Gynaecology oncology
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Cervical Cancer - Detailed Clinical Coverage
1. Epidemiology
Cervical cancer is the third most common gynecologic malignancy in the United States (behind endometrial and ovarian cancer), with over 14,000 new cases and ~4,000 deaths annually. Globally, it remains the second most frequent cause of cancer death in women in developing countries, particularly in Central/South America and Africa, due to lack of access to screening and treatment.
A greater than 80% decrease in incidence since the 1950s has been achieved through Papanicolaou (Pap) smear screening and, more recently, high-risk HPV testing. - Goldman-Cecil Medicine, p. 4608
Risk Factors:
- Early age at first sexual intercourse
- Multiple sexual partners
- HPV infection (most critical factor - present in >99% of cases)
- Immunosuppression (HIV)
- Oral contraceptive use (increases risk with duration; risk returns to baseline within 10 years of stopping)
- Lack of barrier contraception
- Smoking
- High parity
Notably, IUD use appears protective - a meta-analysis showed invasive cervical cancer is approximately one-third less frequent in IUD users. - Berek & Novak's Gynecology
2. Pathobiology - HPV and Oncogenesis
HPVs are small, non-enveloped, double-stranded DNA viruses. Capsid proteins L1 and L2 are targeted by vaccines.
Key oncogenic mechanism:
- E6 protein binds and degrades p53 (tumor suppressor) → inhibits apoptosis → cell immortalization
- E7 protein binds and degrades pRB (retinoblastoma protein) → disrupts cell cycle regulation via cyclins and CDKs
- Both E6 and E7 have immunosuppressive effects enabling immune evasion
HPV types:
- HPV 16 and 18 → 70% of all cervical cancers
- HPV 31, 33, 45, 52, 58 → additional 20%
- ~200 HPV strains exist; ~40 infect the genital tract; high-risk types cause anogenital and oropharyngeal cancers
Natural history:
- Most HPV infections are transient, clear within 1-2 years
- In ~10% of women, persistent infection develops
- Persistent infection → precancerous change (CIN) → invasive carcinoma
- HPV DNA may integrate into host genome or persist as episome - Goldman-Cecil Medicine, p. 4764-4766
3. Pathology (Histologic Types)
| Type | Frequency | Notes |
|---|---|---|
| Squamous cell carcinoma | ~70% | Arising from squamocolumnar junction; most screened for |
| Adenocarcinoma | ~20-25% | Arising from endocervical glands; increasing in incidence; less easily detected by Pap smear |
| Adenosquamous carcinoma | Rare | Mixed histology; worse prognosis |
| Neuroendocrine carcinoma | Very rare | Aggressive; small cell type |
| Sarcoma | Very rare | |
| Malignant melanoma | Very rare |
Adenocarcinomas show a doubling of risk with OC use, reaching an RR of 4.4 with >12 years of OC use. - Berek & Novak's Gynecology
Microinvasion: Irregular tonguelike processes of malignant cells in stroma. Depth measured with micrometer from base of epithelium to deepest invasion point.
4. FIGO Staging (2018 Updated System)
The 2018 FIGO update is a significant revision: it now incorporates imaging and pathologic findings in addition to clinical examination.
| Stage | Description |
|---|---|
| IA | Invasive carcinoma diagnosed only by microscopy; no measurable lesion |
| IA1 | Stromal invasion <3 mm depth |
| IA2 | Stromal invasion 3-5 mm depth |
| IB | Clinically visible lesion or microscopic lesion greater than IA |
| IB1 | Tumor <2 cm greatest dimension (new in 2018) |
| IB2 | Tumor 2-4 cm greatest dimension (new in 2018) |
| IB3 | Tumor >4 cm greatest dimension (new in 2018) |
| IIA | Invades upper 2/3 of vagina, no parametrial involvement |
| IIA1 | Tumor <4 cm |
| IIA2 | Tumor ≥4 cm |
| IIB | Parametrial involvement |
| IIIA | Involves lower 1/3 of vagina, no extension to pelvic wall |
| IIIB | Extension to pelvic wall and/or hydronephrosis/non-functioning kidney |
| IIIC | Lymph node involvement (new in 2018) |
| IIIC1 | Pelvic LN metastasis |
| IIIC2 | Para-aortic LN metastasis |
| IVA | Invades bladder/rectal mucosa |
| IVB | Distant metastasis |
Key 2018 changes:
- Horizontal spread removed from IA criteria; only depth of invasion used
- IB now divided into 3 substages (IB1, IB2, IB3)
- New Stage IIIC for lymph node metastasis detected by imaging (IIIC1r/IIIC2r) or pathology (IIIC1p/IIIC2p)
Staging distribution at diagnosis: Stage I: 38%, Stage II: 32%, Stage III: 26%, Stage IV: 4%. - Berek & Novak's Gynecology, p. 2798-2804
Rule: When stage is in doubt, assign the earlier stage. Stage cannot be changed after treatment begins.
