spongiotic dermatitis ■ Lichen simplex chronicus ■ Drug reaction ■ Mycosis fungoides ■ Dermatophytosis ■ Pustular psoriasis: immunobullous disorders, pustular drug reaction, infection PAS, periodic acid-Schiff.

prominence of neutrophils within the epidermis, they are not prominent within the dermis. Eosinophils are usually not prominent in psoriasis.

ANCILLARY STUDIES A PAS or GMS stain may help exclude a fungal infection associated with a psoriasiform histologic reaction pattern.

DIFFERENTIAL DIAGNOSIS Psoriasis is usually diagnosed based on clinical features alone, without biopsy or ancillary studies. Biopsy is more likely to be performed when the clinical features or response to therapy is unusual. For classic plaques, dermatophytosis, chronic spongiotic dermatitis, psoriasiform drug reactions, necrolytic migratory erythema (NME), and patch or plaque stage MF may enter the differential diagnosis. Reiter syndrome is histopathologically indistinguishable from pustular psoriasis. In

chronic spongiotic dermatitis, the elongated rete ridges are usually less uniform in length, and the granular layer tends to be preserved or even thickened, and spongiosis is more prominent. Vesiculopustular dermatophytosis needs to be excluded. Psoriasis may represent a common underlying etiology of exfoliative erythroderma. However, erythroderma is a final common pathway of several disorders, including MF, Sézary syndrome, atopic dermatitis, PRP, drug reactions, and others. Diagnosis of erythroderma depends on identification of specific histopathologic attributes of the underlying disorder. In many examples of ery­ throderma, specific histopathologic features may be subtle. Spongiotic dermatitis is more likely to become impetiginized than psoriasis, so clusters of coccobacteria may be present within the neutrophilic crusts of spongiotic dermatitis. NME may present as psoriasiform dermatitis and neutrophilic spongiosis, without the prominent necrolysis that would most easily identify it. NME usually exhibits pronounced pallor in the upper epidermis. Patch stage MF often displays psoriasiform hyperplasia with a denser lichenoid infiltrate and disproportionate exocytosis of lymphocytes (epidermotropism).

PROGNOSIS AND TREATMENT Psoriasis exhibits a variable, unpredictable course that is frequently chronic or waxing and waning. Guttate eruptions in children and young adults may have the highest chance of complete remission. Therapy is individualized, largely based on disease severity, and includes topical and intralesional steroids; topical retinoids; topical calcipotriene; topical coal tar or anthralin; broador narrow-band ultraviolet B phototherapy; photochemotherapy (psoralen plus ultraviolet A [PUVA]); or systemic agents such as methotrexate, cyclosporine, and acitretin. Biologic agents include etanercept, infliximab, adalimumab, and ustekinumab.

LICHEN SIMPLEX CHRONICUS AND PRURIGO NODULARIS CLINICAL FINDINGS Lichen simplex chronicus is a localized thickening, hyperpigmentation, and lichenification secondary to chronic rubbing (Fig. 1-10, A). The cause of the rubbing is usually pruritus, which produces a habitual, intractable, itch–scratch cycle. Lesions may appear to arise de novo, but more often lichenification occurs in the setting of chronic spongiotic dermatitis, particularly atopic dermatitis. Prurigo nodularis (picker’s nodule, chronic prurigo) can be regarded as the papulonodular

DERMATOPATHOLOGY



26

HISTOLOGIC FEATURES

A

Lichen simplex chronicus and prurigo nodularis are characterized by compact orthokeratosis, epidermal and follicular epithelial hyperplasia with hypergranulosis resembling acral skin (hairy palm sign), and papillary dermal fibrosis with vertically oriented blood vessels within fibrotic dermal papillae (Fig. 1-10, B, C). Residual mild spongiosis is often present. In prurigo nodularis a dome-shaped configuration is evident, and follicular epithelial hyperplasia and hypergranulosis are prominent.

B

DIFFERENTIAL DIAGNOSIS Any chronic spongiotic dermatitis may eventuate in LSC. Dermatophytosis should still be excluded. Psoriasis may resemble LSC, but LSC typically exhibits a thickened stratum corneum containing predominantly orthokeratosis rather than parakeratosis, hypergranulosis, and more irregular elongation of rete ridges. If hypogranulosis is present, it is confined to areas of visible spongiosis or excoriation. In LSC, there is no tendency to thinned suprapapillary plates, and a variable degree papillary dermal fibrosis, often with a scarlike configuration of collagen fibers oriented parallel to the epi dermal surface, is characteristic. To the extent that papillomatosis is present, an antecedent or regressing verruca vulgaris may be suspected. ­

C

FIGURE 1-10

 

PROGNOSIS AND TREATMENT

Lichen simplex chronicus. A, Thickened, hyperpigmented plaque with decreased numbers of more prominent skin lines. B, C, Compact orthokeratosis, hypergranulosis, papillary dermal fibrosis, and vertically oriented blood vessels within papillary dermal tips. In this case, the dermal fibrosis is more obvious because it displaces solar elastosis.

Lichen simplex chronicus is often refractory to treatment. The itch–scratch cycle may be broken by treatment with potent topical corticosteroids or sedating oral antihistamines such as hydroxyzine, diphenhydramine, or doxepin. Occlusive therapy, with or without corticosteroids, may be helpful. Refractory prurigo nodularis has been reported to improve with phototherapy or thalidomide.

PITYRIASIS RUBRA PILARIS counterpart of LSC. Prurigo nodularis may arise at focal sites of inflammation, such as insect bites or folliculitis, or in patients with generalized pruritus associated with systemic disease such as chronic renal failure. Prurigo nodules are firm, smooth or slightly rough dome-shaped papules or nodules that are often hyperpigmented or crusted. Patients generally admit to manipulating the lesions.

CLINICAL FINDINGS Pityriasis rubra pilaris is a chronic, idiopathic disorder characterized by red-orange follicular papules that coalesce into well-demarcated confluent plaques leaving characteristic islands of sparing (Fig. 1-11, A). Lesions typically progress from rostral to caudal, with many

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

A

B

DIFFERENTIAL DIAGNOSIS Compared with psoriasis, the epidermal hyperplasia in PRP is usually more irregular (rete ridges more variable in length), the granular layer is preserved, and neutrophils in the stratum corneum are not typical of PRP. Follicular plugging is not characteristic of psoriasis. Focal acantholytic dyskeratosis may represent a somewhat characteristic finding in this histologic context but is not present in most examples of PRP. The superficial dermal perivascular lymphocytes in PRP are typically sparse compared with psoriasis and chronic spongiotic dermatitis. If regressing chronic spongiotic dermatitis is sampled, the findings may be indistinguishable from PRP unless additional features, such as follicular plugging or a classic checkerboard pattern in the stratum corneum, are identified. When the histopathologic features are not diagnostic, clinical correlation is essential to establish the diagnosis.

PROGNOSIS AND TREATMENT FIGURE 1-11  Pityriasis rubra pilaris. A, Coalescent orange-red papules with islands of sparing. B, Alternating orthokeratosis and parakeratosis (checkerboard pattern), psoriasiform epidermal hyperplasia, and sparse superficial perivascular lymphocytes.

patients presenting with initial involvement of the face and scalp (hair and teeth are normal), followed by palmoplantar keratoderma and generalized involvement. Erythroderma may ensue. Many patients are photosensitive. Erythroderma may result in severe cases. Localized, familial, and juvenile variants have been described. Acquired cases often exhibit abrupt onset, but familial cases may have a more gradual onset. Nail changes include splinter hemorrhages, yellow-brown discoloration, and nail plate thickening.

HISTOLOGIC FEATURES Pityriasis rubra pilaris is characterized by alternating orthokeratosis and parakeratosis, both vertically and horizontally, producing a checkerboard pattern in the stratum corneum in histologic sections (Fig. 1-11, B). There are usually psoriasiform hyperplasia, preservation of the granular layer, follicular plugging, and sparse superficial perivascular lymphocytes. Spongiosis, if present at all, is minimal. Focal acantholytic dyskeratosis may be present.

Classic, acquired, generalized PRP runs a chronic, waxing and waning course. Familial PRP persists throughout life. Therapy includes topical keratolytics; systemic photochemotherapy; retinoids (including isotretinoin and acitretin); and for refractory cases, cyclosporine, low-dose methotrexate, or other systemic agents.

NECROLYTIC MIGRATORY ERYTHEMA CLINICAL FINDINGS Necrolytic migratory erythema is a paraneoplastic reaction usually associated with an islet cell glucagonsecreting malignancy (glucagonoma) of the pancreas. Patients present with diabetes mellitus, weight loss, anemia, glossitis, and erythematous erosive desquamating plaques that tend to develop in flexural skin folds such as the groin and axilla (Fig. 1-12, A).

HISTOLOGIC FEATURES The histologic features are variable, but the most distinctive finding is pronounced pallor of the upper epidermis associated with necrolysis, which is characterized by vacuoles within the cytoplasm of superficial epidermal keratinocytes, resulting in confluent necrosis in the upper epidermis (Fig. 1-12, B). Confluent

DERMATOPATHOLOGY



28

ANCILLARY STUDIES

A

Serum glucagon levels are typically elevated. Imaging studies usually reveal a pancreatic mass lesion.

DIFFERENTIAL DIAGNOSIS Psoriasis, particularly early lesions, and PRP may exhibit pallor in the upper epidermis but not to the degree that is achieved in the fullest expression of NME, wherein the accompanying necrolytic changes are quite distinctive. Necrolysis is not a feature of psoriasis or PRP. Other forms of deficiency dermatitis, such as zinc deficiency (acrodermatitis enteropathica), riboflavin, and niacin (vitamin B3) deficiency (pellagra), may also exhibit necrolysis and keratinocyte pallor and are best distinguished based on clinical and laboratory features.

B

PROGNOSIS AND TREATMENT Patients with NME often respond dramatically (within hours to days) to surgical removal of the glucagonoma. Patients are typically amino acid deficient, and intravenous amino acid infusion has also been associated with rapid resolution of the skin lesions.

C

FIGURE 1-12

 

INTERFACE DERMATITIS

Necrolytic migratory erythema (glucagonoma syndrome) in a 74-year-old man with markedly elevated serum glucagon level and pancreatic mass. A, Erythematous, erosive desquamating plaques in a flexural distribution. B, Initial biopsy revealed vacuolization and pronounced pallor in the superficial epidermis. Necrolysis is not yet evident. C, Subsequent biopsy revealed only focal subcorneal pustule formation. Thus, prominent necrolysis is not always a feature, and the findings may resemble psoriasis or other inflammatory disorders.

parakeratosis is usually present. Plaques in NME often exhibit psoriasiform hyperplasia. Other findings occasionally present include neutrophilic crust, neutrophilic spongiosis, subcorneal pustule formation (Fig. 1-12, C), sparse eosinophils, or single necrotic or dyskeratotic keratinocytes.

Similar to spongiotic dermatitis and psoriasiform dermatitis, interface dermatitis is a descriptive phrase used by pathologists in dermatopathology reports that is not a specific disease entity (Table 1-3). Interface dermatitis describes a pattern of inflammation in which lymphocytes aggregate around the interface of the dermalepidermal junction, obscuring the junction at scanning magnification. T lymphocytes mediate damage to the basement membrane zone and the keratinocytes above them, the microscopic hallmarks being junctional vacuolar alteration and single keratinocyte necrosis. Vacuolar alteration is characterized by small, empty, circular spaces of varying diameter along the dermalepidermal junction. Single necrotic keratinocytes exhibit homogeneous (nongranular) eosinophilic cytoplasm and a shrunken, pyknotic, intensely basophilic nucleus. Depending on the plane of section, the nucleus may not be visible. In some examples of interface dermatitis, such as lichen planus (LP), the necrotic keratinocytes have been shown to be undergoing apoptosis. In other examples, such as acantholytic dyskeratosis (see Grover’s disease or Darier’s disease), similar-appearing

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

TABLE 1-3  Basic Differential Diagnosis of Interface Dermatitis

Erythema Multiforme

StevensJohnson/Toxic Epidermal Necrolysis

Lichen Planus

Pityriasis Lichenoides

Lupus Erythematosus

Lichen Striatus

Graft versus Host Disease

Vacuolar interface

++

Lichenoid interface

±

++

0

±

±

±

±

0

++

±

±

±

±

Basilar squamatization

±

0

0

++

0

±

0

±

±

Deep perivascular inflammation

0

0

0

±

++

±

0

++

Follicular involvement

0

0

±

0

++

±

++

0

Eccrine involvement

0

0

0

0

++

++

±

0

Fixed Drug Reaction ±

Dermal eosinophils

0

±

±

0

0

±

0

++

Dermal neutrophils

0

±

0

0

0

0

0

±

Lymphocyte exocytosis

±

±

±

++

±

±

±

±

Erythrocyte extravasation

±

±

0

++

0

0

0

0

Epidermal necrosis

±

++

0

±

0

0

±

±

++, characteristic; ±, variable; 0, unusual.

cells are attributable to abnormal differentiation (“dyskeratosis”). Thus, from the standpoint of routine practice, necrotic, dyskeratotic, and apoptotic keratinocytes (also known as “dead reds”) are interchangeable when evaluating routine stained sections of a specimen without prior knowledge of the diagnosis. Secondary spongiosis is invariably present in interface dermatitis, but the presence of interface dermatitis generally takes precedence over spongiosis for the purposes of differential diagnosis. Cases that show overlapping patterns suggest a drug reaction. In addition to mild “secondary” spongiosis, limited exocytosis of lymphocytes into the epidermis is expected. Exocytosis is characteristically more prominent in pityriasis lichenoides (see Table 1-3) or viral exanthems. Interface dermatitis is typically subdivided based on the pattern of inflammation (Ackerman) but alternatively may be subdivided based on associated epidermal changes (LeBoit). Classification based on associated epidermal changes is beyond the scope of this text but recommended for anyone striving to master this subject. Based on the pattern of inflammation, vacuolar interface dermatitis is characterized by sparse lymphocytes along the dermal-epidermal junction with junctional vacuolar alteration and single and/or clustered necrotic keratinocytes. Erythema multiforme (EM) is considered a prototype for this pattern. Lichenoid interface reactions have a bandlike predominantly lymphocytic infiltrate along the dermal-epidermal junction, sometimes filling the entire papillary dermis. LP is the prototype for this category. Thus, the term lichenoid has both a

clinical meaning (lesions resembling lichen, typified by LP) and a histologic one (lesions with a bandlike lymphocytic infiltrate below the dermal-epidermal junction). Less commonly, lymphocytes forming a bandlike pattern in the papillary dermis with minimal or absent vacuolar alteration or necrotic keratinocytes may still be classified as lichenoid dermatitis, e.g., the lichenoid variant of pigmented purpura (lichenoid purpura of Gougerot and Blum).

ERYTHEMA MULTIFORME, STEVENS-JOHNSON SYNDROME, AND TOXIC EPIDERMAL NECROLYSIS CLINICAL FINDINGS Erythema multiforme encompasses a wide clinical spectrum of severity. The three disorders included under this heading are clinically distinct, and classic EM (EM minor) is also considered pathogenetically distinct from Stevens-Johnson syndrome (SJS; EM major) and toxic epidermal necrolysis (TEN), but all three are united here because they cannot be reliably distinguished based on histology alone. Classic EM is an acute, self-limited, benign disorder characterized by targetoid papules, papulovesicles, or plaques on the extremities and trunk, often with involvement of the palms. Classic targetoid lesions have a dusky or violaceous center surrounded by two concentric rings or zones of pallor and erythema

DERMATOPATHOLOGY



30

(Fig. 1-13, A). As the name suggests, multiple morphologies are possible, including bullous lesions (Fig. 1-13, B). EM minor is highly associated with the HSV carrier state, and outbreaks may be accompanied by cold sores or reactivation of latent HSV by ultraviolet light exposure. SJS is a severe acute generalized reaction characterized by involvement of multiple mucosal sites (oral, ocular, genital) in which the disease manifests with

prominent hemorrhagic crusting (Fig. 1-13, C). Associated discrete or coalescent variably purpuric atypical targetoid lesions (two zones, rather than three) may coexist on the trunk and extremities. SJS is usually associated with recent drug exposure but may also be triggered by infection, including Mycoplasma pneumoniae. TEN is the most severe reaction, defined as widespread sloughing of the epidermal surface on greater than 10% B

C

D

E

F

FIGURE 1-13

 

A

Erythema multiforme (EM) and Stevens-Johnson syndrome (SJS). A, Targetoid papule on the lateral finger that resolved with acyclovir therapy. B, Bullous eruption on the palms associated with a cold sore. C, Hemorrhagic crusted lesion with lip involvement in SJS. D, Basket-weave orthokeratosis, vacuolar interface dermatitis, and superficial lymphocytes in the dermis. E, Prominent single necrotic keratinocytes at all levels of the epidermis. F, Biopsy from the patient in part A reveals a denser lichenoid infiltrate.

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

G

H

I

J

FIGURE 1-13, cont’d G, Prominent keratinocyte necrosis. H, Satellite cell necrosis. I, J, SJS is characterized by confluent epidermal necrosis and subepidermal clefting. These changes are indistinguishable from some cases of bullous EM. In toxic epidermal necrolysis, inflammation may be absent or minimal, but biopsy of perilesional skin may reveal changes indistinguishable from SJS or EM.

ERYTHEMA MULTIFORME (MINOR)—DISEASE FACT SHEET

of the total body surface area. TEN is characterized by disproportionate sloughing with minimal erythema compared with EM minor or SJS.

Erythema multiforme (minor) shows similar histologic features with but is clinically distinct from Stevens-Johnson syndrome. Patient Group ■ Most often young adults but may occur at any age ■ Eruption triggered by infection (especially herpes simplex virus) or medication Site of Involvement ■ Extremities (usually upper, especially dorsum of hands and forearms) ■ Face Clinical Findings ■ Abrupt onset of classic target lesions (acrofacial sites) ■ Erythematous urticarial papules and plaques ■ Coalescence of lesions produces a polycyclic appearance Prognosis and Treatment ■ Acute self-limited disease ■ Acyclovir or valacyclovir if associated with herpes simplex

HISTOLOGIC FEATURES Because the onset of EM is acute, there is usually basketweave orthokeratosis and vacuolar interface dermatitis with prominent necrosis of single and clustered necrotic keratinocytes both along and above the basal layer (Fig. 1-13, D, E). Prominent reactions may display a denser lichenoid infiltrate from scanning magnification (Fig. 1-13, F–H), but vacuolar alteration and keratinocyte necrosis remain prominent. When lymphocytes are juxtaposed against necrotic keratinocytes, the term satellite cell necrosis has been used (Fig. 1-13, H). (Satellite cell necrosis is not specific for EM.) There are usually sparse superficial perivascular lymphocytes in the dermis. Dermal eosinophils are typically rare or absent. In bullous variants, confluent keratinocyte necrosis and vacuolar alteration result in full-thickness epidermal

DERMATOPATHOLOGY



32

ERYTHEMA MULTIFORME—PATHOLOGIC FEATURES







Histologic Features ■ Acute vacuolar interface dermatitis ■ Epidermal necrosis, variable ■ May be associated with a secondary subepidermal blister







Differential Diagnosis ■ Stevens-Johnson syndrome/toxic epidermal necrolysis (distinction requires clinical context: prodrome of upper respiratory tract syndrome, mucous membrane involvement, extensive exfoliation, association with medication use) ■ Erythema multiforme–like graft versus host disease ■ Rowell’s syndrome (erythema multiforme–like lesions in patients with lupus erythematosus)

necrosis and subepidermal blistering (Fig. 1-13, I, J). Marked papillary dermal edema is less commonly a second means by which subepidermal blistering may occur. In TEN, perilesional skin may reveal changes indistinguishable from EM or SJS. However, in TEN, there is progression to full-thickness epidermal necrosis and widespread subepidermal blistering and sloughing with sparse inflammation.

ANCILLARY STUDIES Frozen section analysis of a freshly formed blister roof can facilitate rapid distinction between TEN and staphylococcal scalded skin syndrome.

DIFFERENTIAL DIAGNOSIS Although their clinical contexts tend to be mutually exclusive, acute graft versus host disease (GVHD) may be histologically indistinguishable from EM/SJS/TEN. GVHD is more apt to exhibit extension of the vacuolar interface reaction within adnexal epithelium. A frequent clinical differential diagnosis is TEN versus staphylococcal scalded skin syndrome. The latter exhibits a superficial intraepidermal cleavage plane, as per pemphigus foliaceus (see Ancillary Studies). Fixed drug reactions may exhibit similar epidermal changes to EM but usually exhibit neutrophils or eosinophils and sometimes exhibit greater spongiosis, and the inflammation typically involves the deep vascular plexus in the reticular dermis. After repeated episodes, fixed drug reactions also typically have melanophages in the papillary dermis. Pityriasis lichenoides usually exhibits neutrophilic crust, greater lymphocyte exocytosis, and erythrocyte extravasation in the papillary dermis with deep perivascular extension of lymphocytes. However, early lesions

of pityriasis lichenoides et varioliformis acuta (PLEVA) may resemble EM. Acute cutaneous lupus erythematosus (LE) may also resemble EM. Acute lupus usually exhibits compact orthokeratosis, epidermal atrophy, relatively sparse single necrotic keratinocytes, and increased interstitial mucin in the underlying dermis. Chemotherapy-induced interface dermatitis is characterized by cytologically atypical keratinocytes and basilar squamatization. Finally, consistent with its etiologic role in most cases of EM, HSV, and varicella zoster virus infections usually exhibit vacuolar interface dermatitis extending along the dermal-epidermal junction peripheral to the diagnostic viral cytopathologic features within the epidermis or follicular epithelium.

PROGNOSIS AND TREATMENT Erythema multiforme minor is self-limited, but episodes may recur chronically. Sun protection and avoidance may minimize HSV outbreaks. Episodic or suppressive systemic antiviral therapy with acyclovir, famciclovir, or valacyclovir is usually helpful. SJS and TEN are debilitating and potentially life-threatening conditions that warrant hospitalization. Because of the significant morbidity and mortality and special management challenges associated with TEN, these patients are optimally managed in a surgical intensive care burn unit to use frequent dressing changes, management of fluid and electrolyte status, and monitoring and prevention of sepsis (the most frequent cause of death). The mortality rate may approach 10% to 25%. The role of systemic corticosteroids in the acute management of SJS and TEN is controversial and unproved, although they are frequently administered. Plasmapheresis, intravenous immune globulin, and tumor necrosis factor inhibitors represent additional therapeutic options.

FIXED DRUG REACTION CLINICAL FINDINGS Fixed drug reactions are round, erythematous or violaceous macules or patches that occur on one or a few fixed sites repetitively after repeat exposure to the offending agent. Tetracycline, penicillin, acetaminophen, aspirin, nonsteroidal antiinflammatory agents, dapsone, benzodiazepines, and barbiturates are commonly implicated culprits. The face, extremities, and genitalia are common sites, but any site may be involved. The lesions may vesiculate (Fig. 1-14, A). Postinflammatory hyperpigmentation persists for several weeks to months after a single exposure to the offending agent. With repeat exposure, persistent pigmentation intensifies, and additional sites may manifest. The pigmentation is said

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

to have a mercurochrome hue owing to the combination of erythema superimposed on post inflammatory hyperpigmentation.

