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

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Cervical Cancer Screening

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about cervical cancer screening. This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board.

Information about the following is included in this summary:

  • Cervical cancer incidence and mortality statistics and information about cervical cancer risk factors.
  • Cervical cancer screening modalities.
  • Benefits and harms of cervical cancer screening.

This summary is intended as a resource to inform clinicians and other health professionals about currently available cervical cancer screening modalities. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in reporting the evidence of benefit and potential harms associated with each screening modality. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language.

Summary of Evidence

Note: Separate 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 Test

Benefits

Based on solid evidence, regular screening of appropriate women for cervical cancer with the Papanicolaou (Pap) test reduces mortality from cervical cancer. Screening is effective when started after age 25 years [1] but is of little value in women older than 60 years who have previously had negative tests.[2]

Description of the Evidence

STUDY DESIGN: Evidence obtained from population-based and cohort studies.
INTERNAL VALIDITY: Good.
CONSISTENCY: Good.
MAGNITUDE OF EFFECTS ON HEALTH OUTCOMES: Regular Pap screening decreases cervix cancer incidence and mortality by at least 80%.
EXTERNAL VALIDITY: Good.

Harms

Based on solid evidence, regular screening with the Pap test leads to additional diagnostic procedures (e.g., colposcopy) and treatment for low-grade squamous intraepithelial lesions (LSIL) with uncertain long-term consequences on fertility and pregnancy. These harms are greatest for younger women, who have a higher prevalence of LSIL, lesions that often regress without treatment.

Description of the Evidence

  • STUDY DESIGN: Evidence obtained from cohort or case-control studies.
  • INTERNAL VALIDITY: Good.
  • CONSISTENCY: Good.
  • MAGNITUDE OF EFFECTS ON HEALTH OUTCOMES: Additional diagnostic procedures were performed in 50% of women undergoing regular Pap testing. Approximately 5% were treated for LSIL. The number with impaired fertility and pregnancy complications is unknown.
  • 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.

Description of the Evidence

STUDY DESIGN: Evidence obtained from a single cohort study.
INTERNAL VALIDITY: Good.
CONSISTENCY: Good.
MAGNITUDE OF EFFECTS ON HEALTH OUTCOMES: Among women without cervices, fewer than 1 per 1,000 had an abnormal Pap test.
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.

Significance

Natural History, Incidence, and Mortality

In the United States in 2009, it is estimated that 11,270 cases of invasive cervical cancer will be diagnosed and that 4,070 women will die of the disease.[1] These rates have been improving steadily, with a 70% drop between 1950 and 1970 and a 40% drop between 1970 and 1999.[2] This improvement has been attributed largely to screening with the Papanicolaou 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.[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 LSIL) would have never progressed to invasive cancer,[5,6,7] screening also runs the risk of leading to treatment of women who do not need to be treated.

The leading etiologic factor in the development of preinvasive and invasive cervical cancer is infection with specific types of human papillomavirus (HPV), which is transmitted by sexual contact. Thus, sexually inactive women rarely develop cervical cancer, while sexual activity at an early age with multiple sexual partners is a strong risk factor. About 95% of women with invasive cervical cancer have evidence of HPV infection.[8,9,10,11] Many women with HPV infection, however, never develop cervical cancer; thus this infection is necessary but not sufficient for development of cancer.[12]

Although cervical cancer mortality increases with age (maximum mortality for white women is between the ages of 45 years and 70 years; for black women it is in their 70s),[2] 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. About 10% to 20% of women with CIN 3 lesions progress to invasive cancer.[4,7,13]

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 250% higher than for white women.[2] In either case, mortality is rare among women of any age who have regular screening.

References:

1. American Cancer Society.: Cancer Facts and Figures 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed January 6, 2010.
2. Ries LA, Eisner MP, Kosary CL, et al.: SEER Cancer Statistics Review, 1973-1999. Bethesda, Md: National Cancer Institute, 2002. Also available online. Last accessed December 10, 2009.
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. 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.
9. 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.
10. Alani RM, Münger K: Human papillomaviruses and associated malignancies. J Clin Oncol 16 (1): 330-7, 1998.
11. 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.
12. 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.
13. Arends MJ, Buckley CH, Wells M: Aetiology, pathogenesis, and pathology of cervical neoplasia. J Clin Pathol 51 (2): 96-103, 1998.

Evidence of Benefit

The Papanicolaou (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.[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 greater in women who have not been screened.[7,8,9,10] Risk also increases with long duration following 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 increase significantly the risk of finding invasive cervical cancer above the risk expected with annual screening.[12,13]

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 on healthy women aged 30 to 59 years.[14] 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 versus 56.7 per 100,000 person-years for the control. However, the same authors have subsequently reported that human papillomavirus (HPV) testing is superior at reducing cervical cancer mortality using the same cohort.[15] 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.[16]

A study of the feasibility of single-visit management of high-grade cervical lesions was conducted among a predominantly Latina population in California.[17] 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 high-grade squamous intraepithelial lesions (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.

A randomized trial in South Africa evaluated the impact on diagnosis of cervical intraepithelial neoplasia (CIN) 2+ at 6 months with a screen-and-treat approach with VIA and HPV versus delayed evaluation.[18] 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).

