Carcinoma of the cervix was once the most common cause of cancer death in women, but over the past 30 years, the mortality rate has decreased by 50% due to widespread screening with the Pap smear. In 2004, ~10,500 new cases of invasive cervix cancer occurred, and >50,000 cases of carcinoma in situ were detected. There were 3,900 deaths from the disease, and of those patients, ~85% had never had a Pap smear. It remains the major gynecologic cancer in underdeveloped countries. It is more common in lower socioeconomic groups, in women with early initial sexual activity and/or multiple sexual partners, and in smokers. Venereal transmission of human papilloma virus (HPV) has an important etiologic role. Over 66 types of HPVs have been isolated, and many are associated with genital warts. Those types associated with cervical carcinoma are 16, 18, 31, 45, and 51 to 53. These, along with many other types, are also associated with cervical intraepithelial neoplasia (CIN). The protein product of HPV-16, the E7 protein, binds and inactivates the tumor-suppressor gene Rb, and the E6 protein of HPV-18 has sequence homology to the SV40 large T antigen and has the capacity to bind and inactivate the tumor-suppressor gene p53. E6 and E7 are both necessary and sufficient to cause cell transformation in vitro. These binding and inactivation events may explain the carcinogenic effects of the viruses.
Vaccination against pathologic HPV1 appears quite promising as a cervix cancer prevention strategy. The administration of HPV-16 vaccine in a double-blind study of 2392 women completely prevented infection with the virus, and no cases of HPV-16-related CIN2 were seen in vaccinated women. Although this vaccine is promising, polyvalent vaccines incorporating the known pathologic HPV virus types may ultimately be required.
Uncomplicated HPV1 lower genital tract infection and condylomatous atypia of the cervix can progress to CIN3. This lesion precedes invasive cervical carcinoma and is classified as low-grade squamous intraepithelial lesion (SIL), high-grade SIL, and carcinoma in situ. Carcinoma in situ demonstrates cytologic evidence of neoplasia without invasion through the basement membrane, can persist unchanged for 10 to 20 years, but eventually progresses to invasive carcinoma.
The Pap smear is 90 to 95% accurate in detecting early lesions such as CIN4 but is less sensitive in detecting cancer when frankly invasive cancer or fungating masses are present. Inflammation, necrosis, and hemorrhage may produce false-positive smears, and colposcopic-directed biopsy is required when any lesion is visible on the cervix, regardless of Pap smear findings. The American Cancer Society recommends that women after onset of sexual activity, or >age 20, have two consecutive yearly smears. If negative, smears should be repeated every 3 years. The American College of Obstetrics and Gynecology recommends yearly Pap smears with routine annual pelvic and breast examinations. The Pap smear can be reported as normal (includes benign, reactive, or reparative changes); atypical squamous cells of undetermined significance (ASCUS) or cannot exclude high-grade SIL5 (ASC-H); low- or high-grade CIN; or frankly malignant. Women with ASCUS, ASC-H, or low-grade CIN should have repeat smears in 3 to 6 months and be tested for HPV1. Women with high-grade CIN or frankly malignant Pap smears should have colposcopic-directed cervical biopsy. Colposcopy is a technique using a binocular microscope and 3% acetic acid applied to the cervix in which abnormal areas appear white and can be biopsied directly. Cone biopsy is still required when endocervical tumor is suspected, colposcopy is inadequate, the biopsy shows microinvasive carcinoma, or when a discrepancy is noted between the Pap smear and the colposcopic findings. Cone biopsy alone is therapeutic for CIN in many patients, although a less radical electrocautery excision may be sufficient.
Approximately 80% of invasive cervix cancers are squamous cell tumors, 10 to 15% are adenocarcinomas, 2 to 5% are adenosquamous with epithelial and glandular structures, and 1 to 2% are clear cell mesonephric tumors.
Patients with cervix cancer generally present with abnormal bleeding or postcoital spotting that may increase to intermenstrual or prominent menstrual bleeding. Yellowish vaginal discharge, lumbosacral back pain, and urinary symptoms can also be seen.
The staging of cervical carcinoma is clinical and generally completed with a pelvic examination under anesthesia with cystoscopy and proctoscopy. Chest x-rays, intravenous pyelograms, and computed tomography are generally required, and magnetic resonance imaging (MRI) may be used to assess extracervical extension. Stage 0 is carcinoma in situ, stage I is disease confined to the cervix, stage II disease invades beyond the cervix but not to the pelvic wall or lower third of the vagina, stage III disease extends to the pelvic wall or lower third of the vagina or causes hydronephrosis, stage IV is present when the tumor invades the mucosa of bladder or rectum or extends beyond the true pelvis. Five-year survivals are as follows: stage I - 85%, stage II - 60%, stage III - 33%, and stage IV - 7% (
Carcinoma in situ (stage 0) can be managed successfully by cone biopsy or by abdominal hysterectomy. For stage I disease, results appear equivalent for either radical hysterectomy or radiation therapy. Patients with stages II to IV disease are primarily managed with radical radiation therapy or combined modality therapy. Retroperitoneal lymphadenectomy has no proven therapeutic role. Pelvic exenterations, although uncommon, are performed for centrally recurrent or persistent disease. Reconstruction of the vagina, bladder, and rectum can often be done following this operation.
In women with locally advanced disease (stages IIB to IVA), platinum-based chemotherapy given concomitantly with radiation therapy improves survival compared to radiation therapy alone. Cisplatin, 75 mg/m2 over 4 h, followed by 5-fluorouracil (5-FU), 4 g given by 96-h infusion on days 1 to 5 of radiation therapy, is a common regimen. Two additional cycles of chemotherapy are given at 3-week intervals. Concurrent chemoradiotherapy reduced the risk of recurrence by 30 to 50% across a wide spectrum of stages and presentations and is the treatment of choice in stages IIB to IV cervix cancer.
Chemotherapy has been used in patients with unresectable advanced disease or recurrent disease. Active agents with ≥20% response rates include cisplatin, 5-FU6, ifosfamide, and irinotecan. No combination of agents has proved better than single agents. Intraarterial chemotherapy has been studied, either pre- or postoperatively, but is associated with substantial local toxicity and response rates of 20%.
Revision date: June 22, 2011
Last revised: by Jorge P. Ribeiro, MD