Definition/General

Introduction:
-Vulvar Paget disease is a rare intraepithelial adenocarcinoma representing 1-2% of all vulvar malignancies
-It is characterized by large, pale cells (Paget cells) within the epidermis
-Most cases are primary vulvar adenocarcinoma, but 10-20% are associated with underlying invasive adenocarcinoma
-It predominantly affects postmenopausal women aged 60-80 years.
Origin:
-Arises from pluripotent stem cells in the epidermis or adnexal structures
-Can originate from apocrine glands or their ducts
-May arise from aberrant mammary tissue remnants (milk line theory)
-Two theories: epidermotropic spread from underlying adenocarcinoma or primary intraepithelial transformation
-Exact cell of origin remains controversial.
Classification:
-Classified as primary vulvar Paget disease (80-90%) or secondary Paget disease (10-20%)
-Primary type: intraepithelial adenocarcinoma without underlying invasive carcinoma
-Secondary type: associated with underlying invasive adenocarcinoma
-May be associated with distant malignancies (breast, colon, genitourinary)
-Invasive Paget disease when dermis is invaded.
Epidemiology:
-Peak incidence in 6th-7th decades
-Rare before menopause
-No racial predilection
-Associated with underlying adenocarcinoma in 10-20% cases
-May be associated with distant malignancies (breast 5-10%, colorectal 3-5%)
-Synchronous or metachronous tumors possible
-Indian population data limited due to rarity.

Clinical Features

Presentation:
-Erythematous, eczematous plaque with well-demarcated borders
-Chronic pruritus (most common symptom)
-Burning sensation
-Ulceration and bleeding
-White, scaly patches alternating with erythematous areas
-May resemble chronic dermatitis
-Typically unilateral but can be bilateral.
Symptoms:
-Intense pruritus (80-90% cases)
-Burning pain (60-70%)
-Vulvar irritation
-Bleeding (if ulcerated)
-Discharge
-Change in skin texture
-Thickening of vulvar skin
-Soreness during intercourse
-Long-standing symptoms often present for years.
Risk Factors:
-Advanced age (>60 years)
-Fair skin complexion
-History of breast or colorectal cancer
-Immunosuppression
-Chronic vulvar irritation
-Genetic predisposition (rare familial cases)
-Hormonal factors unclear
-Diabetes mellitus (possible association).
Screening:
-No specific screening guidelines
-Careful vulvar examination during routine gynecological visits
-Biopsy of persistent eczematous lesions
-High index of suspicion in elderly women
-Dermoscopy may aid diagnosis
-Whole-body examination to exclude associated malignancies.

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Gross Description

Appearance:
-Erythematous, well-demarcated plaque with irregular borders
-Eczematous appearance with scaling and crusting
-Areas of hyperpigmentation and hypopigmentation
-May show ulceration and weeping
-Thickened, leathery texture
-Size varies from 1-15 cm.
Characteristics:
-Sharply demarcated red-brown plaque
-Velvet-like surface with fine scaling
-Areas of erosion and crusting
-Satellite lesions may be present
-Borders often map-like with geographic pattern
-May extend to perianal area.
Size Location:
-Size ranges from 1-20 cm (mean 5-8 cm)
-Most commonly involves labia majora (60-70%)
-May extend to mons pubis and perianal area
-Bilateral involvement in 20-30% cases
-Multifocal disease common
-Can involve entire vulva in advanced cases.
Multifocality:
-Multifocal disease in 30-40% cases
-Skip lesions common
-May extend beyond clinically apparent borders
-Perianal extension in 20-30% cases
-Involvement of vaginal introitus
-Can extend to inguinal areas.

Microscopic Description

Histological Features:
-Large, pale Paget cells scattered throughout the epidermis
-Cells have abundant pale cytoplasm and large, vesicular nuclei
-Prominent nucleoli
-Cells arranged singly or in small clusters
-Acanthosis of surrounding epidermis
-Underlying chronic inflammation.
Cellular Characteristics:
-Paget cells are large (2-3 times normal keratinocyte size)
-Pale, vacuolated cytoplasm
-Large, vesicular nuclei with prominent nucleoli
-High nuclear-cytoplasmic ratio
-Mitotic figures may be present
-PAS-positive, diastase-resistant cytoplasmic material
-May contain mucin vacuoles.
Architectural Patterns:
-Paget cells predominantly in basal and suprabasal layers
-May extend to upper epidermal layers
-Cells arranged singly or in small nests
-Pagetoid spread pattern
-May involve adnexal structures (hair follicles, sweat glands)
-Underlying dermis shows chronic inflammation.
Grading Criteria:
-No standard grading system
-Assessment based on extent of involvement
-Depth of invasion (if present)
-Mitotic activity
-Presence of underlying adenocarcinoma
-Invasive component changes prognosis significantly
-Lymphovascular invasion indicates aggressive behavior.

