Definition/General
Introduction:
Cervical squamous cell carcinoma (SCC) is the most common malignant tumor of the cervix
It accounts for 75-80% of all cervical cancers
It arises from the transformation zone of the cervix
It is strongly associated with high-risk HPV infection.
Origin:
Originates from the squamous epithelium of the cervix
Specifically from the transformation zone where squamous and glandular epithelium meet
The neoplastic process involves HPV-induced transformation
It progresses through cervical intraepithelial neoplasia (CIN)
It eventually leads to invasive carcinoma.
Classification:
Classified by FIGO staging system
Stage I: confined to cervix
Stage II: beyond cervix but not to pelvic wall
Stage III: extends to pelvic wall or lower third of vagina
Stage IV: beyond pelvis or involves bladder/rectum
Histological grading: well-differentiated, moderately differentiated, poorly differentiated.
Epidemiology:
Peak incidence in 4th-5th decades
Strong association with high-risk HPV (types 16, 18)
Risk factors include multiple sexual partners
Early sexual activity
Smoking
Immunosuppression
Indian population shows high incidence in rural areas
Leading cause of cancer death in developing countries.
Clinical Features
Presentation:
Postcoital bleeding (most common)
Intermenstrual bleeding
Postmenopausal bleeding
Vaginal discharge (foul-smelling, blood-stained)
Pelvic pain
Urinary symptoms
Bowel symptoms (advanced disease).
Symptoms:
Abnormal vaginal bleeding (90% cases)
Vaginal discharge (80%)
Pelvic pain (60%)
Dyspareunia
Urinary frequency
Hematuria (advanced)
Constipation (advanced)
Weight loss
Fatigue.
Risk Factors:
High-risk HPV infection (16, 18, 31, 33, 45)
Multiple sexual partners
Early age at first intercourse (<18 years)
Smoking
Immunosuppression (HIV, transplant)
Long-term oral contraceptive use
High parity
Low socioeconomic status.
Screening:
Pap smear (cervical cytology)
HPV testing (co-testing or primary)
Visual inspection with acetic acid (VIA)
Colposcopy for abnormal screening
Liquid-based cytology
HPV vaccination (prevention).
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Gross Description
Appearance:
Exophytic mass protruding from cervix
Ulcerative lesion with irregular margins
Endophytic growth causing barrel-shaped cervix
Surface may be friable and hemorrhagic
Cut surface shows gray-white solid areas.
Characteristics:
Firm consistency with areas of necrosis
Hemorrhage and ulceration common
Size varies from small lesions to large masses
Surface may show papillary configuration
Cut surface reveals solid gray-white tissue.
Size Location:
Size ranges from microscopic to >10 cm
Commonly arises from transformation zone
May involve anterior or posterior lip
Can extend to vaginal fornices
Advanced cases involve parametrium.
Multifocality:
Usually unifocal at presentation
May show skip lesions in advanced cases
CIN often present in adjacent epithelium
Lymphovascular invasion correlates with stage
Parametrial extension indicates advanced disease.
Microscopic Description
Histological Features:
Malignant squamous cells with intercellular bridges
Keratin formation (well-differentiated)
Nuclear pleomorphism and hyperchromatism
Increased mitotic activity
Basement membrane disruption
Desmoplastic stromal reaction.
Cellular Characteristics:
Pleomorphic squamous cells with irregular nuclei
Prominent nucleoli in poorly differentiated tumors
Eosinophilic cytoplasm with keratinization
Intercellular bridges visible
Individual cell keratinization (dyskeratosis).
Architectural Patterns:
Nests and sheets of malignant cells
Keratinizing type: keratin pearl formation
Non-keratinizing type: minimal keratinization
Basaloid type: small cells with basaloid features
Verrucous type: exophytic growth with minimal cytological atypia.
Grading Criteria:
Well-differentiated: keratin pearls, minimal pleomorphism
Moderately differentiated: some keratinization, moderate pleomorphism
Poorly differentiated: minimal keratinization, marked pleomorphism
Grading based on keratinization, nuclear pleomorphism, and mitotic activity.
