Clinical Differential Diagnosis 4/16/2018 DERMATOPATHOLOGY OF THE GENITALIA AND BREAST NO CONFLICTS TO DISCLOSE
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1 DERMATOPATHOLOGY OF THE GENITALIA AND BREAST JOHN S. METCALF, MD Professor of Pathology and Dermatology MUSC NO CONFLICTS TO DISCLOSE Clinical Differential Diagnosis Plaques: Erythematous Inflammatory Non-infectious» Eczematous dermatitis (irritant contact dermatitis, allergic contact dermatitis, neurodermatitis )» Psoriasis» Lichen Planus and fixed drug Infectious» Bacterial» Dermatophytes» Candidiasis Neoplastic Squamous Cell Carcinoma in situ (Bowen s Disease) Paget s Disease (mammary and extramammary) Inflammatory carcinoma Cutaneous T-Cell Lymphoma (Mycosis Fungoides) 1
2 Spongiotic Dermatitis Acute: Cornified layers show normal architecture; epidermis of normal thickness, but with intercellular edema (spongiosis), superficial perivascular infiltrate (sometimes with eosinophils) Subacute: Usually areas of parakeratosis with serum, some epidermal hyperplasia, less pronounced spongiosis Chronic: Compact orthokeratosis sometimes with areas of parakeratosis, irregular psoriasiform epidermal hyperplasia, sometimes residual spongiosis Acute Spongiotic Dermatitis 2
3 Spongiotic dermatitis with spongiotic vesiculation 3
4 Eczematous dermatitis (contact dermatitis) 4
5 Psoriasis Erythrasma Corynebacterium minutissimum Superfical fungal infection and candidiasis Superfical inflammatory infiltrate, sometimes with neutrophils Cornified layers contain spores and/hyphae or pseudohyphae Diastase Periodic Acid- Schiff stain may be helpful but sometimes not necessary 5
6 CTCL- MF 6
7 Lichenoid Lichen Planus Lichen Sclerosis Plasma cell balanitis Lichen planus-like keratosis (breast) Fixed Drug Erythema Multiforme 7
8 Lichen Planus and Lichen Sclerosis DDX Early stage disease: Both show lichenoid interface inflammation and early on may be impossible to differentiate; however: Loss of basal keratinocytes with squamatization of basal layer, necrotic keratinocytes, and saw-toothing usually not seen in LS Homoginization and sclerosis of papillary dermis often can be identified in early stage LS, but usually not in LP Lichen Planus Lichen Planus 8
9 Lichen Planus Lichen Planus Lichen planus-like keratosis 9
10 Lichen sclerosis Lichen sclerosis Lichen sclerosis 10
11 Plasma cell balanitis (Zoon s) Plasma cell balanitis Fixed Drug Reaction and Erythema Multiforme 11
12 Erythema multiforme Fixed drug Fixed drug 12
13 Fixed drug VESICULOBULLOUS DISORDERS Pemphigoid Bullous Cicatricial Pemphigus Vulgaris Vegitans Hailey-Hailey disease Darier s disease Acantholytic dermatosis of the vulvocrural area Bullous pemphigoid 13
14 Pemphigus vulgaris Hailey-Hailey (benign familial pemphigus) Hailey-Hailey 14
15 Darier s (acantholytic dyskeratosis) Clinical Differential Diagnosis Papules and papulovesicles Inflammatory Non-infectious Flat-topped: lichen planus Fixed drug Infectious Condyloma lata Molluscum contagiosum Herpes Simplex (I and II) and Varicella Zoster Condyloma Lata 15
16 16
17 Clinical Differential Diagnosis Ulcers: Superficial: Infectious: Syphilis Herpes Granuloma inguinale Non-infections Lipschutz ulcer Excoriation or trauma Deep Pyoderma gangrenosum Necrotizing fasciitis 17
18 Steiner Primary syphilis T. Pal Granuloma inguinale 18
19 Pyoderma Gangrenosum vs. Necrotizing Fasciitis and Fournier s Gangrene Pyoderma Gangrenosum Erythematous pustule or nodule becoming an ulcer with undermined edges Sometimes initiated by trauma (or surgery) Often an associated systemic illness such as Ulcerative Colitis, Diabetes Often begins as sterile follicular inflammation with abscess formation Pyoderma gangrenosum 19
20 Pyoderma gangrenosum Necrotizing Fasciitis of the Genitalia (Fournier s Gangrene) Usually associated with diabetes High mortality rate Often polymicrobial as opposed to extragenital NF which is usually caused by Group A strep Deep vessel thrombosis and necrosis of deep soft tissues Positive tissue and blood cultures usually Fournier s gangrene 20
21 Necrotizing fasciitis Necrotizing fasciitis Necrotizing fasciitis 21
