Cervical Cancer Screening (PDQ®): Screening - Health Professional Information [NCI]

Overview

Note: The Overview section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries on Cervical Cancer Prevention, Cervical Cancer Treatment, and Levels of Evidence for Cancer Screening and Prevention Studies are also available.

Screening With the Papanicolaou (Pap) Test: Benefits

Based on solid evidence, regular screening for cervical cancer with the Pap test in an appropriate population of women reduces mortality from cervical cancer. The benefits of screening women younger than 21 years are small because of the low prevalence of lesions that will progress to invasive cancer. Screening is not beneficial in women older than 65 years if they have had a recent history of negative test results.[1,2,3]

Magnitude of Effect: Regular Pap screening decreases cervix cancer incidence and mortality by at least 80%.

Study Design: Population-based and cohort studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Screening With the Pap Test: Harms

Based on solid evidence, regular screening with the Pap test leads to additional diagnostic procedures (e.g., colposcopy) and possible overtreatment for low-grade squamous intraepithelial lesions (LSILs). These harms are greatest for younger women, who have a higher prevalence of LSILs, lesions that often regress without treatment. Harms are also increased in younger women because they have a higher rate of false-positive results. Excisional procedures to treat preinvasive disease has been associated with increased risk of long-term consequences for fertility and pregnancy.[4]

Magnitude of Effect: Additional diagnostic procedures were performed in 50% of women undergoing regular Pap testing. Approximately 5% were treated for LSILs. The number of women with impaired fertility and pregnancy complications is unknown.

Study Design: Evidence obtained from cohort or case-control studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Screening With the Human Papillomavirus (HPV) DNA Test: Benefits

Based on solid evidence, screening with an HPV DNA or HPV RNA test detects high-grade cervical dysplasia, a precursor lesion for cervical cancer. Additional clinical trials show that HPV testing is superior to other cervical cancer screening strategies. In April 2014, the U.S. Food and Drug Administration approved an HPV DNA test that can be used alone for the primary screening of cervical cancer risk in women aged 25 years and older.[5]

Magnitude of Effect: In one prospective, clustered, randomized trial, HPV testing was superior to other strategies for preventing cervical cancer mortality.[6,7]

Study Design: Clustered randomized controlled trial (RCT).

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Screening With the HPV DNA Test: Harms

Based on solid evidence, HPV testing identifies numerous infections that will not lead to cervical dysplasia or cervical cancer. This is especially true in women younger than 30 years, in whom rates of HPV infection may be higher.

Magnitude of Effect: In one study, 86.7% of women with a positive HPV test did not develop cervical cancer or related premalignant disease after more than a decade of follow-up.[8]

Study Design: Long-term observational trials.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Screening With the Pap Test and the HPV DNA Test (Cotesting): Benefits

Based on solid evidence, screening every 5 years with the Pap test and the HPV DNA test (cotesting) in women aged 30 years and older is more sensitive in detecting cervical abnormalities, compared with the Pap test alone. Screening with the Pap test and HPV DNA test reduces the incidence of cervical cancer.[3]

Magnitude of Effect: HPV-based screening provides 60% to 70% greater protection against invasive cervical carcinoma, compared with cytology.[9]

Study Design: RCTs.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Screening With the Pap Test and the HPV DNA Test (Cotesting): Harms

Based on solid evidence, HPV and Pap cotesting is associated with more false-positives than is the Pap test alone. Abnormal test results can lead to more frequent testing and invasive diagnostic procedures.[3]

Magnitude of Effect: The percentage of U.S. women undergoing cotesting who will have a normal cytology test result and a positive HPV test result (and who will therefore require additional testing) ranges from 11% among women aged 30 to 34 years to 2.6% among women aged 60 to 65 years.[3]

Study Design: RCTs.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Screening Women Without a Cervix

Based on solid evidence, screening is not helpful in women who do not have a cervix as a result of a hysterectomy for a benign condition.

Magnitude of Effect: Among women without cervices, fewer than 1 per 1,000 had abnormal Pap test results.

Study Design: Evidence obtained from a single cohort study.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

References:

1. Sasieni P, Castanon A, Cuzick J: Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data. BMJ 339: b2968, 2009.
2. Sawaya GF, McConnell KJ, Kulasingam SL, et al.: Risk of cervical cancer associated with extending the interval between cervical-cancer screenings. N Engl J Med 349 (16): 1501-9, 2003.
3. Moyer VA; U.S. Preventive Services Task Force: Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 156 (12): 880-91, W312, 2012.
4. Kyrgiou M, Athanasiou A, Paraskevaidi M, et al.: Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. BMJ 354: i3633, 2016.
5. Wright TC, Stoler MH, Behrens CM, et al.: Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol 136 (2): 189-97, 2015.
6. Sankaranarayanan R, Nene BM, Shastri SS, et al.: HPV screening for cervical cancer in rural India. N Engl J Med 360 (14): 1385-94, 2009.
7. Szarewski A: Cervical screening by visual inspection with acetic acid. Lancet 370 (9585): 365-6, 2007.
8. Chen HC, Schiffman M, Lin CY, et al.: Persistence of type-specific human papillomavirus infection and increased long-term risk of cervical cancer. J Natl Cancer Inst 103 (18): 1387-96, 2011.
9. Ronco G, Dillner J, Elfström KM, et al.: Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 383 (9916): 524-32, 2014.

