Editorials

New Tests for Cervical Cancer Screening



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Am Fam Physician. 2001 Sep 1;64(5):729-733.

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The article by Nuovo and associates1 highlights some of the successes of cervical cancer screening and discusses some of the remaining dilemmas. Although use of the Papanicolaou (Pap) smear has significantly decreased the rate of cervical cancer, there is still much work to be done. Cytologic screening has served to identify those women who need further diagnostic testing to determine the absence or presence of disease associated with human papillomavirus (HPV) infection. Whether the conventional Pap smear is the best test to identify those women at greatest risk for lower genital neoplasia is the subject of intense debate.

One reason cervical cancer has not been eliminated in the United States is that not all women present for screening or follow-up. A primary issue involves making Pap smear screening accessible to all women and ensuring that women take advantage of screening benefits. In one study2 of 481 women diagnosed with invasive cervical cancer, 28.5 percent had never had a Pap test and of the remaining women who were screened, their last Pap test was five or more years before the diagnosis of invasion. Additionally, less than 83 percent of women with cervical cytology that indicated high-grade intraepithelial lesions or invasion had available documentation of follow-up within six months and less than 88 percent within one year, which underscores the need to implement effective tracking systems to improve compliance.3

Another reason cervical cancer has not been eliminated is that the basic techniques of sampling and interpreting the conventional Pap smear have remained essentially unchanged in the past 50 years. Screening errors, not misdiagnosis, are the major cause of false-negative Pap smear results.4 Education on the proper collection of cervical cells has failed to make a major improvement in the false-negative rate. To reduce sampling errors, cells must be collected from the cervical transformation zone. The sensitivity and specificity of the Pap test remain the same despite the use of improved sampling devices.5 Although specificity of the conventional Pap test has been reported at about 90 percent,6 the mean sensitivity of the Pap smear in low prevalence samples has been determined to be approximately 58 percent.7

Debate centers on whether liquid-based cytology, which has the primary goal of improving the “quality” of the cervical sample analyzed, represents a significant advance over conventional cytologic screening. The argument being made from a public health perspective is that liquid-based cytology increases the detection of minimal cytologic abnormalities that have a high rate of regression and increase costs by requiring additional evaluation and follow-up. Liquid-based cytology did detect more low-grade squamous intraepithelial lesions (LSIL) and atypical squamous cells of undetermined significance (ASCUS) than the conventional Pap smear in the pivotal trials of the U.S. Food and Drug Administration.8,9 Some studies have been criticized because results were based on cytology alone with no histologic confirmation of the squamous intraepithelial lesion. Most of the initial studies of liquid-based cytology used “split samples.” The conventional Pap smear was prepared first. The residual material that remained on the collection device was then transferred to the liquid fixative and a second slide was prepared in the laboratory. Split samples are inherently biased because only the residual cells are used to prepare the liquid-based specimen.

Despite these limitations, in one direct-to-vial study10 the cytologic results of 56,339 liquid-based specimens were compared with results from 74,756 conventional smears obtained from the same source during the same time. Results indicated that detection of LSIL and high-grade squamous intraepithelial lesions (HSIL) increased by 72 percent and 102 percent, respectively, with use of liquid-based cytology. In this same comparison of smears obtained from routine clinical practice, the “satisfactory but limited by” rate was significantly decreased. When cytologic results were compared with histologic diagnoses, the increased rate of both low- and high-grade intraepithelial lesions on liquid-based preparations reflected real detection rather than overdiagnosis.11

The year 2001 represents a landmark time for cervical cancer screening. Until now, nationally recognized management guidelines for triage of the abnormal Pap smear did not exist. Following the publication of the “Interim Guidelines” in 1994,12 there was confusion among physicians about the recommendations, especially regarding the minimally abnormal Pap smear. Now that three major studies1315 have been completed, data are emerging that will impact clinical care. The three trials are the Kaiser-Permanente study,13 the National Cancer Institute (NCI) study in Costa Rica14 and the much anticipated NCI-sponsored ASCUS/LSIL Triage Study.15 From these data, the sensitivity and specificity of HPV DNA testing were compared with liquid-based cytology for the detection of biopsy-confirmed cervical intraepithelial neoplasia (CIN) grade II or higher. Results demonstrated that HPV DNA testing for oncogenic HPV types has greater sensitivity to detect CIN grade III or higher with a specificity comparable to a single additional Pap smear indicating ASCUS or above. For triage of ASCUS, HPV DNA testing for oncogenic HPV types is a sensitive triage method for detection of CIN grade II to III.