HISTOLOGIC FEATURES Fixed drug reactions display vacuolar alteration, single or clustered necrotic keratinocytes within the basal and often upper levels of the epidermis (Fig. 1-14, B). Spongiosis is variable. Confluent epidermal necrosis is associated with subepidermal cleavage in bullous fixed drug reactions. The dermis contains superficial or superficial and deep perivascular lymphocytes, usually with eosinophils, neutrophils, or both. After repeated flares, melanophages are prominent in the papillary dermis.

DIFFERENTIAL DIAGNOSIS The epidermal changes in EM may be indistinguishable from those of fixed drug reactions. Clues that may favor A

fixed drug reaction include melanophages, slight psoriasiform epidermal hyperplasia, a retained polygonal configuration of the necrotic keratinocytes in the stratum spinosum, and greater spongiosis. Fixed drug reactions are much more likely to involve the deep perivascular plexus and contain eosinophils, neutrophils, or both. In the context of vacuolar interface dermatitis, prominent melanophages are generally a clue to the diagnosis of a fixed drug reaction.

PROGNOSIS AND TREATMENT Fixed drug reactions usually resolve within several days. However, with repeat exposure to the offending agent, progressive hyperpigmentation persists. Generalized lesions may develop rarely. Avoidance of the offending drug is curative.

LICHEN PLANUS CLINICAL FINDINGS Lichen planus is a relatively common disorder char­ acterized by flat-topped erythematous or violaceous,

LICHEN PLANUS—DISEASE FACT SHEET Patient Group ■ Usually middle-aged adults (onset usually between ages 30 and 60 years)

B

Site of Involvement ■ Oral mucosa (up to 75% of patients) ■ Skin of wrist, forearm, genitalia, distal lower extremity Clinical Findings ■ Classic skin lesions: flat-topped violaceous papules and plaques ■ Variants: linear, bullous, hypertrophic, atrophic, annular skin lesions ■ Wickham striae (network of fine white lines on surface of lesions) ■ Mucosa: reticular pattern (most common) of whitish linear streaks; atrophic, erosive, papular or plaque lesions ■ Nail: lateral thinning, longitudinal ridging, fissuring pterygium Prognosis ■ Clinical course variable (self-limited to chronic persistent) ■ Ulcerative oral, hypertrophic, and nail lichen planus tend to persist

FIGURE 1-14  Fixed drug reaction. A, Dusky red, hemorrhagic, bullous, round plaque on the wrist. Smaller lesion on the thumb. B, Vacuolar and lichenoid interface dermatitis with prominent necrotic keratinocytes. Dermal eosinophils are present. Melanophages are often prominent.

Treatment ■ Corticosteroids ■ Retinoids ■ Phototherapy

DERMATOPATHOLOGY



34

A

D

B

E

FIGURE 1-15

 

C

Lichen planus. A, Round and polygonal papules with Wickham striae on the inner wrist. B, Reticulated white patch on the buccal mucosa. C, D, Lichenoid interface dermatitis with epidermal hyperplasia, sawtoothshaped rete ridges, and wedge-shaped hypergranulosis. E, Colloid bodies and melanophages in the papillary dermis.

pruritic papules most commonly involving the wrists or ankles in a symmetric fashion. The papules classically have an angulated or polygonal shape (Fig. 1-15, A). Reticulated white lines may be appreciated on the surface of the papules, known as Wickham striae. Oral and genital skin is also commonly involved. In oral LP, the Wickham striae may be the most prominent finding (Fig. 1-15, B). Involvement of the nail unit may result in pterygium formation. Hypertrophic LP is common on

the shins. In dark-complected individuals, the erythema may be subtle, with hyperpigmentation as the predominant feature. In lichen planopilaris (follicular LP), the disorder is centered on the lower infundibulum and isthmus of hair follicles, where scarring alopecia may result. Annular, atrophic, vesiculobullous, actinic, erosive, and hyperpigmented LP are other clinical variants. Two rare overlap syndromes are the LP–LE overlap and LP pemphigoides.

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

HISTOLOGIC FEATURES Fully developed LP is primarily an interface dermatitis typified by a dense lichenoid (bandlike) infiltrate obscuring the dermal-epidermal junction (Fig. 1-15, C-E). The epidermal changes are most characteristic. Classic LP exhibits compact orthokeratosis, wedge-shaped hypergranulosis overlying jagged sawtooth-shaped rete ridges, and squamatization of the basal layer (basilar squamatization). Squamatization of the basal layer refers to the flattening of basilar keratinocytes resembling the physiologic flattening of keratinocytes in the upper epidermis as they enter the stratum granulosum just prior to terminal differentiation into the stratum corneum. Basilar squamatization is often best appreciated in areas where the rete ridges exhibit a jagged or sawtooth shape and overlying hypergranulosis provides optimal contrast. The areas of hypergranulosis represent an exaggeration of the physiologic hypergranulosis associated with adnexal (follicular, sweat duct) epithelium. In hypertrophic LP, there is pronounced epidermal hyperplasia with acanthosis, papillomatosis, and elongated rete ridges. In atrophic LP, there may be attenuation of the rete ridges and a thinned, atrophic epidermis resembling lupus. In hypertrophic LP, which is typically very pruritic, there is epidermal hyperplasia with papillomatosis and often papillary dermal fibrosis secondary to chronic rubbing. In mucosal LP, the epidermal changes may be less specific, with rounded rather than pointed rete ridges and parakeratosis. In all variants, the lichenoid infiltrate is composed predominantly of lymphocytes. Melanophages are usually present. Pertinent negative findings include absence of prominent dermal eosinophils and absence of deep perivascular extension of the dermal

LICHEN PLANUS—PATHOLOGIC FEATURES Histologic Features ■ Epidermal hyperplasia with compact orthokeratosis, hypergranulosis, and bandlike lymphocytic infiltrate ■ Sawtoothing of rete ridges ■ Civatte bodies Ancillary Studies ■ If crust or eosinophils are present, consider PAS stain to exclude dermatophyte ■ Direct immunofluorescence: basement membrane zone fibrinogen Differential Diagnosis ■ Lichen planus–like keratosis ■ Lichenoid drug reaction (distinction best done clinically: nonclassic sites involved, mucous membranes often spared; history of medication use)

infiltrate. Hypertrophic LP may exhibit greater numbers of eosinophils. Mucosal LP usually contains some plasma cells that may be attributable to the mucosal site. The apoptotic keratinocytes exhibit homogeneous eosinophilic cytoplasm and sometimes a pyknotic basophilic nucleus (the nucleus may not be observed depending on the plane of section). They are mostly present along the dermal-epidermal junction but may also be found in the upper levels of the epidermis or in the papillary dermal lichenoid infiltrate. In the context of LP, the anucleate remnants of these apoptotic keratinocytes have been named Civatte bodies (colloid bodies, cytoid bodies) when present in the papillary dermis. Focal subepidermal clefts formed by confluent vacuoles have been termed Max-Joseph spaces.

ANCILLARY STUDIES Although biopsy is typically performed to confirm the diagnosis of LP, DIF studies are not routinely required to establish the diagnosis. However, immunofluorescence studies routinely show globular deposition of IgM at the dermal-epidermal junction, corresponding to the apoptotic cells. LP may be associated with hepatitis C virus (HCV) infection in fewer than 30% of cases.

DIFFERENTIAL DIAGNOSIS Lichen planus may be histologically indistinguishable from a LP-like keratosis (lichenoid keratosis, benign lichenoid keratosis), but the clinical setting is usually sufficient to distinguish these two disorders. Whereas LP is characterized by multiple lesions and usually sampled by punch (trephine) biopsy, LP-like keratoses are solitary lesions, most commonly on the trunk of an adult, and sampled by shave biopsy to rule out carcinoma. Compared with LP, LP-like keratosis usually exhibits some parakeratosis and does not invariably contain the distinctive epidermal changes (basilar squamatization, jagged rete, wedge-shaped hypergranulosis) requisite for LP. Lichenoid drug reactions (e.g., thiazide diuretics, beta-blockers, antimalarials, furosemide, spironolactone) also exhibit parakeratosis, as well as dermal eosinophils and deep dermal perivascular extension of lymphocytes and eosinophils. Lichenoid drug reactions also do not invariably contain the epidermal changes of LP, and single necrotic keratinocytes may be present in the upper epidermis, including the stratum corneum. Lichenoid variants of the pigmented purpuric derma­ toses, including lichenoid purpura (Gougerot-Blum) and lichen aureus, contain extravasated erythrocytes or hemosiderin-containing histiocytes (siderophages), whose pigment can be highlighted by hemosiderin stain.

DERMATOPATHOLOGY



36

The lichenoid variant of chronic GVHD may resemble LP clinically and histopathologically; clinical correlation is required. In lichenoid GVHD, the lichenoid infiltrate is typically sparse, and dermal eosinophils or plasma cells may be present. Discoid LE may exhibit basilar squamatization but, additionally, epithelial atrophy, basement membrane thickening, deeper and denser perivascular and perifollicular lymphocytes (usually devoid of eosinophils), and increased interstitial mucin deposition. Some instances in which features of both LP and lupus were present have been termed lupus erythematosus–LP overlap. Lichen striatus may resemble LP but typically exhibits lymphocytes and sometimes admixed histiocytes associated with eccrine sweat glands in the reticular dermis. Lichen nitidus exhibits a ball-in-claw configuration of rete ridges surrounding the lichenoid lymphohistiocytic infiltrate that may exhibit overt granulomatous features with multinucleated histiocytes. Lichenoid mucositis secondary to candida exhibits spongiosis, neutrophilic pustules, eosinophils, and pseudohyphae within the superficial epithelium.

PROGNOSIS AND TREATMENT

HISTOLOGIC FEATURES Pityriasis lichenoides et varioliformis acuta is characterized by parakeratotic neutrophilic crust, vacuolar interface dermatitis with lymphocyte exocytosis, papillary dermal hemorrhage, and superficial and deep wedgeshaped lymphocytic infiltrates (Fig. 1-16, C, D). Despite the characteristic neutrophilic crust in PLEVA, neutrophilic spongiosis or dermal neutrophilia are not prominent. Dermal eosinophils are rare and often entirely absent. Fully developed lesions have a lichenoid infiltrate below the dermal-epidermal junction. Dense infiltrates of lymphocytes in and around blood vessels is often noted, so-called lymphocytic vasculitis. Additional evidence of vasculitis, namely fibrin within vessel walls, is only occasionally present. In PLC, the perivascular lymphocytes are often sparser and confined to the upper dermis. Parakeratosis, interface dermatitis, and lymphocyte exocytosis are usually present, but a neutrophilic crust and erythrocyte extravasation may be minimal or absent.

DIFFERENTIAL DIAGNOSIS

Lichen planus typically runs a chronic but self-limited course, often resolving after 3 to 5 years. Therapeutic options include potent topical corticosteroids; short courses of systemic corticosteroids; photochemotherapy; systemic retinoids; and for refractory cases, other systemic immune suppressive agents. Chronic erosive lesions should to be examined regularly to rule out secondary squamous cell carcinoma.

PITYRIASIS LICHENOIDES CLINICAL FINDINGS Pityriasis lichenoides is an idiopathic disorder that can be viewed as a clinical and histopathologic spectrum with the clinical disorders PLEVA (Mucha Habermann disease) at one end, and pityriasis lichenoides chronica (PLC) at the other. PLEVA usually affects children and young adults, with widespread vesicles and hemorrhagic, erythematous, minimally symptomatic papules that ulcerate and leave focal varioliform (smallpox-like) scars (Fig. 1-16, A, B). A severe hyperacute ulceronecrotic variant of PLEVA is characterized by fever, constitutional symptoms, and larger ulcerations and has been associated with Epstein-Barr virus or cytomegalovirus infections. PLC runs a mild chronic course with randomly scattered minimally symptomatic erythematous papules in children or adults. PLC typically does not ulcerate or scar. Cases with intermediate or overlapping features of PLEVA and PLC may occur.

Pityriasis rosea may resemble pityriasis lichenoides. Both conditions may exhibit overlapping spongiotic and interface features with lymphocyte exocytosis and erythrocyte extravasation. However, epidermal changes in PR are predominantly spongiotic, but in pityriasis lichenoides, they are predominantly interface. The presence of neutrophilic crust; dense, deep dermal perivascular involvement; or lymphocytic vasculitis favors PLEVA over PR. Neutrophilic crust is also typical of psoriasis, spongiotic dermatitis, and dermatophytosis, but interface dermatitis is not typical of any of these, and histochemical staining for fungi will identify rare cases of dermatophytosis manifesting an interface reaction. Pityriasis lichenoides should not contain atypical lymphocytes. In the past, the designation lymphomatoid pityriasis lichenoides was proposed. However, if atypical lymphocytes with convoluted or cerebriform nuclear contours are present, lymphomatoid papulosis or MF should be suspected. If scattered large atypical CD30positive lymphocytes with prominent nucleoli are present in the dermis, the diagnosis is probably lymphomatoid papulosis (type A pattern). If small to medium convoluted or cerebriform lymphocytes are present within the epidermis, then lymphomatoid papulosis (type B pattern) is a consideration. Lymphocyte exocytosis without overt atypia may be observed in both pityriasis lichenoides and patches of MF. In MF, lymphocytes tend to aggregate in the basilar epidermis, and necrotic keratinocytes, vacuolar alteration, and spongiosis are

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B

A

C

D

FIGURE 1-16  Pityriasis lichenoides. A, Erythematous papules on the trunk and extremities. B, Papulovesicles in pityriasis lichenoides et varioliformis acuta (Mucha Habermann disease). C, Scanning magnification reveals lichenoid interface dermatitis associated with a dense wedge-shaped lymphocytic infiltrate with deep perivascular extension and erythrocyte extravasation in the upper dermis. D, Higher magnification reveals a neutrophilic crust, lymphocyte exocytosis, vacuolar alteration, necrotic keratinocytes, and erythrocyte extravasation.

not prominent. Prominent eosinophils are not typical of pityriasis lichenoides or MF. In pityriasis lichenoides, the lymphocyte are more scattered throughout all levels of the epidermis with greater spongiosis or interface changes, and deep perivascular lymphocytes are typical.

steroids, phototherapy, and oral erythromycin or tetracyclines. Longitudinal observation is advisable because refractory “pityriasis lichenoides” may represent lymphomatoid papulosis or MF.

LUPUS ERYTHEMATOSUS PROGNOSIS AND TREATMENT Pityriasis lichenoides et varioliformis acuta is usually self-limited. Therapeutic options include topical cortico-

CLINICAL FINDINGS Lupus erythematosus is a systemic autoimmune disorder that exhibits both specific and nonspecific cutaneous

DERMATOPATHOLOGY



38

manifestations (e.g., leukocytoclastic vasculitis, livedo reticularis). The specific lesions can be classified into acute, subacute, and chronic cutaneous LE. Whereas acute cutaneous lesions are usually associated with systemic lupus, systemic involvement in subacute or chronic cutaneous lupus lesions may be milder or, in the case of chronic lesions, usually absent. Acute cutaneous lupus lesions include the localized malar (butterfly) rash or more generalized morbilliform (measles-like) eruptions that may extend to involve the dorsal fingers, characteristically sparing the skin overlying the interphalangeal joints. Subacute lesions have a predilection for the trunk and upper extremities and are typically scaly, erythematous circumscribed plaques with an

CUTANEOUS LUPUS ERYTHEMATOSUS—DISEASE FACT SHEET Patient Group ■ Adults; female predominance ■ More common among blacks than whites

annular or psoriasiform appearance. Neonatal LE morphologically, histopathologically, and serologically resembles subacute LE lesions but has a tendency to involve the scalp (Fig. 1-17, A). The most common chronic cutaneous manifestation is discoid lupus, characterized by circumscribed scaly atrophic plaques on the head, neck, or upper trunk that frequently produce atrophy, dyspigmented scars, and follicular plugging (Fig. 1-17, B). Systemic lupus erythematosus (SLE) and subacute LE may rarely produce nonscarring alopecia, but discoid LE usually produces scarring alopecia when it involves the scalp. Variants of chronic cutaneous LE include LE profundus (lupus panniculitis), which involves the subcutaneous fat and manifests as indurated, variably ulcerated deep-seated plaques usually above the waist, and tumid lupus erythematosus, characterized by smooth infiltrated erythematous plaques. Bullous LE represents a rare manifestation of acute LE and is discussed elsewhere.





HISTOLOGIC FEATURES





Site of Involvement ■ Often face, scalp, ears (discoid LE) ■ May occur anywhere (variable)











































Clinical Findings ■ Acute cutaneous LE – Malar erythema (butterfly rash) ■ Subacute cutaneous LE – Annular or psoriasiform lesions – Papulosquamous lesions ■ Chronic cutaneous LE – Discoid LE (most common form of chronic cutaneous LE) • Erythematous scaly plaques • Atrophy and hyperpigmentation common • May result in scarring • Hypertrophic variant exists – Tumid LE • Indurated erythematous plaques without scale – Panniculitis • Subcutaneous nodules – Chilblain lupus • Red or purple papules/plaques on nose or acral sites ■ Other variants – Bullous LE – Erythema multiforme–like (Rowell’s syndrome) – Neonatal LE (infants from mothers with anti-Ro antibodies manifest subacute cutaneous LE–like lesions) Prognosis Acute cutaneous LE is usually associated with systemic LE ■ Most patients with subacute and chronic forms of cutaneous LE do not have significant systemic disease



■







Treatment ■ Corticosteroids ■ Antimalarials ■ Sun protection

All forms of LE, with the exception of many cases of tumid LE and LE profundus, are characterized by interface dermatitis, with single necrotic keratinocytes and vacuolar alteration at the dermal-epidermal junction. There is compact or lamellar ortho(hyper)keratosis, yet the stratum malpighii is often atrophic. In acute LE, subacute LE, neonatal LE, and early discoid LE, dermal lymphocytes may be sparse enough that a vacuolar, rather than lichenoid pattern, and a superficial, rather than superficial and deep pattern, is observed (Fig. 1-17, C, D). Fully developed lesions exhibit moderately dense superficial and deep perivascular and periadnexal (perifollicular and perieccrine) lymphocytes, generally devoid of eosinophils. Plasma cells are typically present. Interstitial acid mucopolysaccharide (mucin) is typically increased. More variable findings include fibrin thrombi or lymphocytic leukocytoclastic debris (nuclear dust) within and around vessels (lymphocytic vasculitis) or in the subepidermal or subcutaneous zones. Discoid lesions exhibit follicular plugging and basilar squamatization (see Lichen Planus) (Fig. 1-17, D–G). Discoid lesions may also exhibit papillated or verrucous epithelial hyperplasia. In acute, subacute, and especially chronic discoid LE, the PAS-positive basement membrane may be thickened. In tumid LE, moderately dense perivascular and periadnexal lymphocytes are associated with increased interstitial mucin, but overlying interface changes are minimal or absent. Lupus erythematosus profundus is characterized by lymphocytes in the lobules of the subcutaneous fat and a hyaline-type homogeneous eosinophilic necrosis of the fat lobules. As in tumid LE, overlying interface dermatitis may be minimal or absent. Unlike other forms of LE, in lupus profundus,

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

A

B

C

E

D

F

FIGURE 1-17  Lupus erythematosus. A, Annular plaque in neonatal lupus. B, Atrophic, dyspigmented plaques of discoid lupus. C, Perivascular and periadnexal lymphocytes with focal interface changes in subacute lupus. D, Orthokeratosis, atrophy (with loss of the rete ridges), vacuolar interface dermatitis, and basilar squamatization typify established subacute (this case) or discoid lupus. E, Discoid lupus exhibits follicular plugging, superficial and deep perivascular and perifollicular lymphocytes. There are interfollicular atrophy and interface dermatitis affecting both the epidermis and follicular epithelium. F, Even in sections or examples that do not exhibit active interface dermatitis, the balance of the dermal inflammation is centered in the deep dermis and surrounds adnexal structures.

Continued

DERMATOPATHOLOGY



40

eosinophils may be present. Bullous LE is characterized by subepidermal vesiculation with neutrophils. These latter two variants are discussed in detail elsewhere.

G

ANCILLARY STUDIES

FIGURE 1-17, cont’d G, Basement membrane thickening may be highlighted by periodic acid-Schiff stain.

CUTANEOUS LUPUS ERYTHEMATOSUS—PATHOLOGIC FEATURES





















Histologic Features ■ Interface dermatitis ■ Variable epidermal thickness, often atrophy ■ Hyperkeratosis (discoid lupus erythematosus [LE])* ■ Follicular plugging (discoid LE)* ■ Basement membrane thickening (discoid LE)* ■ Moderately dense superficial and deep perivascular lymphocytic infiltrate ■ Periadnexal lymphocytic infiltrate (discoid LE)* ■ Melanophages in superficial dermis ■ Dermal mucin deposition ■ Mild vascular damage may be seen











Ancillary Studies ■ Special stains – PAS or PAS-D stain to highlight thickened basement membrane zone – Alcian blue or colloidal iron stain to highlight interstitial mucin ■ Lupus band test: direct immunofluorescence* – Granular or linear IgG, IgA, IgM, or C3 at the dermalepidermal junction (lesional in all forms of LE; nonlesional in systemic LE)















Differential Diagnosis ■ Drug reaction ■ Lichen planus ■ Lichenoid keratosis ■ Polymorphous light eruption ■ Tumid LE: erythema migrans (Lyme disease) ■ Hypertrophic discoid LE: squamous cell carcinoma ■ Lupus profundus: primary cutaneous subcutaneous panniculitislike T cell lymphoma *The histologic features are for classic discoid LE. Acute cutaneous LE often shows less well-developed features and may manifest with a “nonspecific” interface dermatitis. Subacute LE tends to lack basement membrane thickening, follicular plugging, or a marked periadnexal infiltrate. Ig, Immunoglobulin; PAS, periodic acid-Schiff; PAS-D, periodic acid-Schiff with diastase digestion.

Serum antinuclear antibody (ANA) titers are positive in most cases of systemic LE but are usually negative when LE is confined to the skin. Subacute LE is associated with anti-Ro (SSA) or anti-La (SSB) antibodies. Continuous granular or linear deposition of IgG, IgM, IgA, or C3 along the dermal-epidermal junction by DIF represents the lupus band test. Lesional lupus bands are observed in most cases of acute, subacute, and chronic LE. Nonlesional lupus bands from sun-protected sites are specific for systemic LE.

