Definition/General

Introduction:
-Vulvar large cell carcinoma is an extremely rare subtype of vulvar squamous cell carcinoma characterized by large polygonal cells with abundant eosinophilic cytoplasm
-It comprises less than 1% of all vulvar malignancies
-It shows poor differentiation with aggressive clinical behavior
-It requires differentiation from other high-grade vulvar carcinomas.
Origin:
-Arises from the stratified squamous epithelium of the vulva
-Shows progression from usual-type vulvar intraepithelial neoplasia (uVIN)
-Often associated with high-risk HPV infection (HPV 16, 18)
-May arise de novo in elderly patients
-Shows transformation to poorly differentiated phenotype.
Classification:
-Classified as a variant of squamous cell carcinoma
-WHO classification includes it under squamous cell carcinoma, NOS
-Grading follows three-tier system
-Grade 3 (poorly differentiated) most common
-Associated with keratinizing or non-keratinizing patterns.
Epidemiology:
-Peak incidence in 6th-7th decades
-Rare in patients under 40 years
-Associated with HPV infection in younger patients
-Non-HPV related in elderly patients
-Higher incidence in immunocompromised patients
-Indian studies show increasing incidence in urban populations.

Clinical Features

Presentation:
-Vulvar mass or nodule (most common)
-Ulceration with irregular borders
-Bleeding (contact or spontaneous)
-Pruritus and vulvar discomfort
-Rapid growth pattern
-Inguinal lymphadenopathy (30-40% at presentation).
Symptoms:
-Vulvar pain and discomfort (70-80%)
-Bleeding episodes (50-60%)
-Pruritus (40-50%)
-Dysuria (30%)
-Constitutional symptoms (weight loss, fatigue)
-Foul-smelling discharge (infected cases).
Risk Factors:
-High-risk HPV infection (types 16, 18)
-Immunosuppression (HIV, organ transplant)
-Chronic vulvar inflammation
-Previous vulvar intraepithelial neoplasia
-Smoking
-Advanced age (>60 years)
-Multiple sexual partners.
Screening:
-Regular gynecological examination
-Visual inspection of vulva
-Colposcopy for suspicious lesions
-HPV testing in high-risk patients
-Biopsy for definitive diagnosis.

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Gross Description

Appearance:
-Exophytic or ulcerative mass with irregular borders
-Tan to gray-white cut surface
-Areas of necrosis and hemorrhage
-Firm to hard consistency
-May show surface keratinization.
Characteristics:
-Size ranges from 1-8 cm in diameter
-Irregular, infiltrative margins
-Cut surface shows solid areas with necrosis
-May have cystic degeneration
-Surface may be ulcerated or verrucous.
Size Location:
-Variable size (typically 2-5 cm)
-Most commonly affects labia majora (40-50%)
-Labia minora involvement (20-30%)
-Clitoral area (10-15%)
-Perineum (10%)
-May be multifocal (15-20%).
Multifocality:
-Unifocal in majority of cases (80%)
-Multifocal disease in 15-20%
-May extend to adjacent structures
-Inguinal lymph node involvement common
-Distant metastases rare at presentation.

Microscopic Description

Histological Features:
-Characterized by large polygonal cells with abundant eosinophilic cytoplasm
-Vesicular nuclei with prominent nucleoli
-High nuclear-cytoplasmic ratio
-Marked nuclear pleomorphism
-Frequent mitotic figures including atypical forms.
Cellular Characteristics:
-Large tumor cells (3-5 times normal keratinocyte size)
-Abundant eosinophilic cytoplasm
-Vesicular nuclei with irregular contours
-Multiple prominent nucleoli
-Occasional multinucleated giant cells
-High mitotic index (>20/10 HPF).
Architectural Patterns:
-Solid growth pattern predominates
-Sheets and nests of large cells
-Minimal glandular differentiation
-Pushing invasion pattern at tumor front
-Associated desmoplastic stroma
-Surface ulceration common.
Grading Criteria:
-Follows three-tier grading system
-Predominantly Grade 3 (poorly differentiated)
-Based on nuclear pleomorphism
-Mitotic activity assessment
-Degree of keratinization
-Invasion pattern evaluation.

