Description of the Evidence
Natural history, incidence, and mortality
In the United States in 2015, it is estimated that 12,900 cases of invasive cervical cancer will be diagnosed and that 4,100 women will die of the disease. These rates had been improving steadily. However, from 2007 to 2011, rates in women younger than 50 years were stable among whites and decreased by 3.4% per year among blacks; in women aged 50 years or older, rates declined by 2.5% per year in whites and by 3.8% per year in blacks. Mortality rates were stable among women younger than 50 years but decreased by 1.1% per year among women aged 50 years and older. This improvement has been attributed largely to screening with the Papanicolaou (Pap) test.
Invasive squamous carcinoma of the cervix results from the progression of preinvasive precursor lesions called cervical intraepithelial neoplasia (CIN), or dysplasia. CIN is histologically graded into mild dysplasia (CIN 1), moderate dysplasia (CIN 2), or severe dysplasia (CIN 3). Not all of these lesions progress to invasive cancer; many mild and moderate lesions regress. A further categorization, the Bethesda system, is based on cytologic findings: atypical squamous cells of undetermined significance (ASCUS) or cannot rule out low-grade squamous intraepithelial lesions (LSIL), LSIL (consisting of cytologic atypia and CIN 1), and high-grade squamous intraepithelial lesions (HSIL), primarily CIN 2–3 plus carcinoma in situ.
The rate at which invasive cancer develops from CIN is usually slow, measured in years and perhaps decades. This long natural history provides the opportunity for screening to effectively detect this process during the preinvasive phase, thus allowing early treatment and cure. Because many of these preinvasive lesions (especially LSIL) would have never progressed to invasive cancer,[4-6] screening also runs the risk of leading to treatment for women who do not need to be treated.
Human papillomavirus (HPV) is an oncogenic virus and the etiologic agent of cervical cancer and related premalignant disease. HPV is transmitted by sexual contact. Sexually inactive women rarely develop cervical cancer, while sexual activity at an early age with multiple sexual partners is a strong risk factor. Nearly all women with invasive cervical cancer have evidence of HPV infection.[8-11] Most women with HPV infection, however, never develop cervical cancer; thus this infection is necessary but not sufficient for development of cancer.
Although cervical cancer mortality increases with age, the prevalence of CIN is highest among women in their 20s and 30s. Mortality is rare among women younger than 30 years; HSIL is rare among women older than 65 years who have been previously screened. About 70% of ASCUS and CIN 1 lesions regress within 6 years, while about 6% of CIN 1 lesions progress to CIN 3 or worse. In about 10% to 20% of women with CIN 3 lesions, the lesions progress to invasive cancer.[3,6,14]
Cervical cancer mortality is about 40% higher in black women younger than 65 years than in white women of the same age. Among women older than 65 years, cervical cancer mortality for black women is more than 150% higher than for white women. In either case, mortality is rare among women of any age who have regular screenings.
The Pap Test
The Pap test has never been examined in a randomized controlled trial. A large body of consistent observational data, however, supports its effectiveness in reducing mortality from cervical cancer. Both incidence and mortality from cervical cancer have sharply decreased in a number of large populations following the introduction of well-run screening programs.[15-18] In Iceland, the mortality rate declined by 80% for more than 20 years, and in Finland and Sweden by 50% and 34%, respectively.[15,19] Similar reductions have been observed in large populations in the United States and Canada. Reductions in cervical cancer incidence and mortality were proportional to the intensity of screening.[15,19] Mortality in the Canadian provinces was reduced most remarkably in British Columbia, which had screening rates two to five times those of the other provinces.
Case-control studies have found that the risk of developing invasive cervical cancer is three to ten times greater in women who have not been screened.[21-24] Risk also increases with long duration following the last normal Pap test, or similarly, with decreasing frequency of screening.[25,26] Screening every 2 to 3 years, however, has not been found to increase significantly the risk of finding invasive cervical cancer above the risk expected with annual screening.[26,27]
Accuracy of the Pap Test
Ideally, determining the sensitivity and specificity of a screening test would involve a study that applies a “gold standard” test (such as colposcopy with appropriate biopsy) to all participants (whether the screening test is positive or negative). Sensitivity (the percentage of “true-positive” cases that are detected by the screening test) and specificity (the percentage of "true-negative" cases that are negative by the screening test) could be calculated. Such studies have rarely been done for any screening test for cervical cancer. Studies that compare the Pap test with repeat Pap testing have found that the sensitivity of any abnormality on a single test for detecting high-grade lesions is 55% to 80%.[28,29] Because of the usual slow-growing nature of cervical cancer, the sensitivity of a program of regular Pap testing is likely higher.
