Definition/General

Introduction:
-Vulvar squamous cell carcinoma is the most common malignant neoplasm of the vulva, accounting for 85-90% of all vulvar cancers
-It arises from the squamous epithelium of the vulvar skin and mucosa
-The tumor demonstrates keratinizing or non-keratinizing patterns
-It frequently arises in association with high-risk HPV infection or chronic inflammatory conditions.
Origin:
-Originates from the stratified squamous epithelium of the vulvar skin, labia majora, labia minora, clitoris, or vestibule
-Two distinct pathways exist: HPV-related pathway in younger women and non-HPV-related pathway in older women
-The HPV-related pathway involves high-risk HPV types 16 and 18
-The non-HPV pathway is associated with chronic inflammatory conditions like lichen sclerosus.
Classification:
-WHO classification recognizes keratinizing squamous cell carcinoma (most common)
-Non-keratinizing squamous cell carcinoma
-Basaloid squamous cell carcinoma
-Warty squamous cell carcinoma
-Verrucous carcinoma
-Grading follows three-tier system: Grade 1 (well-differentiated)
-Grade 2 (moderately differentiated)
-Grade 3 (poorly differentiated).
Epidemiology:
-Peak incidence in 6th-7th decades for non-HPV-related tumors
-Younger age distribution (4th-5th decades) for HPV-related tumors
-Accounts for 3-5% of all gynecological malignancies
-Risk factors include HPV infection
-Lichen sclerosus
-Smoking
-Immunosuppression
-Multiple sexual partners
-Increasing incidence in younger women due to HPV-related cases.

Clinical Features

Presentation:
-Vulvar mass or nodule (most common presentation)
-Vulvar itching (pruritus vulvae) in 60-70% cases
-Vulvar pain or burning sensation
-Bleeding or discharge from the lesion
-Dysuria (painful urination)
-Skin changes including thickening, discoloration, or ulceration
-Inguinal lymphadenopathy in advanced cases.
Symptoms:
-Chronic vulvar itching (most common symptom)
-Vulvar pain or burning (50-60% cases)
-Bleeding from the lesion (30-40%)
-Vulvar discharge (20-30%)
-Dyspareunia (painful intercourse)
-Urinary symptoms including dysuria and urgency
-Difficulty with sitting or wearing tight clothing.
Risk Factors:
-HPV infection (types 16, 18, 31, 33)
-Lichen sclerosus (10-15% risk of malignant transformation)
-Vulvar intraepithelial neoplasia (VIN)
-Smoking (3-4 fold increased risk)
-Immunosuppression
-Multiple sexual partners
-Early age at first intercourse
-Chronic inflammatory conditions
-History of cervical or vaginal cancer.
Screening:
-No specific screening program exists
-Regular gynecological examination recommended
-Self-examination of vulvar area
-Prompt evaluation of persistent vulvar symptoms
-HPV vaccination for prevention
-Biopsy of suspicious lesions
-High-risk patients require closer surveillance.

Master Vulvar SCC Pathology with RxDx

Access 100+ pathology videos and expert guidance with the RxDx app

Gross Description

Appearance:
-Exophytic or endophytic growth pattern
-Ulcerated or fungating mass with irregular surface
-Gray-white to tan-brown coloration
-Firm to hard consistency
-Well-demarcated or infiltrative margins
-Keratotic surface in keratinizing type
-Necrosis and hemorrhage may be present.
Characteristics:
-Size ranges from few millimeters to >10 cm
-Single or multiple lesions
-Verrucous or papillary surface in some cases
-Deep infiltration into underlying tissues
-Involvement of adjacent structures
-Satellite nodules may be present
-Secondary infection common in ulcerated lesions.
Size Location:
-Labia majora (most common site - 50%)
-Labia minora (30%)
-Clitoris (10%)
-Posterior fourchette (5%)
-Perineum (5%)
-Size varies from microscopic to >15 cm
-Unifocal in 80% cases
-Multifocal disease in 20% cases.

