Definition/General
Introduction:
Vulvar extramammary Paget disease (EMPD) is a rare intraepithelial adenocarcinoma affecting apocrine gland-bearing areas
It represents 1-2% of all vulvar malignancies
Characterized by large, pale Paget cells within the epidermis
Can be primary (arising from apocrine glands) or secondary (extension from underlying adenocarcinoma)
Predominantly affects elderly postmenopausal women.
Origin:
Arises from apocrine glands and their ductal system in the vulvar region
Can originate from pluripotent stem cells in the epidermis
Two main theories: glandular origin theory (from apocrine glands) and keratinocyte transformation theory
May arise from toker cells (clear cells in epidermis)
Embryologic milk line remnants may be involved.
Classification:
Classified as primary EMPD (90-95%) or secondary EMPD (5-10%)
Primary: arising de novo from apocrine structures
Secondary: epidermotropic spread from underlying carcinoma
Invasive EMPD when basement membrane is breached
Pagetoid spread pattern characteristic
Associated with underlying adenocarcinoma in some cases.
Epidemiology:
Peak incidence in 6th-8th decades
Extremely rare before age 50
Female predominance (M:F = 1:4)
Most common in Caucasian and Asian populations
Associated with underlying invasive carcinoma in 10-25%
May be associated with distant malignancies
Recurrence rate high without complete excision.
Clinical Features
Presentation:
Erythematous, eczematous plaque with sharp demarcation
Chronic pruritus (cardinal symptom)
Scaling and crusting
Weeping and maceration
White, thickened areas alternating with erythema
May ulcerate and bleed
Slow-growing lesion over months to years.
Symptoms:
Intense pruritus (85-95% cases)
Burning sensation (60-70%)
Pain and soreness
Bleeding (if ulcerated)
Vulvar irritation
Discharge
Dyspareunia
Sleep disturbance due to itching
Secondary bacterial infection common.
Risk Factors:
Advanced age (>60 years)
Fair skin complexion
Immunosuppression
Chronic vulvar dermatoses
History of breast cancer
Genetic predisposition (rare)
Diabetes mellitus
Obesity
Poor vulvar hygiene.
Screening:
No specific screening protocol
Careful vulvar examination in elderly women
Biopsy of persistent eczematous lesions
High clinical suspicion needed
Dermoscopy may help
Photography for lesion mapping
Examination of other apocrine-bearing areas.
Master Extramammary Paget Disease Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Well-demarcated erythematous plaque with irregular, map-like borders
Eczematous appearance with fine scaling
Velvet-like surface
Areas of hyperpigmentation and hypopigmentation
Thickened, leathery texture
May show erosions and crusting.
Characteristics:
Sharp demarcation from normal skin
Scaling and hyperkeratosis
Areas of weeping and maceration
Satellite lesions may be present
Geographic borders with peninsular extensions
Color varies from pink to dark red.
Size Location:
Size ranges from 2-25 cm (mean 8-12 cm)
Most commonly labia majora (70-80%)
May involve mons pubis (40%)
Perianal extension (30-40%)
Bilateral involvement possible
Extensive disease common at presentation.
Multifocality:
Multifocal disease in 40-50% cases
Skip lesions frequent
May extend beyond clinically apparent borders
Subclinical extension common
Involvement of hair follicles and adnexa
Pagetoid spread pattern.
Microscopic Description
Histological Features:
Large Paget cells scattered throughout epidermis, predominantly in basal and suprabasal layers
Cells have abundant pale, vacuolated cytoplasm
Large vesicular nuclei with prominent nucleoli
Acanthosis and hyperkeratosis
Underlying chronic inflammatory infiltrate.
Cellular Characteristics:
Paget cells 2-3 times larger than normal keratinocytes
Pale, foamy cytoplasm with vacuoles
Eccentric, large nuclei with prominent nucleoli
High nuclear-cytoplasmic ratio
PAS-positive, diastase-resistant material
May contain mucin droplets
Mitotic figures present.
Architectural Patterns:
Cells arranged singly or in small clusters
Pagetoid pattern of spread
May form small glandular structures
Involvement of adnexal structures (hair follicles, sweat ducts)
Full-thickness epidermal involvement possible
Underlying dermis shows chronic inflammation.
Grading Criteria:
No standard grading system
Assessment based on extent of epidermal involvement
Presence of invasive component
Depth of invasion (if present)
Mitotic activity
Lymphovascular invasion
Perineural invasion
Thickness of lesion.