To determine the sensitivity and specificity of the Pap smear, both a test threshold (i.e., the point at which the test will be considered to be “positive”) and a reference-standard threshold (i.e., the point at which the reference standard is considered to be “positive”) must be defined. In practice, ASCUS is often used as the test threshold, and CIN 1 is often used as the reference threshold. This combination gives a sensitivity of about 68% and a specificity of about 75%. A more appropriate test threshold may be LSIL, with a reference threshold of CIN 2–3. This combination gives a sensitivity of 70% to 80%, with a specificity of about 95%.
One important factor in the accuracy of the Pap test is the adequacy of the specimen obtained. Adequate training and using techniques such as the cytobrush may improve sensitivity.
New Screening Technologies
Newer techniques that employ liquid-based cytology (e.g., ThinPrep) have been developed to improve the sensitivity of screening. As with the Pap test, the optimal studies to determine the sensitivity and specificity of these technologies have not been done. Some less-than-optimal studies show that sensitivity is modestly higher for detecting any degree of CIN, with modestly lower specificity.[32,33] One careful study, however, showed that conventional Pap testing was slightly more sensitive and specific than liquid-based cytology.
The evidence is also mixed about whether liquid-based techniques improve rates of test adequacy.[32,33] One advantage of liquid-based cytology is that HPV testing can be done on the same preparation; one disadvantage is that liquid-based approaches are more expensive than conventional Pap testing. No study has examined whether liquid-based cytology actually reduces the number of women dying of cervical cancer compared with conventional Pap testing.
Screening Women Who Have Had a Hysterectomy
Women who have had a hysterectomy with removal of the cervix for benign disease rarely have important abnormalities found on Pap testing. Several studies have shown that the rate of high-grade vaginal lesions or vaginal cancer is less than 1 in 1,000 tests;[35,36] no study has shown that screening for vaginal cancer reduces mortality from this rare condition.
Because cervical cancer is slow growing, considerable uncertainty surrounds the issue of the optimal screening interval. The most direct evidence about this issue comes from a prospective cohort analysis of a randomized controlled trial. Among 2,561 women (mean age 66.7 years) with normal Pap tests at baseline, 110 had an abnormal Pap test within the next 2 years. No woman was found to have CIN 2–3 or invasive cancer, and only one had CIN 1–2. Thus the positive-predictive value (PPV) of screening 1 year after a negative Pap test was 0%; after 2 years, the PPV was 0.9%. The authors concluded that Pap tests should not be repeated within 2 years of a negative test. A large (n = 332,000) prospective cohort study of cervical cytology and HPV DNA co-testing in U.S. women aged 30 years and older found that a negative Pap smear was associated with a low risk for developing CIN 3 or cancer (CIN 3+) for up to 5 years after the test (cumulative incidence of CIN 3+ at 3 and 5 years was 0.17% and 0.36%, respectively).
A large study that included data from the National Breast and Cervical Cancer Early Detection Program together with modeling found little further mortality reduction from cervical cancer for screening every year as compared with screening every 3 years. A similar modeling study from Australia found no differences between every 2 year and every 3 year screening.
Noninvasive cervical squamous cell abnormalities are graded histologically as CIN 1, CIN 2, or CIN 3, according to the severity of the cell changes and the percent of the epithelium replaced by abnormal cell growth. CIN 3 is a reasonably reproducible diagnosis and has an approximate 30% risk of developing into invasive cancer over many years if untreated. CIN 2 has poor interobserver reproducibility, and the biologic behavior is variable. CIN 3 is therefore a more rigorous endpoint for clinical trials, while CIN 2 represents the threshold for treatment to provide an additional measure of safety.
