Description of Evidence
Incidence and Mortality
An estimated 13,170 new cervical cancers and 4,250 cervical cancer deaths will occur in the United States in 2019.[1] When corrected for the prevalence of hysterectomy, the mortality rate for black women is nearly twice the mortality rate for white women.[2] Also, approximately 1,250,000 women will be diagnosed with precancers annually by cytology using the Papanicolaou (Pap) smear. A continuum of pathologic changes may be diagnosed, ranging from atypical squamous cells of undetermined significance to low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions (HSIL) to invasive cancer. The precancerous conditions LSIL and HSIL are also referred to as cervical intraepithelial neoplasia (CIN) 1, 2, and 3. Lesions can regress, persist, or progress to an invasive malignancy, with LSIL (CIN 1) more likely to regress spontaneously and HSIL (CIN 2/CIN 3) more likely to persist or progress. The average time for progression of CIN 3 to invasive cancer has been estimated to be 10 to 15 years.[3]
Factors With Adequate Evidence of an Increased Risk of Cervical Cancer
HPV
Epidemiologic studies to evaluate risk factors for the development of squamous intraepithelial lesions (SIL) and cervical malignancy demonstrate conclusively a sexual mode of transmission of a carcinogen.[4] It is now widely accepted that human papillomavirus (HPV) is the primary etiologic infectious agent that causes virtually all cases of cervical cancer.[5,6] Other sexually transmitted factors, including herpes simplex virus 2 and Chlamydia trachomatis, may play a cocausative role.[7] More than 80 distinct types of HPV have been identified, approximately 30 of which infect the human genital tract. HPV type 16 (HPV-16) and HPV type 18 (HPV-18) are most often associated with invasive disease. Characterization of carcinogenic risk associated with HPV types is an important step in the process of developing a combination HPV vaccine for the prevention of cervical neoplasia. In a population-based study of HPV infection and cervical neoplasia in Costa Rica, 80% of HSIL and invasive lesions were associated with HPV infection by one or more of 13 cancer-associated types.[8] In this study, the risk of about 50% of HSIL and invasive cervical cancer was attributable to HPV-16. HPV-18 was associated with 15% of invasive disease but only 5% of HSIL, suggesting that HPV-18 may have a role in more aggressive cases of cervical malignancy.
Immunosuppression
Most cases of HPV infection are resolved by the host immune system. Immunosuppression leads to persistence of viral infection with a subsequent increased risk of cervical neoplasia. Women with immunosuppression resulting from human immunodeficiency virus (HIV) infection have been studied over the past three decades of the AIDS epidemic. In one North American study, a group of 13,690 HIV-infected women were studied for a median of 5 years. The rate of invasive cervical cancer in the HIV-infected women was 26 cases per 100,000 women, and this was approximately four times greater than an HIV-uninfected control group.[9] HIV-infected women with the lowest CD4 lymphocyte counts were at the highest risk of invasive cancer. Women who are immunosuppressed resulting from organ transplantation are also at risk of invasive cervical cancer, and one meta-analysis found a twofold increased risk.[10]
Sexual activity at an early age and with a greater number of partners
HPV infection has been established as a necessary cause of almost all cases of cervical cancer, and the primary mode of transmission is sexual contact. This provides context for the findings that younger age at first intercourse and an increasing number of lifetime sexual partners are both associated with an increased risk of developing cervical cancer. Pooled, individual, patient-level data from 12 cohort and case-control studies demonstrated statistically significantly increased risks of developing cervical cancer in women who were aged 17 years or younger at first intercourse, compared with women who were aged 21 years or older at first intercourse (relative risk [RR] for squamous cell cancer, 2.24; 95% confidence interval [CI], 2.11–2.38 and RR for adenocarcinoma, 2.06; 95% CI, 1.83–2.33). Similar findings were observed in women who had six or more lifetime sexual partners compared with women who had one lifetime sexual partner (RR for squamous cell cancer, 2.98; 95% CI, 2.62–3.40 and RR for adenocarcinoma, 2.64; 95% CI, 2.07–3.36).[11]
High parity
High parity has long been recognized as a risk factor for cervical cancer, but the relation of parity to HPV infection was uncertain. A meta-analysis of 25 epidemiologic studies, including 16,563 women with cervical cancer and 33,542 women without cervical cancer, showed that the number of full-term pregnancies was associated with increased risk, regardless of age at first pregnancy. This finding was also true if analyses were limited to patients with high-risk HPV infections (RR, 4.99; 95% CI, 3.49–7.13 for seven or more pregnancies vs. no pregnancies; linear trend test X2 = 30.69; P < .001).[12]
Long-term use of oral contraceptives
Long-term use of oral contraceptives has also been known to be associated with cervical cancer, but its relation to HPV infection was also uncertain. A pooled analysis of HPV-positive women from the studies described above was undertaken. Compared with women who have never used oral contraceptives, those who have used them for fewer than 5 years did not have an increased risk of cervical cancer (odds ratio [OR], 0.73; 95% CI, 0.52–1.03). The OR for women who used oral contraceptives for 5 to 9 years was 2.82 (95% CI, 1.46–5.42), and for 10 or more years, the OR was 4.03 (95% CI, 2.09–8.02).[13] A meta-analysis of 24 epidemiological studies confirmed the increased risk associated with oral contraceptives, which is proportionate to the duration of use. Risk decreases after cessation and returns to normal risk levels in 10 years.[14]
Cigarette smoke exposure
Cigarette smoking by women is associated with an increased risk of squamous cell carcinoma.[4,15,16] This risk increases with longer duration and intensity of smoking. The risk among smokers may be present with exposure to environmental tobacco smoke and may be as high as four times that of women who are nonsmokers who are not exposed to environmental smoking.[4] Case-control studies of women infected with HPV have examined the effect of various types and levels of tobacco exposure and found similar results.[16-18]
DES exposure
Diethylstilbestrol (DES) is a synthetic form of estrogen that was prescribed to pregnant women in the United States between 1940 and 1971 to prevent miscarriage and premature labor. DES is associated with a substantially increased risk of developing clear cell adenocarcinoma of the vagina and cervix among the daughters of women who used the drug during pregnancy (standardized incidence ratio, 24.23; 95% CI, 8.89–52.74); the risk persists as these women age into their 40s.[19] Despite the greatly elevated risk relative to the general population, this type of cancer is still rare; about one in 1,000 daughters exposed to DES will develop a clear cell adenocarcinoma.
DES exposure in utero is also associated with an increased risk of developing cervical dysplasia. An evaluation of three cohorts, including the Diethylstilbestrol Adenosis study, the Dieckmann study, and the Women’s Health Study, with long-term follow-up of more than 4,500 women exposed in utero to DES, found that 6.9% of exposed women developed grade II or higher CIN compared with 3.4% of nonexposed women (hazard ratio, 2.28; 95% CI, 1.59–3.27).[20]
Factors With Adequate Evidence of a Decreased Risk of Cervical Cancer
Sexual abstinence
Nearly all cases of cervical cancer are associated with HPV infection, which is transmitted during sexual activity. Therefore, cervical cancer is seen more frequently in women with sexual activity at an early age and with multiple partners.[21] Lifetime abstinence from sexual activity is associated with a near-total reduction in the risk of developing cervical cancer. (Refer to the Human papillomavirus section of this summary for more information.)
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