Natural History, Incidence, and Mortality

In the United States in 2024, it is estimated that 13,820 cases of invasive cervical cancer will be diagnosed and that 4,360 women will die of the disease.[1] These rates have been improving steadily. Incidence rates have stabilized in the most recent decade. Although mortality rates for cervical cancer have stabilized in recent years, the mortality rate in Black and Native American women remains about 65% higher than in White women.[1] This improvement has been attributed largely to screening with the Papanicolaou (Pap) test. When corrected for the prevalence of hysterectomy, the mortality rate for Black women is nearly twice the mortality rate for White women.[2]

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 (LSILs), LSILs (consisting of cytologic atypia and CIN 1), and high-grade squamous intraepithelial lesions (HSILs), primarily CIN 2–3 plus carcinoma in situ.[3]

The rate at which invasive cancer develops from CIN is usually slow, measured in years and perhaps decades.[4] 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 LSILs) would have never progressed to invasive cancer,[5,6,7] 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.[8] Nearly all women with invasive cervical cancer have evidence of HPV infection.[9,10,11,12] Most women with HPV infection, however, never develop cervical cancer; thus, this infection is necessary but not sufficient for the development of cancer.[13]

Although cervical cancer mortality increases with age,[14] the prevalence of CIN is highest among women in their 20s and 30s. Mortality is rare among women younger than 30 years; HSILs are rare among women older than 65 years who have been previously screened. About 70% of atypical squamous cells of undetermined significance 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.[4,7,15]

Historically, cervical cancer mortality rates were substantially higher (twice as high or more) in Black women than in White women younger than 50 years; however, recent (2016–2020) rates have been only modestly (12%) higher in Black women than in White women in this age group. Among women older than 60 years, cervical cancer mortality rates have historically been up to three times as high for Black women than for White women; recent (2016–2020) rates are still almost twice as high in Black women than in White women.[16] In either case, mortality is rare among women of any age who have regular screenings.

References:

1. American Cancer Society: Cancer Facts and Figures 2024. American Cancer Society, 2024. Available online. Last accessed June 21, 2024.
2. Beavis AL, Gravitt PE, Rositch AF: Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States. Cancer 123 (6): 1044-1050, 2017.
3. Solomon D, Davey D, Kurman R, et al.: The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 287 (16): 2114-9, 2002.
4. Holowaty P, Miller AB, Rohan T, et al.: Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst 91 (3): 252-8, 1999.
5. Nasiell K, Roger V, Nasiell M: Behavior of mild cervical dysplasia during long-term follow-up. Obstet Gynecol 67 (5): 665-9, 1986.
6. Nash JD, Burke TW, Hoskins WJ: Biologic course of cervical human papillomavirus infection. Obstet Gynecol 69 (2): 160-2, 1987.
7. Melnikow J, Nuovo J, Willan AR, et al.: Natural history of cervical squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol 92 (4 Pt 2): 727-35, 1998.
8. 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 120 (4): 885-91, 2007.
9. Bosch FX, Manos MM, Muñoz N, et al.: Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 87 (11): 796-802, 1995.
10. Wallin KL, Wiklund F, Angström T, et al.: Type-specific persistence of human papillomavirus DNA before the development of invasive cervical cancer. N Engl J Med 341 (22): 1633-8, 1999.
11. Alani RM, Münger K: Human papillomaviruses and associated malignancies. J Clin Oncol 16 (1): 330-7, 1998.
12. Walboomers JM, Jacobs MV, Manos MM, et al.: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189 (1): 12-9, 1999.
13. Ho GY, Bierman R, Beardsley L, et al.: Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 338 (7): 423-8, 1998.
14. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). National Cancer Institute, 2012. Also available online. Last accessed May 22, 2024.
15. Arends MJ, Buckley CH, Wells M: Aetiology, pathogenesis, and pathology of cervical neoplasia. J Clin Pathol 51 (2): 96-103, 1998.
16. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed March 6, 2024.

The Pap Test

The Papanicolaou (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 after the introduction of well-run screening programs.[1,2,3,4] In Iceland, the mortality rate declined by 80% for more than 20 years, and in Finland and Sweden by 50% and 34%, respectively.[1,5] 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.[1,5] 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.[6]

Case-control studies have found that the risk of developing invasive cervical cancer is three to ten times higher in women who have not been screened.[7,8,9,10] Risk also increases with long duration after the last normal Pap test, or similarly, with decreasing frequency of screening.[11,12] Screening every 2 to 3 years, however, has not been found to significantly increase the risk of finding invasive cervical cancer above the risk expected with annual screening.[12,13,14]

References:

1. Lăără E, Day NE, Hakama M: Trends in mortality from cervical cancer in the Nordic countries: association with organised screening programmes. Lancet 1 (8544): 1247-9, 1987.
2. Christopherson WM, Lundin FE, Mendez WM, et al.: Cervical cancer control: a study of morbidity and mortality trends over a twenty-one-year period. Cancer 38 (3): 1357-66, 1976.
3. Miller AB, Lindsay J, Hill GB: Mortality from cancer of the uterus in Canada and its relationship to screening for cancer of the cervix. Int J Cancer 17 (5): 602-12, 1976.
4. Johannesson G, Geirsson G, Day N: The effect of mass screening in Iceland, 1965-74, on the incidence and mortality of cervical carcinoma. Int J Cancer 21 (4): 418-25, 1978.
5. Sigurdsson K: Effect of organized screening on the risk of cervical cancer. Evaluation of screening activity in Iceland, 1964-1991. Int J Cancer 54 (4): 563-70, 1993.
6. Benedet JL, Anderson GH, Matisic JP: A comprehensive program for cervical cancer detection and management. Am J Obstet Gynecol 166 (4): 1254-9, 1992.
7. Aristizabal N, Cuello C, Correa P, et al.: The impact of vaginal cytology on cervical cancer risks in Cali, Colombia. Int J Cancer 34 (1): 5-9, 1984.
8. Clarke EA, Anderson TW: Does screening by "Pap" smears help prevent cervical cancer? A case-control study. Lancet 2 (8132): 1-4, 1979.
9. La Vecchia C, Franceschi S, Decarli A, et al.: "Pap" smear and the risk of cervical neoplasia: quantitative estimates from a case-control study. Lancet 2 (8406): 779-82, 1984.
10. Herrero R, Brinton LA, Reeves WC, et al.: Screening for cervical cancer in Latin America: a case-control study. Int J Epidemiol 21 (6): 1050-6, 1992.
11. Celentano DD, Klassen AC, Weisman CS, et al.: Duration of relative protection of screening for cervical cancer. Prev Med 18 (4): 411-22, 1989.
12. Screening for squamous cervical cancer: duration of low risk after negative results of cervical cytology and its implication for screening policies. IARC Working Group on evaluation of cervical cancer screening programmes. Br Med J (Clin Res Ed) 293 (6548): 659-64, 1986.
13. Kleinman JC, Kopstein A: Who is being screened for cervical cancer? Am J Public Health 71 (1): 73-6, 1981.
14. Qin J, Saraiya M, Martinez G, et al.: Prevalence of Potentially Unnecessary Bimanual Pelvic Examinations and Papanicolaou Tests Among Adolescent Girls and Young Women Aged 15-20 Years in the United States. JAMA Intern Med 180 (2): 274-280, 2020.

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 results are 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%.[1,2] 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, atypical squamous cells of undetermined significance (ASCUS) are 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%.[3]

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.[4]

References:

1. Soost HJ, Lange HJ, Lehmacher W, et al.: The validation of cervical cytology. Sensitivity, specificity and predictive values. Acta Cytol 35 (1): 8-14, 1991 Jan-Feb.
2. Benoit AG, Krepart GV, Lotocki RJ: Results of prior cytologic screening in patients with a diagnosis of Stage I carcinoma of the cervix. Am J Obstet Gynecol 148 (5): 690-4, 1984.
3. Nanda K, McCrory DC, Myers ER, et al.: Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med 132 (10): 810-9, 2000.
4. Martin-Hirsch P, Lilford R, Jarvis G, et al.: Efficacy of cervical-smear collection devices: a systematic review and meta-analysis. Lancet 354 (9192): 1763-70, 1999.

Newer Screening Technologies

Newer techniques that employ liquid-based cytology (LBC) (e.g., ThinPrep) have been developed to improve the sensitivity of screening. In 1996, the ThinPrep® Papanicolaou (Pap) test became the first LBC approved by the U.S. Food and Drug Administration.[1] As with the Pap test, the optimal studies to determine the sensitivity and specificity of these technologies have not been conducted. Some less-than-optimal studies show that sensitivity is modestly higher for detecting any degree of cervical intraepithelial neoplasia, with modestly lower specificity.[2,3] One study, however, showed that conventional Pap testing was slightly more sensitive and specific than LBC.[4]

The evidence is also mixed about whether liquid-based techniques improve rates of test adequacy.[2,3] One advantage of LBC is that HPV testing can be performed on the same preparation; one disadvantage is that liquid-based approaches are more expensive than conventional Pap testing. No study has examined whether LBC actually reduces the number of women dying of cervical cancer compared with conventional Pap testing.

References:

1. Gibb RK, Martens MG: The impact of liquid-based cytology in decreasing the incidence of cervical cancer. Rev Obstet Gynecol 4 (Suppl 1): S2-S11, 2011.
2. Hartmann KE, Hall SA, Nanda K, et al.: Screening for Cervical Cancer. Rockville, Md: Agency for Health Research and Quality, 2002. Available online. Last accessed April 12, 2024.
3. McCrory DC, Matchar DB, Bastian L, et al.: Evaluation of Cervical Cytology. Rockville, Md: Agency for Health Research and Quality, 1999. Evidence Report/Technology Assessment No. 5. AHCPR Publication No. 99-E010. Also available online. Last accessed April 12, 2024.
4. Coste J, Cochand-Priollet B, de Cremoux P, et al.: Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirus DNA testing for cervical cancer screening. BMJ 326 (7392): 733, 2003.

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;[1,2] no study has shown that screening for vaginal cancer reduces mortality from this rare condition.

References:

1. Fox J, Remington P, Layde P, et al.: The effect of hysterectomy on the risk of an abnormal screening Papanicolaou test result. Am J Obstet Gynecol 180 (5): 1104-9, 1999.
2. Pearce KF, Haefner HK, Sarwar SF, et al.: Cytopathological findings on vaginal Papanicolaou smears after hysterectomy for benign gynecologic disease. N Engl J Med 335 (21): 1559-62, 1996.

