Cervical Cancer
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Cervical Cancer
Epidemiology
Cervical cancer is the third most common gynecologic cancer in the United States. Over 14,000 new cases and more than 4,000 cancer-related deaths occur annually in the US. A greater than 80% decline in incidence since the 1950s is directly attributed to screening - first with Papanicolaou (Pap) cytology and now with high-risk HPV testing. Despite this progress in developed nations, cervical cancer remains a leading cause of cancer death in women worldwide, particularly in Central/South America and Africa, due to limited access to screening and treatment.
Cervical cancer presents at a median age of 48 years. Disparities exist, with higher rates among Hispanic and Black American women.
Etiology - HPV is Central
HPV infection is detected in >99% of cervical cancers and is the essential etiologic agent.
- There are >200 HPV strains; ~40 infect the genital tract
- Low-risk HPV (e.g., types 6, 11): causes genital warts
- High-risk HPV: causes anogenital and oropharyngeal cancers
- HPV 16 & 18 cause 70% of cervical cancers
- HPV 31, 33, 45, 52, 58 cause an additional 20%
- HPV is sexually transmitted (genital-genital or genital-oral contact); most sexually active individuals will be infected at some point, usually early in sexual activity
Risk Factors
| Category | Specific Factors |
|---|---|
| Sexual behavior | Early onset of sexual activity, multiple sexual partners |
| Viral | HPV 16/18 infection (50-fold increase in precancerous lesion risk) |
| Immune status | HIV infection, other immunodeficiency states |
| Reproductive | Multiparity |
| Hormonal | Long-term oral contraceptive use (>5 years), in utero DES exposure |
| Lifestyle | Cigarette smoking |
| Socioeconomic | Lower socioeconomic status, lack of screening access |
| Demographic | Hispanic and Black American women |
A 2007 meta-analysis found a pooled RR of 1.9 (95% CI: 1.69-2.13) for invasive cervical cancer with 5+ years of OC use; this risk returned to baseline within 10 years of stopping. An IUD was associated with approximately one-third reduction in invasive cervical cancer risk.
Pathobiology
HPVs are small, non-enveloped, double-stranded DNA viruses with a capsid formed by late proteins L1 and L2.
Oncogenic mechanism:
- HPV infects the basal cell layer of stratified squamous epithelium at the squamocolumnar junction (transformation zone) of the cervix
- The E6 and E7 oncoproteins of high-risk HPV types are the primary drivers of carcinogenesis:
- E6 binds to and degrades p53 (tumor suppressor), inhibiting apoptosis and contributing to cellular immortalization
- E7 binds to and degrades pRB (retinoblastoma protein) and disrupts cyclins and cyclin-dependent kinases - dysregulating the cell cycle
- Both E6 and E7 have immunosuppressive effects, contributing to immune evasion
Natural history:
- Most HPV infections are transient and clear within 1-2 years
- In ~10% of infected women, HPV persists - producing viral proteins continuously
- Persistent HPV infection is necessary for the development of precancerous cervical intraepithelial neoplasia (CIN) and invasive cancer
- The carcinogenic process takes approximately a decade to progress to malignancy
- The squamocolumnar junction is most susceptible in adolescents and younger women, with declining susceptibility as the cervix matures hormonally
Histology: ~80-85% squamous cell carcinoma; ~10-15% adenocarcinoma (rarer, harder to detect on Pap smear, incidence appears to be increasing)
Precancerous Lesions (CIN)
| Grade | Description |
|---|---|
| CIN 1 (LSIL) | Low-grade dysplasia; often regresses spontaneously |
| CIN 2 | Moderate dysplasia |
| CIN 3 / CIS | High-grade dysplasia / carcinoma in situ; high risk of progression |
Clinical Manifestations
Early-stage disease is largely asymptomatic - detected by screening.
Advanced disease may present with:
- Abnormal vaginal bleeding (postcoital bleeding is classic)
- Vaginal discharge (may be watery, bloody, or foul-smelling)
- Pelvic pain or pain with intercourse (dyspareunia)
- Bowel or bladder dysfunction (hematuria, rectal bleeding) in very advanced disease
- Flank pain from ureteral obstruction
Spread: Local extension to the uterine corpus, vagina, bladder, and parametria is typical. Lymphatic spread to pelvic and para-aortic nodes.
