Definition/General
Introduction:
Vulvar glassy cell carcinoma is an extremely rare variant of poorly differentiated adenosquamous carcinoma characterized by ground-glass cytoplasm
It comprises less than 0.5% of all vulvar malignancies
First described in the cervix, vulvar cases are exceptionally rare
It demonstrates aggressive clinical behavior with poor prognosis.
Origin:
Thought to arise from pluripotent cells capable of both squamous and glandular differentiation
May originate from Bartholin glands or surface epithelium
Shows features of both adenocarcinoma and squamous carcinoma
Often associated with HPV infection in younger patients.
Classification:
Classified as adenosquamous carcinoma variant
WHO classification includes it under rare vulvar tumors
Shows both squamous and glandular differentiation
Considered high-grade malignancy by definition
No standard grading system established.
Epidemiology:
Peak incidence in 4th-6th decades
More aggressive than conventional cervical counterpart
Associated with HPV infection (types 16, 18)
Higher incidence in immunocompromised patients
Extremely rare worldwide with few reported cases.
Clinical Features
Presentation:
Rapidly growing vulvar mass
Ulceration with friable surface
Bleeding (spontaneous or contact)
Early lymph node involvement
Pain and discomfort
May present as Bartholin gland mass.
Symptoms:
Vulvar pain (80-90%)
Bleeding episodes (70-80%)
Rapid symptom progression
Dysuria (40-50%)
Vulvar swelling and mass effect
Constitutional symptoms (fatigue, weight loss).
Risk Factors:
High-risk HPV infection (types 16, 18)
Immunosuppression (HIV, transplant recipients)
Previous vulvar intraepithelial neoplasia
Smoking
Young age (relative to other vulvar cancers)
Multiple sexual partners.
Screening:
Regular gynecological examination
HPV testing in high-risk patients
Colposcopy for suspicious lesions
Early biopsy of any suspicious vulvar lesion
Clinical vigilance for rapid growth.
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Gross Description
Appearance:
Polypoid or ulcerative mass with friable surface
Tan to gray-pink cut surface
Soft to firm consistency
Areas of necrosis and hemorrhage
May show cystic degeneration.
Characteristics:
Size typically 2-6 cm in diameter
Poorly circumscribed margins
Cut surface shows solid areas with necrosis
May have mucoid appearance
Surface often ulcerated and friable.
Size Location:
Variable size (usually 3-5 cm)
Can arise from any vulvar site
Bartholin gland area common location
May involve labia majora or minora
Multifocal disease possible.
Multifocality:
Usually unifocal at presentation
May extend to adjacent structures
Early lymph node involvement common
Distant metastases may occur early
Aggressive local growth pattern.
Microscopic Description
Histological Features:
Characterized by cells with ground-glass cytoplasm (glassy appearance)
Large vesicular nuclei with prominent nucleoli
Mixture of squamous and glandular differentiation
High mitotic activity
Extensive necrosis common.
Cellular Characteristics:
Ground-glass cytoplasm (pathognomonic feature)
Large cells with vesicular nuclei
Prominent eosinophilic nucleoli
Moderate to abundant cytoplasm
Pleomorphic nuclear features
High nuclear-cytoplasmic ratio.
Architectural Patterns:
Solid sheets and nests of tumor cells
Glandular structures may be present
Surface squamous differentiation
Invasive growth pattern
Desmoplastic stroma
Lymphovascular invasion common.
Grading Criteria:
Considered high-grade by definition
High mitotic index (>10/10 HPF)
Marked nuclear pleomorphism
Extensive necrosis
No established grading system
Poor differentiation typical.
Immunohistochemistry
Positive Markers:
CEA (cytoplasmic and membranous)
p16 (block-type staining)
CK7 (variable)
p63 (focal, squamous areas)
CK5/6 (focal)
p53 (often mutant pattern)
Ki-67 (high proliferation index).
Negative Markers:
CK20 (negative)
TTF-1 (negative)
CDX2 (negative)
ER/PR (negative)
Vimentin (negative)
S-100 (negative)
Calretinin (negative).
Diagnostic Utility:
CEA positivity is characteristic feature
p16 helps identify HPV-related cases
p63 confirms squamous component
CK7 may be positive in glandular areas
Combination pattern supports diagnosis.
Molecular Subtypes:
HPV-related type (p16 positive, younger patients)
Mixed squamous-glandular phenotype
High-grade morphology by definition
CEA expression pattern important.
Molecular/Genetic
Genetic Mutations:
HPV integration (especially types 16, 18)
TP53 mutations (common)
PIK3CA mutations
CDKN2A alterations
Similar profile to cervical glassy cell carcinoma
Limited molecular data due to rarity.
Molecular Markers:
p16 overexpression (HPV-related cases)
p53 overexpression (mutant pattern)
High Ki-67 proliferation index (>70%)
HPV DNA detection (PCR/ISH)
CEA overexpression.
Prognostic Significance:
Poor prognosis by definition
HPV status may influence response
High proliferation index indicates aggressive behavior
Early metastasis common
Lymph node status crucial prognostic factor.
Therapeutic Targets:
Limited targeted therapy data
HPV-targeted immunotherapy
Conventional chemotherapy (cisplatin-based)
Radiotherapy may be used
Immunotherapy trials ongoing.
Differential Diagnosis
Similar Entities:
Clear cell carcinoma
Adenosquamous carcinoma (conventional)
Poorly differentiated adenocarcinoma
Metastatic carcinoma (cervical, endometrial)
Sebaceous carcinoma.
Distinguishing Features:
Glassy cell: Ground-glass cytoplasm
Glassy cell: CEA positive
Clear cell: Clear cytoplasm
Clear cell: Hobnail cells
Conventional adenosquamous: Distinct components
Sebaceous: Sebaceous differentiation
Sebaceous: Oil Red O positive.
Diagnostic Challenges:
Recognition of ground-glass cytoplasm
Differentiation from clear cell carcinoma
Identification of dual differentiation
Distinction from metastatic disease
CEA immunostaining helpful.
Rare Variants:
Mixed patterns with conventional squamous carcinoma
Predominantly glandular variant
Neuroendocrine differentiation (rare)
Mixed with other rare vulvar tumors.
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 Glassy Cell Carcinoma
Classification
Classification: Adenosquamous carcinoma, glassy cell variant, high-grade
Histological Features
Shows cells with ground-glass cytoplasm, [squamous and glandular differentiation]
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]
HPV Status
p16 immunostaining: [positive/negative] (block-type pattern)
Immunohistochemistry
CEA: [positive/negative]
p16: [positive/negative]
p63/CK5/6: [positive/negative in squamous areas]
Prognostic Factors
Tumor size, lymphovascular invasion, HPV status, margin status
Final Diagnosis
Vulvar Glassy Cell Carcinoma (Adenosquamous carcinoma, glassy cell variant)