Screening Interval

Because cervical cancer is slow growing, there is considerable uncertainty about the optimal screening interval. The most direct evidence about this issue comes from a prospective cohort analysis of a randomized controlled trial.[1] 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 cervical intraepithelial neoplasia (CIN) 2–3 or invasive cancer, and only one woman 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 human papillomavirus DNA cotesting in U.S. women aged 30 years and older found that a negative Pap smear was associated with a low risk of 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).[2]

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.[3] A similar modeling study from Australia found no differences between screening every 2 years and screening every 3 years.[4]

References:

1. Sawaya GF, Grady D, Kerlikowske K, et al.: The positive predictive value of cervical smears in previously screened postmenopausal women: the Heart and Estrogen/progestin Replacement Study (HERS). Ann Intern Med 133 (12): 942-50, 2000.
2. Katki HA, Kinney WK, Fetterman B, et al.: Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol 12 (7): 663-72, 2011.
3. Sawaya GF, McConnell KJ, Kulasingam SL, et al.: Risk of cervical cancer associated with extending the interval between cervical-cancer screenings. N Engl J Med 349 (16): 1501-9, 2003.
4. Creighton P, Lew JB, Clements M, et al.: Cervical cancer screening in Australia: modelled evaluation of the impact of changing the recommended interval from two to three years. BMC Public Health 10: 734, 2010.

HPV Testing

Noninvasive cervical squamous cell abnormalities are graded histologically as cervical intraepithelial neoplasia (CIN) mild dysplasia (CIN 1), moderate dysplasia (CIN 2), or severe dysplasia (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, if untreated, has an approximate 30% risk of developing into invasive cancer over many years.[1] CIN 2 has poor interobserver reproducibility,[2] and the biological behavior is variable.[3] CIN 3 is therefore a more rigorous end point 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 most infections 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 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 after an equivocal cytology result of atypical squamous cells of undetermined significance (ASCUS); and (2) for primary screening in conjunction with cervical cytology for women aged 30 years and older.[4] Testing for low-risk HPV types does not identify women at risk of developing CIN 2 or 3.[5,6]

Triage

A large randomized clinical trial, the ASCUS/low-grade squamous intraepithelial lesion (LSIL) Triage Study (ALTS), demonstrated the cost-effectiveness of using HPV testing to clarify the risk of an ASCUS Pap result.[7] ALTS randomly assigned women with ASCUS to one of three management strategies: immediate colposcopy regardless of enrollment test results, referral to colposcopy if HPV test results were positive or if the enrollment cytology was high-grade squamous intraepithelial lesion (HSIL), and referral to colposcopy only if the cytology was HSIL. The HPV triage strategy was as sensitive as immediate colposcopy to detection CIN 2+, 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.[8] HPV testing is not recommended for adolescent women with ASCUS because most of these women are HPV positive.[9,10]

HPV DNA testing is generally not appropriate or clinically useful after cytology results of LSIL, which is more severe than ASCUS, and most of these women (84%–96%) are carcinogenic HPV DNA positive.[11] 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.[12]

Primary HPV Screening

Testing for HPV DNA as a primary screening test is an option for 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 frequently. A prospective cohort study of nearly 332,000 U.S. women aged 30 years and older undergoing HPV DNA and cervical cytology cotesting every 3 years found that the cumulative incidence of CIN 3+ in women with negative results for both tests at baseline was 0.047% at 3 years and 0.16% at 5 years.[13] A second study of more than 43,000 women aged 29 to 61 years, one-half of whom underwent three rounds of HPV DNA and cervical cytology cotesting every 5 years, found that the cumulative incidence of CIN 3+ in women with negative results for both tests at baseline was 0.01% (95% confidence interval [CI], 0.00%–0.05%) at 9 years and 0.07% (95% CI, 0.03%–0.17%) after 14 years of follow-up.[14] Screening more frequently than every 3 years would not improve sensitivity significantly but would increase costs and overtreatment.[15,16]

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%).[17,18,19,20,21,22,23,24] 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%.[18]

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.[18] 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 [23] or another more specific molecular assay;[25] 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.[26,27]

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 than in the cytology-alone arm were referred to colposcopy for abnormal findings (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.[28] A Canadian study of 19,000 women aged 25 to 65 years that compared HPV DNA testing with cervical cytology found that HPV DNA testing identified most women with CIN 3 at initial screening. Women who initially tested HPV DNA negative were at low risk for cervical dysplasia 48 months later. Additionally, there were not an excessive number of women referred for additional diagnostic testing.[24]

A study using data from a population-based randomized trial of cervical cancer 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%.[29] In a review of data from a large integrated health system, the added benefit of cotesting versus HPV testing alone would improve detection of CIN 3 or early-stage cervical cancer in very few women. Only 5.1% of locally advanced invasive cancers and 3.6% of CIN 3 were cytology positive and HPV negative, representing a very small fraction of all screened women.[30]

Cytology can be used to triage after primary HPV screening. Triage with cytology can be improved with concomitant detection of p16 and Ki-67 in the same cell (p16/Ki-67 dual stain [DS]). DS can be assessed manually through immunostaining cervical cytology slides. Additionally, artificial intelligence–based deep learning algorithms are currently being investigated and applied to aid in automated identification of p16/Ki-67 dual-stained slides. This approach has been shown to improve specificity without sacrificing sensitivity over manual DS assessment,[31] but it has not yet been validated in population studies.