22 DDX NF: Often deep vessel thrombosis with necrosis and edema of septa and fascia, positive blood and tissue cultures Often minimal epidermal change PG: Often subepidermal edema, undermining inflammation at edge of ulcer Usually no deep vessel thrombosis or deep necrosis Cultures are negative (unless secondarily infected) Clinical Differential Diagnosis Nodules and tumors Ectopic glandular tissue Adnexal tumors Benign Malignant Invasive Carcinomas Mesenchymal tumors Metastatic tumors Hidradenoma papilliferum (MLG adenoma) 22
23 Accessory nipplevulva Adenosis-like glandular proliferation of vulva 23
24 ER P63 Invasive adenocarcinoma with lobular features- vulva 24
25 Adenoid cystic carcinoma (Bartholin s Duct) 25
26 Clinical Differential Diagnosis Papules (con t) Neoplastic Benign Benign keratoses (seborrheic keratosis or seborrheic keratosislike) Condylomata Borderline Bowenoid papulosis 26
27 Seborrheic Keratosis-like Lesions Lesions having the architecture and histologic features characteristic of seborrheic keratosis, but occurring of skin in the genital region, are frequently associated with Human Papilloma Virus infection. 27
28 BOWENOID PAPULOSIS Predilection for sexually active young adults In males, commonly involves glans and foreskin; in females, vulvar lesions which are often pigmented and bilateral Uncommonly gives rise to invasive SCC Usually associated with HPV 16 Differentiation from Bowen s Disease histologically may be impossible 28
29 Bowen s Disease Cutaneous squamous cell carcinoma in situ Predilection for sun-damaged skin (solar irradiation) In genital region, associated chiefly with HPV types 16,18, 31, 33, and others Expanding asymptomatic erythematous plaque 29
30 Bowen s disease Bowen s disease Carcinoma of the Vulva Two pathways: Classic VIN (uvin) Bowen s Disease which is associated with HPV infections (especially types 16 and 18) p16 immunostain usually diffusely positive; high proliferative index Differentiated (simplex) VIN Often accompanied by chronic inflammatory dermatoses Lichen sclerosis Lichen simplex chronicus p-53 immunostain of limited help 30
31 uvin uvin uvin 31
32 uvin uvin 32
33 uvin uvin uvin- Bowen s disease with Pagetoid histology 33
34 uvin with invasion 34
35 Lichen sclerosis with adjacent SCC Differentiated VIN associated with Lichen Sclerosis 35
36 Verrucous Carcinoma of the Genitalia Vulvar verrucous carcinomas are usually not associated with HPV and are typically associated with chronic inflammatory dermatoses. However, HPV (6, 11, 16, 18) have implicated in some verrucous carcinomas of the glans penis and the genitocrural areas- proposed name warty (condylomatous) squamous cell carcinoma Pure verrucous carcinoma is generally slow growing, locally destructive, but seldom metastasizes 36
37 Verrucous Carcinoma of the Genitalia: Strict Criteria Well differentiated verrucous/papillary carcinoma Minimal nuclear atypia Blunt epithelial-stromal interface Absence of co-existing conventional keratinizing SCC 37
38 Expanding Erythematous or Pigmented Plaques with or without associated tumors Epithelial: Paget s Disease Mammary Extramammary Bowen s Disease 38
39 Paget s Disease (mammary and extramammary) (1874) Sir James Paget described an eruption of the nipple/areola complex with characteristics of ordinary chronic eczema or psoriasis which was followed by the development of breast cancer. (1904) H. Jacobaeus concluded that Paget s D. was a carcinoma from its conception, originating from the breast parenchyma and extending along the duct system to the skin. In fewer than 5% of cases is no underlying breast carcinoma found. 39
40 Paget s disease of breast Duct carcinoma in situ with overlying Paget s disease 40
41 Pigmented Paget s disease- Breast 41
42 SOX-10 CK5/6 CEA Extramammary Paget s Disease Tends to occur in sites with a high density of apocrine glands. Erythematous, enlarging plaque. Female predominance with vulva being most common site. 42
43 Extramammary Paget s Disease: Histogenesis: Not thought to be uniform: 25% - underlying adnexal adenocarcinoma 10-15% - internal malignancy (rectum, cervix, prostate, bladder, etc.) If no underlying carcinoma is found: In situ adnexal carcinoma Origin from pluripotential cells in epidermis Extramammary Paget s disease Extramammary Paget s disease 43
44 Extramammary Paget s disease ZOON S BALANITIS AND VULVITIS AB-D-PAS CEA 44
45 Extramammary Paget s disease CK7 cck7 45
