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Screening for cervical cancer

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Summary Of Evidence
Significance
Evidence Of Benefit

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Information from PDQ -- for Health Professionals

SUMMARY OF EVIDENCE

Note: Separate PDQ summaries on Prevention of Cervical Cancer and Cervical Cancer Treatment are also available.

Evidence strongly suggests a decrease in mortality from regular screening with Pap tests (Pap smears) in women who are sexually active or who have reached 18 years of age. The upper age limit at which such screening ceases to be effective is unknown.

Levels of Evidence: 3,4,5

Evidence obtained from well-designed and conducted cohort or case-control studies, preferably from more than one center or research group

Evidence obtained from multiple-time series with or without intervention

Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees

SIGNIFICANCE

Incidence and Mortality

In 2002, an estimated 13,000 cases of invasive cervical cancer are expected to occur, with about 4,100 women dying from this disease.[1] From 1950 to 1970, the incidence and mortality rates of invasive cervical cancer fell impressively by more than 70%. From 1970 to 1995, the same rates decreased by more than 40%.[2] According to incidence and mortality rates, screening for cervical cancer should start in the late teens when these rates begin their upward trend. Rates for carcinoma in situ reach a peak for both black and white women between 20 and 30 years of age.

After the age of 25, however, the incidence of invasive cancer in black women increases rapidly with age, while in white women the incidence rises more slowly. Mortality also increases with advancing age, with dramatic differences between black and white women.

Extra effort is warranted to reach older women who have not been screened. Over 25% of the total number of invasive cervical cancers occur in women older than 65, and 40% to 50% of all women who die from cervical cancer are over 65 years of age.[3,4] A large proportion of women, particularly elderly black women and middle-aged poor women, have not had regular Pap tests (Pap smears).[5] In some areas, as many as 75% of women over 65 have not had a Pap test within the previous 5 years.[6] These patterns underscore the importance of special screening efforts targeted to reach women who do not receive regular screening.

For older women who have a normal PAP smear, the optimum schedule for repeat testing is unknown. In one postmenopausal study population, the incidence of abnormal readings in the first or second year after a normal reading was low (23 per 1000 person years). Among the 110 women with abnormal readings, mostly atypical squamous cells of undetermined significance (ASCUS), an additional 2 years of follow-up revealed only 3 potentially important lesions (1 cervical intraepithelial neoplasia (CIN), grade I to II, 1 vaginal intraepithelial neoplasia (VIN), grade III, and 1 uterine hyperplasia without atypia).[7] Because the positive predictive value of cytology for potentially important histologic diagnoses of the cervix was low (0.0% in the first year following a normal smear and 0.9% in the second year), the investigators concluded that a cervical smear in postmenopausal women should not be repeated within 2 years of a normal result because of unnecessary consequences due to false positive test results.

Although vaginal smears are often done for follow-up of women who have had a hysterectomy for malignancy, a retrospective study suggests little or no benefit of routine vaginal screening for women who have had a hysterectomy for benign conditions.[8] Investigators found a low prevalence of vaginal dysplasia (0.1%) and a high false-positive rate for vaginal smears from women who have had a hysterectomy for benign disease.

References:

  1. American Cancer Society: Cancer Facts and Figures-2002. Atlanta, Ga: American Cancer Society, 2002.
  2. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review 1973-1995. Bethesda, Md: National Cancer Institute, 1998.
  3. Surveillance Program, Division of Cancer Prevention and Control, National Cancer Institute. Unpublished data, 1990
  4. Remington P, Lantz P, Phillips JL: Cervical cancer deaths among older women: implications for prevention. Wisconsin Medical Journal 89(1): 30, 32-34, 1990.
  5. Makuc DM, Freid VM, Kleinman JC: National trends in the use of preventive health care by women. American Journal of Public Health 79(1): 21-26, 1989.
  6. Mandelblatt J, Gopaul I, Wistreich M: Gynecological care of elderly women: another look at Papanicolaou smear testing. JAMA: Journal of the American Medical Association 256(3): 367-371, 1986.
  7. 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). Annals of Internal Medicine 133(12): 942-950, 2000.
  8. Pearce KF, Haefner HK, Sarwar SF, et al.: Cytopathological findings on vaginal Papanicolaou smears after hysterectomy for benign gynecologic disease. New England Journal of Medicine 335(21): 1559-1562, 1996.