DIFFERENTIAL DIAGNOSIS Clinical pathologic correlation is the most effective means of distinguishing acute, subacute, and chronic LE lesions. Likewise, other connective tissue disorders such as dermatomyositis and mixed connective tissue disease may exhibit changes indistinguishable from acute, subacute, or early discoid LE and are best distinguished by correlation of clinical and laboratory features. If scarring alopecia, prominent follicular plugging, or marked basement membrane thickening is present, discoid lesions may be specifically identified based on histology alone. The presence of eosinophils favors a drug reaction over LE. Lichen planus may resemble LE both histologically and clinically by its propensity to cause scarring alopecia (lichen planopilaris). Compared with LP, LE usually exhibits relatively dense and deep dermal inflammation with perieccrine involvement, increased interstitial mucin, basement membrane thickening, and pronounced epidermal thinning (often juxtaposed with focally hyperplastic areas). The clinical context of a solitary lesion is generally sufficient to favor a lichenoid keratosis over LP or LE. Marked papillary dermal edema is a hallmark of polymorphous light eruption (PMLE) that may rarely be seen in LE. Most cases of PMLE do not exhibit significant interface or other epidermal changes. Clinical correlation is required. Superficial and deep dermal perivascular and periadnexal lymphocytes with plasma cells are shared feature of tumid LE and erythema migrans (Lyme disease). The infiltrates in tumid LE tend to be denser and accompanied by increased interstitial mucin. Clinical correlation is required.

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

PROGNOSIS AND TREATMENT Lupus erythematosus, whether associated with systemic involvement or not, runs a chronic course. Morbidity and mortality correlate with the severity of systemic disease. Approximately 10% of patients with chronic lesions only at the time of diagnosis subsequently develop evidence of systemic LE. Subacute LE patients are more likely than discoid patients to develop systemic disease (≈50%), but this subset typically exhibits milder systemic disease than those with acute LE lesions. Neonatal LE is self-limited but may result in heart block if not recognized and managed promptly. Prednisone is generally reserved for systemic LE. Cutaneous LE may respond to sun avoidance, topical or intralesional corticosteroids, antimalarials, thalidomide, dapsone, retinoids, methotrexate, azathioprine, cyclosporine, or sulfasalazine.

contrast, when the dorsal hands are involved by acute cutaneous LE, the knuckles are characteristically spared. Other manifestations include Gottren’s sign (scaly papules over the elbows or knees); periocular or facial erythema and edema with a pink/violet (heliotrope) hue; urticarial, erythematous or poikilodermatous patches or plaques on the trunk or extremities or in a V or shawl (upper trunk, neck, and shoulder) pattern; periungual telangiectasia; and calcinosis cutis. Dermatomyositis sine myositis describes patients with typical skin lesions in the absence of muscle involvement. Subclinical evidence of muscle involvement may be present, and a subset of these patients eventually develops dermatomyositis. There is bimodal incidence, with distinct juvenile and adult subsets, the latter associated with systemic malignancy. Cardiovascular atherosclerosis is a recently identified comorbidity.

DERMATOMYOSITIS CLINICAL FINDINGS Gottren’s papules, violaceous papules over the knuckles, are considered pathognomonic for dermatomyositis. In DERMATOMYOSITIS—DISEASE FACT SHEET Patient Group ■ Children (juvenile dermatomyositis [DM]): most 10 to 15 years old at diagnosis ■ Adults: peak onset between ages 45 and 60 years ■ Women more likely affected than men Site of Involvement ■ Face, especially periocular region ■ Extensor surfaces of extremities, especially knuckles Clinical Findings ■ Violaceous poikiloderma (hyper- or hypopigmentation, telangiectasia, atrophy) ■ Heliotrope sign (periocular pink-purple discoloration) ■ Gottron’s papules (violaceous discoloration over knuckles) ■ Ragged cuticles (cuticular dystrophy) ■ Nailfold telangiectasia ■ Pruritus ■ Calcinosis cutis (juvenile DM) Prognosis ■ Depends on extent of systemic disease (myopathy, interstitial lung disease, cardiac disease) ■ Depends on associated malignancy (restricted to adult DM; incidence of associated malignancy increases with older age at presentation) Treatment ■ Systemic corticosteroids ■ Antimalarials

HISTOLOGIC FEATURES Biopsies from Gottren’s papules, Gottren’s sign, heliotrope rash, and poikilodermatous lesions usually exhibit findings similar or indistinguishable from acute cutaneous lupus erythematosus, with atrophic vacuolar interface dermatitis. The changes may be poorly developed, with only sparse superficial perivascular lymphocytes or only dermal edema and mucin. Compared with lupus, the histopathologic abnormalities are generally less pronounced and more variably present. As in acute lupus, eosinophils are usually absent. DIF is not routinely required to establish the diagnosis and is typically negative for junctional immunoglobulin or complement deposition. Vascular deposits of C5b-9 (membrane attack complex) have been documented in dermatomyositis. Dermatomyositis may be associated with a lobular lymphocytic panniculitis that is indistinguishable from LE profundus.

ANCILLARY STUDIES Characteristic dermatologic features comprise one criterion used to establish the diagnosis of dermatomyositis. Other criteria include the presence of myositis as determined by the results of one or more of the following: neurologic examination, serum muscle enzymes (creatine phosphokinase, aldolase, lactate dehydrogenase) and myositis-specific antibodies, electromyogram, skeletal muscle biopsy, barium swallow, and magnetic resonance imaging.

DERMATOPATHOLOGY



42

Histologic Features ■ Vacuolar interface dermatitis: often subtle ■ Epidermal atrophy (except for Gottron’s papules) ■ Sparse lymphocytic infiltrate ■ Evidence of mild vascular damage

Patient Group ■ Patient’s status post–bone marrow transplantation, allogeneic or autologous







GRAFT VERSUS HOST DISEASE—DISEASE FACT SHEET



DERMATOMYOSITIS—PATHOLOGIC FEATURES





Site of Involvement ■ Eruption tends to begin at acral sites, distal extremities, ear, sides of neck ■ May become generalized



Ancillary Studies ■ Direct immunofluorescence studies: nonspecific or negative using routine test panels

Clinical Findings ■ Acute cutaneous eruption (within 3 months of engraftment) – Erythematous macules and papules (maculopapular) – Blisters – Erythroderma ■ Chronic cutaneous disease (usually ≥100 days after engraftment) – Lichenoid papules – Sclerodermoid lesions – Dyschromia, poikiloderma











Differential Diagnosis ■ Lupus erythematosus ■ Drug reaction ■ Poikilodermatous graft versus host disease





DIFFERENTIAL DIAGNOSIS

PROGNOSIS AND TREATMENT Dermatomyositis is a chronic illness but is generally associated with a fairly good prognosis if appropriately managed with systemic immunosuppressive therapy (usually including corticosteroids), although adult dermatomyositis has been associated with an increased risk of systemic malignancy. Juvenile dermatomyositis usually exhibits a slow progressive course but may rarely evolve rapidly with potentially fatal outcome.

GRAFT VERSUS HOST DISEASE CLINICAL FINDINGS



Prognosis ■ Variable, depending on extent of graft versus host disease and susceptibility to infection Treatment ■ Systemic immunosuppression with corticosteroids, tacrolimus, cyclosporine

The histopathologic features overlap significantly with cutaneous LE as well as other forms of connective tissue disease, including mixed connective tissue disease. Correlation with clinical and laboratory features is required. The histopathologic features of dermatomyositis tend to be milder and more variable than those of LE.

marrow transplantation. Chronic GVHD evolves from acute GVHD and occurs weeks to months after transplantation and may appear lichenoid (LP-like) and eventually sclerodermoid (scleroderma-like) in appearance (Fig. 1-18, B). Similar to acute GVHD, chronic GVHD typically starts on the distal extremities. Chronic GVHD is often associated with pigmentary alterations, typically manifesting as poikiloderma or diffuse hyperpigmentation. Histopathologic features of acute GVHD may be present in patients more than 60 days after transplantation. GI involvement results in nausea, vomiting, and diarrhea.

HISTOLOGIC FEATURES

Graft versus host disease encompasses a spectrum of disease with characteristic cutaneous and systemic manifestations, arising in the setting of bone marrow transplantation and, rarely, solid organ transplantation or blood product transfusion, wherein donor or autologous lymphocytes react against various targets within the host recipient, most commonly the skin, liver, and gastrointestinal (GI) tract. GVHD is classified as acute or chronic. Acute GVHD typically presents as numerous erythematous macules on the face or palms and soles. Generalized eruptions are often morbilliform (Fig. 1-18, A). Acute GVHD usually arises within 60 days of bone

Acute GVHD is vacuolar interface dermatitis (Fig. 1-18, C), including the pattern of satellite cell necrosis, which refers to intraepidermal lymphocytes associated with single or clustered apoptotic (dyskeratotic, necrotic) keratinocytes. The interface dermatitis characteristically involves both epidermis and follicular epithelium (Fig. 1-18, D). The superficial dermis usually contains a lymphocytic infiltrate, which may be sparse in neutropenic patients. Eosinophils are usually rare or absent, but their presence does not exclude GVHD. A grading scale has been applied to the continuum of interface

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

A

B

C

D

FIGURE 1-18  Graft versus host disease (GVHD). A, Acute GVHD may be localized, usually to the distal extremities, or generalized, as exemplified by this morbilliform eruption in a recent bone marrow transplant recipient. B, Chronic GVHD may consist of sclerotic plaques and dyspigmentation. C, Acute GVHD is characterized by a vacuolar interface dermatitis with relatively sparse dermal inflammation. D, Interface dermatitis involving follicular epithelium is characteristic.

changes in acute GVHD as follows: vacuolar alteration (grade 1), necrotic keratinocytes (grade 2), subepidermal microvesicles (grade 3), and epidermal separation (grade 4). Chronic GVHD may simulate LP with a dense bandlike lymphocytic infiltrate and associated epidermal hyperplasia, jagged rete ridges, and squamatization of the basal cell layer. In late lesions, melanophages may be prominent in the papillary dermis with only rare lymphocytes and scattered Civatte bodies (i.e., postinflammatory hyperpigmentation secondary interface dermatitis). Chronic GVHD may have a sclerodermatous

(morphea-like) or poikilodermatous appearance. Features of acute and chronic GVHD may coexist (chronic active GVHD). An uncommon manifestation of chronic GVHD may be panniculitis or fasciitis.

ANCILLARY STUDIES Graft versus host disease frequently involves the GI tract (including the oral mucosa) and hepatobiliary

DERMATOPATHOLOGY



44

tract. Elevated bilirubin and alkaline phosphatase levels are present.

DIFFERENTIAL DIAGNOSIS Clinical correlation is paramount. Acute GVHD may be indistinguishable from EM, the eruption of lymphocyte recovery (which may, in fact, represent a transient, mild acute cutaneous GVHD reaction associated with engraftment), drug eruptions, and some viral exanthema if only basket-weave orthokeratosis is present. However, in acute GVHD, vacuolar interface dermatitis typically involves the adnexal epithelium. Acute GVHD may also be indistinguishable from lupus or dermatomyositis if interstitial mucin deposition is not evident. The sclerosis present in some cases of chronic GVHD is not a feature of LP. Drug reactions typically have eosinophils, but drug reactions with few or absent eosinophils may be impossible to differentiate from GVHD without clinical correlation.

nisone, cyclosporine, or mycophenolate mofetil. Topical corticosteroids, topical tacrolimus ointment, systemic photochemotherapy (PUVA), and acitretin may also be beneficial. Extracorporeal photochemotherapy (photopheresis) may be helpful in chronic GVHD.

LICHEN SCLEROSUS CLINICAL FINDINGS Lichen sclerosus (LS), formerly known as lichen sclerosus et atrophicus, is characterized by atrophic, porcelain white papules and plaques. Lesions most commonly arise on genital skin but may arise anywhere on the body, sometimes at sites of trauma (Fig. 1-19, A). Chronic genital lesions may be associated with ulceration, secondary squamous cell carcinoma, and phimosis. Historically, male genital involvement has been termed balanitis xerotica obliterans, and its occurrence is generally restricted to uncircumcised men. Female genital involvement has been termed kraurosis vulvae. Vulvar LS is typically pruritic and may be painful. Extragenital LS is often asymptomatic.

PROGNOSIS AND TREATMENT Histologic grading of acute GVHD does not correlate highly with the clinical severity of GVHD. Management of GVHD often requires intensification of the patient’s systemic immunosuppression with agents such as pred-

HISTOLOGIC FEATURES Lichen sclerosus is characterized by interface dermatitis, which is often accompanied by compact orthokeratosis,

LICHEN SCLEROSUS—DISEASE FACT SHEET





Site of Involvement ■ Most commonly affects genitalia ■ May occur elsewhere (trunk, proximal extremities)



Prognosis ■ No association with systemic disease ■ Chronic disease Treatment ■ Potent or ultra-potent topical steroids ■ Topical calcineurin inhibitors ■ Topical or systemic retinoids ■ Penicillin (if Borrelia sp. is suspected)





Differential Diagnosis ■ Drug reaction ■ Viral exanthema









Ancillary Studies ■ If eosinophils, consider periodic acid-Schiff stain to exclude dermatophytosis ■ Biopsies of other organ sites (gastrointestinal tract)

Clinical Findings ■ Sclerotic white plaques with epidermal atrophy ■ May cause scarring (e.g., phimosis in men) ■ Pruritus





















Histologic Features ■ Acute graft versus host disease (GVHD) – Interface dermatitis with follicular or sweat ductal involvement – Necrotic or apoptotic keratinocytes with satellitosis – Lymphocytic infiltrate – Eosinophils usually rare or absent but may be present ■ Chronic GVHD – Features of morphea – Features of lichen planus – Features of poikiloderma (atrophy, telangiectasia, melanophages)

Patient Group ■ May occur in children or adults ■ Women more commonly affected than men

GRAFT VERSUS HOST DISEASE—PATHOLOGIC FEATURES

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

A

LICHEN SCLEROSUS—PATHOLOGIC FEATURES Histologic Features ■ Interface dermatitis ■ Layer of hyalinized stroma ■ Band of lymphocytes Differential Diagnosis ■ Chronic graft versus host disease ■ Radiation dermatitis

B

epidermal atrophy, and (at extramucosal sites) follicular plugging (Fig. 1-19, B) in combination with superficial stromal edema and eventually sclerosis. The sclerotic collagen assumes a distinctive homogeneous or hyaline appearance with complete or near complete loss of the normal fibrillary pattern of collagen fibers (Fig. 1-19, C). Lymphocytes are usually present in a patchy or lichenoid pattern beneath the altered connective tissue or at the junction of fibrosed stroma and normal stroma. The very earliest changes in LS are not specifically diagnostic but include psoriasiform hyperplasia and lichenoid infiltrates of lymphocytes with lymphocyte exocytosis into the basilar epidermis to an extent that may resemble patch stage MF.

DIFFERENTIAL DIAGNOSIS

C

Features similar (or identical) to LS can be seen in chronic radiation dermatitis. Chronic radiation dermatitis may contain more ectatic vessels as well as atypical radiation fibroblasts. The differential diagnosis of LS includes also chronic LS-like GVHD and superficial morphea, including guttate morphea (which some authorities regard as indistinguishable from LS). If sclerosis extends into the reticular dermis or subcutis, then LS–morphea overlap is an appropriate consideration.

PROGNOSIS AND TREATMENT

FIGURE 1-19  Lichen sclerosus. A, Porcelain white plaque with peripheral erythema. B, Atrophy, follicular plugging, papillary dermal edema, and sclerosis. C, A lichenoid lymphocytic infiltrate is typically present beneath the zone of altered connective tissue in the subepidermal zone. Analysis of early lesions or the peripheral area of fully developed ones exhibit vacuolar interface dermatitis before the advent of identifiable edema or sclerosis.

Lichen sclerosus is usually chronic and persistent or progressive, although some cases may remit. Ultrapotent (class 1) topical corticosteroids represent first-line treatment. Topical calcineurin inhibitors or topical or systemic retinoids may be used. Phimosis or scarring that impairs function must be managed surgically.

DERMATOPATHOLOGY



46

Chronically eroded or ulcerated lesions should be monitored for secondary squamous cell carcinoma.

A

LICHEN NITIDUS CLINICAL FINDINGS Lichen nitidus is an idiopathic benign disorder that usually occurs in children and young adults, mostly males. It is characterized by innumerate discrete pinhead sized 1- to 2-mm flesh-colored, erythematous, or hypopigmented papules in localized or generalized distribution. The papules usually have a glistening smooth or minimally scaly surface. The Koebner phenomenon may be present. Wickham striae are absent. The papules are usually asymptomatic but may be pruritic. Papules may be clustered or grouped, with a predilection for the flexural skin folds on the trunk and extremities, including the genitalia.

B

HISTOLOGIC FEATURES

C

DIFFERENTIAL DIAGNOSIS

FIGURE 1-20

Clinically, lichen striatus may resemble lichen nitidus or follicular/papular atopic dermatitis in dark-complected children. Lichen striatus may exhibit a granulomatous (i.e., histiocyte predominant) infiltrate, but the lichenoid interface reaction typically affects the epidermis more broadly, and underlying perieccrine lymphocytes are relatively specific for lichen striatus. Small papules of superficial sarcoid may resemble lichen nitidus, but sarcoid is characterized by sarcoidal granulomas. LP may occasionally resemble lichen nitidus, but DIF studies are negative in lichen nitidus because colloid bodies are usually absent, and fibrinogen is often present along the basement membrane zone in LP.

 

­

Lichen nitidus characteristically exhibits a “ball-inclaw” pattern at scanning magnification, in which a very focal lichenoid infiltrate (ball) composed of lymphocytes and histiocytes, spans only one or a few rete ridges, and is surrounded by inward bending rete ridges (claw) (Fig. 1-20, A, B). There is often epidermal hyperplasia surrounding a central zone of atrophy, hypo granulosis, and parakeratosis overlying the lichenoid infiltrate. The infiltrate tends to exhibit a prominent histiocytic component that could be characterized as granulomatous, that is, discrete granulomas are not present, although multinucleated histiocytes may be present (Fig. 1-20, C).

Lichen nitidus. A, Scanning magnification best depicts the “ball-in-claw” configuration of the focal lichenoid interface dermatitis. B, The overlying epidermis is typically parakeratotic, thinned, and hypogranulotic. C, Histiocytes often predominate in the lichenoid infiltrate.

PROGNOSIS AND TREATMENT Most cases of lichen nitidus resolve within the first year, and, if not, within a few years of onset. Because the lesions are usually asymptomatic, reassurance is sometimes all that is necessary. Therapy includes topical corticosteroids or retinoids, and ultraviolet B and PUVA phototherapy.

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LICHEN STRIATUS CLINICAL FINDINGS Lichen striatus is an idiopathic, self-limited, linear dermatosis that usually occurs in children or young adults. It is characterized by 1- to 3-mm smooth or scaly papules that coalesce in linear array usually on one extremity, occasionally extending to the trunk or nails. Pruritus is mild or absent. Genital involvement may occur. Lesions often follow Blaschko’s lines (embryonic migration lines).

HISTOLOGIC FEATURES Lichen striatus usually exhibits a patchy or bandlike lichenoid lymphocytic interface reaction associated with superficial and deep perivascular and periadnexal involvement (Fig. 1-21, A). Perieccrine lymphocytes are

believed to be a relatively characteristic finding (Fig. 1-21, B). Psoriasiform epidermal hyperplasia may be present. A relatively prominent histiocyte population may be present, rendering a focally granulomatous appearance to the upper dermis.

DIFFERENTIAL DIAGNOSIS Lichen nitidus may also exhibit focal lichenoid dermatitis with relatively prominent histiocytic component, but the “ball-in-claw” configuration with overlying parakeratosis and epidermal atrophy is distinctive. Lupus erythematosus may resemble lichen striatus but typically exhibits denser perifollicular lymphocytes and increased interstitial mucin deposition. The epidermal and interface changes of lichen striatus may closely resemble those of LP, but LP typically lacks deep perivascular or periadnexal involvement.

PROGNOSIS AND TREATMENT A

Lichen striatus usually resolves after several months or years. Therapy includes topical corticosteroids.

GRANULOMATOUS DERMATITIS

B

FIGURE 1-21  Lichen striatus. A, Lichenoid lymphocytic infiltrates with deep perivascular and periadnexal involvement. B, Perieccrine lymphocytes are relatively specific for lichen striatus but are not always present.

Granulomatous dermatitis is a phrase that broadly encompasses reactive skin disorders that are characterized by a relative predominance of histiocytes, rather than lymphocytes, in the dermis. (Stereotypical perivascular and interstitial inflammation in the dermis is sometimes termed lymphohistiocytic, but these are generally lymphocyte-predominant infiltrates.) A broad spectrum of disorders can manifest with a granulomatous tissue reaction (Table 1-4). Not all granulomatous dermatitides contain granulomas per se, although granulomas are the discrete nodular aggregates of epithelioid histiocytes that are the most specific hallmark of granulomatous dermatitis. Different types of granulomas are typical of sarcoid, infection (tuberculoid granulomas), and others; the different types of granulomas may coexist and are not completely specific. For example, some foreign body reactions appear sarcoidal. Also not all disorders characterized by tuberculoid granulomas are infectious (e.g., granulomatous rosacea). Other disorders are characterized by subtler or diffuse/interstitial patterns of histiocytes in the dermis and are still considered forms of granulomatous dermatitis, even if discrete granulomas are absent. Examples include the interstitial variant of GA and lichen nitidus. When evaluating granulomatous dermatitis, general rules of practice are to exclude the presence of a polarizable foreign body and infection.

DERMATOPATHOLOGY

TABLE 1-4

 



48

Basic Differential Diagnosis of Granulomatous Dermatitis Sarcoid

Granuloma Annulare

Rheumatoid Nodule

Necrobiosis Lipoidica

Necrobiotic Xanthogranuloma

Foreign Body Reaction

Infection 0

Sarcoidal granuloma

++

0

0

0

0

±

Palisaded granuloma

0

++

++

++

++

±

±

Tuberculoid granuloma

±

0

0

0

0

±

++

Interstitial granulomatous pattern

±

++

0

±

±

±

±

Foreign body identified

±

0

0

0

0

++

0

Plasma cells

0

0

0

++

±

±

±

++, characteristic; ±, variable; 0, unusual.

SARCOID

tial histiocytic infiltrates. Likewise, the presence of a foreign body does not exclude the diagnosis because sarcoid has a tendency to develop at sites of trauma.

Sarcoid (sarcoidosis) is a chronic systemic granulomatous disorder of unknown etiology with frequent pulmonary and cutaneous involvement that may arise in adults and children. Cutaneous lesions occur in at least 20% to 25% of cases and may have a wide variety of appearances, most typically smooth, variably flesh colored to red, purple, or yellow-brown papules or plaques (Fig. 1-22, A), often preferentially arising at sites of prior injection or trauma. Other manifestations include macular, lupus pernio (pernio-like lesions on the face and fingers), subcutaneous, annular (Fig. 1-22, B), follicular, ulcerative, and ichthyosiform lesions. In the United States, sarcoid is more common in blacks. Erythema nodosum may represent a nonspecific manifestation of sarcoid. Löfgren’s syndrome describes the association of erythema nodosum, hilar adenopathy, and acute iridocyclitis.