Approximately 15 cancer-associated (high-risk or carcinogenic) HPV genotypes cause virtually all cases of cervical cancer and precursor lesions of CIN 2 and CIN 3. However, carcinogenic HPV infections are very common, particularly in young women, and the majority clear on their own within 1 to 2 years. Therefore, the challenge of incorporating HPV testing in cervical screening programs is to balance sensitivity for detection of CIN 2 or CIN 2+ and to minimize the over-referral of women with transient HPV infections and cervical changes that are destined to regress.
The U.S. Food and Drug Administration (FDA) has approved several HPV tests. Most of these tests are based on the detection of DNA from one or more oncogenic types of HPV. One test detects HPV RNA. HPV testing is approved for use in two contexts: (1) as a second (i.e., triage) test following an equivocal cytology result of ASCUS; and (2) for primary screening in conjunction with cervical cytology for women aged 30 years and older. Testing for low-risk HPV types does not identify women at risk for CIN 2 or 3.[45,46]
A large randomized clinical trial, the ASCUS/LSIL Triage Study (ALTS), demonstrated the cost-effectiveness of using HPV testing to clarify the risk of an ASCUS Pap result. ALTS randomly assigned women with ASCUS to one of three management strategies: Immediate colposcopy regardless of enrollment test results, referral to colposcopy if the HPV test was positive or if the enrollment cytology was HSIL, and referral to colposcopy only if the cytology was HSIL. The HPV triage strategy was as sensitive for detection of CIN 2+ as immediate colposcopy, while referring only about half of the women for the procedure. Repeat cytology with referral to colposcopy at the threshold of HSIL was less sensitive for CIN 3+ (60%) compared with HPV triage (92%); however, using a cytologic threshold of ASCUS for referral increased sensitivity but resulted in 72% of women with ASCUS undergoing colposcopy. HPV testing is not recommended for adolescent women with ASCUS because most of these women are HPV positive.[49,50]
HPV DNA testing is generally not appropriate or clinically useful following cytology results of LSIL, which is more severe than ASCUS, and most of these women (84%–96%) are carcinogenic HPV DNA positive. One exception may be to clarify the risk for postmenopausal women with cytologic LSIL, which is an interpretation that can be falsely positive, presumably due to atrophic changes.
Testing for HPV DNA as a primary screening test has been FDA approved only in conjunction with cervical cytology and only in women aged 30 years and older. Women who are negative by cytology and HPV testing are at extremely low risk of CIN 3+ and therefore may be screened less often. A prospective cohort study of nearly 332,000 U.S. women aged 30 years and older undergoing HPV DNA and cervical cytology co-testing every 3 years found that the cumulative incidence of CIN 3+ in women negative for both tests at baseline was 0.047% at 3 years and 0.16% at 5 years. Screening more frequently than every 3 years would not improve sensitivity significantly but would increase costs and overtreatment.[53,54]
Numerous studies have demonstrated that, compared with cytology, HPV DNA testing is more sensitive for identifying women who have CIN 2+ (range of sensitivities 84%–97%).[32,55-60] In one randomized trial using both Pap and HPV testing in random order among women aged 30 to 69 years, sensitivity of HPV was 95% compared with 55% for Pap cytology. The combination of HPV and cytology had 100% sensitivity and a referral rate of 7.9%.
The lower specificity of HPV DNA testing compared with cytology is a consideration. Among women older than 30 years, cytology had a specificity of 97% compared with 94% for HPV testing. The specificity of HPV DNA testing would likely be even lower among women younger than 30 years, who have more transient HPV infection that is of little consequence. Thus, detecting such women would potentially increase the number of follow-up diagnostic workups. Potential approaches to minimize over-referral with HPV DNA testing and improve specificity include: (1) triage HPV-positive results with cytology  or another more specific molecular assay; and (2) trigger further workup only after two sequential positive HPV test results because it is the persistence of carcinogenic HPV that confers the greatest risk of CIN 2–3.[62,63]
An Italian population-based randomized, controlled trial of HPV DNA testing versus cervical cytology performed at 3-year intervals in approximately 94,000 women aged 25 to 60 years found a statistically significant decrease in the number of invasive cervical cancer cases diagnosed in the HPV DNA arm at the second round of screening (0 cases vs. 9 cases; P = .004). However, about 48% of individuals in the HPV DNA arm also received conventional cytology testing at the first screening round, making it impossible to discern whether the observed difference resulted from the use of a combined testing strategy or HPV DNA testing alone. Of note, many more women in the HPV DNA arm were referred to colposcopy for abnormal findings than in the cytology-alone arm (4,436 women vs. 1,416 women), prompting the authors to conclude that if the HPV DNA test is used as a primary screening strategy, women with positive test results should be triaged by cytology before referral.
