Cervical cancer develops in the cells of the cervix—the lower part of the uterus that connects to the vagina. The American Cancer Society estimates approximately 13,820 new cases of invasive cervical cancer are diagnosed in the United States each year, with roughly 4,360 deaths. Worldwide, cervical cancer is the fourth most common cancer in women, with approximately 604,000 new cases and 342,000 deaths annually (WHO/GLOBOCAN data). The vast majority of cervical cancers are caused by persistent infection with high-risk strains of human papillomavirus (HPV).
Cervical cancer is one of the most preventable cancers through HPV vaccination and routine screening. In countries with robust screening programs, cervical cancer incidence and mortality have declined dramatically over the past several decades. However, significant disparities persist, and late-stage diagnoses remain common in underserved populations.
The HPV Connection
Human papillomavirus (HPV) is detected in over 99% of cervical cancers. HPV types 16 and 18 together account for approximately 70% of all cervical cancers. Other high-risk HPV types include 31, 33, 45, 52, and 58. HPV infection is extremely common—most sexually active people will acquire HPV at some point—but the immune system clears the majority of infections within 1–2 years. Persistent infection with high-risk HPV types can lead to precancerous changes (cervical intraepithelial neoplasia, CIN) that may progress to invasive cancer over 10–20 years if untreated.
Screening and Prevention
- Pap smear (Pap test) — Detects abnormal cervical cells that may be precancerous or cancerous. Recommended every 3 years for women aged 21–65.
- HPV testing — Detects high-risk HPV DNA or RNA. Can be used alone (primary HPV testing) every 5 years for women aged 25–65, or in combination with Pap testing (co-testing) every 5 years for women aged 30–65.
- HPV vaccination — Gardasil 9 protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. It is highly effective at preventing cervical precancer and cancer when administered before HPV exposure.
Types of Cervical Cancer
Squamous Cell Carcinoma
The most common type, accounting for approximately 70–80% of cervical cancers. It arises from the squamous cells lining the outer surface of the cervix (ectocervix) at the transformation zone where squamous and glandular cells meet. Squamous cell carcinoma is strongly associated with HPV 16.
Adenocarcinoma
Accounts for approximately 20–25% of cervical cancers and arises from the glandular cells of the endocervix. Adenocarcinoma is more strongly associated with HPV 18 and may be harder to detect on Pap smear because it originates higher in the cervical canal. Its incidence has been increasing relative to squamous cell carcinoma.
Adenosquamous Carcinoma
A less common mixed type containing both squamous and glandular components, accounting for approximately 3–5% of cervical cancers. Other rare histological types include small cell neuroendocrine carcinoma (an aggressive subtype treated similarly to small cell lung cancer), clear cell adenocarcinoma (historically associated with in utero DES exposure), and gastric-type adenocarcinoma (not associated with HPV and often detected at a later stage).
Risk Factors
- Persistent high-risk HPV infection — The primary cause of cervical cancer.
- Lack of screening — Women who do not receive regular Pap tests or HPV testing are at significantly higher risk of late-stage diagnosis.
- Smoking — Doubles the risk of cervical cancer. Tobacco byproducts have been found in cervical mucus and may impair local immune response to HPV.
- Immunosuppression — HIV infection and immunosuppressive medications increase risk by impairing HPV clearance.
- Long-term oral contraceptive use — Use for 5+ years modestly increases risk, which decreases after discontinuation.
- Multiple full-term pregnancies — Three or more full-term pregnancies are associated with increased risk.
- Early sexual activity and multiple sexual partners — Increases the likelihood of HPV exposure.