The Bethesda 2001 conference has been completed and new recommendations for terminology and adequacy of the Pap smear are being proposed. A consensus conference on the Cytological Abnormalities and Cervical Cancer Precursors, sponsored by the American Society of Colposcopy and Cervical Pathology (ASCCP), will be held in September 2001. Throughout the summer of 2001, discussion threads for the various cytologic abnormalities have been posted on the ASCCP interactive bulletin board (http://consensus.asccp.org) for public review and commentary. This is a major opportunity for all physicians to give input. After public comments are received and the evidence-based data have been compiled, draft guidelines will be created by the working committees. These guidelines will be presented at the consensus conference to formal participants representing major constituencies with vested interest in women's health care, including the American Academy of Family Physicians.

By the end of 2001, new guidelines for Pap smear terminology and triage will be available. Unlike the “Interim Guidelines” published in 1994, recommendations will be based on high-quality studies. Cost-effectiveness data will soon be available to make rational comparisons among screening tests. No distinction should be made about who should get the “best” test. If a diagnostic screening method is more sensitive than the conventional Pap smear and remains highly specific for detection of significant disease, every woman should have the benefit of receiving it. The goal is to detect women with the highest risk of cervical cancer.

Barbara S. Apgar, M.D., M.S., is clinical professor in the Department of Family Medicine at the University of Michigan Medical School in Ann Arbor, Mich. Dr. Apgar is also an associate editor of American Family Physician.

Address correspondence to Barbara S. Apgar, M.D., M.S., Department of Family Medicine, University of Michigan Medical School, 883 Sciomeadow Dr., Ann Arbor, MI 48103. Reprints are not available from the author.

REFERENCES

1. Nuovo J, Melnikow J, Howell LP. New tests for cervical cancer screening. Am Fam Physician. 2001;64:780–6.

2. Janerich DT, Hadjimichael O, Schwartz PE, Lowell DM, Meigs JW, Merino MJ, et al. The screening histories of women with invasive cervical cancer, Connecticut. Am J Public Health. 1995;85:791–4.

3. Jones BA, Novis DA. Follow-up of abnormal gynecologic cytology: a College of American Pathologists Q-Probes study of 16,132 cases from 306 laboratories. Arch Pathol Lab Med. 2000;124:665–71.

4. Duke University. Evaluation of cervical cytology. U.S. Dept. of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1999. Rockville, Md.: Evidence report/technology assessment no. 5; AHCPR publication no. 99-E010.

5. Buntinx F, Brouwers M. Relation between sampling device and detection of abnormality in cervical smears: a meta-analysis of randomised and quasi-randomised studies. BMJ. 1996;313:1285–90.

6. Fahey MT, Irwig L, Macaskill P. Meta-analysis of Pap test accuracy. Am J Epidemiol. 1995;141:680–9.

7. Nanda K, McCrory DC, Myers ER, Bastian LA, Hasselblad V, Hickey JD, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med. 2000;132:810–9.

8. Lee KR, Ashfaq R, Birdsong GG, Corkill ME, McIntosh KM, Inhorn SL. Comparison of conventional Papanicolaou smears and a fluid-based, thinlayer system for cervical cancer screening. Obstet Gynecol. 1997;90:278–84.

9. Bishop JW, Bigner SH, Colgan TJ, Husain M, Howell LP, McIntosh KM, et al. Multicenter masked evaluation of AutoCyte PREP thin layers with matched conventional smears. Including initial biopsy results. Acta Cytol. 1998;42:189–97.

10. Diaz-Rosario LA, Kabawat SE. Performance of a fluid-based, thin-layer Papanicolaou smear method in the clinical setting of an independent laboratory and an outpatient screening population in New England. Arch Pathol Lab Med. 1999;123:817–21.

11. Vassilakos P, Schwartz D, de Marval F, Yousfi L, Broquet G, Mathez-Loic F, et al. Biopsy-based comparison of liquid-based, thin-layer preparations to conventional Pap smears. J Reprod Med. 2000;45:11–6.

12. Kurman RJ, Henson DE, Herbst AL, Noller KL, Schiffman MH. Interim guidelines for management of abnormal cervical cytology. The 1992 National Cancer Institute Workshop. JAMA. 1994;271:1866–9.

13. Manos MM, Kinney WK, Hurley LB, Sherman ME, Shieh-Ngai J, Kurman RJ, et al. Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA. 1999;281:1605–10.

14. Schiffman M, Herrero R, Hildesheim A, Sherman ME, Bratti M, Wacholder S, et al. HPV DNA testing in cervical cancer screening: results from women in a high-risk province of Costa Rica. JAMA. 2000;283:87–93.

15. Solomon D, Schiffman M, Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst. 2001;93:293–9.


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