Definition/General
Introduction:
Vaginal squamous cell carcinoma (VSCC) is the most common primary malignancy of the vagina, accounting for 85-90% of all vaginal cancers
It arises from the stratified squamous epithelium lining the vaginal mucosa
Most cases are secondary to cervical cancer or represent metastases from other sites
Primary vaginal carcinoma is diagnosed only when the cervix and vulva are uninvolved.
Origin:
Originates from the stratified squamous epithelium of the vaginal mucosa
Most commonly develops in the upper third of the vagina, particularly the posterior wall
The neoplastic transformation is often preceded by vaginal intraepithelial neoplasia (VAIN)
Strong association with high-risk HPV, especially types 16 and 18
The tumor shows progressive invasion through the vaginal wall into surrounding structures.
Classification:
Classified according to FIGO staging system
Stage I: Carcinoma limited to vaginal wall
Stage II: Carcinoma involving paravaginal tissues
Stage III: Extension to pelvic wall
Stage IV: Extension beyond pelvis or involvement of bladder/rectal mucosa
WHO classification includes keratinizing and non-keratinizing variants
Grading follows three-tier system: well-differentiated (Grade 1), moderately differentiated (Grade 2), poorly differentiated (Grade 3).
Epidemiology:
Accounts for 1-2% of all gynecological malignancies
Peak incidence in 6th-7th decades of life
Median age at diagnosis is 60-65 years
HPV-related cases occur in younger women (40-50 years)
Strong association with history of cervical dysplasia or carcinoma
Risk factors include immunosuppression, chronic irritation, and smoking
Indian studies show increasing incidence with improving diagnostic awareness.
Clinical Features
Presentation:
Abnormal vaginal bleeding (80-90% of cases), especially post-coital or post-menopausal bleeding
Vaginal discharge (watery, bloody, or purulent)
Pelvic pain and dyspareunia
Urinary symptoms (frequency, urgency, dysuria) in advanced cases
Bowel symptoms (tenesmus, constipation) with posterior wall involvement
Mass effect symptoms in bulky tumors.
Symptoms:
Vaginal bleeding (most common presenting symptom)
Malodorous discharge with secondary infection
Pelvic pressure and discomfort
Dyspareunia and post-coital bleeding
Urinary incontinence or retention in advanced cases
Fecal incontinence with rectovaginal fistula
Leg edema due to lymphatic obstruction
Constitutional symptoms (weight loss, fatigue) in advanced disease.
Risk Factors:
High-risk HPV infection (types 16, 18, 31, 33, 45)
History of cervical intraepithelial neoplasia or carcinoma
Immunosuppression (HIV, organ transplantation)
Chronic irritation (pessary use, chronic infections)
Smoking and tobacco use
Multiple sexual partners and early sexual activity
Low socioeconomic status and poor hygiene
Previous pelvic radiation therapy.
Screening:
Pap smear may detect vaginal cells
HPV testing for high-risk types
Colposcopy with directed biopsy for suspicious lesions
Annual pelvic examination for high-risk women
Post-hysterectomy surveillance in women with history of cervical dysplasia
Visual inspection with acetic acid (VIA) in resource-limited settings.
Master Vaginal SCC Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Exophytic, polypoid growth with irregular, friable surface
Ulcerative lesions with raised, rolled margins
Flat, plaque-like lesions in early stages
Gray-white to pink coloration with areas of necrosis
Hemorrhage and ulceration in advanced cases
Surface may show keratin formation in well-differentiated tumors.
Characteristics:
Firm to hard consistency depending on degree of keratinization
Friable surface that bleeds easily on manipulation
Irregular margins with infiltrative growth pattern
Necrotic areas with foul-smelling discharge
Involvement of vaginal fornices in upper third tumors
Extension to paravaginal tissues in advanced cases.
Size Location:
Size ranges from small focal lesions to large masses (>5 cm)
Upper third of vagina most commonly affected (60-70%)
Posterior wall more frequently involved than anterior wall
Middle third involvement in 20-30% of cases
Lower third involvement in 10-15% of cases
Multifocal disease can occur, especially in HPV-related cases.
