Purpose of This PDQ Summary
Summary of Evidence

Screening With the Papanicolaou Test         Benefits          Harms Screening Women Without a Cervix Screening Elderly Women

Significance

Natural History, Incidence, and Mortality

Evidence of Benefit

The Papanicolaou (Pap) Test Alternative Screening and Treatment Strategies in Low-Resource Settings

Accuracy of the Papanicolaou Test
New Screening Technologies
Screening Women Who Have Had a Hysterectomy
Screening Interval
HPV Testing
Screening Older Women
Evidence of Harm
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Changes To This Summary (04/10/2008)
Questions or Comments About This Summary
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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 ¹.

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 ² 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 ³, which is written in less technical language.

Summary of Evidence

Note: Separate PDQ summaries on Cervical Cancer Prevention ⁴, Cervical Cancer Treatment ⁵, and Levels of Evidence for Cancer Screening and Prevention Studies ² are also available.

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 within 3 years after first vaginal intercourse.

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.

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.

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.

Based on solid evidence, continued screening in elderly women who have had negative Pap tests is of minimal value.

Description of the Evidence

• Study Design: Evidence obtained from cohort studies.
• Internal Validity: Good.
• Consistency: Good.
• Magnitude of Effects on Health Outcomes: Women aged 60 years and older who have a negative test are very unlikely to have abnormal Pap tests on repeat screening.
• External Validity: Good.

Significance

Natural History, Incidence, and Mortality

In the United States in 2008, it is estimated that 11,070 cases of invasive cervical cancer will be diagnosed and that 3,870 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,[5-7] 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), transmitted by sexual contact. Thus, women not sexually active 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.[8-11] 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 aged 45 to 70 years and for black women 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 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. ⁶ Last accessed October 1, 2008. 
   
   
2. Ries LA, Eisner MP, Kosary CL, et al.: SEER Cancer Statistics Review, 1973-1999. Bethesda, Md: National Cancer Institute, 2002. Also available online. ⁷ Last accessed November 15, 2007. 
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
5. Nasiell K, Roger V, Nasiell M: Behavior of mild cervical dysplasia during long-term follow-up. Obstet Gynecol 67 (5): 665-9, 1986.  [PUBMED Abstract]
   
   
6. Nash JD, Burke TW, Hoskins WJ: Biologic course of cervical human papillomavirus infection. Obstet Gynecol 69 (2): 160-2, 1987.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
10. Alani RM, Münger K: Human papillomaviruses and associated malignancies. J Clin Oncol 16 (1): 330-7, 1998.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
13. Arends MJ, Buckley CH, Wells M: Aetiology, pathogenesis, and pathology of cervical neoplasia. J Clin Pathol 51 (2): 96-103, 1998.  [PUBMED Abstract]
    
    

Evidence of Benefit

The Papanicolaou (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 following the introduction of well-run screening programs.[1-4] 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.[7-10] 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]

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. 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.[15]

A study of the feasibility of single-visit management of high-grade cervical lesions was conducted among a predominantly Latina population in California.[16] 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 human papillomavirus (HPV) versus delayed evaluation.[17] 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 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 found 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 with HPV DNA group, three cases in the VIA group, and eight cases in the delayed evaluation group).

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
8. Clarke EA, Anderson TW: Does screening by "Pap" smears help prevent cervical cancer? A case-control study. Lancet 2 (8132): 1-4, 1979.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
13. Kleinman JC, Kopstein A: Who is being screened for cervical cancer? Am J Public Health 71 (1): 73-6, 1981.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
15. Szarewski A: Cervical screening by visual inspection with acetic acid. Lancet 370 (9585): 365-6, 2007.  [PUBMED Abstract]
    
    
16. 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.  [PUBMED Abstract]
    
    
17. 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.  [PUBMED Abstract]
    
    

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   

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 ⁸. Last accessed February 20, 2007. 
   
   
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 ⁹. Last accessed February 20, 2007. 
   
   
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.  [PUBMED Abstract]
   
   

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   

HPV Testing

As virtually all cervical cancers are thought to result from human papillomavirus (HPV) infection, it would be reasonable to consider testing for HPV DNA as a screening test for cervical cancer. There are several issues to consider regarding using HPV DNA testing as a primary screening test. The first is to find a feasible test that detects the optimal number of types of HPV. The current U.S. Food and Drug Administration-approved test, the Hybrid Capture 2 (HC2) detects the presence of 13 types of HPV that have been associated with cervical cancer. The HC2 test is approved to be used in conjunction with the Papanicolaou (Pap) test. The ranges of sensitivity of this test for detecting cervical intraepithelial neoplasia (CIN) 2–3 is from 84% to 95%.[1,2] In a randomized trial using both Pap and HPV testing in random order among women aged 30 to 69 years; sensitivity of HPV was higher than Pap testing, 95% and 55%, respectively. The combination of both HPV and Pap testing had a 100% sensitivity with a referral rate of 7.9%.[2]

Lowered specificity of HPV DNA testing compared with Pap testing, is a second issue to consider. Among women older than 30 years, the Pap test had a 97% specificity compared with 94% for HPV DNA testing.[2] The specificity of HPV DNA testing would likely be lower among women younger than 30 years, because women, especially younger women, may have transient HPV infection that is asymptomatic and of little clinical consequence. Thus, detecting such women would potentially increase unnecessarily the number of follow-up diagnostic workups.

