Cervical cancer is the third most common gynecologic cancer in the US.[1] More than 90% of cases are squamous cell carcinomas; next most common are adenocarcinomas. Infection by human papillomavirus (HPV) leads to the development of cancer, and HPV can be detected in 99.7% of cervical cancers.

The disease is often asymptomatic. When symptoms do occur, the most common are abnormal vaginal discharge or irregular bleeding, and pain or bleeding after intercourse. Advanced disease may also cause pain in the low back and pelvis with radiation to the posterior aspect of the legs, as well as bowel or urinary symptoms, such as passage of blood and a sensation of pressure.

Risk Factors

In addition to HPV infection, other risk factors for cervical cancer include:

• Age. Incidence is extremely low in women under 20 and peaks in women aged 45 to 49 years.[2]
• Obesity. A 2016 meta-analysis found a weak but significant association between obesity and risk for cervical cancer.[3]
• Sexual activity. History of multiple sexual partners (or a partner with multiple partners), history of sexually transmitted disease, a sexual relationship with a person who has exposure to HPV, and intercourse with an uncircumcised man are associated with increased risk.[4]
• Smoking. Smoking increases the risk for infection with HPV and the risk of developing cancer in those with a high-risk HPV subtype.[5] This may be a result of DNA damage caused by smoking and a compromised immune system in smokers.
• 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.[6]
• Oral contraceptives. The incidence of adenocarcinoma increases with the duration of oral contraception.[7]
• Immunosuppression. Women infected with the human immunodeficiency virus (HIV) are at higher risk for HPV infection.
• Chlamydia. Infection with certain subtypes of chlamydia greatly increases the risk of cervical cancer.[8],[9]
• Diet. See Nutritional Considerations below.

Prevention and Screening

HPV vaccination. In 2006, the Food and Drug Administration approved a recombinant vaccine that protects against four 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. The Centers for Disease Control and Prevention recommend HPV vaccination for both girls and boys beginning at age 11-12, but the vaccine may be administered as early as age 9. It is also recommended for adults through age 26 if they have not been previously vaccinated.[10] The vaccine does not protect against cervical cancer among those already infected with HPV and does not influence the risk of cancers that are not due to these HPV strains.[11]

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.[12],[13] Due in part to the success of screening programs, cervical cancer accounts for only 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.[14]

Pap screening/HPV testing. There is not universal agreement regarding the optimal testing method (Pap test for cytology, HPV testing, or co-testing with both) or frequency.[15],[16],[17],[18],[19] However, the current consensus is that, regardless of age at first sexual intercourse, women aged 21 to 29 years should be screened with a Pap test every 3 years, and women aged 30 years and older should have a Pap test every 3 years or co-testing (Pap plus HPV testing) every 5 years until age 65.

Diagnosis

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.[20]

Treatment

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:[21]

• 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.

Nutritional Considerations

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, particularly carotenoids (both vitamin A and non-vitamin A precursors), folate, and vitamins C and E, on HPV infection. The following factors have been associated with reduced risk:

Fruits and vegetables. A low intake of fruits and vegetables is associated with a 3-fold increase in the risk of cervical intraepithelial neoplasia (CIN) 2-3 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 associated with risk of CIN 3. Higher serum levels of other carotenoids (alpha-carotene, beta-cryptoxanthin, lutein/zeaxanthin, and lycopene) and gamma tocopherol have been found to be associated 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.[22] 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 oz per day.[23]

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.[24] Those with the MTHFR CT/TT genotype with lower plasma folate were more likely to be diagnosed with CIN 2+ compared with women with this genotype who had higher blood folate levels.[25]

Alcohol. Studies have shown a significantly greater risk for HPV persistence in women who consume alcohol regularly, compared with those who consume less or none, especially among those with a high viral load.[26]

In contrast to the more robust body of research on diet and cervical cancer risk, there has been little research on the role of diet in survival after diagnosis.

Orders

See Basic Diet Orders chapter.

Smoking cessation.

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. Infection with HPV 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, vaccinating both girls and boys for HPV, and maintaining a diet rich in fruits and vegetables with high levels of carotenoids, and foods high in folate (legumes, whole grains, fruits, and vegetables).

References