PAP/NGC Program Review

August 2003
Special Section

Getting the most out of Pap and HPV DNA co-testing

R. Marshall Austin, MD, PhD

The Food and Drug Administration announced on March 31 its approval of Digene’s High-Risk HPV DNA Hybrid Capture 2 test as a cervical screening test to be used in conjunction with the Pap test for human papillomavirus infection in women age 30 and older.¹ The landscape of cervical screening risk management and patient safety advocacy has been permanently altered, given findings in published^2,3 and unpublished studies⁴ that co-testing with cytological Pap screening and HPV DNA testing can, for the first time, approach entrenched but previously unrealistic public and professional expectations^5,6 of 100 percent effectiveness for detection of clinically significant cervical lesions. Whether the full promise of “DNAwithPap”⁷ co-testing is realized may now depend on the ability of patient safety advocates to communicate clearly to diverse audiences not only the advantages but also the limitations of HPV DNA testing in cervical cancer screening. This communication is important, since financially driven pressures and messages are already growing to tempt cost-conscious payers to move prematurely toward unproven lengthened screening intervals and a primary screening role for a high-risk HPV DNA test.

Approval of the “DNAwithPap” test was based on a review of international cervical screening studies on more than 77,000 women and more than 1,000 cases of detected high-grade squamous intraepithelial lesions and cancer spanning four continents and 11 countries.4 For most studies, the sensitivity of the Pap test and the Hybrid Capture 2 (HC2) HPV DNA test combined was higher than for either test alone. The negative predictive values were also higher with co-testing: They were consistently over 99 percent, and they reached 100 percent in several studies. Significantly, in the above review there was not a single study in which the sensitivity of the Pap test exceeded or fully equaled the HPV DNA test.

In the only study² in which verification bias concerns were fully addressed by 100 percent colposcopy and cervical biopsy of almost 2,000 previously unscreened high-risk Chinese women, 95 percent of HSIL and invasive cancer (HSIL+) lesions were detected from residual vial fluid by HC2 HPV DNA testing, 94 percent of HSIL+ lesions were detected using direct-to-vial ThinPrep liquid-based cytology (LBC), and virtually all 86 HSIL+ lesions (including 12 invasive cancers) were detected by co-testing. In another significant comparison study of almost 8,000 screened women from Reims, France, HC2 HPV DNA testing detected 100 percent of HSIL+ lesions compared with 58 percent for the conventional Pap smear and 84 percent for direct-to-vial ThinPrep LBC.⁸ Overall, the reviewed studies indicated that HPV DNA testing on average detected 92 percent of HSIL+ lesions compared with an average of only 58 percent HSIL+ detection for conventional Pap smear screening.⁴

Results from several important longitudinal studies have also become available.^3,4,9 These studies indicate that women who are HPV DNA positive but who do not have an abnormal Pap test or suspicious clinical findings should not necessarily be viewed as having a “false-positive” test; rather, they are at significantly increased risk for subsequent development of a significant cervical lesion (HSIL+). Therefore, such women need to be followed closely with repeat testing for persistence of high-risk HPV DNA or development of detectible cytologic abnormality, or both, and subsequent appropriate referral for diagnostic colposcopic and possible tissue biopsy evaluations.⁷

In the United States, previously unrealistic but entrenched public and professional expectations of near 100 percent effectiveness for cervical screening have established a breathtakingly high standard for expected test effectiveness. These expectations have been reflected in significantly rising costs to cover liability exposure from Pap test litigation and an alarming decline in the number of insurers in the indemnity market willing to insure cytotechnologists and pathologists for Pap testing at any price.¹⁰ At the same time, these unrealistic expectations have been further complicated by the significant rising relative and absolute prevalence of endocervical adenocarcinomas.¹¹ Although no conclusive evidence is available from population studies to prove that conventional Pap smear screening has been able in any location to decrease substantially the incidence of or the morbidity and mortality due to endocervical adenocarcinoma,¹² recent reports suggest that enhanced screening with HPV DNA testing^13,14 and ThinPrep LBC^15-17 could improve previously disappointing results.

The lack of data on the impact of the rising incidence of endocervical adenocarcinoma in the most commonly cited cervical cancer models¹⁸ and experience suggesting a diminished screening window of opportunity for detecting cervical adenocarcinoma¹⁹ call into question the prudence of new guideline recommendations for triennial Pap and HPV co-testing.^20,21 In a similar spirit, some international cost-efficiency models have implied that as much as 30 percent of cervical cancer is unavoidable with “efficient” screening policies,²² and in the U.S. some experts have discounted even halving of existing cancer rates in screened populations as perhaps insignificant “small decreases in absolute risk.”²³ Nevertheless, informed individual patients and their legal representatives in the U.S. tort system have not so far consented to the concept of “acceptable cervical cancer rates” in screened patients. This conundrum is exacerbated by the ability of third-party payers to actually improve their bottom lines and decrease their costs by paying only for less-than-optimal screening practices, even while transferring risk without accountability to patients and professionals involved in testing.

Published peer-reviewed and manufacturer-funded model studies indicate that elusive U.S. Healthy People 2010 cervical cancer goals could be met or even exceeded by using more sensitive new screening technologies at existing rates of recruitment to screening.^24,25 Achieving and exceeding these model projections now appears feasible with Pap and HPV DNA co-testing at existing rates of screening. The models and common sense do not, however, suggest that telling women to present themselves less frequently for screening will be helpful in meeting national cervical cancer goals. Co-testing with Pap and HPV DNA tests at existing rates of screening is the policy most consistent with public expectations for high screening effectiveness and the challenge of early detection and treatment of increasingly prevalent, difficult-to-detect endocervical adenocarcinomas. Exhortations to economically justify longer screening intervals and to consider primary HPV testing should rely on accumulation of longitudinal population studies that include substantial numbers of cases of endocervical adenocarcinoma. Assertions that certain rates of cervical cancer may be “irreducible”²⁰ and, by implication, acceptable should await the completion of well-designed U.S. population studies and “informed consent” from credible consumer representatives.