References:

1. Laara 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 Jr, 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. 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.
15. 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.
16. Szarewski A: Cervical screening by visual inspection with acetic acid. Lancet 370 (9585): 365-6, 2007.
17. 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.
18. 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.

Accuracy of the Papanicolaou 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 Papanicolaou (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 is often used as the test threshold and cervical intraepithelial neoplasia (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 low-grade squamous intraepithelial lesions, 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 such techniques 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.

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 Papanicolaou (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 cervical intraepithelial neoplasia, with modestly lower specificity.[1,2] One careful study, however, showed that conventional Pap testing was slightly more sensitive and specific than liquid-based cytology.[3]

The evidence is also mixed about whether liquid-based techniques improve rates of test adequacy.[1,2] One advantage of liquid-based cytology is that human papillomavirus testing (see below) 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.

References:

1. 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 December 10, 2009.
2. 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 December 10, 2009.
3. 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 Papanicolaou (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, 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.[1] Among 2,561 women (mean age 66.7 years) with normal Papanicolaou (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 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 prior negative test.

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.[2]

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. 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.

HPV Testing

Non-invasive cervical squamous cell abnormalities are graded histologically as cervical intraepithelial neoplasia (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.[1] CIN 2 has poor interobserver reproducibility,[2] and the biologic behavior is variable.[3] CIN 3 is therefore a more rigorous endpoint for clinical trials, while CIN 2 represents the threshold for treatment in order to provide an additional measure of safety.

Approximately 15 cancer-associated (high-risk or carcinogenic) human papillomavirus (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.

Currently, the only U.S. Food and Drug Administration (FDA) approved HPV DNA test is Hybrid Capture 2 (HC2), designed to detect 13 carcinogenic HPV types. The HPV HC2 test is performed on a cervical sample, using either residual specimen from liquid-based cytology collection, or a separately collected cervical specimen. The FDA approved threshold for a positive result is 1.0 relative light unit compared with a 1 pg/mL HPV DNA positive control, in which interlaboratory reliability and reproducibility are excellent.[4]

HC2 is approved for use in two contexts: (1) as a second (i.e., triage) test following 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.[5]

Triage

A large randomized clinical trial, the ASCUS/Low-Grade Squamous Intraepithelial Lesions (LSIL) Triage Study (ALTS) demonstrated the cost effectiveness of using HPV testing to clarify the risk of an ASCUS Papanicolaou (Pap) result.[6] 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 the enrollment cytology was high-grade squamous intraepithelial lesions (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.[7] HPV testing is not recommended in adolescent women with ASCUS as the majority of such women are HPV positive.[8,9]

HPV DNA testing is generally not appropriate or clinically useful following cytology results of LSIL, which is more severe than ASCUS, and the vast majority of such women (84%–96%) are carcinogenic HPV DNA positive.[10] 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.[11]

Primary Screening

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 or cancer (CIN 3+) and therefore may be screened less often. Screening more frequently than every three years would not improve sensitivity significantly, but would increase costs and overtreatment.[12,13]

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%).[14,15,16,17,18,19,20] 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%.[15]

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.[15] 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;[20] or another more specific molecular assay;[21] and (2) trigger further workup only after two sequential positive HPV test results as it is the persistence of carcinogenic HPV that confers the greatest risk of CIN 2/3.[22,23]

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%.[24]

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. Carozzi FM, Del Mistro A, Confortini M, et al.: Reproducibility of HPV DNA Testing by Hybrid Capture 2 in a Screening Setting. Am J Clin Pathol 124 (5): 716-21, 2005.
5. New Device Approval: Digene Hybrid Capture 2 High-Risk HPV DNA Test - P890064 S009 A004 . Rockville, Md: U.S. Food and Drug Administration, Center for Devices and Radiological Health, 2003. Available Online. Last accessed December 10, 2009.
6. 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.
7. 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.
8. Wright TC Jr, 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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 December 10, 2009.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.

Screening Benefit According to Age

Cervical cancer mortality, usually occurring among unscreened women, increases with age, with the maximum mortality for white women between the ages of 45 and 70 years and for black women in the 70s.[1,2] (Also available online.) Mortality among women with negative Papanicolaou (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 (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 to 24 years are those most 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.

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 to 6 in 10,000).[4]

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. 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.

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 (LSIL), the majority of which would never progress to cervical cancer. Women with human papillomavirus (HPV)-positive ASCUS or LSIL 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 are more likely to suffer harms from interventions for a condition that often resolves spontaneously.

Based on 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.

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.

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Changes To This Summary (12 / 23 / 2009)

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.

SUMMARY OF EVIDENCE

Revised text to clarify that screening is effective when started after age 25 years but is of little value in women older than 60 years who have previously had negative tests (cited Sasieni et al. as reference 1 and Sawaya et al. as reference 2).

EVIDENCE OF BENEFIT

Added text to state that the same authors have subsequently reported that human papillomavirus testing is superior at reducing cervical cancer mortality using the same cohort (cited Sankaranarayanan et al. as reference 15).

SCREENING BENEFIT ACCORDING TO AGE

Added text to state that mortality among women with negative Papanicolaou (Pap) screening is low at all ages.

Added text to state that 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 (cited Sasieni et al. as reference 3).

Added text to state that women aged 20 to 24 years are those most 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.

Added text to state that 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.

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Date Last Modified: 2009-12-23

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