Cervical cancer is the third most common gynecologic cancer in the United States. Cervical cancer occurs in several varieties: squamous cell carcinoma (60% of cases), adenocarcinoma (25%) and other histologies (6%). It is now clear that human papillomavirus (HPV) is the cause of the abnormal cell changes that lead to the development of cancer and can be detected in 99.7% of cervical cancers.
Cervical cancer is often asymptomatic. When symptoms do occur, the most common are abnormal vaginal discharge or irregular bleeding and bleeding after intercourse. Advanced disease may also cause pain in the low back and pelvis with radiation into the posterior legs, as well as bowel or urinary symptoms, such as passage of blood and a sensation of pressure.
In addition to HPV infection, other risk factors for cervical cancer include:
- Sexual activity. Early sexual intercourse, history of multiple sexual partners (or a partner with multiple partners), history of sexually transmitted disease, sexual relationship with a person who has exposure to HPV, and intercourse with an uncircumcised man are associated with increased risk.
- Smoking. Smoking increases the risk for infection with the HPV virus and increases the risk of developing cancer in those with a high-risk HPV infection.
- Pregnancy history. Early age at first birth (younger than 20 years old) and women with 3 or more full-term pregnancies are at increased risk.
- Oral contraceptives. The proportion of adenocarcinoma increases with the duration of oral contraception.
- Immunosuppression. Women infected with the human immunodeficiency virus (HIV), which damages the immune system, are at higher risk for HPV infections.
- Diet. High consumption of fruit and vegetables appears to lower the risk of cervical cancer.
Prevention and Screening
HPV vaccination. In 2006, the FDA approved a recombinant vaccine that protects against 4 strains of the human papillomavirus (HPV 6, 11, 16, and 18) that are implicated in up to 70% of cases of cervical intraepithelial neoplasia, a precursor to cervical cancer, and 90% of cases of female genital warts. However, the vaccine does not protect against cervical cancer among those already infected with HPV, and it does not influence risk of cases not due to these HPV strains.
Since the inception of annual Pap smear screening, HPV testing, and HPV vaccination, there has been a 75% decline in cervical cancer incidence and mortality. The majority of cases now occur in women who have not been adequately screened. , Due in part to the success of screening programs, cervical cancer only accounts for about 1% of all cancer deaths in developed countries. In contrast, women with cervical cancer in developing nations have much higher mortality (nearly 50%), due to the scarcity of screening programs. Cervical cancer is age related; incidence is extremely low in women under 20 and peaks in women aged 45 to 49 years.
Pap screening/ HPV testing. The optimal testing method (Pap test, HPV testing, or both) and frequency are debated. , , , , In general, the consensus is that women aged 21 to 29 years be screened with a Pap test every 3 years. Women 30 and older should have a Pap test every 3 years or co-testing (Pap plus HPV testing) every 5 years until age 65.
Due to the frequent asymptomatic presentation of cervical cancer, diagnosis is often made on routine pelvic examination or Pap test screening. An abnormal Pap smear requires further evaluation, which may include colposcopy with directed biopsy of abnormal cervical tissue or conization. If a cervical lesion is visible, the diagnosis of cervical cancer is confirmed via biopsy.
If a histologic diagnosis of invasive cervical cancer is made, a full clinical staging evaluation via clinical examination, radiography, blood work (which may include tumor markers), and endoscopy is recommended.
Cervical cancer is staged using the system established by the International Federation of Gynecology and Obstetrics (FIGO) through clinical (as opposed to pathological or surgical) evaluation. The following stages include multiple subtypes that further classify the cervical cancer:
- Stage 0: Carcinoma remains in situ.
- Stage I: Carcinoma is limited to the uterus.
- Stage II: Carcinoma has spread from the uterus but does not include the lower third of the vagina or pelvic wall.
- Stage III: Carcinoma has spread to the lower third of the vagina or pelvic wall or causes hydronephrosis.
- Stage IV: Carcinoma has spread to the bladder or rectum or to distant organs beyond the pelvic area.
In general, squamous cell carcinoma, adenocarcinoma, and adenosquamous cervical cancers are treated similarly with radical hysterectomy (with regional lymphadenectomy) or radiation plus chemotherapy. Radiation and chemotherapy may also be administered after surgery in women at high risk of recurrence (e.g. positive surgical margins or lymph nodes, or parametrial invasion).
Surgery preserves the ovaries and may be preferable to radiation and chemotherapy for premenopausal women. In addition to causing hormone-deficient vaginal stenosis, radiation and chemotherapy may damage the vagina, which could lead to dyspareunia in sexually active women.
Women with early cervical cancer who want to retain fertility may select a conization procedure or other surgical options that remove the cancerous lesion but permit pregnancy.
Epidemiologic studies suggest that dietary factors may influence risk for cervical cancer. Part of the effect of diet may be attributable to the suppressive action of certain micronutrients on HPV infection, particularly carotenoids (both vitamin A and non-vitamin A precursors), folate, and vitamins C and E. The following factors have been associated with reduced risk:
Fruits and vegetables. A review of dietary strategies for prevention of cervical cancer concluded that low intakes of fruits and vegetables are associated with a 3-fold increase in the risk of cervical intraepithelial neoplasia (CIN) classes 2 and 3 in women with a high HPV viral load. Low serum levels of nutrients associated with fruit and vegetable intake (e.g., vitamin A and lycopene) tended to be positively associated with risk of CIN class 3; however, higher serum levels of other carotenoids (alpha-carotene, beta-cryptoxanthin, lutein/zeaxanthin, and lycopene) and gamma tocopherol were found in association with a reduced risk of high-grade CIN. These nutrients may enhance the clearance of high-risk HPV infections, but are not associated with the clearance of persistent infections. In the European Prospective Investigation into Cancer and Nutrition study that included nearly 300,000 women, fruit intake was inversely associated with the risk for invasive squamous cervical cancer (ISC), with a 17% lower risk of ISC for consumption of an additional 3.5 ounces per day.