HISTOLOGIC FEATURES Despite the varied clinical appearances, the histopathologic common denominator is the presence of sarcoidal granulomas in the dermis or subcutis. The classic sarcoidal granuloma is a circumscribed collection of epithelioid histiocytes that, compared with other types of granulomas, is relatively devoid of lymphocytes (naked granulomas) or central necrosis (Fig. 1-22, C–E). In practice, many exceptions to the classic profile have been described, including tuberculoid granulomas, suppurative granulomas, lichenoid inflammation, and intersti-

ANCILLARY STUDIES Systemic evaluation may reveal evidence of systemic involvement, most often on chest radiographs (lym phadenopathy or parenchymal involvement). Serum angiotensin-converting enzyme (ACE) levels are typically elevated, although an elevated ACE level is not specific for sarcoid. Infection should be reasonably excluded with special stains or cultures. ­

CLINICAL FINDINGS

DIFFERENTIAL DIAGNOSIS Foreign body granulomas may sometimes exhibit a sarcoidal granulomatous pattern. Polarized microscopy will reveal birefringent foreign bodies, but sarcoid may be more likely to develop at sites of foreign body implantation (so-called scar sarcoid), so clinical correlation is ultimately required to establish a diagnosis of sarcoid.

PROGNOSIS AND TREATMENT Sarcoid is a chronic, incurable disorder. The number of skin lesions does not correlate with the severity of systemic disease. However, the type of cutaneous lesion may be important. Patients with macular and papular

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

A

B

C

D

E

FIGURE 1-22  Sarcoid (sarcoidosis). A, Smooth, firm, red-brown plaque on the elbow. B, Annular sarcoid on the neck. C, Scanning magnification reveals nodules of relatively pale staining cells. D, Discrete sarcoidal granulomas. E, These noncaseating granulomas are composed of epithelioid histiocytes with relatively few lymphocytes.

lesions (with the exception of eyelid papules) tend to have the lowest risk of systemic disease, but those with annular lesions, plaques, scalp involvement, and ichthyosiform lesions have been reported to have a higher risk of chronic, systemic disease. Lupus pernio is associated with upper airway and bone involvement. Systemic corticosteroids are the mainstay of treatment for managing systemic sarcoid. Anecdotally, cutaneous lesions may respond to topical or intralesional corticosteroids, oral antimalarials, methotrexate, minocycline, thalidomide, isotretinoin, allopurinol, or photochemotherapy.

GRANULOMA ANNULARE CLINICAL FINDINGS Granuloma annulare is an idiopathic self-limited disorder characterized by smooth annular papules and plaques that may be asymptomatic or pruritic. Lesions may be localized, generalized, perforating (transepidermal elimination of collagen), and subcutaneous. Localized lesions usually appear on the distal extremities of

DERMATOPATHOLOGY



50

Patient Group ■ Children and young adults ■ Affects women more often than men

Histologic Features ■ Palisading granuloma surrounding areas of dermis with mucin deposition ■ Often multiple small foci separated by normal dermis ■ Granulomas and eosinophils common ■ May also show interstitial pattern of histiocytes

Ancillary Studies ■ Alcian blue to highlight mucin







Site of Involvement ■ Extremities (majority of lesions are on hands and arms) ■ May occur at sites of trauma (e.g., insect bite reaction, zoster) ■ May occur anywhere, especially in generalized GA









GRANULOMA ANNULARE—PATHOLOGIC FEATURES



GRANULOMA ANNULARE—DISEASE FACT SHEET







Prognosis ■ Benign self-limited disease ■ May be associated with systemic disease (e.g., diabetes mellitus)

Differential Diagnosis ■ Necrobiosis lipoidica (little or no normal dermis between granulomatous foci, minimal or no mucin) ■ Deep granulomata annulare: rheumatoid nodule, epithelioid sarcoma ■ Infection ■ Interstitial mycosis fungoides ■ Interstitial granulomatous drug reaction







Clinical Findings ■ Papules coalescing into an arciform/annular plaque ■ Solitary papules may be umbilicated ■ Clinical variants: generalized, perforating (crusted), subcutaneous GA







Treatment ■ Watch and wait ■ Topical steroids ■ Local destructive therapy (e.g., cryotherapy, laser)

variant GA, there are overlying epidermal hyperplasia and transepidermal elimination of abnormal collagen fibers. In subcutaneous GA, palisaded granulomas are centered in the subcutis.

children and young adults as smooth, flesh-colored to erythematous, firm papules that may coalesce, with central clearing, into an annular papule or plaque (Fig. 1-23, A). Subcutaneous lesions, also known as pseudorheumatoid nodules, occur in children and may also involve the scalp or forehead. Perforating GA is associated with overlying hyperkeratosis (Fig. 1-23, B). In the arcuate dermal erythema variant, lesions appear as round or arcuate erythematous patches that may clinically resemble erythema migrans (Lyme disease) (Fig. 1-23, C).

HISTOLOGIC FEATURES Granuloma annulare is characterized by palisaded granulomas consisting of palisades of histiocytes with central alteration of collagen fibers and increased interstitial mucin deposition (Fig. 1-23, D, E). Subtle palisading is best appreciated at scanning magnification. The altered (degenerating, necrobiotic) collagen fibers are smudgy and indistinct and may be more intensely eosinophilic or basophilic. Associated with these palisaded granulomas are perivascular and interstitial lymphocytes and occasionally neutrophils and nuclear dust (leukocytoclastic or karyorrhectic nuclear debris). In the incomplete or interstitial variant, there is only an interstitial histiocytic infiltrate with minimal or absent palisading or increased mucin (Fig. 1-23, F). In the perforating

ANCILLARY STUDIES An Alcian blue stain can assist in identifying mucin deposition.

DIFFERENTIAL DIAGNOSIS Rheumatoid nodules contain fibrin rather than mucin in the center of the palisaded granulomas and more prominent multinucleated histiocytes within their palisades and are generally present in the subcutis, where they may closely resemble subcutaneous GA. Whereas the presence of multinucleated histiocytes within the palisaded granulomas favors the diagnosis of rheumatoid nodule, the presence of mucin within the center of the palisaded granulomas favors subcutaneous GA. Necrobiosis lipoidica (NL) is characterized by diffuse, rather than focal, involvement of the dermis or subcutis, plasma cells are usually present, and there is minimal if any increase in mucin. Dermatofibroma may mimic the interstitial pattern of granulomas annulare, but the factor 13a–positive spindle cells in dermatofibroma are surrounded by thickened collagen fibers cut in crosssection and often overlying epidermal hyperplasia and hyperpigmentation. Patch stage Kaposi sarcoma may

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

A

B

C

D

E

F

FIGURE 1-23  Granuloma annulare (GA). A, Typical annular red plaques. B, Perforating GA. C, Arcuate dermal erythema variant. D, E, Palisaded granuloma containing mucin. F, Interstitial or incomplete variant.

also resemble the interstitial variant of GA but is characterized by slitlike vascular channels surrounding preexisting vessels, plasma cells, erythrocyte extravasation, and hemosiderin, as well as immunopositivity for HHV-8 latent nuclear antigen. Moreover, each of these disorders in the histologic differential diagnosis is clinically distinct. Palisaded neutrophilic and granulomatous dermatitis usually presents as symmetric nonannular erythematous, variably crusted papules, usually on the extremities, in patients with connective tissue disorders such as lupus or rheumatoid arthritis. In early lesions, there is leukocytoclastic vasculitis with broad collars of

fibrin surrounding affected vessels. In fully developed lesions, palisaded granulomas are present. In older lesions, palisaded granulomas are associated with fibrosis, and neutrophils or vasculitis are absent.

PROGNOSIS AND TREATMENT Localized GA is usually self-limited within months to a few years. Generalized GA may be self-limited or chronic. Topical and intralesional corticosteroids,

DERMATOPATHOLOGY



52

cryotherapy, and diagnostic biopsy have been associated with resolution of lesions. Generalized and adult onset lesions tend to persist. Various therapeutic modalities include systemic retinoids, dapsone, niacinamide, potassium iodide, aspirin, antimalarials, and photochemotherapy. No systemic therapy is consistently highly effective.

RHEUMATOID NODULE Rheumatoid nodules are subcutaneous nodules that typically arise on the extensor surfaces of the extremities of patients with rheumatoid arthritis (Fig. 1-24, A). They are also described in Chapter 2 but are mentioned here to complete the differential diagnosis. Histologically, the nodules are characterized by palisaded granulomas in the subcutis containing increased fibrin within their centers (Fig. 1-24, B–D). Leukocytoclasis and strands of basophilic nuclear debris may also be present, but mucin is not prominent.

NECROBIOSIS LIPOIDICA CLINICAL FINDINGS Formerly known as necrobiosis lipoidica diabeticorum, NL is now known to occur in patients without diabetes mellitus. Up to two thirds of individuals with NL have been said to have underlying diabetes mellitus, but recent studies have suggested that the incidence of diabetes mellitus associated with NL may be 15%. Furthermore, very few (less than 1%) of individuals with diabetes mellitus develop NL. Necrobiosis lipoidica may occur at any site but usually occurs on one (usually eventually both) pretibial surface in individuals with diabetes mellitus (Fig. 1-25, A). The lesions appear as well-demarcated red-brown papules that coalesce into flat yellow-brown atrophic plaques with telangiectasia and peripheral erythema. Some lesions ulcerate. The severity of disease does not correlate highly with the severity or control of the diabetes.

B A

FIGURE 1-24

D

 

C

Rheumatoid nodule. A, Subcutaneous nodule on the elbow. B, Palisaded granulomas typically situated in the subcutis. C, D, The palisade of histiocytes surrounds a more intensely eosinophilic, homogeneous, smudgy-appearing substance, fibrin.

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CHAPTER 1  Inflammatory Diseases of the Dermis and Epidermis

A

NECROBIOSIS LIPOIDICA—DISEASE FACT SHEET Patient Group ■ Adults ■ A subset of patients (15% to 65%) have diabetes mellitus Site of Involvement ■ Shin Clinical Findings ■ Plaques (violaceous to red brown rim with yellow-brown center) ■ Atrophy and telangiectasia Prognosis and Treatment ■ Benign condition; may persist or resolve spontaneously ■ Topical steroids may be effective

HISTOLOGIC FEATURES B

C

The palisaded granulomas in NL involve the dermis diffusely (and also sometimes the subcutaneous fat), so the histologic features typically extend to the deep and lateral margins of a punch or incisional biopsy specimen. From scanning magnification, a distinctive pattern is often appreciated that has been compared with a layer cake (Fig. 1-25, B). The center of the palisaded granulomas contains eosinophilic, smudgy (degenerating or necrobiotic) collagen fibers similar to those sometimes observed in GA. In NL the palisades of histiocytes do not completely encircle the degenerating collagen, so as the granulomas merge together, confluent zones of abnormal collagen fibers form broad zones of necrobiosis oriented parallel to the epidermal surface (Fig. 1-25, C). Fully developed lesions of NL usually contain predominantly lymphocytes and histiocytes, with occasional multinucleated cells, including Touton giant cells. Plasma cells are characteristic. Early lesions may contain neutrophils. Vasculitis is not a typical feature, but has been described in early lesions.

DIFFERENTIAL DIAGNOSIS FIGURE 1-25  Necrobiosis lipoidica. A, Red and yellow, atrophic, telangiectatic plaques most commonly arise on the shins of patients with diabetes. B, Scanning magnification best depicts the layer cake pattern of horizontally oriented tiers of degenerating, necrobiotic collagen extending to the deep and lateral biopsy margins. C, Palisaded granulomas are often incomplete and flattened; that is, oriented parallel to the epidermal surface. Plasma cells and scattered multinucleated histiocytes are usually present.

Other sites of involvement include the ankles, calves, thighs, and feet and less commonly above the waist. The lesions are usually asymptomatic but may be pruritic or painful.

Compared with granulomas annulare, the granulomas in NL involve the dermis more extensively, but the individual granulomas are less discrete. The presence of plasma cells supports NL. Necrobiotic xanthogranuloma (NXG) may also exhibit a similar “layer cake” appearance at scanning magnification, but NXG exhibits more prominent necrobiosis of collagen, more prominent Touton giant cells, and is much more likely to exhibit cholesterol cleft formation. As with all inflammatory skin diseases, clinical correlation is often essential in attaining the best clinical-pathologic diagnosis.

DERMATOPATHOLOGY



54

NECROBIOSIS LIPOIDICA—PATHOLOGIC FEATURES









Histologic Features ■ Palisading granulomatous dermatitis ■ Involvement of most of the dermis (little or no intervening normal dermis) ■ No or only minimal mucin ■ Plasma cells



Ancillary Studies ■ Alcian blue to highlight mucin

Necrobiosis lipoidica is usually chronic and does not necessarily resolve if the diabetes is more tightly controlled. Spontaneous remission may occur but is unpredictable. Therapy is symptomatic and includes topical and intralesional corticosteroids and local wound care for ulcerated lesions. Anecdotally effective modalities include oral niacinamide, aspirin, and cyclosporine, but no treatment is consistently highly effective.

NECROBIOTIC XANTHOGRANULOMA





Differential Diagnosis ■ Granuloma annulare ■ Necrobiotic xanthogranuloma (necrosis, cholesterol clefts)

PROGNOSIS AND TREATMENT

CLINICAL FINDINGS Necrobiotic xanthogranuloma is a rare disorder that usually presents as smooth yellow papules or plaques on the head, neck, or upper trunk with a particular

B A

FIGURE 1-26

 

C

Necrobiotic xanthogranuloma (NXG). A, Scanning magnification may be similar to necrobiosis lipoidica (see Fig. 1-25, B), with broad zones of necrobiotic collagen extending to the biopsy margins. B, Cholesterol clefts are relatively specific for NXG but are not always present. C, Touton giant cells are required for the diagnosis.

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Inflammatory Diseases of the Dermis and Epidermis

predilection for the periorbital region. The vast majority of cases are associated with paraproteinemia, although the onset of skin involvement may precede the presence of a detectable serum paraprotein. Many cases are also associated with cryoglobulinemia. The paraproteinemia may evolve into multiple myeloma. Less commonly, cases conforming to established histopathologic criteria have been reported without periorbital lesions or paraproteinemia.

HISTOLOGIC FEATURES Necrobiotic xanthogranuloma is characterized by broad zones of degenerating or necrobiotic collagen surrounded by palisades of histiocytes, including foamy histiocytes and Touton giant cells, throughout the dermis, often extending into the subcutis. Multinucleated histiocytes may be large or bizarre appearing. Cholesterol clefts are characteristically present (Fig. 1-26, A–C). Plasma cells and reactive lymphoid follicles may also be present.

ANCILLARY STUDIES

DIFFERENTIAL DIAGNOSIS

h a

t

corticosteroids and chlorambucil has been recommended for treatment as well as other chemotherapeutic agents. Partial or temporary remission has been associated with prednisone, radiation therapy, and plasmapheresis.

FOREIGN BODY GRANULOMAS CLINICAL FINDINGS There is no single clinical presentation for foreign body granulomatous reactions. Similar to contact dermatitis, the distribution of lesions depends on the distribution of exposure, either localized or generalized, and can often be revealed from the clinical history. Thus, some of the specimens submitted for microscopic analysis are the very ones that escaped earlier detection, but others simply represent therapeutic procedures.

Histologically, NL may overlap significantly with NXG, including the “layer cake” pattern of necrobiosis that is associated with NL. NXG often exhibits more prominent necrobiosis and more prominent Touton giant cells. The multinucleated histiocytes in NXG are often larger, more prominent, and more atypical appearing compared with NL. In the differential diagnosis of palisaded granulomatous disorders, cholesterol clefts are most distinctive of NXG. Infection should be reasonably excluded.

PROGNOSIS AND TREATMENT Necrobiotic xanthogranuloma exhibits a chronic progressive course. It may precede the development of hematologic malignancies. A combination of low dose

d ti e

G R V

HISTOLOGIC FEATURES

Foreign body granulomas may assume a variety of microscopic appearances, including sarcoidal, tuberculoid, or palisaded patterns. One classic example is the “Swiss cheese” pattern caused by paraffin or silicone that is removed during tissue processing and leaves innumerate empty circular spaces surrounded by histiocytes (Fig. 1-27, A, B). Round, empty lipid vacuoles characterize chalazion of the eyelid. Nonpolarizable (nonbirefringent) foreign include red tattoo pigment, injectable collagen, and injected triamcinolone. Commonly encountered birefringent foreign materials include retained suture material and cotton gauze fibers.

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Serum or urine protein electrophoresis study results are usually positive. Histochemical stains to exclude acidfast or fungal infection may be indicated. As with any granulomatous disorder, polarized microscopy to screen for birefringent material is prudent.

9 ri 9

55



 

CHAPTER 1

ANCILLARY STUDIES Polarized microscopy should be performed on any granulomatous dermatitis without obvious etiology, particularly if discrete granulomas are present.

DIFFERENTIAL DIAGNOSIS The presence of a foreign body in association with sarcoidal granulomas does not exclude the diagnosis of sarcoid because sarcoid has a tendency to develop at sites of trauma. Zirconium may produce a sarcoidal foreign body reaction pattern. Histochemical stains for microorganisms, particularly mycobacteria and fungi, should be performed or at least considered in every instance.

DERMATOPATHOLOGY



56

ing” are characteristic. Metastatic Crohn’s disease is a term used to describe similar lesions occurring at sites other than the mouth or anus, often presenting around a stoma, or as nodules or plaques with a predilection for flexural skin folds.

A

HISTOLOGIC FEATURES Cutaneous Crohn’s disease is characterized by lymphocytes, plasma cells, and noncaseating granulomas in the dermis, in some cases extending into subcutis. Palisaded granulomas and neutrophils may be present. Granulomatous vasculitis is a variable feature.

B

ANCILLARY STUDIES Ancillary studies include cultures or special stains to exclude infection.

FIGURE 1-27

 

DIFFERENTIAL DIAGNOSIS

Foreign body granuloma (paraffinoma). A, Histiocyte predominant dermal infiltrate. B, Numerous round, empty spaces correspond to the foreign body that was removed during tissue processing. Mineral oil and silicone may also impart this Swiss cheese appearance.

PROGNOSIS AND TREATMENT Surgical removal is the only effective method of therapy for disfiguring or disabling persistent foreign body reactions. Implanted foreign bodies usually persist, although some may undergo transepidermal elimination or be broken down by macrophages and gradually cleared. Many foreign body reactions are clinically stable and do not impart significant morbidity.

CUTANEOUS CROHN’S DISEASE

Granulomatous rosacea, granulomatous perioral dermatitis, cheilitis granulomatosa (Miescher-MelkerssonRosenthal syndrome), superficial sarcoid, and granulomatous reactions to infection may enter the differential diagnosis for perioral lesions. Clinical correlation is generally required to distinguish among these entities. The granulomas in granulomatous rosacea and granulomatous perioral dermatitis usually are perifollicular in location. In Miescher-Melkersson-Rosenthal syndrome, the lip swelling that represents cheilitis granulomatosa is accompanied by unilateral facial paralysis and geographic tongue. Sarcoidal granulomas are composed of a more homogenous population of epithelioid histiocytes, with relatively few admixed lymphocytes and plasma cells. Caseating granulomas are most associated with infectious etiologies.

PROGNOSIS AND TREATMENT

CLINICAL FINDINGS The most common cutaneous manifestations of Crohn’s disease, as well as ulcerative colitis, are erythema nodosum and pyoderma gangrenosum (covered elsewhere in this chapter). Some patients with Crohn’s disease develop cutaneous lesions that are histopathologically comparable with those involving the GI tract. Perianal skin tags; fistulas; abscesses; and oral lip swelling, ulceration or fissuring, and mucosal “cobbleston-

Cutaneous Crohn’s disease may arise before or after the GI disease is identified. Cutaneous lesions may or may not respond to therapy directed against Crohn’s disease.

SWEET’S SYNDROME Neutrophilic dermatitis describes a group of disorders characterized by predominantly neutrophils in the

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CHAPTER 1

A

SWEET’S SYNDROME—DISEASE FACT SHEET





Patient Group ■ Usually middle-aged adults ■ May be associated with infection (e.g., Streptococcus, Yersinia), chronic disease (e.g., Crohn’s disease, rheumatoid arthritis), malignancy (e.g., leukemia, lymphoma) or drug-induced (e.g., G-CSF)





Site of Involvement ■ Head and neck region and upper extremities most often affected ■ May occur anywhere

B









Clinical Findings ■ Smooth erythematous plaques, may be hyperkeratotic or annular ■ Tender, usually not pruritic ■ May blister and ulcerate ■ Associated systemic symptoms include fever and malaise



Prognosis and Treatment ■ Benign condition, which may resolve on its own, but usually rapidly responds to oral steroids G-CSF, Granulocyte colony-stimulating factor.

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dermis. Vasculitis associated with neutrophils (e.g., leukocytoclastic vasculitis) is discussed elsewhere.

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SWEET’S SYNDROME AND SWEET’S-LIKE REACTIONS CLINICAL FINDINGS

d ti e

G R V

C

t

FIGURE 1-28

 

h a

Cutaneous lesions of Sweet’s syndrome, also known as acute febrile neutrophilic dermatosis, are typically accompanied by the acute onset of fever and elevated neutrophils count and consist of tender, intensely erythematous or violaceous firm, sharply bordered, elevated papules, plaques, or nodules on the face, neck, trunk, and extremities (Fig. 1-28, A). Pseudovesicular or pseudobullous lesions are common. Pustular and subcutaneous nodules may occur. Patients may experience arthralgias, myalgias, headache, and malaise. Oropharyngeal and internal organ involvement occurs less commonly. Sweet’s syndrome is often associated with systemic disease, including various malignancies, including acute myeloid leukemia, and other conditions, including inflammatory bowel disease, upper respiratory tract infection, or pregnancy. Medications such as minocycline, trimethoprim–sulfamethoxazole, all-trans retinoic acid, and granulocyte colonystimulating factor have been reported to induce Sweet’s syndrome.

Acute febrile neutrophilic dermatosis (Sweet’s syndrome). A, Acute onset of tender, edematous plaques on the arms and hands. B, Scanning magnification reveals marked papillary dermal edema and dense inflammation in the upper dermis. C, Most of the cells are neutrophils, and nuclear dust (leukocytoclasis), but not vasculitis, is prominent.

HISTOLOGIC FEATURES Sweet’s syndrome is characterized microscopically by a diffuse, variably dense infiltrate of neutrophils with marked papillary dermal edema that may involve the

DERMATOPATHOLOGY



58

NEUTROPHILIC DERMATOSIS—PATHOLOGIC FEATURES







Histologic Features ■ Dense infiltrate of neutrophils ■ Dermal edema ■ Minimal or no vascular damage





Ancillary Studies ■ Special stains for bacterial, mycobacterial, or fungal organisms (negative) ■ Cultures (negative)















Differential Diagnosis ■ Infection (cellulitis) ■ Pyoderma gangrenosum ■ Behçet’s disease ■ Bullous lesions – Pustular drug reactions – Bullous lupus erythematosus – Dermatitis herpetiformis – Linear bullous IgA dermatosis

clinical correlation to distinguish them from Sweet’s syndrome. Infection should be excluded. In cellulitis, interstitial neutrophils within an edematous dermis are usually relatively sparse. The histopathology of pyoderma gangrenosum is variable but may include in its superficial expression features that are indistinguishable from Sweet’s syndrome. The evanescent macular eruption associated with juvenile rheumatoid arthritis (Still’s disease) is most prominent when the patient is febrile and microscopically is characterized by superficial perivascular neutrophils and papillary dermal edema. Subcutaneous Sweet’s syndrome may resemble other forms a lobular neutrophilic panniculitis, including alpha-1antitrypsin deficiency panniculitis, factitial panniculitis, infection, pancreatic panniculitis, and lupus panniculitis (lupus profundus).



