General
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• First described in 1901 by Dubreuilh (Case Rep Oncol Med 2012;2012:854827)
• Constitutes < 1-2% of vulvar malignancies (Gynecol Oncol 2011;122:42)
• Based on origin, several classification schemes have been proposed:
  • Type 1: primary vulvar cutaneous origin (Int J Gynecol Cancer 2006;16:1212)
  • Type 2: secondary to primary anal or rectal adenocarcinoma
  • Type 3: secondary to urothelial carcinoma
• OR
  • Type I: Paget disease of primary cutaneous origin (Hum Pathol 2002;33:549)
    • Ia: As a primary intraepithelial neoplasm
    • Ib: As an intraepithelial neoplasm with invasion
    • Ic: As a manifestation of underlying adenocarcinoma of skin appendage or vulval glandular origin
  • Type II: Paget disease of non-cutaneous origin
    • IIa: Secondary to anorectal carcinoma
    • IIb: Secondary to urothelial neoplasia
    • IIc: As a manifestation of another non-cutaneous carcinoma: endocervical, endometrial or ovarian adenocarcinoma, etc.

Terminology
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• Synonyms: extramammary Paget (Paget's) disease

Epidemiology
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• Common in elderly, postmenopausal, Caucasian women

Sites
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• Labia majora > clitoris

Etiopathogenesis
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• Intraepithelial adenocarcinoma that can be:
  • Primary, arising from intraepidermal glandular cells or pluripotent cells of epidermis/folliculosebaecous or eccrine units
  • Secondary, due to either direct spread from an underlying in situ or invasive adenocarcinoma or rarely epidermotropic metastasis
• The underlying neoplasms may be colorectal, urothelial, ovarian, endometrial or cervical in origin
• May become invasive and eventually metastasize to regional lymph nodes

Clinical features
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• Slowly expanding, erythematous or eczematous, focally eroded or crusted plaques
• The lesions are frequently sharply demarcated
• Often pruritic, may be painful or associated with burning sensation, rarely asymptomatic
• Often accompanied by discharge
• Frequently multifocal

Diagnosis
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• Must be confirmed by histologic examination
• An underlying neoplasm should be ruled out by complete pelvic examination, colposcopy and radiologic examination

Prognostic factors
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• Clinical detection of a nodule within the primary lesion, palpable lymphadenopathy, the level of tumor invasion, and lymph node metastases are the most important prognostic indicators (Dermatol Surg 2012;38:1938)
• The following histologic features are associated with tumor progression and invasion:
  • Increased expression of p53 (Hum Pathol 2003;34:880)
  • Combined expression of cyclin D1 and increased Ki67 (J Dermatol Sci 2008;50:177)
  • Reduced expression of E-cadherin (Mod Pathol 2008;21:1192)
• Clearance of disease with wide margins remains a challenge due to the multifocal nature of the disease
• However, positive margins and lesion size are not predictive of progression free survival (Int J Gynecol Pathol 1999;18:351, Int J Clin Oncol 2012;17:569)
• Patients with clitoral involvement may require more aggressive treatment (Gynecol Oncol 2000;77:183)

Case reports
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• 43 year old woman with painful vulvar lesion and recurrent vaginal discharge (Case Rep Oncol Med 2012;2012:854827)
• 59 year old woman with vulvar Paget disease (J Dermatol Case Rep 2011;5:42)
• 60 year old woman with bladder Paget disease 18 years after vulvar Paget disease (Gynecol Oncol Case Rep 2014;8:27)
• 62 year old woman with pruritic plaque on perineal skin (Indian J Dermatol 2015;60:105)
• 65 year old women with vulvar Paget disease (Proc R Soc Med 1956;49:89, J Midlife Health 2012;3:100)
• 75 year old woman (BMJ Case Rep 2013 Nov 21;2013)
• Pigmented extramammary Paget disease (Acta Derm Venereol 2011;91:380)

Treatment
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• Mohs micrographic surgery (J Am Acad Dermatol 2013;68:632) or wide local excision
• Topical imiquimod (J Obstet Gynaecol 2013;33:479, South Med J 2006;99:396, J Low Genit Tract Dis 2012;16:59) or topical 5-fluorouracil (Cutis 2006;77:245)
• Radiotherapy, photodynamic therapy (Gynecol Oncol 2006;103:581) or CO2 laser ablation
• Trastuzumab (Gynecol Oncol 2008;111:568)
• References: Cochrane Database Syst Rev 2013;10:CD009245, Australas J Dermatol 2013;54:9