Folic acid and other B vitamins. Interactions appear to exist between folate status, mutations in the folate-dependent enzyme methylene-tetrahydrofolate reductase (MTHFR), plasma homocysteine, and HPV that influence cervical cancer risk. Women with higher plasma folate concentrations were significantly less likely to be diagnosed with CIN 2+, especially when vitamin B12 levels were in the normal range. Those with the MTHFR CT/TT genotype with lower plasma folate were more likely to be diagnosed with CIN 2+ compared to women with this genotype who had higher blood folate levels.
Obesity. A recent meta-analysis found a significant but weak association between obesity and risk for cervical cancer.
Alcohol. Studies have shown a significantly greater risk for HPV persistence in women who consume alcohol regularly compared with those who are low or non-consumers, especially among those with a high viral load.
While an important body of research on diet and cervical cancer risk exists, there has been little research on the role of diet in survival after diagnosis.
HPV vaccination, when indicated.
Routine Pap screening and HPV testing, when indicated.
What to Tell the Family
Cervical cancer is treatable if detected early. For this reason, Pap smear evaluations and HPV testing should be conducted regularly. Cervical cancer risk is closely tied to cancer-causing forms of HPV. HPV infection may be chronic or transient, and it is affected by diet, tobacco use, and genetic factors. Men can also be screened for HPV. Risk of cervical cancer is reduced by avoiding multiple sexual partners, receiving the HPV vaccine, and maintaining a diet of fruits and vegetables especially high in carotenoids and foods high in folic acid (legumes, whole grains, fruits, and vegetables).
- Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61(4):212-36. [PMID:21685461]
- Ries LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2004 . Bethesda, MD: National Cancer Institute; 2007.
- Castellsagué X, Bosch FX, Muñoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med. 2002;346(15):1105-12. [PMID:11948269]
- Fonseca-Moutinho JA. Smoking and cervical cancer. ISRN Obstet Gynecol. 2011;2011:847684. [PMID:21785734]
- Berrington de González A, Green J, International Collaboration of Epidemiological Studies of Cervical Cancer. Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer. 2007;120(4):885-91. [PMID:17131323]
- International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby P, Beral V, et al. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet. 2007;370(9599):1609-21. [PMID:17993361]
- Chih HJ, Lee AH, Colville L, et al. A review of dietary prevention of human papillomavirus-related infection of the cervix and cervical intraepithelial neoplasia. Nutr Cancer. 2013;65(3):317-28. [PMID:23530631]Chih HJ, Lee AH, Colville L, et al. A review of dietary prevention of human papillomavirus-related infection of the cervix and cervical intraepithelial neoplasia. Nutr Cancer. 2013;65(3):317-28. [PMID:23530631]
- Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356(19):1928-43. [PMID:17494926]
- Hildesheim A, Hadjimichael O, Schwartz PE, et al. Risk factors for rapid-onset cervical cancer. Am J Obstet Gynecol. 1999;180(3 Pt 1):571-7. [PMID:10076130]
- Janerich DT, Hadjimichael O, Schwartz PE, et al. The screening histories of women with invasive cervical cancer, Connecticut. Am J Public Health. 1995;85(6):791-4. [PMID:7762711]
- SEER cancer statistics review 1973-1999. National Cancer Institute website. Available at: http://seer.cancer.gov . Published April 7, 2005. Accessed July 14, 2017.
- Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012;62(3):147-72. [PMID:22422631]
- Moyer VA, U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;156(12):880-91, W312. [PMID:22711081]
- Practice Bulletin No. 157: Cervical Cancer Screening and Prevention. Obstet Gynecol. 2016;127(1):e1-e20. [PMID:26695583]
- Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Gynecol Oncol. 2015;136(2):178-82. [PMID:25579107]
- Sawaya GF, Kulasingam S, Denberg TD, et al. Cervical Cancer Screening in Average-Risk Women: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. 2015;162(12):851-9. [PMID:25928075]
- Benedet JL, Bender H, Jones H, et al. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet. 2000;70(2):209-62. [PMID:11041682]
- Pecorelli S, Zigliani L, Odicino F. Revised FIGO staging for carcinoma of the cervix. Int J Gynaecol Obstet. 2009;105(2):107-8. [PMID:19342051]
- González CA, Travier N, Luján-Barroso L, et al. Dietary factors and in situ and invasive cervical cancer risk in the European prospective investigation into cancer and nutrition study. Int J Cancer. 2011;129(2):449-59. [PMID:20853322]
- Piyathilake CJ, Macaluso M, Chambers MM, et al. Folate and vitamin B12 may play a critical role in lowering the HPV 16 methylation-associated risk of developing higher grades of CIN. Cancer Prev Res (Phila). 2014;7(11):1128-37. [PMID:25145486]
- Badiga S, Johanning GL, Macaluso M, et al. A lower degree of PBMC L1 methylation in women with lower folate status may explain the MTHFR C677T polymorphism associated higher risk of CIN in the US post folic acid fortification era. PLoS ONE. 2014;9(10):e110093. [PMID:25302494]
- Poorolajal J, Jenabi E. The association between BMI and cervical cancer risk: a meta-analysis. Eur J Cancer Prev. 2016;25(3):232-8. [PMID:25932869]
- Oh HY, Kim MK, Seo S, et al. Alcohol consumption and persistent infection of high-risk human papillomavirus. Epidemiol Infect. 2015;143(7):1442-50. [PMID:25185457]