PROGNOSIS AND TREATMENT

entire dermis but typically only the upper dermis (Fig. 1-28, B, C). Leukocytoclastic nuclear debris (nuclear dust) is typically prominent, but as a rule, there is no primary vasculitis. Vasculitis has been observed in a minority of cases, wherein it is has been judged to be a minor or secondary feature. The histopathologic correlate of the pseudobullous lesions that are often observed clinically is the marked papillary dermal edema with impending or actual subepidermal blister formation. Similar to leukocytoclastic vasculitis, the overlying epidermis may exhibit a variety of nonspecific secondary changes, including neutrophilic spongiosis, neutrophilic spongiotic vesicles, or subcorneal pustules.

ANCILLARY STUDIES An elevated neutrophil cell count and elevated erythrocyte sedimentation rate are typically present. A Gram stain may help exclude bacterial infection. In the absence of concomitant granulomatous inflammation, fungal or mycobacterial infection is less likely but must still be reasonably excluded with histochemical stains or lesional tissue culture.

Sweet’s syndrome is self-limited within weeks to months, especially if an underlying cause can be identified and managed. Lesions usually resolve without scarring. Even in cases associated with chronic disease or malignancy, systemic corticosteroids are the first-line treatment. Other options include topical or intralesional corticosteroids, potassium iodide, colchicine, indomethacin, and clofazimine.

NEUTROPHILIC ECCRINE HIDRADENITIS CLINICAL FINDINGS Neutrophilic eccrine hidradenitis (NEH) is a reaction pattern originally described in association with systemic administration of certain chemotherapeutic agents such as cytarabine and subsequently other chemotherapeutic agents. NEH may manifest clinically as tender erythematous papules, plaques, or nodules most often on the trunk. A second clinical subset occurs on the palms or soles of children (idiopathic plantar hidradenitis, palmoplantar eccrine hidradenitis, PlayStation palmar hidradenitis) and is not associated with chemotherapy or systemic disease.

HISTOLOGIC FEATURES DIFFERENTIAL DIAGNOSIS The possibility of the rare disorders bowel bypass syndrome and rheumatoid neutrophilic dermatitis requires

Neutrophilic eccrine hidradenitis is characterized by predominantly neutrophilic infiltrates surrounding and infiltrating eccrine glands. Associated vacuolar alteration and necrosis of the eccrine gland and

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squamous metaplasia (squamous syringometaplasia) may be present.

ANCILLARY STUDIES

usually associated with Streptococcus pyogenes or S. aureus. The term pyoderma is a more general term sometimes used to describe localized cellulitis.

HISTOLOGIC FEATURES

Special stains should be performed to evaluate for infectious eccrine hidradenitis (e.g., Staphylococcus sp., Nocardia spp.).

DIFFERENTIAL DIAGNOSIS The differential diagnosis of NEH includes other neutrophilic dermatitides, including Sweet’s syndrome, pyoderma gangrenosum, and infectious eccrine hidradenitis. Preferential involvement of the eccrine glands by neutrophils is the distinguishing feature of NEH. Most cases of palmoplantar eccrine hidradenitis are indistinguishable from chemotherapy-associated NEH, but in addition to the differing clinical presentation and anatomic site, squamous metaplasia is typically absent in palmoplantar eccrine hidradenitis.

The diagnosis of cellulitis is usually established clinically without biopsy. Histopathologic features include sparse perivascular and interstitial neutrophils and usually some lymphocytes. Dermal edema and dermal necrosis are variable findings.

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ANCILLARY STUDIES

Blood culture is the most sensitive and specific diagnostic test. Demonstration of microorganisms in tissue sections or from culture of lesional skin biopsy is helpful if positive but insensitive enough that negative study results do not exclude the diagnosis of cellulitis.

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DIFFERENTIAL DIAGNOSIS

PROGNOSIS AND TREATMENT

The lesions of NEH typically resolve within several days to weeks after exposure to the offending agent or withdrawal of triggering activity. Idiopathic palmoplantar eccrine hidradenitis also usually resolves but may episodically recur.

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CELLULITIS CLINICAL FINDINGS

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Cellulitis refers to the clinical presence of dermal inflammation secondary to a skin infection, usually bacteria. A single extremity is typically affected. S. aureus is the most common etiology, but a variety of bacteria and occasionally fungi may cause clinical cellulitis. Cellulitis is characterized clinically by a diffuse, variably circumscribed zone of erythema, swelling, heat, pain, and tenderness that may extend several centimeters, sometimes involving the majority of the affected extremity. Disproportionate pain may signify subcutaneous or fascial involvement, necrotizing fasciitis, a medical emergency demanding immediate surgical intervention. Erysipelas is a clinically distinct form of cellulitis that often occurs on the face, characterized by erythematous plaque with a well-demarcated, rapidly advancing edge. Ecthyma is characterized by punched out crusted ulcers and is

The specific diagnosis depends on isolation of the organisms from culture of lesional tissue or blood. Other disorders characterized histopathologically by dermal neutrophils usually can be distinguished from cellulitis through clinical pathologic correlation. Infectious or noninfectious vasculitis usually presents as purpuric papules and microscopically with perivascular leukocytoclasis, erythrocyte extravasation, vascular thrombosis, and fibrin obscuring vessel walls. Because diagnostic features of vasculitis may be focal, deeper sections may be required. Acute febrile neutrophilic dermatosis (Sweet’s syndrome), bowel bypass syndrome, rheumatoid neutrophilic dermatosis, and pyoderma gangrenosum (see the following) may all exhibit dermal neutrophils, but typically the neutrophil infiltrates are substantially denser than those in cellulitis. Erythema marginatum, the transient erythema associated with acute rheumatic fever, is clinically quite distinct from cellulitis, and typically exhibits perivascular neutrophils usually confined to the upper dermis.

PROGNOSIS AND TREATMENT Cellulitis typically responds to oral or intravenous antistaphylococcal antibiotic therapy. Uncommonly, cellulitis secondary to infection by S. aureus or other organisms may progress to potentially fatal septic shock.

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PYODERMA GANGRENOSUM

Sweet’s syndrome there are no associated constitutional symptoms.

CLINICAL FINDINGS Pyoderma gangrenosum is an idiopathic ulcerative disorder characterized by one or more painful ulcers with elevated, ragged borders, usually on the extremities (Fig. 1-29, A). Lesions characteristically exhibit pathergy, meaning they flare or progress in response to trauma such as surgical débridement. Clinical variants include the classic ulcer, superficial pustules, bullous, and granulomatous. Analogous to Sweet’s syndrome, pyoderma gangrenosum may be associated with a variety of systemic disorders, including myeloid leukemia, inflammatory bowel disease, and arthritis. In contrast to

A

HISTOLOGIC FEATURES The histologic features of pyoderma gangrenosum are somewhat characteristic but variable and not specifically diagnostic on histology alone (Fig. 1-29, B, C). In all forms, there are typically neutrophils in the dermis or subcutis. Suppurative folliculitis has been posited to be the earliest manifestation, but more nodular or diffuse neutrophilic infiltrates are typical. The clinically characteristic undermining inflammation at the ulcer

B

FIGURE 1-29

 

C

Pyoderma gangrenosum. A, Ulcer with an elevated, ragged border. B, In this example, there is a nodular dermatitis. Although the pattern is usually nodular or diffuse, there is no single characteristic pattern. C, Although biopsies of pyoderma gangrenosum are never specifically diagnostic, some degree of tissue neutrophilia is generally required to be compatible with the diagnosis if vasculitis and infection have been excluded. Clinical correlation is required, and many cases are diagnosed without biopsy.

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edge may be appreciated, as well as dermal edema, microabscess formation, vascular thrombosis, and dermal necrosis. Vasculitis, if present, is typically a secondary finding confined to the ulcer base. Superimposed granulomatous inflammation characterizes the superficial granulomatous variant.

ANCILLARY STUDIES Ancillary studies include cultures and special stains to exclude infection.

DIFFERENTIAL DIAGNOSIS Infection must be ruled out. The neutrophilic infiltrates in cellulitis are typically sparse. Clinical correlation is required to distinguish pyoderma gangrenosum from other neutrophilic dermatoses such as Sweet’s syndrome or bowel bypass syndrome, but the presence of folliculitis or perifollicular neutrophilic abscess formation favors early pyoderma gangrenosum. Ultimately, the diagnosis of pyoderma gangrenosum is primarily made clinically. Usually the pathologist’s contribution is to exclude other diagnoses such as infection or malignancy and to confirm the presence of findings compatible with pyoderma gangrenosum.

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PROGNOSIS AND TREATMENT

ered to avoid missing other diagnostic features, such as parakeratosis, spongiosis, interface dermatitis, or folliculitis. (2) Because inflammatory skin lesions evolve and exhibit recognizable differences in their early versus late stages, a biopsy of perivascular dermatitis may represent an early or waning stage or a partially treated expression of a disorder that exhibits more specific diagnostic features in its fullest expression. One example is the urticarial stage of bullous pemphigoid, which may be histologically indistinguishable from a drug reaction, urticaria, or a mild arthropod bite reaction. (3) Perivascular dermatitis also represents the fullest expression or primary pattern of some disorders. Examples include urticaria, some urticarial drug reactions, some examples of PUPPP, some paraneoplastic reactions, and a variety of poorly documented pruritic eruptions designated variably by dermatologists (e.g., itchy red bump disease, urticarial papulosis) and dermatopathologists (e.g., DHRs, urticarial hypersensitivity reactions). After multiple sections have established that no additional diagnostic features are present, attention may turn to the pattern (superficial, superficial and mid, or superficial and deep) and the presence of cell types, usually eosinophils or neutrophils. Superficial perivascular dermatitis involves the papillary dermis. Superficial and deep perivascular dermatitis involve both the papillary and reticular dermis. Superficial and mid perivascular dermatitis is a term used by some pathologists to describe lesions that fall in between (i.e., perivascular lymphocytes extend into the upper reticular dermis but not the deep reticular dermis). On most of the trunk and extremities, the dermis is two to five times thicker than the papillary dermis, so the superficial and mid pattern is commonly encountered.

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Pyoderma gangrenosum exhibits a variable, but often chronic, waxing and waning course; however, complete remission is possible. Mild cases may be managed with topical or intralesional corticosteroids. Appropriate wound care and avoidance of trauma are essential. The gold standard is systemic corticosteroids. Cyclosporine, among others, is a commonly used steroid sparing agent.

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PERIVASCULAR DERMATITIS WITHOUT EPIDERMAL CHANGES Considering the frequency that perivascular dermatitis is encountered in routine practice, relatively little attention has been devoted to the subject. The somewhat disarming (or boring) simplicity of this pattern belies the inherent challenges in managing these cases because they are only rarely diagnostic on histology alone. Diagnostic considerations unique to perivascular dermatitis include the following: (1) Perivascular dermatitis is the least common denominator for virtually all inflammatory skin disorders. Thus, deeper sections should be consid-

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URTICARIA CLINICAL FINDINGS Urticaria is a common disorder characterized by pruritic, erythematous edematous papules or plaques (wheals) that occur transiently on any part of the body (Fig. 1-30, A). The lesions are smooth surfaced and often surrounded by a peripheral rim of pallor secondary to dermal edema. As a rule, excoriation does not occur because individual lesions generally resolve within hours or 1 to 2 days at most. Urticaria can be classified as acute (less than 6 weeks) or chronic (longer than 6 weeks) depending on overall disease duration, but in all instances, individual lesions come and go within hours to days. Many cases are idiopathic. A wide variety of drugs (aspirin, opiates, radiocontrast media), infections (parasites), and food allergies (shellfish, nuts, chocolate) have been implicated. Physical urticaria may be induced by cold, heat, pressure, or sun exposure. Cholinergic urticaria is a common, self-limited variant arising in

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A

B

FIGURE 1-30

 

C

Urticaria. A, Transient, edematous, red, often annular plaques that resolve within 24 hours. B, Scanning magnification reveals sparse perivascular and interstitial lymphocytes without overlying epidermal alteration. C, Collagen fibers are relatively widely spaced (evidence of dermal edema), and a few eosinophils are noted at high magnification.

young adults as numerous small red macules and papules in association with heat, exercise, or emotional stress. Urticaria may represent a sign of systemic malignancy, although this is generally not the case in otherwise healthy individuals with chronic urticaria.

URTICARIA—DISEASE FACT SHEET







Patient Group ■ May occur at any age ■ Women more commonly affected than men ■ Associated allergies Site of Involvement ■ May occur anywhere

HISTOLOGIC FEATURES







Clinical Findings ■ Wheals: pruritic pink or pale transient superficial dermal plaques (individual lesions disappear within 24–48 hours) ■ Angioedema: deep dermal or subcutaneous or submucosal swellings ■ May occur spontaneously or be induced (physical or mechanical urticaria, cold/heat urticaria, contact urticaria)



Prognosis ■ Benign condition, may become chronic with frequent recurrences







Treatment ■ Avoidance of triggers ■ Antihistamines ■ Antipruritic lotions

The vast majority of urticaria is diagnosed clinically without the need for biopsy. However, lesions of urticaria may be biopsied to rule out urticarial vasculitis, urticarial pemphigoid, urticarial eczematous dermatitis, urticarial dermatitis herpetiformis, urticarial arthropod bite reactions (papular urticaria), and others. Although the histopathologic features alone in urticaria are not pathognomonic, the clinical history will facilitate specific diagnosis. Urticaria is characterized by sparse superficial and mid or superficial and deep perivascular and interstitial lymphocytes with variable numbers of neutrophils or eosinophils. Diffuse dermal edema may be appreciated. The overlying epidermis should be uninvolved (Fig. 1-30, B, C).

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URTICARIA—PATHOLOGIC FEATURES







Histologic Features ■ Dermal edema ■ Variably dense (minimal to moderate) perivascular inflammatory cell infiltrate ■ Lymphocytes, neutrophils, and eosinophils





Differential Diagnosis ■ Urticarial vasculitis (evidence of vascular damage) ■ Drug reaction

nosis. Similarly, a poorly documented and probably underrecognized condition that often frustrates patients and their dermatologists has been recently designated urticarial papulosis and is characterized clinically by multiple edematous pruritic papules on the trunk and proximal extremities that are histologically identical to urticaria. Clinically, these lesions resemble those of papular urticaria (arthropod bite reactions), but the distribution is proximal rather than distal, lesions are more numerous than those of papular urticaria, and there is no history of pets or arthropod exposure. These lesions resemble those of papular dermatitis (itchy red bump disease; see the preceding). Histologically, they show minimal, if any, epidermal alteration.

ANCILLARY STUDIES Urticaria is often associated with a very wide variety of possible systemic food or medication allergies or infections. A smaller proportion of individuals, mostly adults who present with urticaria, have an associated systemic malignancy. Thus, routine laboratory screening, imaging studies, and allergy testing are often performed on patients with unexplained chronic urticaria. Contact allergens may rarely cause urticaria and may be diagnosed by patch, prick, or serum radioallergosorbent testing (RAST) (e.g., latex rubber).

DIFFERENTIAL DIAGNOSIS

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Urticaria, especially acute urticaria, is usually selflimited. If an underlying cause can be identified and removed, the condition subsides. However, many cases go unsolved despite extensive inquiry and testing. Symptomatic therapy includes daily administration of sedating (e.g., hydroxyzine, diphenhydramine, doxepin) and minimally sedating (e.g., cetirizine) levocetirizine or nonsedating (e.g., fexofenadine) oral antihistamines, either alone or in combination. In contrast to most inflammatory skin disorders, topical corticosteroid therapy is ineffective.

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Multiple sections should be obtained to rule out more specific findings. Fully developed lesions of urticarial vasculitis are essentially identical to those of small vessel leukocytoclastic vasculitis but not infrequently biopsies from patients fulfilling other criteria for the diagnosis of urticarial vasculitis exhibit only minimal evidence of vasculitis, such as perivascular neutrophils and leukocytoclasis but no significant fibrin deposition around vessel walls. Thus, the histopathologic findings of urticarial vasculitis may fall on a spectrum ranging from an appearance that is virtually indistinguishable from classic urticaria to those of fully developed leukocytoclastic vasculitis. Other disorders presenting with urticarial lesions should exhibit histologic evidence of those disorders. One exception is urticarial pemphigoid, wherein eosinophils tend to aggregate in the papillary dermis near the dermal-epidermal junction. This may be associated with exocytosis of eosinophils into the epidermis (eosinophilic spongiosis), but subepidermal vesiculation may not be present. DIF studies should reveal linear deposition of C3 and often IgG in urticarial pemphigoid. PUPPP, usually arising during the third trimester, often exhibit mild spongiosis but may be histologically indistinguishable from urticaria, but clinical correlation is generally sufficient to establish this diag-

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ERYTHEMA ANNULARE CENTRIFUGUM CLINICAL FINDINGS

Erythema annulare centrifugum is a cutaneous reaction pattern with multiple possible underlying causes. EAC has been divided into two clinical variants, superficial and deep. The superficial variant is characterized by erythematous macules or edematous papules that rapidly clear centrally, leaving only thin annular, serpiginous, or polycyclic rings of erythema and a ridge of scale that typically resides on the trailing edge of the advancing border (Fig. 1-31, A). The buttocks and trunk are most commonly affected. Some cases are associated with dermatophytosis, but most are idiopathic despite extensive inquiry. In the deep variant, the annular plaques do not exhibit an overlying scale.

HISTOLOGIC FEATURES Erythema annulare centrifugum is characterized by perivascular lymphocytes that are “tightly cuffed” around blood vessels (coat sleeving), meaning that there

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A

B

FIGURE 1-31

 

C

Erythema annulare centrifugum. A, Annular plaques on the trunk. B, Superficial and deep perivascular lymphocytes with focal, if any, epidermal alteration. C, The perivascular lymphocytes are tightly cuffed, with minimal interstitial involvement (“coat sleeving”).

is minimal interstitial extension of inflammatory cells. This “cost sleeving” is most consistently observed in the deep variant of EAC. In the deep variant of EAC, epidermal changes are usually absent. The dermis contains superficial and deep tightly cuffed perivascular lymphocytes (Fig. 1-31, B, C). In superficial EAC, sections through the ring of scale at the lesion edge reveal focal spongiosis and parakeratosis. Spongiotic microvesiculation may be present. Rarely, multiple areas of spongiosis may be present. A minority component of dermal eosinophils, and less commonly, neutrophils, are variably present within the predominantly lymphocytic infiltrate. Plasma cells are not prominent.

DIFFERENTIAL DIAGNOSIS A fungal stain is prudent to exclude dermatophytosis in the superficial variant. Some authors consider the

histopathologic features of the superficial variant of EAC to be often indistinguishable from those of PR (see the preceding), although lymphocyte exocytosis and papillary dermal extravasation of erythrocytes are more characteristic of PR. Both disorders are usually diagnosed clinically by dermatologists and not routinely biopsied unless the clinical features are atypical. The deep variant of EAC is more likely to present a diagnostic challenge to the clinician and histologically may resemble the tumid variant of LE; Jessner’s lymphocytic infiltrate; and, if the infiltrates are dense enough, pseudolymphoma (cutaneous lymphoid hyperplasia) or cutaneous marginal zone (B-cell) lymphoma. The rest of the dermal lymphocytes in lupus, with its prominent perifollicular infiltrates, are usually situated in the deep dermis in concert with increased interstitial mucopolysaccharide (mucin). However, increased interstitial mucin has been reported in EAC, so it may not be possible to distinguish the deep variant of EAC from tumid LE in patients who do not have additional evidence of

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LE. Erythema migrans (see the following) is characterized by plasma cells accompanying the superficial and deep perivascular lymphocytes. PMLE (see the following) and erythema gyratum repens, a rare paraneoplastic disorder, may also exhibit similar features, and such cases are best confirmed by clinical correlation. Clinically, erythema gyratum repens is characterized by greater induration and denser (zebralike) concentric banding pattern of the lesions. Erythema marginatum, the eruption of rheumatic fever, is a transient eruption that typically exhibits neutrophils accompanying superficial perivascular lymphocytes.

A

PROGNOSIS AND TREATMENT Erythema annulare centrifugum is a benign disorder. Superficial EAC is usually self-limited. Deep EAC may run a chronic waxing and waning course. Symptomatic therapy includes topical corticosteroids and antihistamines. Refractory cases may require intermittent systemic corticosteroid therapy.

ERYTHEMA MIGRANS

B

CLINICAL FINDINGS Erythema migrans, formerly known as erythema chronicum migrans, is the most common cutaneous manifestation of Lyme disease (Borrelia burgdorferi) in the United States, consisting of one or a few round or oval, minimally symptomatic, erythematous, smooth patches up to several centimeters in diameter (Fig. 1-32, A). Central clearing routinely produces an annular configuration. The primary lesion starts at the site where the individual was bitten by an infected tick (ticks generally must be attached for greater than 48 hours to transmit Lyme disease), but if untreated, secondary lesions may subsequently develop elsewhere. Fever, arthralgia, myalgia, and headache may accompany the initial infection. In oral pathology, the term erythema migrans is synonymous with geographic tongue, an unrelated disorder.

C

HISTOLOGIC FEATURES The annular border of lesions of erythema migrans is characterized by superficial and mid or superficial and deep perivascular lymphocytes and plasma cells (Fig. 1-32, B, C). Eosinophils and neutrophils are variable. There is usually no overlying epidermal alteration. Biopsy of the central portion of a lesion reveals nonspecific changes consistent with an arthropod bite reaction.

FIGURE 1-32  Erythema migrans. A, A hiker from upstate New York with a large erythematous patch expanding centrifugally from the site of an infected tick’s bite. B, Superficial and deep perivascular lymphocytes without epidermal alteration. C, Plasma cells are typically present.

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66

ANCILLARY STUDIES Warthin-Starry stain may reveal small numbers of spirochetal forms in the upper dermis; however, a negative or equivocal study result does not exclude the diagnosis. Serum titers for B. burgdorferi usually confirm the diagnosis of Lyme disease in clinically ambiguous cases. The testing methods and pathogenic strains of B. burgdorferi differ among the United States, Europe, and elsewhere. Thus, intercontinental travelers whose exposure and testing occur in different locations may have a higher chance of false-negative test results.

DIFFERENTIAL DIAGNOSIS The deep variant of EAC may exhibit nearly identical features. Typically, the perivascular lymphocytes are relatively sparse, so tumid LE and pseudolymphoma bear less resemblance than some cases of deep EAC might. The presence of plasma cells is the best available histopathologic clue to the diagnosis of erythema migrans. Early lesions of secondary syphilis may exhibit perivascular lymphocytes and plasma cells, but fully developed lesions typically display epidermal hyperplasia with variable spongiosis, slight interface dermatitis, and a neutrophilic crust.