Microscopic Description

Histological Features:
-Malignant squamous cells arranged in sheets, nests, and cords
-Keratinization with keratin pearl formation (keratinizing type)
-Intercellular bridges (desmosomes) characteristic of squamous differentiation
-Nuclear pleomorphism and hyperchromatism
-Increased mitotic activity
-Stromal invasion with desmoplastic reaction
-Inflammatory infiltrate at tumor-stroma interface.
Cellular Characteristics:
-Large polygonal cells with abundant eosinophilic cytoplasm
-Enlarged hyperchromatic nuclei with irregular contours
-Prominent nucleoli in poorly differentiated tumors
-Individual cell keratinization (dyskeratosis)
-Mitotic figures including atypical forms
-Variable degree of pleomorphism depending on grade
-Glycogen-rich cytoplasm (PAS positive).
Architectural Patterns:
-Keratinizing type: Well-formed keratin pearls, extensive keratinization
-Non-keratinizing type: Minimal keratinization, solid growth pattern
-Basaloid type: Small basophilic cells, peripheral palisading
-Warty type: Papillary architecture, koilocytosis
-Verrucous type: Warty surface, pushing borders, minimal atypia.
Grading Criteria:
-Grade 1 (Well-differentiated): >75% keratinization, minimal nuclear atypia, <5 mitoses/10 HPF
-Grade 2 (Moderately differentiated): 25-75% keratinization, moderate atypia, 5-10 mitoses/10 HPF
-Grade 3 (Poorly differentiated): <25% keratinization, marked atypia, >10 mitoses/10 HPF
-Depth of invasion measured from basement membrane
-Lymphovascular invasion affects staging.

Immunohistochemistry

Positive Markers:
-p63 (nuclear positivity in basal/squamous cells)
-CK5/6 (high molecular weight cytokeratins)
-CK14 (squamous differentiation marker)
-p40 (specific squamous cell marker)
-CK17 (expressed in squamous carcinomas)
-p16 (block-like positivity in HPV-related tumors)
-EMA (variable positivity).
Negative Markers:
-CK7 (usually negative, helps exclude adenocarcinoma)
-CK20 (negative in primary vulvar tumors)
-TTF-1 (negative, excludes lung primary)
-CDX2 (negative, excludes GI primary)
-ER/PR (usually negative)
-S-100 (negative, excludes melanoma)
-Vimentin (negative in epithelial tumors).
Diagnostic Utility:
-p16 immunostaining helps identify HPV-related tumors (block-like positivity)
-p53 staining pattern: Wild-type in HPV-related, mutant pattern in non-HPV-related
-Squamous markers (p63, CK5/6) confirm squamous differentiation
-CK7 negativity helps exclude metastatic adenocarcinoma
-S-100 negativity excludes melanoma
-Ki-67 proliferation index correlates with grade.
Molecular Subtypes:
-HPV-related subtype: p16 positive, p53 wild-type, younger patients
-Non-HPV-related subtype: p16 negative, p53 mutant pattern, older patients
-Keratinizing type: Usually non-HPV-related, p16 negative
-Non-keratinizing/basaloid type: Usually HPV-related, p16 positive
-Warty type: HPV-related, p16 positive.