Immunohistochemistry

Positive Markers:
-CK7 (90-100% positive)
-CEA (85-95%)
-EMA (80-90%)
-GCDFP-15 (70-80%)
-Mammaglobin (60-70%)
-CK20 (variable, 20-40%)
-CDX2 (negative in primary, positive if secondary to colorectal)
-Her2/neu (30-50%).
Negative Markers:
-S-100 (negative)
-Melanoma markers (HMB-45, Melan-A negative)
-p63 (negative)
-High molecular weight cytokeratins (negative)
-TTF-1 (negative)
-WT-1 (negative)
-Vimentin (negative).
Diagnostic Utility:
-Essential for differential diagnosis from melanoma and squamous cell carcinoma
-CK7 and CEA are most reliable markers
-CDX2 positivity suggests secondary Paget from colorectal primary
-GCDFP-15 and mammaglobin support apocrine differentiation
-CK20 pattern helps distinguish primary from secondary.
Molecular Subtypes:
-Primary vulvar type: CK7+, CEA+, CDX2-, CK20 variable
-Secondary colorectal type: CK7+/-, CEA+, CDX2+, CK20+
-Secondary breast type: CK7+, CEA+, GCDFP-15+, mammaglobin+
-Her2/neu amplification in subset of cases
-p53 mutations common.

Molecular/Genetic

Genetic Mutations:
-TP53 mutations (40-60%)
-PIK3CA mutations (20-30%)
-KRAS mutations (15-25%)
-Her2/neu amplification (20-40%)
-PTEN loss (10-20%)
-BRAF mutations (rare, <5%)
-CDH1 mutations (E-cadherin).
Molecular Markers:
-Chromosomal instability common
-Microsatellite stability (most cases)
-Her2/neu overexpression in subset
-p53 overexpression
-Ki-67 proliferation index variable
-Loss of heterozygosity at multiple loci
-DNA ploidy abnormalities.
Prognostic Significance:
-Invasive component most important prognostic factor
-Tumor thickness correlates with outcome
-Lymphovascular invasion indicates poor prognosis
-Her2/neu amplification may predict response to targeted therapy
-p53 mutations associated with invasive behavior
-Multifocal disease increases recurrence risk.
Therapeutic Targets:
-Her2/neu targeting: Trastuzumab (amplified cases)
-Topical therapies: 5-fluorouracil, imiquimod
-Photodynamic therapy
-Laser therapy
-Surgical excision remains gold standard
-Radiation therapy for unresectable cases
-Immunotherapy under investigation.

Differential Diagnosis

Similar Entities:
-Malignant melanoma (especially amelanotic)
-Squamous cell carcinoma in situ
-Vulvar intraepithelial neoplasia (VIN)
-Chronic dermatitis
-Psoriasis
-Lichen sclerosus
-Contact dermatitis
-Seborrheic dermatitis.
Distinguishing Features:
-Paget disease: CK7 and CEA positive
-Paget: Melanoma markers negative
-Melanoma: S-100 and melanoma markers positive
-SCC in situ: p63 positive, CEA negative
-VIN: p16 positive, HPV-related
-Dermatitis: No atypical cells
-Biopsy essential for differentiation.
Diagnostic Challenges:
-Distinguishing from amelanotic melanoma
-Pagetoid melanoma vs Paget disease
-Secondary vs primary Paget disease
-Extensive sampling needed for invasive component
-Multifocal disease assessment
-Correlation with clinical appearance essential.
Rare Variants:
-Invasive Paget disease (10-20% of cases)
-Pagenoid squamous cell carcinoma
-Paget disease with sebaceous differentiation
-Clear cell variant
-Signet ring cell variant
-Paget disease in hidradenitis suppurativa.

Sample Pathology Report

Template Format

Sample Pathology Report

Complete Report: This is an example of how the final pathology report should be structured for this condition.

Specimen Information

Vulvar excision, [site], measuring [size] cm in greatest dimension

Diagnosis

Vulvar Paget disease, [primary/secondary if known]

Classification

Classification: [Intraepithelial/Invasive], extent: [superficial/full-thickness]

Histological Features

Shows [Paget cell distribution] with [cellular morphology] and [epidermal changes]

Invasion Status

Invasive component: [present/absent], depth: [X mm if present]

Margins

Margins are [clear/involved] with Paget cells [X] mm from closest margin

Lymphovascular Invasion

Lymphovascular invasion: [present/absent]

Extent of Involvement

Paget cells involve [epidermal layers] and [adnexal structures]

Special Studies

IHC: CK7: [positive/negative], CEA: [result], CDX2: [result]

Molecular: [test performed]: [result]

[other study]: [result]

Prognostic Factors

Prognostic factors: invasive component, margins, multifocal disease

Final Diagnosis

Vulvar Paget disease, [intraepithelial/invasive], margins [status]