References:

1. McCredie MR, Sharples KJ, Paul C, et al.: Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol 9 (5): 425-34, 2008.
2. Stoler MH, Schiffman M; Atypical Squamous Cells of Undetermined Significance-Low-grade Squamous Intraepithelial Lesion Triage Study (ALTS) Group: Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA 285 (11): 1500-5, 2001.
3. Castle PE, Schiffman M, Wheeler CM, et al.: Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstet Gynecol 113 (1): 18-25, 2009.
4. Halfon P, Trepo E, Antoniotti G, et al.: Prospective evaluation of the Hybrid Capture 2 and AMPLICOR human papillomavirus (HPV) tests for detection of 13 high-risk HPV genotypes in atypical squamous cells of uncertain significance. J Clin Microbiol 45 (2): 313-6, 2007.
5. Thomsen LT, Frederiksen K, Munk C, et al.: High-risk and low-risk human papillomavirus and the absolute risk of cervical intraepithelial neoplasia or cancer. Obstet Gynecol 123 (1): 57-64, 2014.
6. Castle PE, Hunt WC, Langsfeld E, et al.: Three-year risk of cervical precancer and cancer after the detection of low-risk human papillomavirus genotypes targeted by a commercial test. Obstet Gynecol 123 (1): 49-56, 2014.
7. Kulasingam SL, Kim JJ, Lawrence WF, et al.: Cost-effectiveness analysis based on the atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion Triage Study (ALTS). J Natl Cancer Inst 98 (2): 92-100, 2006.
8. ASCUS-LSIL Traige Study (ALTS) Group: Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 188 (6): 1383-92, 2003.
9. Wright TC, Massad LS, Dunton CJ, et al.: 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 197 (4): 346-55, 2007.
10. Sherman ME, Schiffman M, Cox JT, et al.: Effects of age and human papilloma viral load on colposcopy triage: data from the randomized Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS). J Natl Cancer Inst 94 (2): 102-7, 2002.
11. ASCUS-LSIL Traige Study (ALTS) Group: A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol 188 (6): 1393-400, 2003.
12. Zuna RE, Wang SS, Rosenthal DL, et al.: Determinants of human papillomavirus-negative, low-grade squamous intraepithelial lesions in the atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesions triage study (ALTS). Cancer 105 (5): 253-62, 2005.
13. Katki HA, Kinney WK, Fetterman B, et al.: Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol 12 (7): 663-72, 2011.
14. Dijkstra MG, van Zummeren M, Rozendaal L, et al.: Safety of extending screening intervals beyond five years in cervical screening programmes with testing for high risk human papillomavirus: 14 year follow-up of population based randomised cohort in the Netherlands. BMJ 355: i4924, 2016.
15. Saslow D, Runowicz CD, Solomon D, et al.: American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 52 (6): 342-62, 2002 Nov-Dec.
16. Goldie SJ, Kim JJ, Wright TC: Cost-effectiveness of human papillomavirus DNA testing for cervical cancer screening in women aged 30 years or more. Obstet Gynecol 103 (4): 619-31, 2004.
17. Arbyn M, Sasieni P, Meijer CJ, et al.: Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses. Vaccine 24 (Suppl 3): S3/78-89, 2006.
18. Mayrand MH, Duarte-Franco E, Rodrigues I, et al.: Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med 357 (16): 1579-88, 2007.
19. Naucler P, Ryd W, Törnberg S, et al.: Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med 357 (16): 1589-97, 2007.
20. Bulkmans NW, Berkhof J, Rozendaal L, et al.: Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 370 (9601): 1764-72, 2007.
21. Cuzick J, Szarewski A, Cubie H, et al.: Management of women who test positive for high-risk types of human papillomavirus: the HART study. Lancet 362 (9399): 1871-6, 2003.
22. Hartmann KE, Hall SA, Nanda K, et al.: Screening for Cervical Cancer. Rockville, Md: Agency for Health Research and Quality, 2002. Available online. Last accessed April 12, 2024.
23. Cuzick J, Clavel C, Petry KU, et al.: Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 119 (5): 1095-101, 2006.
24. Ogilvie GS, van Niekerk D, Krajden M, et al.: Effect of Screening With Primary Cervical HPV Testing vs Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 Months: The HPV FOCAL Randomized Clinical Trial. JAMA 320 (1): 43-52, 2018.
25. Carozzi F, Confortini M, Dalla Palma P, et al.: Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 9 (10): 937-45, 2008.
26. Koshiol J, Lindsay L, Pimenta JM, et al.: Persistent human papillomavirus infection and cervical neoplasia: a systematic review and meta-analysis. Am J Epidemiol 168 (2): 123-37, 2008.
27. Castle PE: Invited commentary: is monitoring of human papillomavirus infection for viral persistence ready for use in cervical cancer screening? Am J Epidemiol 168 (2): 138-44; discussion 145-8, 2008.
28. Ronco G, Giorgi-Rossi P, Carozzi F, et al.: Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol 11 (3): 249-57, 2010.
29. Naucler P, Ryd W, Törnberg S, et al.: Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst 101 (2): 88-99, 2009.
30. Schiffman M, Kinney WK, Cheung LC, et al.: Relative Performance of HPV and Cytology Components of Cotesting in Cervical Screening. J Natl Cancer Inst 110 (5): 501-508, 2018.
31. Wentzensen N, Lahrmann B, Clarke MA, et al.: Accuracy and Efficiency of Deep-Learning-Based Automation of Dual Stain Cytology in Cervical Cancer Screening. J Natl Cancer Inst 113 (1): 72-79, 2021.