Molecular/Genetic

Genetic Mutations:
-HPV integration in 30-50% of cases (types 16, 18, 31, 33)
-TP53 mutations (60-80% in non-HPV-related tumors)
-PIK3CA mutations (20-30%)
-CDKN2A deletions (20-25%)
-HRAS mutations (5-10%)
-FGFR3 mutations (rare)
-NOTCH1 mutations (10-15%).
Molecular Markers:
-p16 overexpression in HPV-related tumors (surrogate marker)
-p53 accumulation in non-HPV-related tumors
-Ki-67 proliferation index (higher in high-grade tumors)
-EGFR overexpression (40-60%)
-Cyclin D1 overexpression
-bcl-2 expression (variable)
-VEGF expression (angiogenesis marker).
Prognostic Significance:
-HPV status: HPV-related tumors have better prognosis
-TP53 mutation: Associated with poor prognosis in non-HPV tumors
-Tumor grade: Higher grade associated with worse outcome
-Lymphovascular invasion: Increased risk of metastasis
-Depth of invasion: >1 mm associated with lymph node involvement
-Tumor size: >2 cm associated with poor prognosis.
Therapeutic Targets:
-EGFR inhibitors: Cetuximab for EGFR-positive tumors
-PD-1/PD-L1 inhibitors: Pembrolizumab for advanced disease
-mTOR pathway inhibitors: For PIK3CA-mutated tumors
-CDK4/6 inhibitors: For tumors with intact Rb pathway
-Anti-angiogenic agents: Bevacizumab for advanced disease
-Immunotherapy: Particularly effective in HPV-related tumors.

Differential Diagnosis

Similar Entities:
-Vulvar melanoma (amelanotic type may mimic SCC)
-Vulvar adenocarcinoma (Bartholin gland, Skene gland origin)
-Metastatic carcinoma (cervical, endometrial, colorectal)
-Vulvar basal cell carcinoma
-Vulvar Paget disease
-Pseudoepitheliomatous hyperplasia
-Verrucous carcinoma.
Distinguishing Features:
-Vulvar SCC: p63 positive, CK5/6 positive, squamous differentiation
-Melanoma: S-100 positive, Melan-A positive, HMB-45 positive
-Adenocarcinoma: CK7 positive, mucin production, glandular pattern
-Metastatic tumors: Site-specific markers (TTF-1 for lung, CDX2 for GI)
-Basal cell carcinoma: Basaloid cells, peripheral palisading, BerEP4 positive
-Paget disease: Large pale cells, CK7 positive, mucin positive.
Diagnostic Challenges:
-Distinguishing SCC from pseudoepitheliomatous hyperplasia: Lack of stromal invasion in hyperplasia
-Verrucous carcinoma vs well-differentiated SCC: Pushing borders and minimal atypia in verrucous type
-HPV-related vs non-HPV-related SCC: p16 immunostaining crucial
-Primary vs metastatic SCC: Clinical correlation and immunohistochemistry
-Grade assessment: May be challenging in small biopsies.
Rare Variants:
-Spindle cell squamous carcinoma: Sarcomatoid features, vimentin positive
-Acantholytic squamous carcinoma: Pseudoglandular spaces, acantholysis
-Clear cell squamous carcinoma: Clear cytoplasm, glycogen rich
-Papillary squamous carcinoma: Papillary architecture
-Lymphoepithelioma-like carcinoma: Dense lymphocytic infiltrate.

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

Vulvectomy specimen, [partial/radical], measuring [X x Y x Z] cm

Diagnosis

Invasive squamous cell carcinoma, [keratinizing/non-keratinizing] type

Histological Grade

Grade [1/2/3] ([well/moderately/poorly] differentiated)

Histological Features

Tumor shows [architectural pattern] with [cellular features] and [degree of keratinization]

Size and Extent

Tumor size: [X] cm, depth of invasion: [X] mm, extent: [anatomical involvement]

Surgical Margins

Margins: [involved/close/clear], closest margin: [X] mm from [location]

Lymphovascular Invasion

Lymphovascular invasion: [present/absent]

Perineural Invasion

Perineural invasion: [present/absent]

Lymph Node Status

Lymph nodes: [X] positive out of [Y] examined, largest deposit [X] mm

Immunohistochemistry

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

p16: [positive/negative - block-like/patchy/negative]

[Other relevant markers and results]

Associated Lesions

Background vulvar changes: [VIN/lichen sclerosus/normal/other]

Pathological Staging

pT[stage] pN[stage] - FIGO Stage [stage]

Final Diagnosis

Invasive squamous cell carcinoma of vulva, [type], Grade [grade], pT[stage]N[stage]