References

1. U.S. Food and Drug Administration. FDA News: FDA approves expanded use of HPV test. Available at: www.fda.gov/bbs/topics/news/2003/new00890.html. Accessed July 14, 2003.
   
2. Belinson JH, Qiao YI, Pretorius R, et al. Shanxi Province Cervical Cancer Screening Study: a cross-sectional comparative trial of multiple techniques to detect cervical neoplasia. Gynecol Oncol. 2001; 83: 439–444.
   
3. Bory JP, Cucherousset J, Lorenzato M, et al. Recurrent human papillomavirus infection detected with the hybrid capture II assay selects women with normal cervical smears at risk for developing high grade cervical lesions: a longitudinal study of 3,091 women. Int J Cancer. 2002; 102:519–525.
   
4. Lorincz AT, Richart RM. Human papillomavirus DNA testing as an adjunct to cytology in cervical screening programs. Arch Pathol Lab Med. 2003;127:959–968.
   
5. Austin RM. Human papillomavirus reporting: minimizing patient and laboratory risk. Arch Pathol Lab Med. 2003;127:973–977.
   
6. Austin RM. Public expectations, reliable screening sensitivity, and the standard of practice. Cancer Cytopathol. 2003; 99: 1–3.
   
7. Digene. Clinical Information: With DNAwithPap, now you can be more certain. Available at: www.digene.com/clinician_1_3.html. Accessed July 14, 2003.
   
8. Clavel C, Masure M, Bory JP, et al. Human papillomavirus testing in primary screening for the detection of high grade cervical lesions: a study of 7,932 women. Br J Cancer. 2001;84:1616–1623.
   
9. Sherman ME, Lorincz AT, Scott DR, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. JNatl Cancer Inst. 2003;95:46–52.
   
10. Austin RM. In: Allen KA, Holladay EB, eds. Preface. Risk Management for the Cytology Laboratory. Raleigh, NC: American Society for Cytotechnology; 2002:6–9.
    
11. Smith HO, Tiffany MF, Qualls CR, et al. The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States—a 24-year population-based study. Gynecol Oncol. 2000; 78: 97–105.
    
12. Kinney W, Sawaya G, Sung HY, et al. Stage at diagnosis and mortality in patients with adenocarcinoma and adenosquamous carcinoma of the uterine cervix diagnosed as a consequence of cytologic screening. Acta Cytol. 2003; 47: 167–171.
    
13. Ronnett BM, Manos MM, Ransley JE, et al. Atypical glandular cells of undetermined significance: cytopathologic features, histopathologic results, and human papillomavirus DNA detection. Human Pathol. 1999; 30:816–825.
    
14. Andersson S, Rylander E, Larsson B, et al. The role of human papillomavirus in cervical adenocarcinoma carcinogenesis. Eur J Cancer. 2001;37:246–250.
    
15. Bai H, Sung CJ, Steinhoff MM. ThinPrep Pap test promotes detection of glandular lesions of the endocervix. Diagn Cytopathol. 2000;23:19–24.
    
16. Ashfaq R, Gibbons D, Vela C, et al. ThinPrep Pap test. Accuracy for glandular disease. Acta Cytol. 1999; 43: 81–85.
    
17. Schorge JO, Hossein SM, Hynan L, et al. ThinPrep detection of cervical and endometrial adenocarcinomas: a retrospective cohort study. Cancer Cytopathol. 2002; 96: 338–343.
    
18. McCrory DC, Mather DB, Bastian L, et al. Evaluation of Cervical Cytology, Evidence Report/Technology Assessment No. 5, Rockville, Md: Agency for Health Care Policy and Research; 1999. AHCPR publication No. 99-E010.
    
19. Janerich DT, Hadjimichael O, Schwartz PE, et al. The screening histories of women with invasive cervical carcinoma, Connecticut. Am J Publ Health. 1995;7 9: 791–794.
    
20. 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. 2002; 52: 342–362.
    
21. Austin RM. Too much emphasis on screening interval, too little on safety. CAP TODAY. 2003;17(5):12–15.
    
22. Van den Akker-van Marle ME, van Ballegooijen MV, van Oartmarssen GJ, et al. Cost-effectiveness of cervical cancer screening: comparison of screening policies. JNatl Cancer Inst. 2002;94:193–204.
    
23. Miller GM, Sung HY, Sawaya GF, et al. Screening interval and risk of invasive squamous cell cervical cancer. Obstet Gynecol. 2003;101:29–37.
    
24. Hutchinson ML, Berger BM, Farber FL. Clinical and cost implications of new technologies for cervical cancer screening: the impact of test sensitivity. Am J Managed Care. 2000;6:766–780.
    
25. Montz FJ, Farber FL, Bristow RE, et al. Impact of increasing Papanicolaou test sensitivity and compliance: a modeled cost and outcomes analysis. Obstet Gynecol. 2001; 97:781–788.
    

Dr. Austin, a member of the CAP Cytopathology Committee, is medical director and director of cytopathology and gynecologic pathology, Coastal Pathology Laboratories, Charleston, SC.