PROGNOSIS AND TREATMENT Erythema migrans is effectively treated by appropriate antibiotic regimens. Untreated cases may progress to potentially disabling systemic involvement.

TELANGIECTASIA MACULARIS ERUPTIVA PERSTANS

cells in the upper dermis, in concert with slightly dilated thin-walled dermal blood vessels. The changes may be subtle enough that a definite histopathologic diagnosis cannot be established without clinical correlation. Comparison with nonlesional skin may be helpful to establish the presence of increased mast cells in lesional skin. Roughly three to seven perivascular mast cells can usually be identified, on average, in normal skin. Hyperpigmentation of the overlying epidermis may be present.

ANCILLARY STUDIES Ancillary studies include histochemical (e.g., Giemsa, toluidine blue, Von Leder) or immunohistochemical studies for tryptase or c-kit (CD117) to identify mast cells.

DIFFERENTIAL DIAGNOSIS Telangiectasia macularis eruptiva perstans may resemble nonspecific, sparse perivascular dermatitis because the increase in mast cells relative to nonlesional skin may be impossible to discern without mast cell–specific stains and normal control skin. In some examples of the urticaria pigmentosa variant of mastocytosis, the increase in mast cells may be mild, but mast cells are usually more than twice normal in number. In mastocytosis, the mast cells are sometimes larger and acquire a fusiform shape.

PROGNOSIS AND TREATMENT Telangiectasia macularis eruptiva perstans is usually chronic and progressive. Topical corticosteroids and systemic antihistamines may be used. It is prudent to equip patients with injectable epinephrine (EpiPen).

CLINICAL FINDINGS Telangiectasia macularis eruptiva perstans (TMEP) is a variant of cutaneous mastocytosis that typically arises in adults, characterized by numerous telangiectatic macules, usually on the trunk. Darier’s sign (urtication on scratching) is variably elicited.

HISTOLOGIC FEATURES In contrast to other forms of mastocytosis, the mast cell infiltrates in TMEP are typically subtle, with slightly increased numbers of perivascular and interstitial mast

PLASMACYTOSIS MUCOSAE CLINICAL FINDINGS Plasmacytosis mucosae encompasses a group of idiopathic, noninfectious inflammatory disorders affecting mucosal surfaces, typically genital skin (Zoon’s balanitis or balanitis circumscripta plasmacellularis in men; Zoon’s vulvitis, vulvitis circumscripta plasmacellularis in women) or lips (plasmacytosis circumorificialis, plasma cell cheilitis). Lesions are usually solitary, erythematous smooth minimally symptomatic patches.

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HISTOLOGIC FEATURES Plasmacytosis mucosae are characterized by a lichenoid or nodular accumulation of mature plasma cells (plasmacytes) in the upper dermis or submucosa. Plasma cells are recognizable by their relatively abundant cytoplasm, eccentrically situated nucleus, pale paranuclear halo (paranuclear or perinuclear Hof), and clumped chromatin at the periphery of the nucleus (clock face nucleus). The paranucleur Halo results from a prominent Golgi apparatus that reflects increased immunoglobulin secretion. Vascularity and dermal edema may be prominent. Extravasated erythrocytes, other lymphocytes, mast cells, eosinophils, or neutrophils may be present. There is no significant cytologic atypia. Russell bodies (intracytoplasmic eosinophilic accumulations of immunoglobulins and glycoproteins) may be present.

ANCILLARY STUDIES Immunohistochemical studies, if performed, reveal a κ : λ ratio within physiologic limits (≈2 : 1).

mia, or extramedullary plasmacytomas. The presence of high-grade atypia and large atypical cells with plasmacytic features (plasmablasts) correlates with a poor prognosis even in cases that appear to be primary cutaneous at presentation.

PROGNOSIS AND TREATMENT Plasmacytosis mucosae is a benign but chronic disorder. There is no association with increased risk of plasma cell malignancy. Anecdotally, lesions may respond to topical corticosteroid therapy.

■  MISCELLANEOUS INFLAMMATORY DISORDERS A few selected inflammatory dermatoses are discussed here that show variable features that do not neatly fit into any of the other categories used to broadly classify inflammatory diseases in this chapter.

POLYMORPHOUS LIGHT ERUPTION DIFFERENTIAL DIAGNOSIS Several other disorders are also characterized by plasma cell–rich infiltrates, most notably primary or secondary syphilis. In addition to distinct clinical and serologic features, the inflammatory infiltrates in syphilitic chancre (primary) and syphilids (secondary) usually contain lymphocytes and neutrophils as well as plasmacytes, and secondary lesions typically exhibit psoriasiform epidermal hyperplasia. Primary syphilis (chancre) is typically ulcerated. In contrast, the epidermis overlying the dermal component of plasmacytosis mucosae is often attenuated, but ulceration is uncommon. Spirochetes may be visualized in primary and secondary lesions with a Steiner stain. Plasma cells may be prominent at any chronically inflamed site and are often a prominent component of the host response directed against squamous cell carcinoma or basal cell carcinoma. If the infiltrate is unusually homogenous and dense, serum protein electrophoresis studies may be worthwhile to search for an occult plasma cell dyscrasia. Sinus histiocytosis with massive lymphadenopathy (Destombes-Rosai-Dorfman disease) may also show numerous plasma cells but is associated with a florid xanthogranulomatous infiltrate containing S100 protein–positive histiocytes. Cutaneous plasmacytoma may rarely represent a slowly growing primary cutaneous disorder but most commonly represents a cutaneous manifestation of multiple myeloma, plasma cell leuke-

CLINICAL FINDINGS True to its name, the clinical appearance of PMLE is polymorphous and may take the form of papules, plaques, papulovesicles, vesicles, targetoid lesions, or other. Lesional morphology varies more among individuals, with individual patients tending to manifest the same morphologic pattern from season to season. PMLE usually arises acutely on newly sun-exposed areas such as the V of the neck and upper extremities (rather than the face or dorsal hands) within days of the individual’s first significant exposure to ultraviolet light, generally in the spring (Fig. 1-33, A). The eruption is usually less severe with subsequent exposure (hardening), but the ultraviolet sensitivity is reset during the winter, so the process repeats itself the following spring. Many patients have mild transient eruptions for which medical attention is never sought.

HISTOLOGIC FEATURES Polymorphous light eruption usually exhibits a superficial and deep moderately dense predominantly lymphocytic perivascular dermatitis (Fig. 1-33, B, C). Additional findings generally correlate with the clinical morphology. Marked papillary dermal edema with impending or actual subepidermal blister formation may be present

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DIFFERENTIAL DIAGNOSIS

A

Actinic prurigo is a genetically inherited eruption that clinically and histologically may be identical to PMLE. However, actinic prurigo is most common in Mestizos (individuals of mixed European and Amerindian ancestry) and usually presents with a distinctive conjunctivitis and cheilitis. The inflammatory infiltrate in actinic prurigo may be deeper and denser, often containing eosinophils and reactive lymphoid follicles, and there are usually psoriasiform spongiotic epidermal changes. If spongiosis and eosinophils are present, photoallergic contact dermatitis should also be considered. Acute radiation dermatitis and phototoxic dermatitis are characterized by scattered single necrotic keratinocytes in the mid epidermis (sunburn cells) and junctional vacuolar alteration.

B

PROGNOSIS AND TREATMENT Polymorphous light eruption often improves in adulthood. Sun protection and avoidance are usually sufficient to manage PMLE. Incremental ultraviolet light exposure under medical supervision can induce the “hardening” before significant environmental exposure, minimizing the initial eruption.

C

ARTHROPOD BITE REACTIONS

FIGURE 1-33

 

CLINICAL FINDINGS

Polymorphous light eruption. A, Erythematous papules and plaques on the extensor surface of the forearm and dorsal hand. B, Moderately dense dermal infiltrate with deep perivascular involvement. C, Lymphocytes predominate. Variable histopathologic findings, as the name suggests, include papillary dermal edema, spongiosis, and some eosinophils or neutrophils in the infiltrate.

(clinical correlate: urticarial lesions, blisters). Spongiosis is variable (clinical correlate: eczematous or papulovesicular lesions). Erythrocyte extravasation is variable (clinical correlate: purpuric lesions).

Typical arthropod bite reactions in the United States are presumably caused by bites of mosquitoes, fleas, animal mites, chiggers, ticks, and possibly others. Bite reactions are typically pruritic erythematous papules. Papular urticaria is a descriptive synonym for a common presentation of arthropod bite reactions, most common in children. Lesions are usually distributed on the distal extremities or other exposed sites. The lesions are often clustered or grouped, suggesting multiple bites from the same assailant (breakfast, lunch, and dinner). Family members and close contacts are often not affected because the reaction is partly dependent on the host’s immune response.

HISTOLOGIC FEATURES ANCILLARY STUDIES Phototesting usually reveals increased sensitivity to ultraviolet A, or less commonly, ultraviolet B light, or both.

Typical arthropod bite reactions are focal, wedge-shaped reactions that usually extend into the reticular dermis or even subcutis (Fig. 1-34, A). Optimal sections will reveal a centrally situated focus of epidermal disruption, including spongiosis, necrosis, erosion, or ulceration

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A

B

DIFFERENTIAL DIAGNOSIS Excoriated lesions of papular dermatitis, folliculitis, some drug/medication reactions, or the urticarial stage of bullous pemphigoid may be histologically indistinguishable from an arthropod bite reaction. The differential diagnosis also includes scabies. Multiple sections typically usually reveal folliculitis, if present. However, arthropod bites may be centered on hair follicles. Papular dermatitis, PUPPP, and drug reactions should be distinguished primarily by clinical correlation but often exhibit more superficial and sparse dermal inflammation compared with arthropod bite reactions. Pemphigoid may be diagnosed by direct immunofluorescent analysis of perilesional skin. Lymphomatoid papulosis (type A) exhibits wedge-shaped mixed cell infiltrates with eosinophils but contains large atypical CD30+ T cells with prominent nucleoli. CD30 may be present in reactive infiltrates, including arthropod bite reactions, usually in smaller numbers compared to lymphomatoid papulosis.

PROGNOSIS AND TREATMENT Arthropod bite reactions are self-limited. Insect repellents are effective. Symptomatic therapy consists of topical corticosteroids and oral antihistamines. C

TRANSIENT ACANTHOLYTIC DYSKERATOSIS (GROVER’S DISEASE) CLINICAL FINDINGS Transient acantholytic dyskeratosis (Grover’s disease) is characterized by multiple small variably pruritic erythematous or skin-colored papules and crusted papulovesicles usually involving the trunk of adults (Fig. 1-35, A). Men and women are approximately equally affected, although men older than 40 years of age are most commonly affected. Grover’s disease may be precipitated by excessive sweating or fever.

FIGURE 1-34  Arthropod bite reaction. A, Scanning magnification reveals superficial and deep, often wedge-shaped, perivascular dermatitis. Depending on the plane of section, central epidermal disruption may be present. B, C, Eosinophils are typically prominent. A portion of the arthropod is retained in the tissue specimen.

and sometimes retained arthropod parts within the overlying epidermis (Fig. 1-34, B). Eosinophils are characteristically present and typically numerous (Fig. 1-34, C). Neutrophils are variable and may be more prominent in bite from fleas, mosquitoes, and fire ants.

HISTOLOGIC FEATURES Similar to the focal papular lesions that characterize Grover’s disease clinically, the microscopic findings in Grover’s disease are focal. The five histologic variants include Darier’s pattern (acantholytic dyskeratosis) (Fig. 1-35, B), Hailey-Hailey pattern (full-thickness acantholysis), pemphigus vulgaris pattern (suprabasilar acantholysis) (Fig. 1-35, C), pemphigus foliaceus pattern

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very focal, usually extending no more than 2 or 3 mm along the surface of the biopsy. If the changes affect the epidermis more broadly, clinical correlation may be required to distinguish Grover’s disease from the diseases it mimics. Other disorders exhibiting acantholytic dyskeratosis include Darier’s disease (keratosis follicularis) and acantholytic acanthoma. In Darier’s disease, acantholytic dyskeratosis affects the epidermis more broadly and is associated with epidermal hyperplasia, follicular plugging, and relatively prominent dyskeratosis. In acantholytic acanthoma, the changes affect one circumscribed zone of epidermis, and the clinical impression is that of single or multiple lesions, not an inflammatory skin disorder such as Grover’s or Darier’s disease. Focal acantholytic dyskeratosis is a frequent incidental finding in large excision specimens.  

A

B

PROGNOSIS AND TREATMENT Grover’s disease may run a transient or chronic course. Symptomatic therapy includes topical corticosteroids or oral antihistamines.

FIBROSING DERMATITIS

C

Fibrosing disorders are characterized by increased dermal collagen deposition and usually increased numbers of spindled mononuclear cells (fibrocytes, dendritic cells). Sclerosis is a subset of fibrosis characterized by thickened collagen fibers with normal or decreased numbers of spindle cells.

SCAR

 

CLINICAL FINDINGS FIGURE 1-35

Transient acantholytic dyskeratosis (Grover’s disease). A, Numerous red, variably crusted papules on the trunk. B, Focal acantholytic dyskeratosis (Darier’s disease pattern). C, Focal suprabasilar clefting (pemphigus vulgaris pattern).

(intragranular acantholysis), and spongiotic pattern. Combinations or overlap among these patterns may be observed in single biopsy specimens or different specimens from the same patient. The findings are variably associated with sweat ducts or glands.

DIFFERENTIAL DIAGNOSIS Compared with other disorders whose patterns it may resemble, the changes in Grover’s disease are, as a rule,

Scars represent a stereotypical wound healing response secondary to compromise of dermal integrity. Scarring may result from external trauma or other inflammatory processes that are significant enough to cause permanent loss or alteration of the collagen fiber architecture, such as folliculitis. Ordinary scars have a smooth, firm quality and may appear erythematous, telangiectatic, hyperpigmented, hypopigmented, or depigmented. Clinically hypertrophic scars are elevated but do not extend beyond the confines of the initial trauma. Acne scars often result in focal depressions in the skin surface (termed ice pick scars when the scars are very welldemarcated). In contrast, keloids extend beyond the site of initial trauma and may be very large and disfiguring. Keloids tend to occur along the jawline, earlobe (secondary to ear piercing), sternum, and shoulder girdle, more often in dark-complected individuals.

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HISTOLOGIC FEATURES Initially, the wound healing reaction is characterized by fibromyxoid stroma with increased vascularity (i.e., granulation tissue). In the chronic state, ordinary scars exhibit increased collagen fiber deposition in which the fibers and spindled fibrocyte nuclei are oriented parallel to one another as well as to the overlying atrophic epidermal surface. Blood vessels are oriented perpendicular to the collagen fibers and epidermal surface. The atrophic epidermis is thinned, with attenuation or loss of the rete ridge pattern. Ordinary scars are generally flat and do not significantly displace the underlying subcutis or adjacent adnexal structures. In contrast, hypertrophic scars are characterized by a nodular proliferation of haphazardly oriented fascicles whose collagen fibers maintain a parallel array within one another within a given fascicle. The fascicles are demarcated by small, thin-walled blood vessels. Keloids are histopathologically similar to hypertrophic scars but additionally exhibit zones containing markedly broad or thickened collagen fibers (keloidal collagen, so-called “red crayons”) that are typically situated in the centers of the fibrotic nodules. Keloids may be quite large. The diagnosis of keloid is usually clinically apparent.

DIFFERENTIAL DIAGNOSIS Hypertrophic scars and keloids represent points along a histopathologic continuum. Dermal or subcutaneous neoplasms may resemble hypertrophic scars or keloids. Examples include desmoplastic melanoma, dermatofibroma, dermatofibrosarcoma protuberans, and the fibrotic stroma of cutaneous endometriosis. Immunohistochemical studies or analysis of incisional or excisional biopsy specimens may be required to arrive at a specific diagnosis. Keloidal collagen fibers may develop within a variety of disorders, including dermatofibroma and basal cell carcinoma.

PROGNOSIS AND TREATMENT Scars are usually a cosmetic concern, and the erythema and dyspigmentation of scars may continue to slowly improve for at least a year, after which the appearance usually stabilizes. Pitted scars may be temporarily improved using injectable fillers (e.g., collagen, hyaluronic acid). Laser or intense pulsed light (IPL), dermabrasion, or chemical peels offer variable degree of partial improvement in contour and dyspigmentation. Intralesional corticosteroids, administered monthly, usually flatten and soften hypertrophic scars and keloids.

Silicone gel sheeting has been used. Surgical excision of keloids is effective in the short term, but there is a significant risk of keloid recurrence. Occasionally, small keloids spontaneously regress.

MORPHEA CLINICAL FINDINGS Morphea (localized scleroderma) is a disorder of unknown etiology characterized by indurated, hard plaques with variable surface erythema or dyspigmentation. Lesions may be few in number, generalized, linear (coup de sabre on the forehead), or quite deep (morphea profunda).

HISTOLOGIC FEATURES In early lesions, there are perivascular lymphocytes and plasma cells, sometimes accompanied by increased interstitial mucin deposition without obvious sclerosis. Fully developed lesions become progressively less inflamed, with a predominance of thickened (sclerotic) collagen fibers and narrowing or virtual elimination of the empty spaces between adjacent fibers. At scanning magnification, tissue sections from a punch biopsy exhibit notably straight, parallel edges (cookie cutter

MORPHEA—DISEASE FACT SHEET Patient Group ■ Usually adults but may also occur in children (especially the linear variant) ■ Women more commonly affected than men Site of Involvement ■ Scalp, trunk, or extremities Clinical Findings ■ Indurated plaque ■ May be erythematous with a lilac border ■ May show pigmentary alteration ■ Clinical variants: linear (e.g., en coup de sabre is a manifestation of linear morphea of the forehead), generalized, guttate, deep, nodular or keloidal, or bullous Prognosis and Treatment ■ In contrast to systemic sclerosis, no associated extracutaneous disease ■ Difficult to treat; may spontaneously regress or progress ■ Generalized progressive morphea can lead to disabling constrictions

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DIFFERENTIAL DIAGNOSIS

MORPHEA—PATHOLOGIC FEATURES Histologic Features ■ “Square punch biopsy” ■ Reticular dermal fibrosis extending into subcutis ■ Inflammation at dermal/subcutaneous junction ■ Lymphocytes and plasma cells







Cutaneous lesions of systemic scleroderma, including limited (CREST [calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia in limited systemic scleroderma] syndrome) and generalized (progressive systemic sclerosis) forms, are typically less inflammatory than morphea but cannot be reliably distinguished from morphea based on histopathologic features alone. Sclerodermoid lesions associated with porphyria cutanea tarda are also best distinguished from morphea by clinical correlation. Chronic radiation dermatitis may exhibit sclerosis at all levels of the dermis and is typically associated with scattered large, bizarre mononuclear cells (radiation fibroblasts). Eosinophilic fasciitis (Schulman’s syndrome) is clinically very distinct but microscopically overlaps significantly with morphea profunda; the changes in eosinophilic fasciitis are centered in the fascia rather than overlying deep dermis or subcutis, and eosinophils are usually, although not always, present in concert with peripheral eosinophilia.







Differential Diagnosis ■ Postradiation dermatitis or panniculitis ■ Chronic graft versus host disease ■ Sclerosing injection site reaction

FIGURE 1-36

 

PROGNOSIS AND TREATMENT

Morphea. Sclerosis of collagen fibers centered in the deep reticular dermis. At scanning magnification, the junction between the reticular dermis and subcutaneous fat is often smoother and more prominent (line sign). Perivascular lymphocytes, including plasma cells, encircle blood vessels in the reticular dermis; subcutis; and characteristically, the juncture between these two compartments.

The prognosis in patients with morphea is good with most patients achieving complete remission within several months to years. There are no proven, consistently highly effective treatments, but topical corticosteroids, oral calcitriol, various phototherapy regimens, and other systemic agents have been used. In contrast, systemic sclerosis typically mandates more aggressive therapy.

NEPHROGENIC SYSTEMIC FIBROSIS sign, square biopsy). Within the tissue section, the sclerosis effects a sharpening (because of the denser collagen) and straightening (because of loss of the rounded contour of the underlying subcutaneous fat lobules at the dermal interface) of the junction between the dermis and fat (line sign) (Fig. 1-36). The deep dermal sclerosis causes eccrine glands to appear displaced superficially into the mid dermis. Sparse perivascular lymphocytes and plasmacytes characteristically surround vessels at the junction of the reticular dermis and subcutis. Although the sclerosis is typically centered in the deep dermis, it may extend into the subcutaneous septa (morphea profunda) or more superficially into the papillary dermis. Rarely, the histopathologic features may be limited to the upper dermis (superficial morphea) where superimposed features of LS may be present.

CLINICAL FINDINGS Nephrogenic systemic fibrosis (NSF, aka nephrogenic fibrosing dermopathy) is highly associated with renal insufficiency in a variety of clinical settings that includes acute or chronic renal failure and renal transplantation. The majority of patients were also previously exposed to gadolinium-containing contrast media. NSF usually affects adults and is characterized by one or a few indurated papules that coalesce into plaques most commonly arising on the extremities in a symmetric fashion. The advancing edge of plaques may have an irregular ameboid shape. Lesions often arise between the ankle and mid-thigh or between the wrist and mid-upper arm.

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HISTOLOGIC FEATURES Early lesions are characterized by a diffuse dermal proliferation of epithelioid, spindled and dendritic fibrocytes, increased thick and thin collagen fibers, and variably increased interstitial mucin broadly affecting the dermis and sometimes into subcutaneous septa. Multinucleated giant cells are occasionally present in small numbers. The dermal fibrocytes appear to be derived from circulating fibrocytes coexpressing CD34 and procollagen-1 that are recruited to the dermis in NSF. In older lesions, interstitial mucin is decreased or absent. Regressed lesions resemble a scar.

throughout the third decade or even beyond. The individual lesions may be noninflammatory; for example, they may be open comedones (blackheads) and closed comedones (whiteheads), erythematous papules or pustules, or larger nodules and cysts. Typically, the face is primarily involved, with additional involvement of the neck, upper trunk, and shoulders in moderate to severe cases. Acne lesions frequently leave postinflammatory hyperpigmentation and scars. Keloids may rarely form. The lesions are usually minimally symptomatic or tender (when inflamed). Acne may be pruritic. Some patients habitually pick their lesions, leaving only crusted papules or scars rather than primary lesions. Distinct clinical subsets of acne include neonatal acne, steroid acne (Fig. 1-37, A), chloracne, and acne fulminans.

DIFFERENTIAL DIAGNOSIS NSF was originally reported as a scleromyxedema-like disorder associated with renal disease. Scleromyxedema (papular mucinosis, lichen myxedematosus) typically exhibits more prominent interstitial mucin deposition (e.g., pools of mucin) and an accompanying inflammatory infiltrate of lymphocytes, including plasma cells. The plasma cells in scleromyxedema may be clonally restricted. In clinical practice, the presence or absence of CD34 or procollagen-1 immunohistochemical staining is insufficient to confirm or exclude NSF. Clinically, scleromyxedema typically involves the face and trunk rather than the extremities.