Clinical images
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Lesion on perineal area

Preoperative

Erythematosquamous lesion

Before and after treatment

Asymmetrical brown lesion

Gross description
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• Sharply demarcated plaque

Micro description
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• Microscopic disease almost always extends well beyond the grossly visible lesion
• Epidermis is frequently acanthotic, accompanied by hyperkeratosis, parakeratosis, erosion or ulceration
• Intraepidermal scattering of single or clusters of large cells characterized by abundant eosinophilic, clear or amphophilic cytoplasm, round / ovoid vesicular nuclei, open chromatin and small nucleoli
• These cells may be seen in combinations of several histologic patterns: glandular, acantholysis-like, suprabasal nests, vertical nests, budding and sheet-like (J Dermatol 2011;38:1054)
• Basal layer is preserved, but may be attenuated
• Clefting between tumor cells and the surrounding epidermis may be present, due to absence of desmosomes
• Fibroepithelioma-like hyperplasia or papillomatous hyperplasia may be seen (Am J Surg Pathol 2000;24:543)
• May resemble invasive disease due to marked intraepithelial proliferation within deep epithelial invaginations, tangential sectioning of rete and papillary dermal fibrosis (Arch Pathol Lab Med 1998;122:471)
• Sometimes, the glandular nature of the infiltrating cells is highlighted by mucinous differentiation and signet ring-like morphology
• Rarely, the cytologic atypia can be marked with anaplastic features; these are seen more frequently in secondary Paget disease
• Exceptionally, the cells may be pigmented
• There may be an associated lichenoid lymphohistiocytic inflammatory infiltrate in the superficial dermis

Micro images
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Paget cells

Epidermis with keratinization

PAS

 

CK7

CK7+, CK20-

 

Low power-subtle disease on left

Eyeliner sign

   

Medium power

 

High power

 

Invasive

Cytology description
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• Round to columnar, moderately enlarged atypical cells, dispersed or in loose groups, with abundant clear cytoplasm, vesicular nuclei and prominent nucleoli (Acta Cytol 2010;54:1007, Acta Cytol 2010;54:898, Diagn Cytopathol 2010;38:127)

Positive stains
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• Special stains: diastase-periodic acid-Schiff (D-PAS), mucicarmine, rarely alcian blue, colloidal iron
• CK7, CAM 5.2, AE1/AE3, EMA/MUC1, CEA, GCDFP15, MUC5AC (positive more often in primary than secondary), Androgen receptor, HER2, COX2, CD23
• Secondary Paget disease cells of colorectal origin are CK20+ and CK7+
• Secondary Paget disease cells of urothelial origin are positive for CK7, CK20 and uroplakin III

Negative stains
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• S100, MelanA, HMB45, PR, p63, p40

Differential diagnosis
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• Clinical:
  • Bowen disease
  • Candidiasis
  • Dermatitis: contact, irritant or other
  • Erosive lichen planus
  • Inverse psoriasis
  • Langerhan cell histiocytosis
  • Lichen sclerosus
  • Lichen simplex chronicus
  • Mycosis fungoides
  • Seborrheic dermatitis
  • Tinea cruris
• Histologic:
  • Benign mucinous metaplasia: difficult to distinguish, but lacks cytologic atypia
  • Clear cell papulosis: thought to represent benign Toker cell hyperplasia
  • Intraepidermal spread of sebaceous carcinoma
  • Melanoma
  • Pagetoid dyskeratosis: suprabasal cells with abundant eosinophilc cytoplasm with no cytologic atypia, and are not glandular in origin
  • Squamous cell carcinoma in situ

Additional references
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• Bolognia: Dermatology (2nd Edition, Chapter 73; now 3rd Edition-2012), Calonje: McKee's Pathology of the Skin (2011), 4th Edition, Chapter 30, Am J Obstet Gynecol 2002;187:281, Am J Obstet Gynecol 1999;180:24, Gynecol Oncol 2013;129:412, Gynecol Oncol 2012;127:S30

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