Cervical Cancer Staging (FIGO 2018)
| Stage | Description | 5-Year Survival Rate |
|---|---|---|
| Stage I | Confined to the cervix (IA: microscopic; IB: clinically visible) | ~80–92% |
| Stage II | Extends beyond the cervix but not to the pelvic sidewall or lower third of vagina | ~58–75% |
| Stage III | Extends to pelvic sidewall, lower third of vagina, or causes hydronephrosis; includes pelvic/para-aortic lymph node involvement (IIIC) | ~32–50% |
| Stage IV | Extends beyond the true pelvis or involves bladder/rectal mucosa (IVA) or distant metastasis (IVB) | ~5–18% |
Survival rates from SEER data and FIGO annual report. The 2018 FIGO revision incorporates imaging and pathological findings including lymph node status.
Treatment by Stage
Early-Stage Disease (Stages IA–IB1)
For early-stage cervical cancer, surgery is the primary treatment. Options include:
- Cone biopsy or simple hysterectomy — For stage IA1 without lymphovascular space invasion (LVSI).
- Radical hysterectomy with pelvic lymph node dissection — The standard surgery for stage IA2–IB1 disease. Sentinel lymph node mapping is increasingly used to reduce surgical morbidity.
- Radical trachelectomy — A fertility-preserving option for select patients with tumors ≤2 cm who wish to maintain reproductive potential.
Sentinel Lymph Node Mapping
Sentinel lymph node (SLN) mapping is increasingly used in early-stage cervical cancer (tumors ≤2 cm) to identify and sample the first draining lymph nodes, potentially avoiding complete pelvic lymphadenectomy and its associated morbidity (lymphedema, vascular injury). The SENTICOL III trial and NCCN guidelines support SLN mapping as an acceptable approach for appropriately selected patients.
Locally Advanced Disease (Stages IB2–IVA)
Concurrent chemoradiation is the standard treatment for locally advanced cervical cancer. This consists of external beam radiation therapy (EBRT) plus brachytherapy, combined with weekly cisplatin as a radiosensitizer. The GOG 120 and other landmark trials demonstrated that concurrent cisplatin-based chemoradiation improves overall survival by 30–50% compared to radiation alone.
Recurrent or Metastatic Disease (Stage IVB)
Treatment options for advanced or recurrent cervical cancer have expanded significantly:
- Pembrolizumab (Keytruda) — Approved for PD-L1–positive recurrent or metastatic cervical cancer, both in combination with chemotherapy ± bevacizumab (KEYNOTE-826 trial) and as monotherapy for previously treated PD-L1+ tumors.
- Bevacizumab (Avastin) — Added to chemotherapy (cisplatin/paclitaxel or topotecan/paclitaxel) based on the GOG 240 trial, which demonstrated an overall survival benefit.
- Tisotumab vedotin (Tivdak) — An antibody-drug conjugate approved for recurrent or metastatic cervical cancer after prior chemotherapy.
Fertility Preservation
Cervical cancer often affects women of reproductive age, making fertility preservation an important consideration. Radical trachelectomy preserves the uterus and enables future pregnancy in select patients with early-stage disease. For patients requiring chemoradiation, oocyte or embryo cryopreservation should be discussed before treatment begins. Ovarian transposition can protect ovarian function from pelvic radiation. Patients should be counseled that pregnancy after trachelectomy carries increased risks, including preterm delivery, and requires close obstetric monitoring.
Radiation and Brachytherapy
Radiation therapy is a critical component of cervical cancer treatment, particularly for locally advanced disease. External beam radiation therapy (EBRT) targets the primary tumor and regional lymph nodes, while intracavitary brachytherapy delivers a high dose of radiation directly to the cervix. Image-guided brachytherapy (IGBT) using MRI-based planning has improved local control rates and reduced toxicity compared to conventional 2D planning. The EMBRACE studies have demonstrated that MRI-guided adaptive brachytherapy achieves local control rates exceeding 90% for tumors up to 5 cm.
Side effects of pelvic radiation include fatigue, diarrhea, bladder irritation, and long-term risks of vaginal stenosis, lymphedema, and premature ovarian failure. Ovarian transposition (oophoropexy) before radiation can preserve ovarian function in premenopausal women. Vaginal dilator use and regular follow-up help manage long-term effects.