Immunohistochemistry
Positive Markers:
CK7 (95-100% positive)
CEA (80-95%)
EMA (85-95%)
GCDFP-15 (60-80%, apocrine marker)
Androgen receptor (70-90%)
CK20 (variable, 10-30%)
Her2/neu (25-40%)
Mammaglobin (40-60%).
Negative Markers:
S-100 (negative)
Melanoma markers (HMB-45, Melan-A negative)
p63 (negative)
CK5/6 (negative)
CDX2 (usually negative)
TTF-1 (negative)
High molecular weight cytokeratins (negative).
Diagnostic Utility:
Essential for differential diagnosis
CK7 and CEA are most consistent markers
GCDFP-15 positivity supports apocrine origin
Androgen receptor useful in EMPD diagnosis
Her2/neu assessment for targeted therapy
CK20 and CDX2 help exclude secondary spread.
Molecular Subtypes:
Primary vulvar EMPD: CK7+, CEA+, GCDFP-15+, AR+
Secondary type: Variable pattern based on primary site
Her2/neu amplified subset
Hormone receptor expression variable
p53 aberrant expression in high-grade lesions.
Molecular/Genetic
Genetic Mutations:
PIK3CA mutations (30-50%)
TP53 mutations (25-40%)
Her2/neu amplification (25-40%)
HRAS mutations (20-30%)
BRAF mutations (rare, <10%)
PTEN loss (15-25%)
KRAS mutations (10-20%).
Molecular Markers:
Microsatellite stability (most cases)
Her2/neu overexpression in subset
p53 overexpression correlates with invasive behavior
Ki-67 proliferation index variable
Chromosomal instability
DNA methylation abnormalities.
Prognostic Significance:
Invasive component most important prognostic factor
Invasion depth correlates with lymph node metastasis
Her2/neu amplification may predict therapy response
p53 mutations associated with aggressive behavior
Multifocal disease increases recurrence risk
Positive margins predict recurrence.
Therapeutic Targets:
Her2/neu targeted therapy: Trastuzumab (amplified cases)
Topical immunomodulators: Imiquimod
Photodynamic therapy
Laser ablation
Wide local excision remains standard
Radiotherapy for unresectable disease
Androgen receptor targeting under investigation.
Differential Diagnosis
Similar Entities:
Malignant melanoma (amelanotic variant)
Squamous cell carcinoma in situ
Seborrheic keratosis
Chronic dermatitis
Lichen sclerosus
Vulvar intraepithelial neoplasia
Contact dermatitis
Psoriasis.
Distinguishing Features:
EMPD: CK7, CEA, GCDFP-15 positive
EMPD: Melanoma markers negative
Melanoma: S-100, HMB-45 positive
SCC in situ: p63 positive, CK7 negative
Dermatitis: No atypical cells
VIN: p16 positive, HPV-related
Immunohistochemistry essential.
Diagnostic Challenges:
Distinguishing from amelanotic melanoma
Secondary vs primary EMPD
Extensive sampling needed for invasive component assessment
Margin assessment challenging due to pagetoid spread
Skip lesions may be missed
Clinical correlation essential.
Rare Variants:
Invasive EMPD (10-25% of cases)
Signet ring cell variant
Clear cell variant
Sebaceous differentiation
Squamous differentiation
Neuroendocrine features
Apocrine carcinoma transformation.
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 from [site], measuring [size] cm in greatest dimension
Diagnosis
Vulvar extramammary Paget disease
Classification
Classification: [Intraepithelial/Invasive], type: [Primary/Secondary]
Histological Features
Shows [Paget cell distribution] with [cellular morphology] and [epidermal changes]
Invasion Assessment
Invasive component: [present/absent], depth of invasion: [X mm if present]
Margins
Margins: [clear/involved], closest margin [X] mm from Paget cells
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Adnexal Involvement
Adnexal structures: [involved/uninvolved]
Special Studies
IHC: CK7: [result], CEA: [result], GCDFP-15: [result], Her2/neu: [result]
Molecular: [test if performed]: [result]
[other study]: [result]
Prognostic Factors
Prognostic factors: invasion status, margin status, multifocality
Final Diagnosis
Vulvar extramammary Paget disease, [intraepithelial/invasive], margins [status]