Another issue with this and other screening modalities is the potential for overdiagnosis of cervical lesions that would not progress to cancer. This issue was addressed in a randomized trial comparing screening HPV plus Pap test to Pap test on subsequent high risk cervical lesions or cancer that was conducted in Sweden among women aged 23 to 50 years.[3] Grade 3 cervical lesions and cancer were reduced by 47% at the first incident screening, however, grade 2 lesions detected at a higher rate at the prevalence screen were not followed by a reduction in detection at subsequent screens suggesting that some of the increased diagnosis of grade 2 lesions is due to overdiagnosis.[3] This trial had an average of only 4 years of follow-up, which covered the first incident screening round, thus limiting the assessment of the impact of overdiagnosis and the overall effect of screening on subsequent grade 3 cervical intraepithelial neoplasia and invasive cancer.

The ASCUS/LSIL Triage Study (ALTS) found that HPV testing was most useful in triaging women with the ambiguous atypical squamous cells of undetermined significance (ASCUS) findings on cytologic screening. This trial randomly assigned women with ASCUS to one of three evaluation strategies: immediate colposcopy, triage-to-colposcopy based on HPV results from HC2 testing, and conservative management. The HPV-triage strategy detected about as many cases of CIN 2+ as the immediate-colposcopy strategy, but only 56% of women underwent colposcopy. Thus, the study concluded that HPV testing of the large number of women with ASCUS findings for triage to colposcopy is a more efficient strategy than immediate colposcopy. This strategy was also more efficient than conservative repeat-cytologic testing.[4]

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 ⁸. Last accessed February 20, 2007. 
   
   
2. 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.  [PUBMED Abstract]
   
   
3. 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.  [PUBMED Abstract]
   
   
4. Solomon D, Schiffman M, Tarone R, et al.: Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst 93 (4): 293-9, 2001.  [PUBMED Abstract]
   
   

Screening Older Women

As noted above, cervical cancer mortality increases with age (maximum mortality for white women aged 45 to 70 years and for black women in their 70s). Predominantly, however, these are women who have not had recent screening.[1,2] (Also available online ¹⁰.) Among women who have had negative cytologic screening, mortality at all ages is low.

The prevalence of cervical intraepithelial neoplasia (CIN) is highest among women in their 20s and 30s. High-grade squamous intraepithelial lesions are rare among women older than 65 years who have been previously screened. Fewer than 1 woman in 1,000 (in some studies as few as 2–6 in 10,000) who were aged 60 years and older at the time of a negative Papanicolaou test had a new diagnosis of CIN 3+ on repeat screening.[3]

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
3. 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.  [PUBMED Abstract]
   
   

Evidence of Harm

The major potential harm of screening for cervical cancer lies in the detection of many lesions such as atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) that would never progress to cervical cancer. Women with LSIL or high-grade squamous intraepithelial lesions (HSIL) on Papanicolaou (Pap) testing are usually referred for colposcopy and treated with cryotherapy or loop electrosurgical excision procedure. These procedures permanently alter the cervix and have unknown consequences on fertility and pregnancy. Because younger women are most likely to acquire human papillomavirus infections and to be diagnosed with LSIL, they are thus most 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.[1] For each death prevented, the authors estimated that over 150 women have an abnormal result, over 80 are referred for investigation, and over 50 have treatment.

Annually in the United States, 50 million women undergo screening; about 3.5 million (7%) will be referred for further evaluation. Of these, more than 2 million will be referred for further evaluation of ASCUS.[2] About 11,000 cases of invasive cervical cancer are expected in 2007. Thus, Pap test screening results in a large number of colposcopies for benign conditions. Strategies to improve the specificity of the cervical cytopathology test are being evaluated by the ASCUS/LSIL Triage Study (ALTS).[3]

References

1. 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.  [PUBMED Abstract]
   
   
2. Solomon D, Schiffman M, Tarone R, et al.: Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst 93 (4): 293-9, 2001.  [PUBMED Abstract]
   
   
3. Schiffman M, Adrianza ME: ASCUS-LSIL Triage Study. Design, methods and characteristics of trial participants. Acta Cytol 44 (5): 726-42, 2000 Sep-Oct.  [PUBMED Abstract]
   
   

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Changes To This Summary (04/10/2008)

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.

HPV Testing ¹⁴

Added text ¹⁵ about a randomized trial using both Pap and HPV testing in random order among women aged 30 to 69 years; sensitivity of HPV was higher than Pap testing, 95% and 55%, respectively (cited Mayrand et al. as reference 2).

Added text ¹⁶ to state that among women older than 30 years, the Pap test had a 97% specificity compared with 94% for HPV DNA testing.

Added text ¹⁷ about a randomized trial comparing screening HPV plus Pap test to Pap test on subsequent high risk cervical lesions or cancer that was conducted in Sweden among women aged 23 to 50 years (cited Naucler et al. as reference 3).

Questions or Comments About This Summary

If you have questions or comments about this summary, please send them to Cancer.gov through the Web site’s Contact Form ¹⁸. We can respond only to email messages written in English.

More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database ¹⁹.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment ²⁰

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment ²¹

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care ²²

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer) ²³

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention ²⁴

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics ²⁵

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine ²⁶

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).