PROGNOSIS AND TREATMENT The course to date has been variable, with some cases persisting or progressing but others exhibiting regression. The clinical subset associated with chronic renal failure appears to have the lowest chance of spontaneous remission. There are no established effective therapies for NSF.

HISTOLOGIC FEATURES The diagnosis of acne is usually made clinically; biopsy confirmation is exceptional. The histopathologic features correlate with the clinical lesions. Comedones resemble milia, essentially representing small follicular cysts. However, comedones differ from milia in that their content includes not just cornified cells and variable numbers of hair shafts but also the secretory lipid products of the sebaceous gland (sebum) and associated bacteria, usually Propionibacterium acnes. Comedones arise from the lower infundibulum or upper isthmic portion of the follicle (i.e., at the entrance of the sebaceous duct). Closed comedones extend to the epidermal surface with a wide opening, but open comedones do not. Although lymphocytes have been reported to be the earliest inflammatory cell affecting the hair follicle, inflamed papules and pustules promptly attract neutrophils, leading to suppurative folliculitis with variable follicular rupture (Fig. 1-37, B, C). The precursor lesion to inflammatory acne lesions is usually the closed comedone or a microcomedone (subclinical comedone). Granulomatous inflammation may follow follicular rupture, but discrete granuloma formation is often lacking.

■  FOLLICULITIS ACNE VULGARIS CLINICAL FINDINGS Acne vulgaris (pimples) is a very common disorder affecting, to some extent, the majority of adolescents. Typical adolescent acne begins at the onset of puberty and usually subsides by the end of the second or third decade of life. However, acne may occasionally persist

DIFFERENTIAL DIAGNOSIS The differential diagnosis for acne vulgaris includes the all variants of acne and rosacea, including steroid acne, perioral dermatitis, and steroid rosacea. Clinical correlation is required to distinguish among these acneiform disorders. Suppurative folliculitis (Fig. 1-38) secondary to infection (usually S. aureus) is also indistinguishable from acutely inflamed papules of acne or rosacea unless microorganisms can be identified. The comedones in

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A

FIGURE 1-38

 

B

Suppurative folliculitis. An erythematous pustule, most commonly associated with Staphylococcus aureus infection.

carcinomatous epithelial hyperplasia. An acneiform drug reaction can be seen in association with novel cancer treatments aimed at inhibiting the epidermal growth factor receptor pathway.

PROGNOSIS AND TREATMENT C Although acne often persists into the third decade, it usually slowly improves and eventually resolves. Topical therapy options include benzoyl peroxide, tretinoin and other retinoids, clindamycin or other antibiotics, or dapsone gel. Systemic therapy includes oral tetracyclines and isotretinoin. Women may occasionally benefit from certain oral contraceptives and spironolactone.

EOSINOPHILIC FOLLICULITIS

FIGURE 1-37

 

CLINICAL FINDINGS

Steroid-induced acne. A, Acneiform papules (i.e., comedones and pustules) on the cheek of a 16-year-old girl hospitalized for an acute asthma attack. The skin lesions arose within a few days of initiation of systemic corticosteroid therapy. B, C, Suppurative folliculitis. Neutrophils surround and infiltrate the follicular epithelium, typically present in large numbers within the follicular canal. This pattern of inflammation may be observed in any acneiform disorder, including acne vulgaris, rosacea, perioral dermatitis, and infectious folliculitis.

chloracne have been reported to possess a bottle or column shape in histologic sections. Other halogenoderma may exhibit nodular and diffuse suppurative and granulomatous inflammation with prominent pseudo-

As a clinical term, eosinophilic folliculitis corresponds to a trio of uncommon but distinctive disorders characterized by the histopathologic least common denominator of folliculitis with numerous eosinophils. The classic variant, eosinophilic pustular folliculitis (Ofuji), is more common in Japan and rare in the United States, usually manifesting as pustules, sometimes forming circinate plaques on the face, proximal extremities, and trunk and sometimes the palms and soles. Before the advent of improved antiretroviral therapy directed against HIV infection, the most commonly encountered variant was HIV-associated eosinophilic folliculitis, typified by numerous pruritic urticarial papules on the upper trunk,

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head, and neck in patients with AIDS with a helper T cell count below 300/µl. Pustules may not be present. Pediatric eosinophilic folliculitis is a self-limited disorder characterized by multiple papules and pustules on the scalp.

HISTOLOGIC FEATURES In all of the clinical variants of eosinophilic folliculitis, there is folliculitis with lymphocytes and prominent eosinophils centered in the infundibulum with inflammation often extending superficially to the epidermis, where pustules may be observed, and inferiorly to the follicular isthmus (Fig. 1-39). Follicular rupture is variable. Granuloma formation is not typical.

ANCILLARY STUDIES Ancillary studies include PAS-D or GMS stain to rule out Pityrosporum folliculitis or a follicular dermatophyte infection. Patients with eosinophilic folliculitis may have circulating or bone marrow eosinophilia.

DIFFERENTIAL DIAGNOSIS Fungal folliculitis, including tinea capitis and Majocchi’s granuloma, and scabies often contain numerous eosinophils. Multiple tissue sections may be required to identify the etiologic agent in both cases.

PROGNOSIS AND TREATMENT HIV-associated eosinophilic folliculitis is usually extremely pruritic and may be managed with topical and systemic corticosteroids, oral antihistamines, or other antiinflammatory agents. Many other agents, including phototherapy, have been reported to be effective. Ofuji’s eosinophilic pustular folliculitis is usually less pruritic. As mentioned, pediatric eosinophilic folliculitis is usually localized and self-limited.

INFECTIOUS FOLLICULITIS CLINICAL FINDINGS In clinical practice, the most common cause of infectious folliculitis is S. aureus, presenting as tender erythematous pustules, often on the buttock or trunk. However, a wide variety of organisms may infect the hair follicle, including other bacteria such as Pseudomonas aeruginosa (e.g., hot tub folliculitis). Fungal folliculitis may be mediated by dermatophytes (Majocchi’s granuloma, tinea capitis, tinea barbae), Pityrosporum sp., or Candida sp. Varicella zoster virus and molluscum contagiosum virus also affect the follicular unit. Demodex mites colonize the follicular canal in many individuals and occasionally mediate clinical folliculitis in predisposed individuals.

HISTOLOGIC FEATURES Similar to the inflammatory lesions of acne vulgaris, S. aureus folliculitis is a suppurative folliculitis with variable follicular rupture. Clusters of gram-positive coccobacteria may be observed within the follicle. A neutrophilic abscess may surround the follicular unit, resulting in furunculosis or carbunculosis (multiple follicles involved). Other forms of folliculitis may exhibit suppurative, eosinophilic, granulomatous, or mixed patterns of inflammation centered on the follicular unit. Syphilitic folliculitis is usually associated with plasma cells. Fungal folliculitis usually has eosinophils in the inflammatory infiltrate.

ANCILLARY STUDIES

FIGURE 1-39  Eosinophilic folliculitis. Eosinophils surround and infiltrate the follicular epithelium at the level of the infundibulum and isthmus. Clinical correlation is required to distinguish the classic, HIV-associated, and pediatric variants. The differential diagnosis includes an infectious etiology.

Cultures of fresh lesional skin are the most sensitive and specific means of identifying most forms of infection when histologic analysis is inconclusive. Direct fluorescent antibody testing can provide very rapid diagnostic confirmation.

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DIFFERENTIAL DIAGNOSIS Because the essential findings may be focal, multiple sections are recommended whenever the clinical description or clinical differential diagnosis includes folliculitis but none is identified on initial sections. Likewise, if folliculitis is identified but no organisms are seen, additional histochemical stains should be considered. If pathogenic organisms cannot be visualized or cultured, the differential diagnosis includes the acneiform disorders, acne and rosacea, which are rarely biopsied in routine clinical practice. Clinical correlation is essential to establish the diagnosis of an acneiform disorder.

A

Spongiosis, particularly atopic dermatitis and seborrheic dermatitis, occasionally is localized to the follicular infundibula (sometimes the term infundibulofolliculitis is used) and may resemble true folliculitis. In follicular spongiosis, there is infundibular follicular epithelial intercellular edema; if there is exocytosis of inflammatory cells into the follicular epithelium, the cells are lymphocytes or Langerhans cells (or both), not neutrophils. Recurrent and disseminate infundibulofolliculitis is a rare disorder characterized by widespread follicular papules resembling papular atopic dermatitis, but it occurs in individuals without an atopic history. Follicular mucinosis may affect deeper portions of the follicular epithelium and may appear similar to follicular spongiosis, but it is identified based on the presence of mucin between follicular keratinocytes that is readily appreciated on routine analysis. Follicular mucinosis may be associated with dense lymphocytic infiltrates with variable cytologic atypia. Many examples of follicular mucinosis represent a manifestation of the folliculotropic variant of MF (Fig. 1-40).

PROGNOSIS AND TREATMENT If the pathogenic organism can be identified or at least suspected, appropriate antibiotic therapy is generally curative. Systemic therapy is often required because topical antibiotics do not always penetrate the follicular canal effectively. In some instances, such as hot tub folliculitis, the condition is self-limited.

ROSACEA CLINICAL FINDINGS Rosacea (acne rosacea) is very common but rarely biopsied. The earliest manifestation is central facial erythema, typically exacerbated by exposure to heat (e.g., sunlight, exercise, hot drinks, spicy foods). Over time the repeated episodes of erythema or flushing eventuate in persistent erythema and telangiectasia. Acneiform lesions (comedones, papules, pustules) may be superimposed on the erythema. Chronic involvement of the nose in men may lead to rhinophyma. The onset of more persistent, firm papules may represent granulomatous rosacea.

B

HISTOLOGIC FEATURES  

FIGURE 1-40

Follicular mucinosis. A, Smooth, infiltrated plaques behind the ears in a man with biopsy-proven generalized patch or plaque stage mycosis fungoides (cutaneous T-cell lymphoma). B, Dense infiltrates of atypical lymphocytes surround and infiltrate follicular epithelium whose keratinocytes are separated by basophilic mucin (acid mucopolysaccharide).

Perivascular and perifollicular lymphocytes are typically associated with vascular dilation (telangiectases). Acneiform papules usually represent folliculitis that may

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be suppurative, lymphocytic, or granulomatous. Plasma cells, neutrophils, or eosinophils may be present in small numbers. Rhinophyma specimens contain increased fibrosis, vascularity, nodular solar elastosis, or sebaceous gland hyperplasia.

ANCILLARY STUDIES Infection and foreign body granuloma should be excluded with special stains. Granulomatous lesions should be examined under polarized light.

DIFFERENTIAL DIAGNOSIS Perioral or periorificial dermatitis is an acneiform disorder in which acneiform papules are localized around the mouth (sparing the vermilion border of the lips) and sometimes the nose and eyes. There are variable photosensitivity and superimposed seborrheic dermatitis, but the follicular inflammation in perioral dermatitis is otherwise indistinguishable from rosacea, including the possibility of secondary granulomatous inflammation. Both perioral dermatitis and a more generalized facial eruption, steroid rosacea, are associated with the use of halogenated topical steroids on the face. If a patient has been using halogenated topical steroids (usually mid to high potency), the condition often flares temporarily on withdrawal of the steroid. Granulomatous rosacea must be distinguished from granulomatous infection, sarcoid, and foreign body granulomas. Severe presentations of granulomatous rosacea may be classified as rosacea fulminans, pyoderma faciale, or lupus miliaris disseminatus faciei. To the extent that a perifollicular distribution of granulomas can be discerned, the diagnosis favors the granulomatous rosacea group of disorders. The histopathologic features of rhinophyma are not specifically diagnostic, but tissue is generally submitted in cosmetic procedures in which the diagnosis is not in question. Occasionally, a prominent papule within a rhinophymatous may be sampled to rule out basal cell carcinoma.

PROGNOSIS AND TREATMENT Rosacea is a chronic, slowly progressive disorder. The rate of progression may be stalled by preventive measures (e.g., avoidance of sun, ethanol ingestion), topical metronidazole, sulfacetamide, tretinoin or azelaic acid, or oral administration of tetracycline antibiotics. Rhinophyma is largely irreversible and requires surgical ablation or resurfacing.

DRUG REACTIONS CLINICAL FINDINGS The most common drug reaction is a morbilliform (measles-like) maculopapular rash concentrated on the trunk and spreading peripherally toward the distal extremities in a symmetric fashion. Pruritus is variable and may be the only feature. Other distinctive reactions include the fixed drug reaction, pustular drug reactions (e.g., acute generalized exanthematous pustulosis), urticaria, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). However, drug reactions may mimic or mediate nearly any inflammatory skin disorders (e.g., pseudoporphyria, drug-induced pemphigoid, lymphomatoid drug reactions, acneiform drug reactions, psoriasiform drug reactions, spongiotic drug reactions, interstitial granulomatous reactions, erythema nodosum, or telogen effluvium, to name just a few), and a comprehensive review is beyond the scope of this chapter. Likewise, virtually any drug may elicit skin changes. The diagnosis is usually based primarily on the temporal relationship between initiation of the offending agent and the onset of the eruption combined with the reputation of the suspected drug. Some of the most common offending agents include trimethoprim– sulfamethoxazole and other sulfa-containing agents such as hydrochlorothiazide, penicillin and its derivatives, other antibiotics, and antiseizure medications. Drug reactions typically arise within 1 or 2 weeks of initiation of the medication. Severe reactions may occur

DRUG REACTIONS—DISEASE FACT SHEET Patient Group ■ Individuals taking medication (especially antibiotics, nonsteroidal antiinflammatory agents, psychotropic drugs and beta-blockers) Site of Involvement ■ Lesions tend to appear first on the trunk and spread peripherally to extremities Clinical Findings ■ Erythematous macules and papules (most common) ■ May simulate almost any inflammatory dermatosis: miscellaneous patterns include pustular, psoriatic, eczematous, erythema multiforme–like, bullous, acneiform, purpuric or vasculitic, Sweet’s-like, panniculitic, erythrodermic, and others ■ May induce pigmentary alterations Prognosis and Treatment ■ Usually resolution with cessation of drug ■ Prognosis depends on severity of eruption (e.g., significant morbidity and mortality associated with Stevens-Johnson syndrome and toxic epidermal necrolysis) ■ May require systemic steroids

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within hours, and reactions may arise more than 1 month after the medication has been introduced. As new drugs become available, new cutaneous manifestations with novel patterns are detected (e.g., eruptions associated with epidermal growth factor receptor inhibitors). Drug reactions are not restricted to inflammatory changes (“rashes”) but also include tumor-induction (e.g., verrucous keratoses, keratoacanthomas or squamous cell carcinomas secondary to treatment with BRAF inhibitors).

ANCILLARY STUDIES The diagnosis of a drug reaction is established by correlation of the clinical history with the estimated likelihood of candidates from the patient’s medication list. Allergy testing (prick, intradermal, provocation) can provide more specific confirmation but is not widely available in dermatology practices and should only be conducted in a properly supervised setting. Rechallenge or desensitization is usually not attempted unless medically mandated.

HISTOLOGIC FEATURES The classic morbilliform drug reaction exhibits an interface reaction with single necrotic keratinocytes and vacuolar alteration along the dermal-epidermal junction with superficial and deep perivascular lymphocytes and eosinophils. Often there is also mild patchy spongiosis. However, drug reactions can mimic virtually any pattern of inflammatory skin disease, sometimes in combination (e.g., combined spongiotic and interface), in itself a potential clue to the diagnosis. Pleomorphic, dyskeratotic epidermal keratinocytes may reflect chemotherapyinduced dysmaturation.

DIFFERENTIAL DIAGNOSIS Drug reactions may mimic nearly every pattern of inflammatory skin disease. In disorders usually characterized by superficial perivascular inflammation such as spongiotic, interface, or psoriasiform dermatitis or perivascular dermatitis without epidermal alteration, the presence of deep perivascular inflammation with eosinophils is often invoked as evidence to include the differential diagnosis of a drug reaction.

PROGNOSIS AND TREATMENT

DRUG REACTIONS—PATHOLOGIC FEATURES









Histologic Features ■ Almost any inflammatory reaction pattern may be seen ■ Clues to drug reaction – Mixed histologic pattern (e.g., combination of subtle spongiosis with interface dermatitis and superficial dermal perivascular lymphocytic infiltrate) – Eosinophils (but their absence does not exclude a drug etiology) – Maturational disturbance of keratinocytes (cytotoxic drug reaction) – Evidence of minor vascular damage (endothelial cell swelling, extravasation of red blood cells)

By definition, drug reactions resolve after discontinuation of the drug, but in some cases, the reaction may persist for days, weeks, or months and may worsen for a few days after the drug has been discontinued. Symptomatic therapy with topical corticosteroids and oral antihistamines is usually sufficient to manage a morbilliform drug reaction. In rare circumstances, patients may be allergic to the very topical or systemic corticosteroids or oral antihistamines used to manage drug reactions.





SUGGESTED FURTHER READING



Ancillary Studies ■ Special stains to exclude infection (depending on the reaction pattern, e.g., granulomatous, pustular, or neutrophilic)









Differential Diagnosis ■ Miscellaneous inflammatory dermatoses ■ Infection ■ Paraneoplastic process ■ Nonmedication-related hypersensitivity reaction (e.g., food allergy)

Ackerman AB. Histologic diagnosis of inflammatory skin diseases, Philadelphia, 1978, Lea & Febiger. Fung MA. The clinical and histopathologic spectrum of “dermal hypersensitivity reactions,” a nonspecific histologic diagnosis that is not very useful in clinical practice, and the concept of a “dermal hypersensitivity reaction pattern”, J Am Acad Dermatol 47:898– 907, 2002. Hannon GR, Wetter DA, Gibson LE. Urticarial dermatitis: clinical features, diagnostic evaluation, and etiologic associations in a series of 146 patients at Mayo Clinic (2006-2012), J Am Acad Dermatol 70(2):263–268, 2014. LeBoit PE. Interface dermatitis. How specific are its histopathologic features?, Arch Dermatol 129:1324–1328, 1993. Phelps RG, Miller MK, Singh F. The varieties of “eczema”: clinicopathologic correlation, Clin Dermatol 21:95–100, 2003. Rabinowitz LO, Zaim MT. A clinicopathologic approach to granulomatous dermatoses, J Am Acad Dermatol 35:588–600, 1996. Weedon D. Skin pathology, London, 2002, Churchill Livingstone.

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2  Panniculitis ■  Maxwell A. Fung

This chapter reviews inflammatory diseases involving the subcutaneous fat tissue (panniculitis). Although panniculitis is typically centered on the subcutis, many forms of panniculitis are associated with internal organ involvement or represent a manifestation of an associated systemic disease. The focus here will be on the most distinctive and commonly encountered histopathologic features of the major forms of panniculitis. Panniculitis is classically divided into mostly septal (i.e., those affecting predominantly the subcutaneous fibrous septa) versus mostly lobular (i.e., those predominantly affecting the fat lobules).

■  VASCULITIS INVOLVING THE SUBCUTIS In addition to assessing for a mostly septal versus mostly lobular pattern at scanning magnification, another initial step in the evaluation of a panniculitis is to determine if vasculitis is present and, if present, whether the vasculitis is a primary or predominant feature of the case, and which type of vessel is involved. Small arteries, arterioles, veins, and venules may be involved. Vasculitis involving subcutaneous vessels may be regarded as a distinct subset of panniculitis and of vasculitis. Examples include cutaneous polyarteritis nodosa, erythema induratum (nodular vasculitis), granulomatosis with polyangiitis (Wegener’s), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), and Behçet’s disease. With the exception of erythema induratum (nodular vasculitis), the vasculitis is further discussed primarily in Chapter 4.

■  PANNICULITIS WITHOUT VASCULITIS The following classification is based on an initial assessment at scanning magnification for a mostly septal versus mostly lobular pattern (in the absence of significant vasculitis) followed by assessment of cell types, the

type(s) of adipocyte necrosis, and other distinctive features. In some cases, a specific diagnosis may be favored. However, it is commonly the case that only a differential diagnosis can be derived, and correlation with clinical features will be required for specific diagnosis or to at least narrow the differential diagnosis to the smallest number of disorders.

Classification of Panniculitis Mostly Septal Inflammation 1. Erythema nodosum 2. Subcutaneous involvement by granulomatous dermatitis 3. Subcutaneous involvement by sclerosing disorders Mostly Lobular Inflammation 1. Neutrophilic +/− granulomatous a. Reaction secondary to ruptured follicular cyst b. Infectious panniculitis c. Pancreatic panniculitis d. α-1-Antitrypsin deficiency panniculitis 2. Lymphocytic a. Lupus panniculitis (lupus profundus) b. Dermatomyositis 3. Granulomatous or histiocytic a. Erythema induratum (nodular vasculitis) b. Lipodermatosclerosis (sclerosing panniculitis) c. Traumatic panniculitis d. Factitial panniculitis e. Sclerosing postradiation panniculitis f. Subcutaneous fat necrosis of the newborn g. Sclerema neonatorum h. Gout i. Oxalosis j. Calciphylaxis k. Cold panniculitis l. Poststeroid panniculitis m. Cytophagic histiocytic panniculitis 4. Eosinophilic panniculitis 5. Neutrophilic panniculitis 6. Drug-induced panniculitis 7. Loss of fat a. Lipoatrophy and lipodystrophy b. Lipedema

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■  MOSTLY SEPTAL PANNICULITIS ERYTHEMA NODOSUM CLINICAL FEATURES Classic erythema nodosum (EN) is a distinctive acute reaction pattern that is widely considered to be the most common form of panniculitis. EN typically affects adolescents and young adults, and women are more often affected than men. Localization is symmetrical and usually involves the anterior shins (Fig. 2-1). Less commonly, the thighs, hands, forearms, and face may be involved. Usually there are multiple smooth, erythematous, tender nodules. The nodules may resemble a bruise (erythema contusiformis). The lesions do not ulcerate and generally involute within a few weeks without leaving a depressed scar. Affected individuals may experience an acute disease phase characterized by fever, headache, malaise, or arthropathy. Systemic disorders associated with EN include infections (bacterial, fungal, protozoal, viral), malignancies, reactions to medications, and other miscellaneous conditions. Frequently associated bacterial infections are streptococcal infection, tuberculosis, Yersinia enterocolitica infection, brucellosis, leptospirosis, tularemia, Chlamydia infection, and Mycoplasma pneumoniae infection. The most frequently associated fungal infections are coccidioidomycosis, histoplasmosis, dermatophytosis, aspergillosis, and blastomycosis, depending on the geographic location and immune status of the patient. Protozoal infections, such as toxoplasmosis, amebiasis, and Giardia infections, can cause EN. Among the associated viral and rickettsial infections are herpes simplex, infectious mononucleosis (resulting from Epstein-Barr virus infection), lymphogranuloma venereum, and psittacosis.