5. Patterns of Spread
- Direct extension - into vagina, parametria, bladder, rectum
- Lymphatic - most important route; pelvic nodes first, then para-aortic
- Hematogenous - lung, liver, bone (late-stage)
Depth of invasion directly predicts lymph node metastasis risk:
- <3 mm invasion: rarely metastasizes
- 3-5 mm invasion: pelvic LN positive in 3-8% of cases - Berek & Novak's, p. 2784
6. Clinical Evaluation and Diagnosis
Symptoms:
- Early: often asymptomatic; detected by screening
- Abnormal vaginal bleeding (post-coital, intermenstrual, postmenopausal)
- Vaginal discharge (watery, mucoid, bloody, malodorous)
- Pelvic pain (advanced disease)
Colposcopic findings of invasion:
- Abnormal vessels, irregular surface contour, erosion, necrosis
Staging workup (as permitted by FIGO):
- Physical examination including pelvic exam
- Biopsy
- Chest X-ray
- IVP (to detect hydronephrosis)
- Barium enema
- Cystoscopy / proctosigmoidoscopy (for advanced disease)
- MRI - best for local staging, parametrial involvement
- PET-CT - excellent for lymph node metastases in advanced disease
- CT scan
7. Treatment
General Principle
Treatment depends on stage. Radiation therapy can be used in all stages; surgery is limited to stages I-IIA.
"The 5-year survival rate for stage I cervical cancer is approximately 85% with either radiation therapy or radical hysterectomy." - Berek & Novak's, p. 2991
Optimal therapy uses one modality alone to limit combined morbidity. Adding chemoradiation post-surgery significantly increases morbidity.
Surgical Options
| Procedure | Indication |
|---|---|
| Cone biopsy | Stage IA1 without LVSI (fertility-sparing); also diagnostic |
| Simple (extrafascial) hysterectomy | Stage IA1 with no LVSI, no fertility desire |
| Radical trachelectomy | Stage IA1-IB1; fertility preservation in young women |
| Radical hysterectomy (type III) | Stages IA2, IB, IIA; removes uterus, parametria, upper vaginal cuff |
| Sentinel lymph node biopsy | Evolving role; reduces morbidity of full lymphadenectomy |
| Pelvic exenteration | Recurrent central disease after radiation |
Radical hysterectomy advantages over radiation (especially for younger women):
- Ovarian conservation possible
- Avoids vaginal fibrosis and atrophy
- Surgical injuries can usually be repaired; radiation injuries (fibrosis, decreased vascularity) are permanent
- Chronic bladder/bowel problems in up to 8% with radiation - Berek & Novak's, p. 2997-3003
Contraindication to surgery: Lesions >4 cm diameter (would require post-op radiation, compounding morbidity); urinary fistula rate <2% and operative mortality <1% when properly selected.
Complications of radical hysterectomy:
- Blood loss (~0.8 L average)
- Ureterovaginal fistula (1-2%)
- Vesicovaginal fistula (1%)
- Pulmonary embolus (1-2%)
- Febrile morbidity (25-50%)
- Bladder dysfunction (most common subacute complication)
- Lymphocyst formation (<5%)
- Chronic bladder hypotonia/atony (~3%)
Radiation Therapy
External beam radiotherapy (EBRT) + brachytherapy (intracavitary) = standard for locally advanced disease.