A study using data from a population-based randomized trial of cervical screening among women aged 32 to 38 years compared 11 different screening strategies using HPV DNA testing and cytology. The strategy of initial screening with an HPV DNA test and a triage of HPV-positive results with cytology, and subsequent repeat HPV DNA testing after 1 year for women who were HPV positive but cytology negative, increased the sensitivity for detection of CIN 3+ by 30% compared with cytology alone, and increased the total number of screening tests performed by only 12%.
Screening Benefit According to Age
Cervical cancer mortality, usually occurring among unscreened women, increases with age, with the maximum mortality for white women between age 45 years and 70 years, and for black women in their 70s.[53,66] (Also available online.) Mortality among women with negative Pap screening is low at all ages.
Screening by Pap testing with associated diagnostic testing and treatment is effective in reducing the incidence of all histologies and stages of invasive cervical cancer. The benefit increases with age. Whereas the odds ratio (OR) is 0.79 (95% CI, 0.57–1.1) among women screened at age 30 to 31 years for developing cancer at age 35 to 39 years, it improves to 0.26 (95% CI, 0.19–0.36) among women screened at age 52 to 54 years for developing cancer at age 55 to 59 years.
Women aged 20 years and younger are more likely to have Pap abnormalities leading to further testing and treatment (refer to the Evidence of Harm section of this summary for more information), so forgoing Pap testing in these women may improve the benefit-risk balance for this intervention. Women in this age group have a very low risk of cervical cancer and a high likelihood that cervical cell abnormalities will go away on their own.
HSIL are rare among women older than 65 years who have been previously screened. For women with a negative Pap test at age 60 years and older, the likelihood of having a new diagnosis of CIN 3+ on repeat screening is less than 1 in 1,000 (in some studies, as few as 2–6 in 10,000).
Alternative Screening and Treatment Strategies in Low-resource Settings
Choice in methods of screening for cervical cancer in resource-limited countries or underserved populations has prompted the evaluation of one-time screen-and-treat approaches for cervical cancer screening.
A clustered, randomized, controlled trial in rural India evaluated the impact of one-time visual inspection of the cervix with acetic acid (VIA) and immediate colposcopy, directed biopsy, and cryotherapy (where indicated) on cervical cancer incidence and mortality in healthy women aged 30 to 59 years. Fifty-seven clusters (n = 31,343 women) received the intervention, while 56 control clusters (n = 30,958 women) received counseling and education about cervical cancer screening. After 7 years of follow-up, with adjustments for age, education, marital status, parity, and cluster design, there was a 25% relative reduction in cervical cancer incidence in the intervention arm compared with the control group (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.55–0.95). Using the same adjustments, cervical cancer mortality rates demonstrated a 35% relative reduction in the intervention arm compared with the control group (HR, 0.65; 95% CI, 0.47–0.89); the age-standardized rate of death due to cervical cancer was 39.6 per 100,000 person-years for the intervention group versus 56.7 per 100,000 person-years for the control group. However, the same authors have subsequently reported that HPV testing is superior at reducing cervical cancer mortality using the same cohort. This population was essentially screen naive at entry into the study and demonstrated a much higher overall risk for cervical cancer death (11% of the controls) than that observed in the U.S. population; the applicability of these findings to the United States and similar western health care systems is therefore difficult to assess. Histological diagnosis of cervical lesions happened after treatment had already taken place, and approximately 27% of patients in this trial received cryotherapy for lesions later determined to be nonmalignant.