Immunohistochemistry

Positive Markers:
-p63 (diffusely positive)
-CK5/6 (positive)
-p16 (block-type staining in HPV-related)
-p53 (often mutant pattern)
-CK14 (positive)
-p40 (positive)
-EMA (focal positive).
Negative Markers:
-CK7 (negative)
-CK20 (negative)
-TTF-1 (negative)
-CDX2 (negative)
-S-100 (negative)
-Desmin (negative)
-ER/PR (negative).
Diagnostic Utility:
-p63 and CK5/6 confirm squamous differentiation
-p16 helps identify HPV-related cases
-p53 pattern indicates mutation status
-Helps differentiate from poorly differentiated adenocarcinoma
-Useful in metastatic workup.
Molecular Subtypes:
-HPV-related type (p16 positive, younger patients)
-HPV-independent type (p16 negative, elderly patients)
-p53 mutant pattern common
-Different therapeutic implications.

Molecular/Genetic

Genetic Mutations:
-TP53 mutations (60-70% of cases)
-HPV integration (30-40% of cases)
-PIK3CA mutations (20-30%)
-CDKN2A deletions (15-25%)
-NOTCH1 mutations (10-20%)
-TERT promoter mutations (10-15%).
Molecular Markers:
-p16 overexpression (HPV-related cases)
-p53 overexpression (mutant cases)
-High Ki-67 proliferation index (>50%)
-Loss of CDKN2A expression
-HPV DNA detection (PCR/ISH).
Prognostic Significance:
-HPV status correlates with prognosis
-p53 mutation indicates poor prognosis
-High Ki-67 associated with aggressive behavior
-Nodal involvement major prognostic factor
-Tumor size correlates with outcome.
Therapeutic Targets:
-Limited targeted therapy options
-Immunotherapy (PD-1/PD-L1 inhibitors)
-HPV vaccination for prevention
-Chemotherapy (cisplatin-based)
-Radiotherapy sensitivity variable.

Differential Diagnosis

Similar Entities:
-Poorly differentiated squamous cell carcinoma (conventional type)
-Undifferentiated carcinoma
-Metastatic carcinoma (lung, kidney)
-Amelanotic melanoma
-Anaplastic large cell lymphoma.
Distinguishing Features:
-Large cell: Large polygonal cells
-Large cell: Abundant eosinophilic cytoplasm
-Conventional SCC: Smaller cells
-Conventional SCC: Variable keratinization
-Melanoma: S-100 positive
-Melanoma: Melanin pigment
-Lymphoma: CD30 positive
-Lymphoma: Lymphoid markers.
Diagnostic Challenges:
-Distinguishing from poorly differentiated adenocarcinoma
-Separation from undifferentiated carcinoma
-Identification of metastatic disease
-HPV status determination
-Immunohistochemistry essential for accurate diagnosis.
Rare Variants:
-Large cell neuroendocrine carcinoma (neuroendocrine markers positive)
-Large cell carcinoma with sarcomatoid features
-Giant cell variant
-Mixed patterns with conventional squamous carcinoma.

Sample Pathology Report

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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 Large Cell Carcinoma

Classification

Classification: Squamous cell carcinoma, large cell variant, Grade [I/II/III]

Histological Features

Shows large polygonal cells with [nuclear features] and [mitotic activity]

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

p63: [positive/negative], CK5/6: [positive/negative]

p16: [positive/negative]

[other markers]: [results]

Prognostic Factors

Tumor size, grade, HPV status, lymphovascular invasion

Final Diagnosis

Vulvar Large Cell Carcinoma, Grade [I/II/III], [HPV-related/HPV-independent]