Diagnosis
- Pap smear - detects abnormal cytology; primary screening tool
- HPV testing - high-risk HPV DNA testing (co-test or primary HPV screen)
- Colposcopy - directed biopsy of abnormal areas under magnification
- Cone biopsy / LEEP - for women without gross lesions or with microinvasive disease to define depth of invasion
- Direct biopsy - for obvious lesions; Pap smear is not adequate diagnostically in these cases
Staging (FIGO 2018)
The 2018 FIGO system incorporates imaging and pathologic findings (updated from the purely clinical 1971 system).
| Stage | Description |
|---|---|
| I | Confined to cervix |
| IA | Microscopic invasive carcinoma; depth ≤5 mm |
| IA1 | Depth ≤3 mm |
| IA2 | Depth 3-5 mm |
| IB | Clinically visible lesion or microscopic >stage IA |
| IB1 | <2 cm (fertility-sparing surgery candidates) |
| IB2 | 2-4 cm |
| IB3 | >4 cm |
| II | Beyond cervix, not to pelvic wall or lower third of vagina |
| IIA | Without parametrial involvement |
| IIB | With parametrial involvement |
| III | Extends to pelvic wall, lower third vagina, or causes hydronephrosis; includes nodal metastases (added 2018) |
| IIIC1 | Pelvic lymph node metastases |
| IIIC2 | Para-aortic lymph node metastases |
| IVA | Adjacent organ invasion (bladder/rectum) |
| IVB | Distant metastases |
Incidence by stage at diagnosis: Stage I 38%, Stage II 32%, Stage III 26%, Stage IV 4%.
CT scan demonstrating stage IVA cervical cancer (tumor invading bladder wall, hydronephrosis, and enlarged pelvic lymph node):
From Grainger & Allison's Diagnostic Radiology: Axial and coronal CT images show a heterogeneous cervical tumor (T) extending into parametrial fat bilaterally, invading the posterior bladder wall (black arrows), causing right-sided hydronephrosis, and with an enlarged right external iliac lymph node - representing stage IVA disease.
Imaging in Staging
- MRI pelvis: best for local extent, parametrial involvement, and tumor size
- CT chest/abdomen/pelvis: assesses lymph nodes and distant metastases
- FDG-PET/CT: particularly useful for advanced disease (FIGO IIB-IVB); sensitivity 75-100% and specificity 87-100% for lymph node metastases; can detect unexpected supra-diaphragmatic nodal spread; less useful for early-stage (I-IIA)
- Cystoscopy and proctoscopy may be used for suspected bladder/bowel involvement
Treatment
Treatment is guided by stage, tumor size, fertility desire, age, and comorbidities. Survival is better when managed by a gynecologic oncologist.
Early-Stage Disease (Stage IA-IB1/IIA1)
| Situation | Treatment |
|---|---|
| Microscopic disease / Stage IA1 | Cone biopsy (conization) or LEEP may suffice |
| Low-volume disease limited to cervix | Radical hysterectomy (open approach preferred over minimally invasive - provides better disease-free survival) |
| Very-low-risk disease | Simple hysterectomy is an alternative |
| Fertility desired (selected patients, stage IB1) | Radical trachelectomy (removal of cervix only) |
Adjuvant Therapy Indications Post-Hysterectomy
When pathology reveals high-risk features: lymphovascular space invasion, deep cervical stromal involvement, larger-than-expected tumor, positive margins, parametrial involvement, or nodal metastases - adjuvant radiation therapy is recommended.
Locally Advanced Disease (Stage IIB-IVA)
Definitive chemoradiation is the standard of care:
- Weekly cisplatin (radiation sensitizer) + external beam radiation therapy (EBRT) + brachytherapy
Recurrent / Metastatic Disease
- Platinum-taxane doublet chemotherapy (e.g., cisplatin/paclitaxel or carboplatin/paclitaxel)
- Bevacizumab (anti-VEGF monoclonal antibody): added to chemotherapy; provides incremental survival benefit
- Pembrolizumab (PD-1 checkpoint inhibitor): used in combination with chemotherapy +/- bevacizumab for PD-L1-positive tumors
- Pelvic exenteration: highly selected patients with central recurrence; very morbid but curative in 25-50%
- Palliative localized radiation for symptom management
Screening Guidelines
| Age Group | Recommendation |
|---|---|
| <21 years | No screening |
| 21-29 years | Pap smear alone every 3 years |
| 30-65 years | Pap + HPV co-test every 5 years (preferred) OR Pap alone every 3 years OR primary HPV test every 5 years |
| >65 years | Discontinue if adequate prior negative screening |
| Post-hysterectomy (benign) | Discontinue |
Prevention: HPV Vaccination
- Gardasil-9 (9-valent): covers HPV 6, 11, 16, 18, 31, 33, 45, 52, 58 - potentially prevents up to 90% of cervical cancers
- Recommended: ages 9-26 routinely; may be given up to age 45 with shared decision-making
- Most effective when given before sexual debut (before HPV exposure)
- HPV vaccination does NOT eliminate the need for ongoing cervical cancer screening
Prognosis (5-Year Survival by Stage)
| Stage | Approximate 5-Year Survival |
|---|---|
| IA | ~93-98% |
| IB | ~80-90% |
| IIA | ~70-80% |
| IIB | ~65-70% |
| III | ~40-50% |
| IVA | ~15-20% |
| IVB | ~<10% |
Sources: Goldman-Cecil Medicine, 26th Ed.; Berek & Novak's Gynecology, 16th Ed.; Grainger & Allison's Diagnostic Radiology; Goodman & Gilman's Pharmacological Basis of Therapeutics
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