Multifocality:
Multifocal presentation in 10-20% of cases, especially in immunocompromised patients
Skip lesions may be present along the vaginal canal
Concurrent cervical involvement must be excluded for primary vaginal carcinoma diagnosis
Vulvar extension may occur in lower third tumors
Association with multicentric VAIN lesions.
Microscopic Description
Histological Features:
Invasive nests and cords of malignant squamous cells extending into vaginal stroma
Keratin pearl formation in well-differentiated tumors
Nuclear pleomorphism with enlarged, hyperchromatic nuclei
Prominent nucleoli and increased nuclear-cytoplasmic ratio
Mitotic activity with atypical mitoses
Desmoplastic stromal response with chronic inflammation.
Cellular Characteristics:
Polygonal cells with eosinophilic cytoplasm in keratinizing type
Intercellular bridges (desmosomes) characteristic of squamous differentiation
Individual cell keratinization with pyknotic nuclei
Non-keratinizing type shows larger cells with less cytoplasm
Basaloid pattern in poorly differentiated tumors
Koilocytic changes in HPV-associated cases.
Architectural Patterns:
Invasive nests and cords with irregular infiltrative pattern
Large tumor islands in well-differentiated cases
Single cell infiltration in poorly differentiated tumors
Perineural invasion may be present in aggressive cases
Lymphovascular invasion indicates metastatic potential
Surface ulceration with reactive epithelial changes at margins.
Grading Criteria:
Well-differentiated (Grade 1): >75% keratinization with keratin pearls
Moderately differentiated (Grade 2): 25-75% keratinization with moderate nuclear pleomorphism
Poorly differentiated (Grade 3): <25% keratinization with marked nuclear pleomorphism
Mitotic count and nuclear grade contribute to overall grading
Presence of koilocytes suggests HPV association.
Immunohistochemistry
Positive Markers:
p40 (nuclear, highly sensitive for squamous differentiation)
p63 (nuclear, marks basal and squamous cells)
CK5/6 (cytoplasmic, squamous epithelial marker)
CK14 (cytoplasmic, basal and squamous cells)
p16 (nuclear and cytoplasmic, HPV-associated cases show diffuse positivity)
Ki-67 (nuclear, proliferation marker, elevated in malignant cases).
Negative Markers:
CK7 (negative in most squamous cell carcinomas)
CK20 (negative, helps exclude colorectal origin)
TTF-1 (negative, helps exclude lung primary)
ER/PR (negative in most cases)
CDX2 (negative, excludes gastrointestinal origin)
PAX8 (negative, excludes gynecological adenocarcinomas).
Diagnostic Utility:
p16 overexpression indicates high-risk HPV association and better prognosis
p40/p63 positivity confirms squamous differentiation
CK5/6 expression helps differentiate from adenocarcinoma
Ki-67 index correlates with tumor grade and prognosis
Negative CK7 helps exclude metastatic adenocarcinoma
Panel approach recommended for accurate classification.
Molecular Subtypes:
HPV-positive type (p16 positive, better prognosis, younger age)
HPV-negative type (p16 negative, worse prognosis, older age)
Keratinizing type (often HPV-negative, worse prognosis)
Non-keratinizing type (often HPV-positive, better prognosis)
Basaloid variant (usually HPV-positive)
Verrucous variant (HPV-associated, indolent behavior).
Molecular/Genetic
Genetic Mutations:
HPV integration leads to E6 and E7 protein expression in 70-80% of cases
TP53 mutations (40-60%, more common in HPV-negative cases)
PIK3CA mutations (20-30% of cases)
CDKN2A/p16 alterations (except in HPV-positive cases with p16 overexpression)
PTEN mutations (15-20% of cases)
RB pathway alterations (common in HPV-positive cases).
Molecular Markers:
p16 overexpression (surrogate marker for HPV integration)
Ki-67 overexpression (indicates high proliferative activity)
p53 overexpression (more common in HPV-negative cases)
Cyclin D1 amplification (subset of cases)
EGFR overexpression (potential therapeutic target)
PD-L1 expression (predictive marker for immunotherapy).