A second cluster-randomized trial of VIA screening in low socioeconomic areas of urban Mumbai, India, similarly demonstrated its efficacy in reducing cervical cancer mortality. In this trial, primary community health workers (as opposed to medical personnel) were trained to provide biennial VIA screening to 75,360 women aged 35 to 64 years. Women with positive screening results were referred to a central hospital for free diagnostic confirmation (including Pap smear, colposcopy, and biopsy, if indicated) and treatment—where warranted—according to hospital protocol. A control group (n = 76,178) received general cancer education. After 12 years, the relative risk of dying from cervical cancer was reduced by 31% in the screening arm (rate ratio, 0.69; 95% CI, 0.54–0.88), corresponding to about 5 fewer deaths per 100,000 woman-years. Compliance with treatment was about 15% lower for those in the control arm, which may have inflated the observed mortality benefit somewhat.
A study of the feasibility of single-visit management of high-grade cervical lesions was conducted among a predominantly Latina population in California. Women were randomly assigned to a single-visit group (n = 1,716) in which the Pap test was evaluated immediately and treatment administered the same day for women with HSIL or atypical glandular cells of undetermined significance (AGUS) results; or to usual care (n = 1,805), with results of the Pap test provided within 2 to 4 weeks and referrals for treatment based on results. The program was feasible, with a high degree of acceptability and results in 14 of 16 (88%) women with abnormal test results completing treatment by 6 months versus 10 of 19 (53%) women in the usual care arm completing treatment by 6 months. Follow-up at 12 months was also higher among women in the single-visit group with HSIL/AGUS than among those in the usual-care arm; among all women, only 36% in each group had a follow-up Pap test at 1 year.
Self-collected HPV testing may be an alternative method for cervical screening in communities with limited access to health care providers. A pooled analysis of cervical screening studies conducted in China compared sensitivity and specificity of self-collection of cervical specimens for HPV DNA testing, physician-collected specimens for HPV testing, liquid-based cytology (LBC) and visual inspection of the cervix with acetic acid (VIA). The study included 13,004 participants in the analysis. Women had all three sampling methods; in one study included in the pooled analysis, all women had colposcopy and biopsies. Of note, the women were instructed in the self-collection methodology by physicians, which likely affected the quality of specimen collection and thus the accuracy of the test in these studies. Physician-collected specimen HPV DNA testing had the highest sensitivity 97% for CIN 2+ (95% CI, 95.2%–98.3%) and 97.8 for CIN 3+ (95% CI, 95.3%–99.2%). Self-collected specimen HPV testing had moderate agreement with physician-collected specimen testing (k = 0.67). Pooled sensitivity for self-collected HPV testing was 86.2% for CIN 2+ (95% CI, 82.9%–89.1%) and 86.1% for CIN 3+ (95% CI, 81.4%–90.0%). Pooled specificity for self-collected HPV DNA testing was 80.7% (95% CI, 75.6%–85.8%) for CIN 2+ and 79.5% (95% CI, 74.1%–84.8%) for CIN 3+. The specificity of HPV testing was lowest of all screening modalities. Whereas pooled sensitivity was highest for physician-based HPV testing, it was lowest for the VIA screening methods—50.3% for CIN 2+ and 55.7% for CIN 3+. Pooled specificity was highest for LBC—94.0% for CIN 2+ and 92.8% for CIN 3+.
A randomized trial in South Africa evaluated the impact on diagnosis of CIN 2+ at 6 months with a screen-and-treat approach with VIA and HPV versus delayed evaluation. Women underwent HPV DNA testing and VIA testing (n = 6,555) and then returned in 2 to 6 days and were randomly assigned to one of three groups to receive (1) cryotherapy if the HPV DNA test result was positive (n = 2,163; 473 HPV+ and 467 treated); (2) cryotherapy if the VIA test result was positive (n = 2,227; 492 VIA+ and 482 treated); or (3) delayed evaluation (n = 2,165). At 6 months, CIN 2+ was diagnosed in 0.80% of women in the HPV+/cryotherapy group, in 2.23% of the VIA+/cryotherapy group, and in 3.55% of the delayed evaluation group. Differences in the prevalence of CIN 2+ persisted among the subset of women evaluated at 12 months. For the secondary outcome of CIN 3+, prevalence of CIN 3+ lesions was low among the three groups but followed the same pattern (two cases in the HPV DNA group, three cases in the VIA group, and eight cases in the delayed evaluation group).
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