46 Clinical Differential Diagnosis Pigmented lesions Benign Melanotic macules Melanocytic nevi (special site features) Malignant Pigmented Bowen s disease Pigmented Paget s disease Melanoma Genital melanotic macule (melanosis); aka labia lentigo 46
47 Characteristics of Special Site Nevi Usually occur in young women A mostly nested junctional component: Nests variably sized, but may be large, and oriented vertically or horizontally Cells within nests may be dyshesive Sometimes a crowded junctional component with ill-defined nests and single unit melanocytes Pagetoid spread present in a minority of cases, but is focal and centrally located Histologic Patterns of Special Site Nevi 1. Nested: large nests perpendicular or parallel to DEJ 2. Dyshesive: junctional nests approaching confluence, with cellular dyshesion 3. Crowded: poorly defined nests with interspersed single cells, obscuring DEJ Additional Features Concerning features: Epithelioid cells with prominent nucleoli Occasional pagetoid scatter, centrally Dermal fibrosis Reassuring features: Symmetry Sharp dermarcation Maturation of dermal component Low dermal proliferation 47
48 Vulvar nevus- 37 y.o. Special site nevus of breast 48
49 Special site nevus, breast, with congenital features (38 y.o) 49
50 Sp. Site nevus (congenital features) 32y.o. man 50
51 Sp. Site nevusinguinal crease- 6 y.o. 6 y.o. girl (inguinal crease) 51
52 ssuprapubic nevus 52
53 Vulvar Melanoma 53
54 Vulvar melanoma- 88 y.o. woman 54
55 Melanoma of Breast- 46 y.o. woman 55
56 Molecular Diagnosis 1) Multiple chromosomal gains or losses can be detected by FISH or CGH and can be of assistance in differentiating melanoma from melanocytic nevi. 2) Current FISH probes are fairly successful in differentiating histologically benign nevi from melanomas. 3) However up to this point, in histologically ambiguous melanocytic tumors, FISH test results do not generally show unequivocal features of melanoma or nevi, but rather show inconsistencies (borderline melanocytic tumors). 56
57 Endothelial Tumors of the Skin of the Breast (post-irradiation) Atypical vascular proliferation Mitoses usually lacking (Ki67 may be helpful) C-MYC negative Post-irradiation angiosarcoma Mitoses usually present C-MYC usually positive Lymphangiosarcoma arising in the setting of chronic lymphedema (Stewart-Treves) Post-irrad AVL (Ki67) 57
58 Post irradiation angiosarcoma Post-irradiation angiosarcoma Post-irrad angiosarc (Ki67) 58
59 C-MYC Stewart-Treves 59
60 Inflammatory Carcinoma of the Breast 60
61 61
62 Case presentation 66 y.o. woman with a biopsy of right breast skin. History of lung cancer with metastasis. 62
63 Pitfalls in Diagnosis of Breast Carcinoma (related to skin) Experience will teach you things you wish you didn t have to learn - Harv Read Case Presentation 56 y.o. woman with a core needle biopsy of the left breast (12:00, 1 cm from nipple) Clinical Information: Breast mass- fibroadenoma vs debris-filled cyst vs cancer 63
64 Triple negative The rest of the story: Previously: pt3b N2c melanoma (with satellites) resected from right face 64
65 MART-1- breast SOX10- lung Case Presentation: 60 y.o. woman with a history of poorly differentiated invasive duct carcinoma of the breast (with negative nodes) five years ago, presented with a well defined right axillary mass. Core needle biopsy performed. GATA 3 and CK7 positive 65
66 Lumpectomy performed with axillary dissection (negative) 66
67 67
68 Nodule arising adjacent to mastectomy scar Nodular hidradenoma 68
69 Selected References Smith GL, Bunker CB, and Dinneen MD. Fournier s Gangrene (Review). British Journal of Urology (1998):81: Weedon s Skin Pathology (4 th Ed). Editor: James W. Patterson. Churchill Livingstone Reyes M C and Cooper K. An update on vulvar intraepithelial neoplasia: terminology and a practical approach to diagnosis. J Clin Pathol 2014 Apr.;67(4): Ueda Y, et. Al. (Review article) Two distinct pathways to development of squamous cell carcinoma of the vulva. Journal of skin cancer. Vol 2011 Mason AR, et al. Nevi of Special Sites. Clinics in laboratory Medicine, 2011, 31: Muhlbauer A, et.al. The correlation of the standard 5 probe FISH assay with melanocytic tumors of uncertain malignant potential. Annals of Diagnostic Pathology. June pp Hoda SA, et al. Rosen s Breast Pathology, 4 th Ed. Wolters Kluver2014. Chapter 39 (Sarcoma), pp
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