Prognostic Significance:
HPV status is the most important prognostic factor (HPV-positive cases have better survival)
Tumor grade correlates with prognosis (well-differentiated tumors have better outcomes)
Stage at presentation is crucial (early-stage disease has 80-90% 5-year survival)
Lymph node involvement significantly worsens prognosis
p53 mutations associated with worse outcomes
Age at diagnosis influences prognosis (younger patients with HPV-positive tumors do better).
Therapeutic Targets:
HPV E6/E7 proteins (therapeutic vaccines under development)
EGFR (cetuximab for EGFR-positive cases)
PI3K/AKT pathway (PI3K inhibitors in PIK3CA-mutated cases)
PD-1/PD-L1 (pembrolizumab for PD-L1 positive cases)
DNA damage response (PARP inhibitors in homologous recombination deficient tumors)
Angiogenesis (bevacizumab in recurrent disease).
Differential Diagnosis
Similar Entities:
Vaginal adenocarcinoma (CK7 positive, mucin production)
Metastatic squamous cell carcinoma from cervix or vulva
Vaginal melanoma (S-100, melanoma markers positive)
Vaginal sarcoma (mesenchymal markers positive)
Vaginal clear cell adenocarcinoma (PAX8 positive, clear cell morphology)
Vaginal endometrioid adenocarcinoma (ER/PR positive, glandular architecture).
Distinguishing Features:
Primary vs metastatic: Requires clinical correlation and absence of cervical/vulvar involvement
SCC vs adenocarcinoma: p40/p63 positive vs CK7/PAX8 positive
SCC vs melanoma: p40 positive vs S-100/SOX10 positive
Keratinizing vs non-keratinizing: Presence of keratin pearls and individual cell keratinization
HPV-positive vs negative: p16 expression pattern (diffuse vs focal/negative)
Well vs poorly differentiated: Degree of keratinization and nuclear pleomorphism.
Diagnostic Challenges:
Distinguishing primary from metastatic disease requires thorough clinical examination and imaging
Small biopsy interpretation may be challenging due to sampling issues
Reactive changes from radiation or infection can mimic malignancy
VAIN vs invasive carcinoma: Assessment of basement membrane integrity crucial
HPV status determination: p16 interpretation requires proper scoring criteria
Grade assessment in poorly preserved specimens.
Rare Variants:
Verrucous carcinoma (HPV 6/11 associated, locally aggressive but non-metastasizing)
Basaloid squamous cell carcinoma (HPV-associated, aggressive behavior)
Warty (condylomatous) carcinoma (HPV-associated, intermediate behavior)
Papillary squamous cell carcinoma (exophytic growth pattern)
Spindle cell (sarcomatoid) carcinoma (biphasic tumor with squamous and spindle components)
Adenosquamous carcinoma (mixed squamous and glandular differentiation).
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
Vaginal biopsy/excision from [location] measuring [size] cm
Diagnosis
Invasive squamous cell carcinoma of vagina
Classification and Grade
[Keratinizing/Non-keratinizing] squamous cell carcinoma, Grade [1/2/3]
Histological Features
Shows invasive nests of malignant squamous cells with [degree] keratinization, [nuclear grade] nuclear pleomorphism, and [mitotic activity] mitotic activity
Invasion and Extent
Depth of invasion: [X] mm, extent: [superficial/deep stromal/paravaginal]
Margins
Margins are [involved/uninvolved], closest margin [X] mm from tumor
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Special Studies
p40: [positive/negative], p63: [positive/negative], p16: [positive/negative/focal]
HPV status: [positive/negative] (by p16 immunohistochemistry)
Ki-67 index: [percentage]%
FIGO Staging
FIGO Stage: [I/II/III/IV] - [staging description]
Prognostic Factors
HPV status: [positive/negative], Grade: [1/2/3], Stage: [I/II/III/IV], LVI: [present/absent]
Final Diagnosis
Primary vaginal squamous cell carcinoma, [keratinizing/non-keratinizing], Grade [1/2/3], FIGO Stage [I/II/III/IV]