- Intensity-Modulated Radiation Therapy (IMRT): Allows higher dose to tumor with sparing of adjacent normal tissues
- Brachytherapy is essential - provides high dose to central tumor; cannot be omitted
Concurrent Chemoradiation
Standard of care for stages IIB-IVA:
- Cisplatin-based chemotherapy concurrent with radiotherapy
- Five landmark RCTs showed a 30-50% reduction in mortality with concurrent chemoradiation vs. radiation alone
- Weekly cisplatin 40 mg/m² is the most common regimen
- Results in improved local control and overall survival - Berek & Novak's
Adjuvant chemoradiation is also indicated post-radical hysterectomy when high-risk pathologic features are found:
- Positive surgical margins
- Parametrial involvement
- Positive lymph nodes
Treatment by Stage (Summary)
| Stage | Treatment |
|---|---|
| IA1, no LVSI | Cone biopsy (fertility desired) or simple hysterectomy |
| IA1, LVSI+ | Modified radical hysterectomy + pelvic LND |
| IA2 | Radical hysterectomy + pelvic LND, or radiation |
| IB1-IB2, IIA1 | Radical hysterectomy + pelvic LND, or definitive chemoradiation |
| IB3, IIA2 | Definitive chemoradiation (cisplatin + EBRT + brachytherapy) |
| IIB-IVA | Definitive chemoradiation |
| IVB | Palliative chemotherapy ± radiation |
Chemotherapy Regimens (Systemic/Palliative)
- Cisplatin - most active single agent
- Cisplatin + paclitaxel - standard doublet for recurrent/metastatic
- Cisplatin + paclitaxel + bevacizumab - GOG 240 trial showed improved OS; bevacizumab added for eligible patients
- Pembrolizumab - approved for recurrent/metastatic PD-L1+ cervical cancer (KEYNOTE-158, KEYNOTE-826)
8. Recurrent Cervical Cancer
Central recurrence (confined to pelvis, no prior radiation):
- Pelvic exenteration (anterior, posterior, or total) - potentially curative; 5-year survival 20-60%
- Laterally extended endopelvic resection (LEER) - for lateral pelvic wall recurrence
Systemic recurrence:
- Cisplatin-based combination chemotherapy
- Immunotherapy (pembrolizumab for PD-L1+)
- Palliative radiation for symptom control
Prognosis in recurrence: Poor; median survival with chemotherapy alone ~12-15 months.
9. Prognosis by Stage
| Stage | 5-Year Survival |
|---|---|
| IA | 95-98% |
| IB | ~85% |
| IIA | ~70-75% |
| IIB | ~60-65% |
| IIIA | ~40% |
| IIIB | ~35% |
| IVA | ~15-20% |
| IVB | <10% |
Adverse prognostic factors:
- Lymph node metastasis (most important)
- Large tumor size (>4 cm)
- Parametrial involvement
- Lymphovascular space invasion (LVSI)
- Positive surgical margins
- Non-squamous histology (adenocarcinoma slightly worse)
10. Special Considerations
Cervical Cancer in Pregnancy
- Diagnosed in ~1 per 10,000 pregnancies
- Management depends on gestational age and stage
- MRI is safe and preferred for local staging in pregnancy
- Definitive treatment often deferred to after delivery if early-stage and gestational age is viable
Barrel-Shaped Cervix
- Large endocervical tumors expanding the cervical stroma
- Poor prognosis; parametrial and nodal spread more likely
- May require combined surgery + radiation
Cancer of the Cervical Stump
- After subtotal hysterectomy; treated similarly to intact cervix
- Brachytherapy is more challenging technically
11. Prevention
Screening
- Pap smear (cytology) every 3 years from age 21
- Co-testing (Pap + HPV) every 5 years from age 30-65
- Primary HPV testing every 5 years is now an acceptable alternative
- Screening can stop at age 65 with adequate prior negative screening
HPV Vaccination
Three approved vaccines:
- Gardasil 9 (9-valent): HPV 6, 11, 16, 18, 31, 33, 45, 52, 58 - preferred
- Gardasil (quadrivalent): HPV 6, 11, 16, 18
- Cervarix (bivalent): HPV 16, 18
Recommended for females and males ages 9-26 years (ideally before sexual debut); shared decision-making for ages 27-45. A 2025 Cochrane meta-analysis (PMID 41276263) confirmed robust efficacy of HPV vaccines for cervical cancer prevention, particularly when given before HPV exposure.
Primary sources: Berek & Novak's Gynecology | Goldman-Cecil Medicine (International Edition) | Recent literature: Cochrane HPV vaccine network meta-analysis (PMID 41276263, 2025)
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