Immunohistochemistry
Positive Markers:
p16 (diffuse positive in HPV-related)
CK5/6 and CK14
p63 (nuclear staining)
p40 (specific for squamous differentiation)
CK7 (variable)
EMA
Ki-67 (high proliferation index).
Negative Markers:
CEA (helps distinguish from adenocarcinoma)
CK20
TTF-1
ER and PR (usually negative)
Vimentin (usually negative)
Melanoma markers (S-100, melanA).
Diagnostic Utility:
p16 positivity indicates HPV infection
Essential for distinguishing from adenocarcinoma
p63/p40 positivity confirms squamous differentiation
Ki-67 assesses proliferation
Helps in grading and prognosis.
Molecular Subtypes:
HPV-positive (most cases, better prognosis)
HPV-negative (rare, poorer prognosis)
Keratinizing type (often HPV 16-related)
Non-keratinizing type (often HPV 18-related).
Molecular/Genetic
Genetic Mutations:
HPV integration (E6 and E7 oncoproteins)
p53 inactivation (via E6 protein)
pRb inactivation (via E7 protein)
PIK3CA mutations (20-30%)
KRAS mutations (10-15%)
TP53 mutations (in HPV-negative cases).
Molecular Markers:
p16 overexpression (surrogate for HPV)
Ki-67 high expression
p53 overexpression (variable)
Cyclin E overexpression
HPV DNA integration
Loss of heterozygosity at multiple loci.
Prognostic Significance:
HPV status determines prognosis
HPV-positive tumors have better prognosis
p16 positivity associated with better response to therapy
Ki-67 index correlates with grade
FIGO stage most important prognostic factor.
Therapeutic Targets:
HPV vaccination (prevention)
Immunotherapy (pembrolizumab for advanced cases)
Bevacizumab (anti-VEGF therapy)
Cisplatin-based chemotherapy
Radiation therapy
Targeted therapy under investigation.
Differential Diagnosis
Similar Entities:
Adenocarcinoma (glandular differentiation, different IHC)
Adenosquamous carcinoma (mixed features)
Small cell carcinoma (neuroendocrine features)
Sarcoma (mesenchymal differentiation)
Metastatic carcinoma.
Distinguishing Features:
SCC: p63/p40 positive
SCC: intercellular bridges
SCC: keratinization
Adenocarcinoma: CEA positive
Adenocarcinoma: glandular architecture
Small cell: neuroendocrine markers
Sarcoma: vimentin positive.
Diagnostic Challenges:
Distinguishing poorly differentiated SCC from adenocarcinoma
Small cell carcinoma vs poorly differentiated SCC
Adenosquamous carcinoma diagnosis
Metastatic vs primary carcinoma
Immunohistochemistry essential for accurate diagnosis.
Rare Variants:
Verrucous carcinoma (HPV 6/11-related, indolent)
Warty carcinoma (condylomatous features)
Papillary carcinoma (exophytic growth)
Basaloid carcinoma (aggressive variant)
Lymphoepithelioma-like carcinoma.
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
Invasive squamous cell carcinoma of cervix
Classification
FIGO Stage: [stage], Histological grade: [grade]
Histological Features
Shows [keratinization pattern] with [nuclear features] and [architectural pattern]
Size and Extent
Tumor size: [X] cm, depth of invasion: [X] mm
Margins
Margins are [involved/uninvolved] with closest margin [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Lymph Node Status
Lymph nodes: [X] positive out of [X] examined
Special Studies
p16: [positive/negative], p63: [positive/negative]
HPV status: [positive/negative/not tested]
[other study]: [result]
Prognostic Factors
FIGO stage, tumor size, grade, lymph node status, HPV status
Final Diagnosis
Invasive squamous cell carcinoma of cervix, FIGO Stage [stage], Grade [grade]