Erythema nodosum may occur in the setting of leukemia, Hodgkin’s disease, non-Hodgkin’s lymphomas, as well as with some other cancers, particularly after irradiation or other treatment releases antigens into the circulation by tumor necrosis. Among the miscellaneous associations is sarcoid, which can have EN as part of a symptom complex, including fever, hilar adenopathy, and arthralgias (Lofgren’s syndrome) or fever, uveitis, and parotitis (uveoparotid fever or Heerford’s syndrome). Medications implicated in EN include sulfonamides, estrogens, and oral contraceptives.

HISTOLOGIC FEATURES The histologic changes in EN are centered on the septa (Fig. 2-2, A). Epidermal and dermal involvement is typically minimal to absent, with sparse superficial and deep perivascular lymphocytes at most. In early EN, there is

ERYTHEMA NODOSUM—DISEASE FACT SHEET Patient Group ■ Most often young adults (20–40 years of age) ■ Women more often affected than men Site of Involvement ■ Lower extremities (shins), usually bilateral Clinical Features ■ Skin: erythematous non-ulcerated nodules, often tender; may arise in crops ■ Commonly associated with other diseases (e.g., poststreptococcal infection, sarcoidosis), drugs (e.g., sulfonamides), or pregnancy but may be idiopathic ■ Systemic symptoms: fever, aches, possible arthralgias Pathophysiology ■ Delayed hypersensitivity reaction (e.g., to bacterial antigens, medication) Prognosis ■ Lesions tend to resolve spontaneously without a scar

 

FIGURE 2-1

Erythema nodosum. Discrete, non-ulcerated, erythematous subcutaneous nodules on the legs.

Treatment ■ Directed at associated symptoms (e.g., nonsteroidal antiinflammatory drugs, bedrest) ■ Directed at underlying disease or causes: antibiotics for associated infection ■ Cessation of possible causative medication ■ Colchicine, if associated with Behçet’s disease ■ Steroids or potassium iodide if necessary

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A

B

C D

FIGURE 2-2  Erythema nodosum. A, Inflammation is concentrated within the subcutaneous septa, especially at the junction between septa and lobules. B, Miescher’s radial granuloma is a collection of nonenlarged macrophages and often also neutrophils surrounding an empty cleft-shaped space. C, Multinucleated giant cells in the septa may contain intracytoplasmic clefts. D, Eosinophils are commonly present within widened, edematous septa. Extravasated erythrocytes may be present, but vasculitis is not typical.

ERYTHEMA NODOSUM—PATHOLOGIC FEATURES Histologic Features ■ Mostly septal panniculitis (fibrosis and inflammation) ■ Miescher’s radial granulomas (small aggregates of histiocytes associated with cleftlike spaces; neutrophils variable) ■ Mixed infiltrate. Neutrophils prominent in early lesions. Multinucleated histiocytes prominent in late or chronic lesions. Ancillary Studies ■ Special stains, cultures, or antistreptolysin titers to exclude infection ■ Chest radiography to assess for sarcoid or pneumonia Differential Diagnosis ■ Infection ■ Subcutaneous involvement by granulomatous dermatitis

edema of the septa with a mixed lymphohistiocytic infiltrate with neutrophils and eosinophils. Focal fibrin deposition and extravasation of erythrocytes may be seen. Often the inflammation is most intense at the periphery of the edematous septa and extends into the periphery of the fat lobules, creating a “paraseptal” or even mixed septal and lobular pattern. Neutrophils are typically present and sometimes prominent in early lesions. A fairly sensitive and specific feature of EN, including early lesions, is Miescher’s radial granuloma, a cluster of non-enlarged macrophages, often with neutrophils, surrounding an empty cleft-shaped space (Fig. 2-2, B). Multinucleated histiocytes are typically most prominent in late stages of EN, sometimes in loosely formed granulomas. Multinucleated histiocytes con­ taining intracytoplasmic clefts likely reflect the disintegration of Miescher’s radial granuloma (Fig. 2-2, C). The typical infiltrate is mixed, with mostly small

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lymphocytes in concert with histiocytes, neutrophils, and eosinophils. Eosinophils within widened edematous septa are common (Fig. 2-2, D). Adipocyte necrosis is not prominent. Vasculitis is not characteristic but has rarely been documented in patients with acute EN secondary to infections; in Behçet’s syndrome; and secondary to medications, including estrogenic oral contraceptives.

ANCILLARY STUDIES Special stains and cultures for microorganisms are needed to exclude an infectious etiology. Differential studies reveal only nonspecific findings.

DIFFERENTIAL DIAGNOSIS Erythema nodosum must be distinguished from erythema induratum (nodular vasculitis). Vasculitis and zones of fat necrosis are absent in EN and typical of erythema induratum. In exceptionally rare patients suspected to have EN but with arteritis, rather than venulitis, cutaneous polyarteritis nodosa must be considered. In polyarteritis, arteries rather than veins or venules are affected. Mycobacterial and fungal infections typically evoke a granulomatous host response. Subcutaneous tuberculosis can mimic EN in lesions that extend into the subcutis from underlying organs, soft tissues, or bone. Whereas subcutaneous tuberculosis can spare the upper portion of the panniculus, EN usually does not. Syphilitic gummas are ulcerative irregular granulomatous lesions that produce depressed scars. EN does not have discrete granulomas or dermal sclerosis and thus can be distinguished from most cases of sarcoidosis, scleroderma, ruptured follicular cysts, and factitial traumatic panniculitis. Crohn’s disease can be associated with EN, and the two diseases can be difficult to distinguish from each other histologically in the skin unless there is ulceration, which does not occur in EN. Other associated conditions are ulcerative colitis and Behçet’s disease. The panniculitis in Behçet’s disease may resemble EN clinically.

CHRONIC ERYTHEMA NODOSUM

CLINICAL FEATURES The rare chronic form of EN is also known as EN migrans or subacute nodular migratory panniculitis. Chronic EN is predominantly found in women. In contrast to classic acute EN, the presentation is more often unilateral or even a solitary lesion, and constitutional symptoms are usually absent. The lesions may migrate. Individual nodules tend to enlarge by peripheral extension into plaques, often with central clearing. The duration may be from several months to several years.

HISTOLOGIC FEATURES In chronic EN, the microscopic appearances are essentially those of late stage classic EN with widened, fibrotic septa and more chronic inflammation (Fig. 2-3). Multinucleated histiocytes and lipophages may be sparse or prominent. There is vascular proliferation and thickening of the endothelium with extravasation of erythrocytes. In some lesions, numerous discrete granulomas can be found and consist of epithelioid and multinucleated histiocytes without caseous necrosis. Although vasculitis has been observed by some authors, others have found vascular changes to be slight or absent.

ANCILLARY STUDIES As for classic EN, mycobacterial or fungal infection in particular should be ruled out.

PROGNOSIS AND TREATMENT

FIGURE 2-3

 

Most cases of EN are self-limited and resolve spontaneously. Drug-induced EN must be clinically excluded. Beyond symptomatic care, prognosis and specific treatment are dictated by the underlying systemic condition. Symptomatic treatments for uncomplicated EN include nonsteroidal antiinflammatory agents and bed rest.

Erythema nodosum (EN), late stage. The septa are widened and fibrotic in the late stage of classic or acute EN as well as chronic EN.

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DIFFERENTIAL DIAGNOSIS

A

The distinction from classic acute EN is primarily clinical. As per classic EN, infection, and subcutaneous involvement by granulomatous dermatitis must be excluded.

PROGNOSIS AND TREATMENT The evaluation and management for classic acute EN applies. However, chronic EN is usually idiopathic and follows a chronic course spanning several months or years. Tetracycline and minocycline have been reported effective in refractory cases of chronic EN.

B

SUBCUTANEOUS INVOLVEMENT BY GRANULOMATOUS DERMATITIS Granulomatous dermatitis is characterized by prominent histiocytes within a dermal inflammatory infiltrate and is reviewed in detail in Chapter 1. Discrete nodular collections of histiocytes are termed granulomas and may exhibit sarcoidal (lymphocyte poor), tuberculoid (lymphocyte rich), or palisaded appearances. Palisaded granulomas have an organized palisade of enlarged histiocytes around a central zone of altered stroma, including necrobiotic degenerated collagen, fibrin, or interstitial mucin; granuloma annulare (GA) is the prototype (Fig. 2-4, A). Subcutaneous GA is characterized by palisaded granulomas that contain mucin (Fig. 2-4, B) and sometimes also fibrin (Fig. 2-4, C). Fibrin is most characteristic of rheumatoid nodules, which typically involve the subcutis but occurs in a different clinical setting. Other forms of granulomatous dermatitis that may occasionally involve the subcutis include necrobiosis lipoidica and necrobiotic xanthogranuloma; in these cases, there is direct extension into the septa from the overlying reticular dermis. A significant differential diagnosis is epithelioid sarcoma, a rare sarcoma that is notorious for its resemblance to palisaded granulomatous dermatitis. In addition, both epithelioid sarcoma and GA frequently involve the deep dermis or subcutis of the distal upper extremities in young persons. The tumor cells in epithelioid sarcoma exhibit cytologic atypia and eosinophilic cytoplasm. The immunophenotypic profile of epithelioid sarcoma is also distinctive, with immunopositivity for vimentin, cytokeratin, EMA, and often CD34, with loss of staining for INI-1. Subcutaneous sarcoid tends to exhibit a lobular or mixed septal and lobular pattern (Fig. 2-5, A). Although lymphocytes are typically sparse, fibrosis can be relatively prominent around the sarcoidal granulomas (Fig. 2-5, B).

C

FIGURE 2-4  Subcutaneous granuloma annulare (GA). A, The fat lobule is largely obscured by a palisaded granulomatous infiltrate. B, Alcian blue stain highlights mucin (blue) in the center of the palisaded granuloma. C, Deep GA may also contain fibrin (pink) (hence the term pseudorheumatoid nodule).

SUBCUTANEOUS INVOLVEMENT BY SCLEROSING DISORDERS Fibrosis and sclerosis are characterized by excess collagen. In fibrosis (e.g., scar), reactive fibroblasts and

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DERMATOPATHOLOGY

A

B

 

FIGURE 2-5

Subcutaneous sarcoidosis. A, Discrete noncaseating granulomas involve the septa and the lobules of the subcutis. B, Fibrosis surrounding subcutaneous granulomas is characteristic.

fibrocytes are proportionally increased, but in sclerosis, they are relatively decreased in number. Thus, sclerosing disorders may be classified as a subset of fibrosing disorders or fibrosing dermatitis, in some cases representing the end stage of a fibrotic process. Sclerotic disorders may begin in the superficial dermis (e.g., lichen sclerosus), deep dermis (e.g., morphea), subcutaneous septa (e.g., morphea profunda), or underlying connective tissue fascia (e.g., eosinophilic fasciitis). Sclerosing disorders enter the differential diagnosis of septal panniculitis when septa are widened secondary to sclerosis of collagen. With the exception of eosinophilic fasciitis, most sclerosing disorders typically involve the dermis with only variable involvement of the subcutis and are discussed in detail in Chapter 1. Lipodermatosclerosis (sclerosing panniculitis) and sclerosing postradiation panniculitis also exhibit septal sclerosis and are each addressed later in this chapter.

Involvement of the subcutaneous septa may occur in the deep variant of morphea (localized scleroderma), also known as morphea profunda, as well as systemic scleroderma (including limited and diffuse variants). Morphea profunda typically involves the deep dermis in continuity with significant involvement of subcutaneous septa (Fig. 2-6, A), with associated inflammatory infiltrates centered at the junction between reticular dermis and subcutis and containing plasma cells (Fig. 2-6, B). The distinction between morphea and systemic scleroderma is made clinically (one or more discrete plaques in morphea; calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia in limited systemic scleroderma [CREST syndrome]) and more diffuse sclerosis and systemic involvement in diffuse systemic scleroderma (progressive systemic sclerosis). Eosinophilic fasciitis (Shulman’s syndrome) exhibits histologic overlap with morphea profunda. Clinically, eosinophilic fasciitis is distinctive, presenting as an acute, bilateral, symmetrical fasciitis often occurring after an episode of exceptionally strenuous physical exertion. If the biopsy is deep enough to sample the fascia, there are variable sclerosis and edema of the collagenous fascia associated with lymphocytes, plasma cells, and eosinophils (Fig. 2-6, C, D). Fibrin may be present. Eosinophilic fasciitis responds promptly to systemic steroids, but scleroderma usually does not. Injections of substances (e.g., Talwin) or foreign material such as silica can induce sclerosis that histologically resembles scleroderma. Examination of tissue sections under polarized light may detect silica or other birefringent foreign material. Of historical note, in 1981 the ingestion of contaminated cooking oil was implicated in the toxic oil syndrome in Spain, with vasculitis and systemic manifestations resembling scleroderma as well as neurotoxicity and several hundred fatalities.

■  MOSTLY LOBULAR PANNICULITIS Lobular panniculitis reflects inflammation that is localized predominantly in the subcutaneous fat lobule. In many instances, the inflammatory process may secondarily involve the septa, resulting in a mixed septal and lobular pattern. Because the differential diagnosis for lobular panniculitis is lengthy, key attributes include the composition of the inflammatory infiltrate (neutrophilic, lymphocytic, granulomatous, eosinophilic) and the type(s) of adipocyte necrosis present. Subclassification based on the composition of the inflammatory infiltrate is unavoidably imprecise because neutrophils or histiocytes may predominate at early or late stages, respectively, of a single disease process. Some lymphocytes are present in all forms of panniculitis.

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A C

B

D

FIGURE 2-6  Deep sclerosing disorders. A, Sclerosis of the deep dermis is associated with widened, sclerotic septa in morphea profunda. There is a perivascular and periadnexal lymphocytic host response with aggregates along the dermal subcutaneous junction. B, Plasma cells are usually present in morphea. C, In eosinophilic fasciitis, the sclerosis usually involves the subcutis but is centered on the underlying fascia. D, Variable sclerosis and edema are associated with a mixed inflammatory infiltrate that usually contains eosinophils.

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DERMATOPATHOLOGY

A

INFECTIOUS PANNICULITIS—DISEASE FACT SHEET Patient Group ■ Any age or gender ■ Immunocompromised at greater risk Site of Involvement ■ Any site. Direct inoculation results in localized lesions. Systemic infection (septicemia) is associated with multiple or generalized lesions. Clinical Features ■ Erythematous tender nodules ■ May be ulcerated and drain pus Prognosis and Treatment ■ Depends on immune status, comorbidities, virulence of the pathogen ■ Antibiotics

B

INFECTIOUS PANNICULITIS—PATHOLOGIC FEATURES Histologic Features ■ Any pattern (septal, lobular or mixed) (Fig. 2-7) ■ Typically a mixed neutrophilic (suppurative) or granulomatous infiltrate FIGURE 2-7

 

Ancillary Studies ■ Lesional cultures ■ Histochemical stains for bacterial, mycobacterial, or fungal pathogens ■ Specific serologic, immunohistochemical, or molecular studies

Infectious panniculitis secondary to Mycobacterium tuberculosis, direct infection of the subcutis. A, Septa are widened and the inflammation is around the periphery of the fat lobules. B, Numerous mycobacteria are detected on acid-fast staining.

Differential Diagnosis ■ Ruptured follicular cyst ■ Noninfectious neutrophilic or granulomatous panniculitis

HISTOLOGIC FEATURES PANCREATIC PANNICULITIS

CLINICAL FEATURES Panniculitic panniculitis usually arises in the setting of pancreatic insufficiency, most commonly acute or chronic pancreatitis. Rare associations include pancreatic cancer; vaccine therapy for pancreatic cancer; hepatic cancer; pancreas divisum; or other rare causes of pancreatitis, including viral hepatitis, lupus pancreatitis, medication-induced pancreatitis (sulindac), or allograft pancreatitis. Lesions typically arise on the legs, often the ankles and knees, but may also arise on the proximal upper and lower extremities, buttock, trunk, or scalp. Ulcerated lesions emit an oily brown exudate.

In the early stage of pancreatic panniculitis, there is a neutrophilic lobular panniculitis (Fig. 2-8, A). Established lesions exhibit enzymatic fat necrosis, with “ghost” adipocytes characterized by the faintly stained outlines of adipocyte membranes with loss of nuclear staining and associated calcification (Fig. 2-8, B, C). Enzymatic fat necrosis is nearly pathognomonic for pancreatic panniculitis.

ANCILLARY STUDIES Serologic or imaging studies may be required to determine the nature of the pancreatic or other underlying disease. Fungal stains may be considered to definitively

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CHAPTER 2  Panniculitis

PANCREATIC PANNICULITIS—DISEASE FACT SHEET

A

Patient Group ■ Patients with pancreatic disease (pancreatitis, cancer, cyst, or fistula) Site of Involvement ■ Most often on legs but may occur elsewhere Clinical Features ■ Erythematous nodules ■ May be painful, ulcerate, and discharge oily material Prognosis ■ Variable; depends on underlying disease Treatment ■ Lesions may resolve weeks after acute pancreatitis ■ Lesions may resolve after surgical resection of tumor ■ Octreotide

B

PANCREATIC PANNICULITIS—PATHOLOGIC FEATURES Histologic Features ■ Mostly lobular panniculitis with neutrophils ■ “Ghost cells” are the outlines of necrotic lipocytes with loss of nuclear staining (enzymatic fat necrosis) ■ Calcification

C

Ancillary Studies ■ Infection must be ruled out. Differential Diagnosis ■ Infectious panniculitis (ghost cells may be seen in mucormycosis and aspergillosis) ■ α-1-Antitrypsin deficiency panniculitis

rule out infections that may rarely produce ghost adipocytes. FIGURE 2-8 

DIFFERENTIAL DIAGNOSIS In early lesion, infection and α-1-antitrypsin (AAT) deficiency panniculitis may be considered. Neutrophilic panniculitis may also be seen in early factitial panniculitis, myelodysplasia, and as a medication reaction (e.g., vemurafenib). In fully developed lesions, the histologic appearances are distinctive. However ghost-type adipocytes have rarely been documented in mucormycosis and aspergillosis.

Pancreatic panniculitis. A, Neutrophils and granular basophilic material reflecting mostly nuclear debris characterize early lesions. Fully developed (B) and late stage (C) lesions contain ghost adipocytes and calcification.

PROGNOSIS AND TREATMENT The prognosis is favorable to the extent that the underlying cause can be successfully managed. In addition to supportive care and identification and management of complications, there is limited evidence supporting the use of the somatostatin analogue octreotide. Surgical

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DERMATOPATHOLOGY

excision of a pancreatic tumor may induce remission of the panniculitis.

A

α-1-ANTITRYPSIN DEFICIENCY PANNICULITIS

CLINICAL FEATURES α-1-Antitrypsin deficiency panniculitis is associated with mutations of the SERPINA1 gene that encodes the serine protease, AAT. SERPINA1 has more than 120 alleles; only phenotypes (e.g., homozygous) associated with significantly decreased serum AAT activity produce clinical manifestations. Hepatic cirrhosis and panlobular emphysema of the lungs are expected complications. The clinical onset may be in childhood or adulthood. Similar to pancreatic panniculitis, the skin nodules may ulcerate and discharge oily fluid. Lesions typically arise on the thighs but may also arise on the trunk, upper extremities, or face.

B

HISTOLOGIC FEATURES

FIGURE 2-9

 

The overall pattern in AAT deficiency panniculitis may be mostly lobular, mixed septal and lobular, or occasionally mostly septal. Separation or lysis of the septa from the lobules may result in “floating” lobules (Fig. 2-9, A). Neutrophils can be found in the septa of the subcutis and interstitium of the deep reticular dermis (Fig. 2-9, B). A granular or amphophilic liquefactive-type necrosis may be present. Secondary vasculitis may be present.

α-1-Antitrypsin deficiency panniculitis. A, Panniculitis associated with separation of lobules from surrounding septa. B, Neutrophils dissect through the collagen of the septa and the deep dermis.

ANCILLARY STUDIES Decreased serum AAT levels (usually 40 mm/hr Elevated RF and cryoglobulins and low complement Chest radiograph: infiltrates or cavities Hematuria or proteinuria or abnormal creatinine Hypocomplementemia Abnormal blood count cANCA (PR3) pANCA (MPO)

Infection, hematologic malignancies, systemic inflammatory disorders CV GPA, EGPA, MPA, malignancy Dermal-renal vasculitis syndrome: GPA, MPA, HSP, SLE UV associated with SLE Infection, hematologic malignancy, systemic inflammatory disorders GPA MPA, EGPA

Histologic examination

Deep dermal and/or subcutaneous small and/or muscular vessel vasculitis Palisaded neutrophilic and granulomatous dermatitis Tissue neutrophilia or tissue eosinophilia

Systemic vasculitis syndrome (GPA, EGPA, MPA, CV, RV, LV, septic vasculitis) GPA, EGPA, LV, RV SLE or EGPA, respectively

Direct immunofluorescence

Isolated or predominant IgA vascular deposits Lupus band (IgG, IgM, and/or C3 at the BMZ)

HSP LV, UV associated with SLE

CV, Cryoglobulinemic vasculitis; EGPA, eosinophilic granulomatosis with polyangiitis; GPA, granulomatosis with polyangiitis; HSP, Henoch-Schönlein purpura; LV, lupus vasculitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; PAN, polyarteritis nodosa; PR3, proteinase 3; RF, rheumatoid factor; RV, rheumatoid vasculitis; SLE, systemic lupus erythematosus; UV, urticarial vasculitis. *Purpura plus ulcers, nodules, bullae, livedo reticularis, and so on. Adapted from Russell JP, Gibson LE: Primary cutaneous small vessel vasculitis: approach to diagnosis and treatment. Int J Dermatol 2006;45(1):3–13.

After cutaneous vasculitis is documented pathologically, then the clinician must correlate clinical and laboratory data to arrive at a specific diagnosis.

on whether or not a patient has received a new medication before the onset of the vasculitis, is septic, or has a history and associated other symptoms of CTD is critical for the correct interpretation of a cutaneous vasculitis.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of cutaneous vasculitis is broad and involves many different clinical settings. The correct diagnosis often depends on correlating clinical findings with a number of laboratory parameters, of which a skin biopsy is only one part. When a skin biopsy confirms the presence of vasculitis, certain histologic features or additional ancillary studies may help narrow the differential diagnosis. Special stains and cultures for microorganisms play an important role in the workup of a patient with vasculitis because infections can simulate almost any histologic reaction pattern associated with cutaneous vasculitis. Most important, however, is clinical context. For example, information

PROGNOSIS The distinction between localized (cutaneous) versus systemic vasculitis is thought to be the most crucial point in determining patient outcome. Patients with strictly cutaneous disease have an excellent prognosis, but those with evidence of systemic disease are at risk for permanent organ damage and death. Pooled data from retrospective studies have shown that fewer than 20% (up to 43% in one study) of patients have evidence of visceral vasculitis, most commonly kidney involvement (so-called renal-dermal vasculitis). The likelihood of chronicity or progression to systemic disease is

 

100%

82%–100% —

Rare

6%–23%

Skin disease

DIF + (C3 or Ig), vessels BMZ

ANCA (any type, IIF) PR3/cANCA MPO/pANCA

Systemic symptoms‡

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—

—

14%–65%

Cardiac disease

Ocular disease

Arthralgias or arthritis

75%

Rare

Rare

10%