Screening Benefit According to Age

Cervical cancer mortality, usually in unscreened women, increases with age, with the maximum mortality for White women between the ages of 45 years and 70 years, and for Black women in their 70s.[1,2] (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.[3] The benefit increases with age. Whereas the odds ratio is 0.79 (95% confidence interval [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, so forgoing Pap testing in these women may improve the benefit-risk balance for this intervention. For more information, see the Evidence of Harm section. 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.[4]

High-grade squamous intraepithelial lesions 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).[5]

References:

1. Saslow D, Runowicz CD, Solomon D, et al.: American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 52 (6): 342-62, 2002 Nov-Dec.
2. National Institutes of Health Consensus Development Conference Statement: cervical cancer, April 1-3, 1996. National Institutes of Health Consensus Development Panel. J Natl Cancer Inst Monogr (21): vii-xix, 1996.
3. Sasieni P, Castanon A, Cuzick J: Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data. BMJ 339: b2968, 2009.
4. 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 62 (3): 147-72, 2012 May-Jun.
5. Sawaya GF, Grady D, Kerlikowske K, et al.: The positive predictive value of cervical smears in previously screened postmenopausal women: the Heart and Estrogen/progestin Replacement Study (HERS). Ann Intern Med 133 (12): 942-50, 2000.

Alternative Screening and Treatment Strategies Including Low-Resource Settings

Choice in methods of screening for cervical cancer in resource-limited countries or underserved populations has prompted the evaluation of alternative methods, including self-collected human papillomavirus (HPV) tests and one-time screen-and-treat approaches.

Visual Inspection of the Cervix With Acetic Acid (VIA)

A clustered, randomized, controlled trial in rural India evaluated the impact of one-time visual VIA and immediate colposcopy, directed biopsy, and cryotherapy (where indicated) on cervical cancer incidence and mortality in healthy women aged 30 to 59 years.[1] 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 had 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 caused by 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, using the same cohort, the same authors subsequently reported that HPV testing is superior at reducing cervical cancer mortality.[2] This population was essentially screen naive at study entry and demonstrated a much higher overall risk of cervical cancer death (11% in the control group) than that observed in the U.S. population; therefore, these findings are not applicable to U.S. and similar Western health care. 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.[3]

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 (RR) 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.[4]

A demonstration project in Kolkata, India, enrolled 39,740 women aged 30 to 60 years who underwent screening with VIA and Hybrid Capture II HPV DNA testing with colposcopy referral for a positive test, followed by biopsy and treatment if indicated. Estimated test performance for detection of cervical intraepithelial neoplasia (CIN) severe dysplasia (CIN 3+), corrected for verification bias, demonstrated that VIA achieved a sensitivity of 59.9% (95% CI, 49.9%–69.1%) and a specificity of 93.2% (95% CI, 92.9%–93.4%) compared with HPV testing, which resulted in a sensitivity of 91.2% (95% CI, 85.4%–95.7%) and a specificity of 96.9% (95% CI, 96.7%–97.0%). HPV testing identified an additional 32 CIN 3+ cases and 7 invasive cancer cases missed by VIA.[5]

A randomized trial in South Africa evaluated the impact on diagnosis of CIN moderate dysplasia (CIN 2+) at 6 months with a screen-and-treat approach with VIA and HPV versus delayed evaluation.[6] 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+, the 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).

While VIA is practical in resource-limited settings, the accuracy and reproducibility are low. Advances in machine deep learning may help improve these metrics. A supervised, deep learning–based approach to predicting cervical precancers and cancers was investigated in a retrospective data set of 9,406 women who underwent cervical cancer screening using photographic images of the cervix. The archived digitized cervical images, taken with a fixed-focus camera (cervicography), were used for training and validation of the deep learning–based algorithm. The automated algorithm achieved better accuracy in predicting precancer and cancer compared with the original physician readers who interpreted the cervicography; it also compared favorably to conventional Pap smear cytology. This automated visual evaluation method needs to be transferred from digitized cervigrams (now obsolete) to contemporary digital cameras.[7]

A study of the feasibility of single-visit management of high-grade cervical lesions was conducted among a predominantly Latina population in California.[8] 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 HSILs or atypical glandular cells of undetermined significance (AGUS); 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: 14 of 16 women (88%) with abnormal test results completed treatment by 6 months, while 10 of 19 women (53%) in the usual-care arm completed treatment by 6 months. Follow-up at 12 months was also higher among women in the single-visit group with HSILs/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-Collection of HPV Tests

Self-collected HPV testing may be an alternative method for primary cervical screening. Incorporating self-collection of samples for HPV testing may improve access to cervical cancer screening, especially in communities with limited access to health care providers. A pooled analysis of cervical screening studies conducted in China compared the sensitivity and specificity of self-collected cervical specimens for HPV DNA testing, physician-collected specimens for HPV testing, liquid-based cytology (LBC), and VIA. The study included 13,004 participants in the analysis. Women underwent screening with all three sampling methods; in one study included in the pooled analysis, all women had colposcopy and biopsy. 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. HPV DNA testing on physician-collected specimens had the highest sensitivity, 97.0% for CIN 2+ (95% CI, 95.2%–98.3%) and 97.8% for CIN 3+ (95% CI, 95.3%–99.2%). The results of HPV DNA testing on self-collected specimens had moderate agreement with that of physician-collected specimens (kappa statistic, 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-collected 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+.[9]