EVIDENCE OF BENEFIT

The widespread acceptance of the Pap test (Pap smear) makes the possibility of testing the efficacy of cervical cytology by randomized trials remote. There is, nevertheless, substantial evidence from observational studies that mortality from cervical cancer can be reduced by screening.

Mortality from cervical cancer has decreased in several large populations following the introduction of well-run screening programs.[1-4] Data from several large Scandinavian studies show sharp reductions in incidence and mortality following the initiation of organized screening programs. Iceland reduced mortality rates by 80% over 20 years, and Finland and Sweden reduced their mortality by 50% and 34%, respectively.[1] Similar reductions have been found in large populations in the United States and Canada.

Reductions in incidence and mortality seem to be proportional to the intensity of screening efforts. The Scandinavian countries with the highest rates of screening activity reported greater reductions in mortality than those countries with lower rates of screening.[1,5] Mortality in the Canadian provinces was reduced most remarkably in British Columbia, which had screening rates 2 to 5 times those of the other provinces.[6]

Case-control studies have found that the risk of developing invasive cervical cancer is 3 to 10 times greater in women who have not been screened.[7-10] Risk also increases with longer 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]

The analysis of survival data shows that survival appears to be directly related to the stage of disease at diagnosis. The 5-year relative survival rate for cervical cancer is 88% for women with an initial diagnosis of localized disease. For those initially diagnosed with distant disease, the survival rate is only 13%. Early detection, using cervical cytology, is currently the only practical means of detecting cervical cancer in localized or premalignant stages.

Targeting high-risk patients

Progress in mortality reduction will be accelerated most significantly by increasing the percentage of cervical neoplasms discovered in the precancerous or localized stages. This can be accomplished most effectively by screening women at greatest risk for cervical cancer, i.e., those who have not had a Pap test or those who have not had one for several years. Often, these women are older, of lower socioeconomic status, and may be members of minority groups, and are often seen by physicians for a variety of acute and chronic conditions unrelated to preventive medical care.[13-17] Women infected with human immunodeficiency virus (HIV) represent another important group at increased risk for development of cervical cancer. These women have been shown to have a 2.28-fold increased risk of invasive cervical cancer (95% confidence interval 1.9-3.0) compared to otherwise similar women. HIV seropositive women also show an increased frequency of abnormal Pap test results (12.5 times higher than seronegative women) and show a concomitant increase in cervical and anal human papillomavirus (HPV).[18,19] Other well-known risk factors, such as early age of first intercourse and multiple sexual partners, have less practical clinical significance due to the difficulty in obtaining adequate histories of these risk factors. Advances in understanding the relationship between specific HPV types and the risk of cervical neoplasia may have future applications in targeting high-risk groups for screening and other preventive interventions. The FDA has approved a molecular test, Hybrid Capture II, that identifies the presence of HPV DNA of 1 or more cancer-associated types included in the test probe. The use of HPV testing for primary population-based screening is not recommended due to low specificity, particularly among young sexually active women. HPV testing has also been proposed as a secondary test following an abnormal, equivocal or low-grade, screening cytology result. The utility of HPV testing for determining triage to colposcopy, in the context of an abnormal cytology result, may differ in women with low-grade squamous intraepithelial lesions (LSIL) versus those with atypical squamous cells of undetermined significance (ASCUS). A study of women with cytologic diagnoses of LSIL demonstrated a high percentage (83%) with positive HPV DNA test results, limiting the triage utility of the assay. Relatively few women would be spared referral to colposcopy based on a negative HPV result, therefore the cost of testing could not be justified.[20] HPV testing, however, may be an option for women and their doctors to consider after a screening cytology result of ASCUS. In one study of nearly 1,000 women, HPV testing was shown to be as or more sensitive compared to a single repeat cytology test for the colposcopic detection of high-grade cervical intraepithelial neoplasia (CIN) 2-3.[21] The program sensitivity of multiple repeat cytology tests, however, has not been evaluated in comparison to HPV testing.

