Definition/General
Introduction:
Vulvar clear cell carcinoma is a rare adenocarcinoma subtype characterized by cells with clear or eosinophilic cytoplasm
It comprises less than 1% of all vulvar malignancies
Shows distinctive hobnail cell morphology
Associated with diethylstilbestrol (DES) exposure in some cases
Demonstrates aggressive clinical behavior.
Origin:
Arises from Bartholin glands or embryonic remnants
May originate from mesonephric duct remnants
Can arise from endometriotic foci
Shows müllerian differentiation
Associated with DES exposure (maternal ingestion).
Classification:
Classified as adenocarcinoma, clear cell type
WHO classification includes under glandular tumors
Shows similar morphology to cervical and vaginal clear cell carcinoma
High-grade malignancy by definition
No standard grading system.
Epidemiology:
Peak incidence in 3rd-5th decades
Younger than conventional vulvar cancers
Associated with DES exposure (in utero)
Higher incidence in nulliparous women
No clear HPV association
Extremely rare entity worldwide.
Clinical Features
Presentation:
Vulvar mass or nodule
May present as Bartholin gland cyst
Bleeding (contact or spontaneous)
Vulvar pain and discomfort
Rapid growth pattern
Early lymph node involvement possible.
Symptoms:
Vulvar pain (60-70%)
Bleeding episodes (50-60%)
Vulvar swelling and mass effect
Dysuria (30-40%)
Asymptomatic mass (20-30%)
Constitutional symptoms (advanced cases).
Risk Factors:
DES exposure (in utero)
History of pelvic endometriosis
Previous vulvar adenosis
Nulliparity
Young age (relative to other vulvar cancers)
No established HPV association.
Screening:
Regular gynecological examination
Special attention in DES-exposed patients
Clinical examination of vulva
Early biopsy of suspicious lesions
Imaging for extent assessment.
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Gross Description
Appearance:
Well-circumscribed nodular mass
Tan to gray-white cut surface
Soft to firm consistency
May show cystic areas
Areas of hemorrhage and necrosis.
Characteristics:
Size typically 2-8 cm in diameter
Relatively well-circumscribed margins
Cut surface shows solid areas with cysts
May have mucoid appearance
Surface may be intact or ulcerated.
Size Location:
Variable size (usually 3-6 cm)
Commonly arises from Bartholin gland area
May involve vestibule
Posterior fourchette involvement
Can be deeply seated
May extend to adjacent structures.
Multifocality:
Usually unifocal
May be associated with vulvar adenosis
Local extension common
Lymph node involvement in advanced cases
Distant metastases possible.
Microscopic Description
Histological Features:
Characterized by cells with clear or eosinophilic cytoplasm
Hobnail cell morphology (protruding nuclei)
Tubulocystic and papillary patterns
PAS-positive, diastase-resistant cytoplasm
Basement membrane thickening.
Cellular Characteristics:
Clear cytoplasm (glycogen-rich)
Hobnail cells with protruding nuclei
Cuboidal to columnar cells
Moderate nuclear pleomorphism
Prominent nucleoli
Variable mitotic activity.
Architectural Patterns:
Tubulocystic pattern (most common)
Papillary architecture
Solid areas with clear cells
Cribriform pattern
Mixed architectural patterns common
Hyalinized stroma.
Grading Criteria:
Considered high-grade by definition
Nuclear grade assessment important
Mitotic activity variable
Architectural complexity
Stromal invasion pattern
No standardized grading system.
Immunohistochemistry
Positive Markers:
PAX8 (positive)
CA-125 (positive)
CK7 (positive)
EMA (positive)
Napsin A (positive)
WT1 (positive)
Vimentin (positive)
ER (variable).
Negative Markers:
CK20 (negative)
TTF-1 (negative)
CDX2 (negative)
p63 (negative)
CK5/6 (negative)
CEA (negative)
Calretinin (negative).
Diagnostic Utility:
PAX8 positivity supports müllerian origin
Napsin A helps distinguish from metastatic renal carcinoma
CK7 positive, CK20 negative pattern
p63 negativity excludes squamous carcinoma
ER variability noted.
Molecular Subtypes:
DES-related vs sporadic types
Müllerian phenotype (PAX8+, CK7+)
Different from renal clear cell carcinoma
Distinct immunoprofile.
Molecular/Genetic
Genetic Mutations:
PIK3CA mutations (20-30%)
PTEN loss (15-25%)
TP53 mutations (variable)
ARID1A mutations (10-20%)
Different from renal clear cell carcinoma profile
Limited molecular data due to rarity.
Molecular Markers:
PAX8 overexpression
CA-125 elevation
Variable ER expression
Napsin A positivity
Ki-67 proliferation index (moderate)
Loss of PTEN expression.
Prognostic Significance:
Stage at presentation most important factor
Size correlates with prognosis
Lymph node status crucial
Histological pattern may influence outcome
Early detection improves prognosis.
Therapeutic Targets:
Limited targeted therapy options
Platinum-based chemotherapy
Possible benefit from antiangiogenic agents
Hormonal therapy (ER-positive cases)
Immunotherapy under investigation.
Differential Diagnosis
Similar Entities:
Metastatic clear cell carcinoma (renal, ovarian)
Yolk sac tumor
Bartholin gland adenocarcinoma
Metastatic endometrial carcinoma
Sebaceous carcinoma.
Distinguishing Features:
Vulvar clear cell: PAX8 positive
Vulvar clear cell: Napsin A positive
Renal clear cell: RCC marker positive
Renal clear cell: PAX8 negative (usually)
Yolk sac: AFP positive
Yolk sac: Young age
Sebaceous: Oil Red O positive.
Diagnostic Challenges:
Differentiation from metastatic renal carcinoma
Distinction from yolk sac tumor (young patients)
Separation from Bartholin gland adenocarcinoma
Immunohistochemistry essential
Clinical correlation important.
Rare Variants:
Mixed patterns with other adenocarcinoma types
Predominantly solid variant
Signet ring features (rare)
Mixed with squamous elements (rare).
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
[specimen type], measuring [size] cm in greatest dimension
Diagnosis
Vulvar Clear Cell Carcinoma
Classification
Classification: Adenocarcinoma, clear cell type, high-grade
Histological Features
Shows clear cells with [architectural pattern] and [hobnail morphology]
Size and Extent
Size: [X] cm, extent: [local/regional]
Margins
Margins are [involved/uninvolved] with closest margin [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Immunohistochemistry
PAX8: [positive/negative], CA-125: [positive/negative]
Napsin A: [positive/negative]
p63: [negative], RCC marker: [negative]
Prognostic Factors
Tumor size, architectural pattern, lymphovascular invasion, margin status
Final Diagnosis
Vulvar Clear Cell Carcinoma (Adenocarcinoma, clear cell type)