A randomized noninferiority trial conducted in the Netherlands found that there was no difference in the CIN 2+ sensitivity or specificity of HPV testing between self-sampling based on written instructions and clinician-based sampling (relative sensitivity, 0.96 [95% CI, 0.90–1.03]; relative specificity, 1.00 [95% CI, 0.99–1.01]).[10] A population-based cluster-randomized trial in Argentina, comparing screening uptake using self-collection of samples for HPV DNA testing with that of clinic-based cervical sample collection with cytology and HPV triage, found that self-collection was associated with increased screening (RR, 4.02; 95% CI, 3.44–4.71), which translated into higher detection of CIN 2+ and treatment.[11] A Dutch study among women who participated in the national cervical cancer screening program found that vaginal self-sampling was highly concordant (96.8%; 95% CI, 96.0%–97.5%) with high-risk HPV prevalence in physician-collected samples and was both convenient and user friendly. Vaginal self-sampling will be offered in the Dutch national screening program for those who do not participate in their routine screening.[12]

A randomized trial within the U.S. Kaiser Permanente health care system evaluated the effectiveness of mailed HPV self-sampling kits versus usual-care reminders for in-clinic screening to increase the uptake of cervical cancer screening and the detection of CIN 2+. A total of 19,851 women who were overdue for screening were randomly assigned to either the self-sampling intervention or the usual-care control group. Screening uptake was higher in the intervention group (26.3%) than in the control group (17.4%) (RR, 1.51; 95% CI, 1.43–1.60). In the intervention group, 12 participants with CIN 2+ were detected compared with 8 participants in the control group (RR, 1.49; 95% CI, 0.61–3.64), and 12 patients were treated compared with 7 of those in the control group (RR, 1.70; 95% CI, 0.67–4.32).[13] As a follow-up to this study, the authors conducted the STEP study (self-testing options in the era for primary HPV screening for cervical cancer), a pragmatic, parallel, single-blinded, randomized clinical trial that compared cervical cancer screening completion across strata of individuals due for screening (screening adherent), overdue for screening, or with unknown screening histories.[14] Overall, 31,355 English-speaking individuals enrolled in Kaiser Permanente Washington were included and randomly assigned to receive usual care (patient reminders and clinical electronic health record alerts), education (usual care plus educational material about screening), direct mail (usual care plus educational materials plus a mailed HPV self-sampling kit), or to opt in (usual care plus educational materials plus the option to request a self-sampling kit). Direct mailing (of HPV self-sampling kits to individuals) increased cervical cancer screening by more than 14% in individuals who were due or overdue for cervical cancer screening, compared with education alone (attention control). Compared with the education group, time-to-screening completion was shorter for the direct-mail and opt-in groups. Time-to-screening completion for the education and the usual-care groups was similar across all screening-history strata. Furthermore, the education and usual-care groups had similar screening rates in this study population. Strengthened by the pragmatic design, this trial was highly inclusive of a diverse patient population with regards to age, race, ethnicity, health care utilization, and household income. Nevertheless, the generalizability of these study results may be limited given that participants were English-speaking and enrolled in a mixed-model managed care system, with both access to health care and insurance coverage. Notably, the HPV self-sampling test used in this study is now approved by the U.S. Food and Drug Administration for use in a health care setting.

A study including underscreened ethnic minority groups and immigrant populations in South Florida evaluated the effectiveness of HPV self-sampling by randomizing women to self-collection via a mailed self-sampling kit or through an in-person visit by a community health worker.[15] The participants self-identified as Hispanic, Haitian, or non-Hispanic Black women between the ages of 30 years and 65 years. After adjusting for study site, age, income, insurance education, Pap smear history, marital status, and citizenship status, women who received the self-sampling intervention via an in-person visit from a community health worker were more likely to complete the self-sampling (odds ratio, 1.81; 95% CI, 1.22–2.69). Completion of HPV self-sampling was high in both study arms, with 81.0% (n = 243) among the in-person visit group and 71.6% (n = 214) among those who received the self-sampling HPV kit via mail.

References:

1. Sankaranarayanan R, Esmy PO, Rajkumar R, et al.: Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-randomised trial. Lancet 370 (9585): 398-406, 2007.
2. Sankaranarayanan R, Nene BM, Shastri SS, et al.: HPV screening for cervical cancer in rural India. N Engl J Med 360 (14): 1385-94, 2009.
3. Szarewski A: Cervical screening by visual inspection with acetic acid. Lancet 370 (9585): 365-6, 2007.
4. Shastri SS, Mittra I, Mishra GA, et al.: Effect of VIA screening by primary health workers: randomized controlled study in Mumbai, India. J Natl Cancer Inst 106 (3): dju009, 2014.
5. Basu P, Mittal S, Banerjee D, et al.: Diagnostic accuracy of VIA and HPV detection as primary and sequential screening tests in a cervical cancer screening demonstration project in India. Int J Cancer 137 (4): 859-67, 2015.
6. Denny L, Kuhn L, De Souza M, et al.: Screen-and-treat approaches for cervical cancer prevention in low-resource settings: a randomized controlled trial. JAMA 294 (17): 2173-81, 2005.
7. Hu L, Bell D, Antani S, et al.: An Observational Study of Deep Learning and Automated Evaluation of Cervical Images for Cancer Screening. J Natl Cancer Inst 111 (9): 923-932, 2019.
8. Brewster WR, Hubbell FA, Largent J, et al.: Feasibility of management of high-grade cervical lesions in a single visit: a randomized controlled trial. JAMA 294 (17): 2182-7, 2005.
9. Zhao FH, Lewkowitz AK, Chen F, et al.: Pooled analysis of a self-sampling HPV DNA Test as a cervical cancer primary screening method. J Natl Cancer Inst 104 (3): 178-88, 2012.
10. Polman NJ, Ebisch RMF, Heideman DAM, et al.: Performance of human papillomavirus testing on self-collected versus clinician-collected samples for the detection of cervical intraepithelial neoplasia of grade 2 or worse: a randomised, paired screen-positive, non-inferiority trial. Lancet Oncol 20 (2): 229-238, 2019.
11. Arrossi S, Thouyaret L, Herrero R, et al.: Effect of self-collection of HPV DNA offered by community health workers at home visits on uptake of screening for cervical cancer (the EMA study): a population-based cluster-randomised trial. Lancet Glob Health 3 (2): e85-94, 2015.
12. Ketelaars PJW, Bosgraaf RP, Siebers AG, et al.: High-risk human papillomavirus detection in self-sampling compared to physician-taken smear in a responder population of the Dutch cervical screening: Results of the VERA study. Prev Med 101: 96-101, 2017.
13. Winer RL, Lin J, Tiro JA, et al.: Effect of Mailed Human Papillomavirus Test Kits vs Usual Care Reminders on Cervical Cancer Screening Uptake, Precancer Detection, and Treatment: A Randomized Clinical Trial. JAMA Netw Open 2 (11): e1914729, 2019.
14. Winer RL, Lin J, Anderson ML, et al.: Strategies to Increase Cervical Cancer Screening With Mailed Human Papillomavirus Self-Sampling Kits: A Randomized Clinical Trial. JAMA 330 (20): 1971-1981, 2023.
15. Kobetz E, Seay J, Koru-Sengul T, et al.: A randomized trial of mailed HPV self-sampling for cervical cancer screening among ethnic minority women in South Florida. Cancer Causes Control 29 (9): 793-801, 2018.

Evidence of Harm

Annually in the United States, an estimated 65 million women undergo cervical cancer screening;[1] about 3.9 million (6%) will be referred for further evaluation.[2] About 11,000 cases of invasive cervical cancer were diagnosed in 2008. Thus, Papanicolaou (Pap) test screening results in a large number of colposcopies for benign conditions.

The major potential harm of screening for cervical cancer lies in the screening detection of many cytologic abnormalities such as atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSILs), the majority of which would never progress to cervical cancer. Women with human papillomavirus (HPV)-positive ASCUS or LSILs on Pap testing are usually referred for colposcopy. Histological CIN 2+ is treated with cryotherapy or loop electrosurgical excision procedure. These procedures permanently alter the cervix and have consequences on fertility and pregnancy.[3] Younger women are more likely to acquire HPV infections and be referred for diagnostic workup, and they are more likely to suffer harms from interventions for a condition that often resolves spontaneously.

On the basis of an analysis of screening records from nearly 350,000 women in Bristol, England, investigators projected that 1,000 women would need to be screened for cervical cancer for 35 years to prevent one death from the disease. For each death prevented, the authors estimated that more than 150 women have an abnormal result, more than 80 women are referred for investigation, and more than 50 women have treatment.[4]

References:

1. Solomon D, Breen N, McNeel T: Cervical cancer screening rates in the United States and the potential impact of implementation of screening guidelines. CA Cancer J Clin 57 (2): 105-11, 2007 Mar-Apr.
2. Davey DD, Woodhouse S, Styer P, et al.: Atypical epithelial cells and specimen adequacy: current laboratory practices of participants in the college of American pathologists interlaboratory comparison program in cervicovaginal cytology. Arch Pathol Lab Med 124 (2): 203-11, 2000.
3. Sadler L, Saftlas A, Wang W, et al.: Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA 291 (17): 2100-6, 2004.
4. Raffle AE, Alden B, Quinn M, et al.: Outcomes of screening to prevent cancer: analysis of cumulative incidence of cervical abnormality and modelling of cases and deaths prevented. BMJ 326 (7395): 901, 2003.

Latest Updates to This Summary (05 / 23 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Alternative Screening and Treatment Strategies Including Low-Resource Settings

Added text about a follow-up study called STEP (self-testing options in the era for primary human papillomavirus [HPV] screening for cervical cancer) (cited Winer et al. as reference 14). This study was a pragmatic, parallel, single-blinded, randomized clinical trial that compared cervical cancer screening completion across strata of individuals due for screening, overdue for screening, or with unknown screening histories. Compared with the education group, time-to-screening completion was shorter for the direct-mail and opt-in groups. Time-to-screening completion for the education and the usual-care groups was similar across all screening-history strata. Furthermore, the education and usual-care groups had similar screening rates in this study population. Nevertheless, the generalizability of these study results may be limited given that participants were English-speaking and enrolled in a mixed-model managed care system, with both access to health care and insurance coverage. Also added text to state that the HPV self-sampling test used in this study is now approved by the U.S. Food and Drug Administration for use in a health care setting.

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about cervical cancer screening. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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PDQ® Screening and Prevention Editorial Board. PDQ Cervical Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/cervical/hp/cervical-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389177]

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Last Revised: 2024-05-23