The addition of liquid-based cytology has been shown to increase the sensitivity of detection of high- and low-grade cervical lesions over conventional Pap test without concomitant loss in specificity. The improvement afforded by the use of liquid-based cytology technology is attributable to more uniform sampling of collected cells and the display of the cells as a monolayer on the slide. An additional benefit of liquid-based cell collection is the compatibility with screening for other sexually transmitted diseases, particularly HPV.[22-24]

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): 1247-1249, 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): 1357-1366, 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. International Journal of Cancer 17(5): 602-612, 1976.
  4. Johannesson G, Geirsson G, Day N: The effect of mass screening in Iceland, 1965-1974, on the incidence and mortality of cervical carcinoma. International Journal of Cancer 21(4): 418-425, 1978.
  5. Sigurdsson K: Effect of organized screening on the risk of cervical cancer: evaluation of screening activity in Iceland, 1964-1991. International Journal of Cancer 54(4): 563-570, 1993.
  6. Benedet JL, Anderson MB, Matisic JP: A comprehensive program for cervical cancer detection and management. American Journal of Obstetrics and Gynecology 166(4): 1254-1259, 1992.
  7. Aristizabal N, Cuello C, Correa P: The impact of vaginal cytology on cervical cancer risks in Cali, Colombia. International Journal of 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): 779-782, 1984.
  10. Herrero R, Brinton LA, Reeves WC, et al.: Screening for cervical cancer in Latin America: a case-control study. International Journal of Epidemiology 21(6): 1050-1056, 1992.
  11. Celentano DD, Klassen AC, Weisman CS, et al.: Duration of relative protection of screening for cervical cancer. Preventive Medicine 18(4): 411-422, 1989.
  12. International Agency for Research on Cancer Working Group on Evaluation of Cervical Cancer Screening Programmes: Screening for squamous cervical cancer: duration of low risk after negative results of cervical cytology and its implication for screening policies. British Medical Journal 293(6548): 659-664, 1986.
  13. Kleinman JC, Kopstein A: Who is being screened for cervical cancer? American Journal of Public Health 71(1): 73-76, 1981.
  14. Surveillance Program, Division of Cancer Prevention and Control, National Cancer Institute. Unpublished data, 1990
  15. Remington P, Lantz P, Phillips JL: Cervical cancer deaths among older women: implications for prevention. Wisconsin Medical Journal 89(1): 30, 32-34, 1990.
  16. Makuc DM, Freid VM, Kleinman JC: National trends in the use of preventive health care by women. American Journal of Public Health 79(1): 21-26, 1989.
  17. Mandelblatt J, Gopaul I, Wistreich M: Gynecological care of elderly women: another look at Papanicolaou smear testing. JAMA: Journal of the American Medical Association 256(3): 367-371, 1986.
  18. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and Mortality Weekly Report 41(RR-17): 1-19, 1992.
  19. Palefsky JM, Minkoff H, Kalish LA, et al.: Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women. Journal of the National Cancer Institute 91(3): 226-236, 1999.
  20. Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Leisions Triage Study (ALTS) Group. Journal of the National Cancer Institute 92(5): 397-402, 2000.
  21. Manos MM, Kinney WK, Hurley LB, et al.: Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA: Journal of the American Medical Association 281(17): 1605-1610, 1999.
  22. Papillo JL, Zarka MA, St. John TL: Evaluation of the ThinPrep Pap test in clinical practice: a seven-month, 16,314-case experience in northern Vermont. Acta Cytologica 42(1): 203-208, 1998.
  23. Sherman ME, Mendoza M, Lee KR, et al.: Performance of liquid-based, thin-layer cervical cytology: correlation with reference diagnoses and human papillomavirus testing. Modern Pathology 11(9): 837-843, 1998.
  24. Sherman ME, Schiffman MH, Lorincz AT, et al.: Cervical specimens collected in liquid buffer are suitable for both cytologic screening and ancillary human papillomavirus testing. Cancer 81(2): 89-97, 1997.
Date Last Modified: 07/2002

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