Gynecology Topic 21. Etiology and precancerous states of cervical cancer

I. Cervical Cancer Etiology

Basic Concepts

• Cervical cancer is usually preceded by cervical intraepithelial neoplasia (CIN).
• Most important cause: persistent high-risk HPV infection.
• Most cervical cancers arise in the transformation zone.
• Main invasive histology: squamous cell carcinoma; adenocarcinoma arises from glandular/endocervical epithelium.

Transformation Zone

• Transformation zone: area between original and new squamocolumnar junction.
• Contains metaplastic squamous epithelium → susceptible to HPV-related dysplasia.

HPV Infection

• High-risk HPV types: 16 and 18 most important; also 31, 33, 45 and others.
• Low-risk HPV 6/11: genital warts and many low-grade lesions, not typical cancer drivers.
• Most HPV infections are transient; persistent high-risk HPV is dangerous.
• Persistent high-risk HPV infection → precancerous lesion → invasive cancer over years.

HPV Carcinogenesis

1. High-risk HPV infects basal cells of the transformation zone.
2. Persistent infection → E6/E7 oncogene expression / viral DNA integration.
3. E6 inhibits p53 → impaired apoptosis and DNA repair.
4. E7 inhibits Rb → uncontrolled cell-cycle progression.
5. Abnormal epithelial proliferation above basement membrane → CIN.
6. Basement membrane invasion → invasive cervical cancer.

• Koilocyte: HPV-infected squamous epithelial cell with perinuclear halo and nuclear atypia.

Risk Factors

• High-risk HPV infection, especially persistent HPV 16/18.
• Sexual behavior: early coitarche and multiple sexual partners.
• Smoking.
• Immunosuppression: HIV, transplant medication, chronic immunosuppressive therapy.
• Additional exam-relevant risks: poor screening access, high parity, long-term OCP use mainly with persistent HPV.

Natural History of HPV Infection

1. Latent infection: HPV DNA positive, cytology/histology may be negative.
2. Subclinical infection: cytologic/histologic abnormality → CIN.
3. Clinical disease: condyloma, precancer, carcinoma, other HPV-related lesions.

II. Cervical Intraepithelial Neoplasia

Definition

• CIN: premalignant squamous epithelial dysplasia of the cervix above an intact basement membrane.
• Not all CIN progresses to cancer; regression is common, especially low-grade lesions.
• CIN is usually asymptomatic → detected by screening.

CIN Grading and Bethesda Terminology

1. CIN I: mild dysplasia, lower 1/3 of epithelium → LSIL

• Usually transient HPV infection → high chance of spontaneous regression.

2. CIN II: moderate dysplasia, lower 2/3 of epithelium → HSIL

• Greater risk of persistence/progression.

3. CIN III: severe dysplasia involving >2/3 or full thickness → HSIL

• Includes carcinoma in situ.

Bethesda Cytology Terms

• ASC-US: atypical squamous cells of undetermined significance.
• ASC-H: atypical squamous cells, cannot exclude HSIL.
• LSIL: low-grade squamous intraepithelial lesion, usually CIN 1/HPV effect.
• HSIL: high-grade squamous intraepithelial lesion, usually CIN 2-3.
• AGC/AIS: glandular abnormality; needs careful evaluation.

III. Diagnosis of CIN

Detection

• CIN is usually found after abnormal cervical screening.
• Screening tools: Pap smear/cervical cytology, high-risk HPV DNA test, or co-testing.
• Detailed age-based screening belongs to G22.

Evaluation of Abnormal Screening

• Abnormal cytology or persistent high-risk HPV → colposcopy according to risk.
• Colposcopy: magnified examination of cervix after acetic acid/Lugol iodine.
• Acetic acid positive area: acetowhite epithelium → suspicious for dysplasia.
• Biopsy is required for histologic diagnosis: punch biopsy from abnormal area.
• ECC: used when endocervical disease is suspected or transformation zone not fully visible.
• Positive ECC or unsatisfactory colposcopy → diagnostic excision/cone biopsy is often needed.
• Pregnancy: colposcopy can be performed by experienced clinician, but ECC is contraindicated; treatment usually postponed unless invasion suspected.

IV. Treatment of Precancerous Lesions

Low-Grade Lesions

• CIN 1 / LSIL: observation is usually preferred.
• Follow-up: repeat cytology/HPV testing or colposcopy according to risk/local protocol.
• Reason: most CIN 1 lesions regress spontaneously.

High-Grade Lesions

• CIN 2-3 / HSIL: treatment is usually required because risk of progression is significant.
• Aims: remove/destroy transformation-zone lesion, exclude occult invasive carcinoma, preserve fertility when possible.

Excisional Treatment

• Conization: diagnostic and therapeutic excision of transformation zone.
• LEEP / LLETZ: loop electrosurgical excision procedure / large loop excision of transformation zone.
• Cold-knife conization: scalpel cone biopsy.
• Advantage: tissue for histology and margin assessment.
• Preferred if invasion cannot be excluded, glandular lesion suspected, ECC positive, or colposcopy unsatisfactory.

Ablative Treatment

• Laser ablation or cryotherapy destroys abnormal epithelium.
• No tissue specimen → only appropriate when invasive cancer is confidently excluded.
• Requirements: entire lesion and transformation zone visible, no suspicion of invasion/glandular disease, negative endocervical sampling when indicated.

Follow-up After Treatment

• Post-treatment surveillance is mandatory because CIN can recur.
• HPV-based testing is commonly used after treatment.
• HPV vaccination reduces future HPV-related disease risk and may reduce recurrence after CIN 2-3 treatment in eligible patients.