August 2008
PAP/NGC Programs Review

Andrew H. Fischer, MD

A new CAP study by Ann Moriarty, et al., explores how cytology laboratories are incorporating HPV testing (Moriarty AT, Schwartz MR, Eversole G, et al. Human papillomavirus testing and reporting rates: practices of participants in the College of American Pathologists’ Interlaboratory Comparison Program in Gynecologic Cytology in 2006. Arch Pathol Lab Med. 2008; 132: 1290–1294). Based on a 2007 survey sampling a wide range of practice settings, the study compares practice patterns in 2006 with those reported in a previous CAP survey in 2003. The study is worth a careful reading for its evidence on how to improve cervical cancer screening, for its help in pre­dicting workflow changes in the future, and for its broader implications for health care policy.

More than 10 million HPV tests are performed annually in the U.S., and the market for testing has been growing by 40 percent in each of the past five years. Third Wave Technologies estimates that the U.S. market for HPV testing is only 28 percent penetrated and that the potential worldwide market at saturation is $1 billion annually (Third Wave press release, March 11, 2008, www.twt.com).

The CAP study reports that only about 80 percent of cytology laboratories offered HPV testing in 2003, whereas all labs responding to the survey offered testing in 2006. The CAP data help to disclose how labs accomplished the increased offering of HPV testing, with reference labs appearing to pick up new work from smaller cytology labs. Seventy-three percent of cytology laboratories sent material to reference labs for HPV testing in 2006, a major increase from the 62 percent referral rate in 2003. HPV testing was performed within 4.7 percent of cytology laboratories in 2003, where­as 8.9 percent performed testing in 2006. Intra-institution testing outside the cytology laboratory also increased from 13 percent to 18 percent. Though most cytology labs sent their HPV tests to reference labs, the median monthly volume of testing sent to the reference labs was only 36 tests, whereas cytology labs performed a median of 129 tests, and intra-institutional labs outside of cytology performed a median of 230 tests per month in 2006.

Most labs used Digene Hybrid Capture II (Digene, Gaithersburg, Md.) in 2003 and 2006, but a growing number of labs offer a non-Digene (and therefore non-FDA-approved) HPV testing method. In 2003, 12.8 percent of labs offered non-Digene HPV testing, and in 2006, 19.1 percent. Rigorous validation is required for offering a non-FDA-approved test, for example by following CAP guidelines that meet the requirements for high-complexity testing as defined by the Centers for Medicare and Medicaid Services and set forth under CLIA ’88 (Seabrook JM, Hubbard RA, et al. Achieving quality reproducible results and maintaining compliance in molecular diagnostic testing of human papillomavirus. Arch Pathol Lab Med. 2003; 127: 978– 983).

A surprising finding is that many cytology labs are apparently not helping providers follow evidence-based guidelines for HPV testing. For example, 45 percent of laboratories in 2006 offered low-risk HPV testing a test with no proven clinical utility. More than 20 percent of labs offered reflex testing for HPV in patients with HSIL, a utilization that has not been recommended in the American Society for Colpos­copy and Cervical Pathology guidelines (Wright TC, et al. Am J Obstet Gynecol. 2007. 197: 346 – 355, available at www.asccp.org/consensus/cytological.shtml). Testing that is within evidence-based guidelines is surprisingly not offered by many labs. Dual or co-testing with HPV plus Pap for women over age 30 is highly sensitive for detecting abnormalities, and it is cost-effective because screening intervals can be lengthened from yearly to every three years if both tests are negative. Only 25 percent of labs offer combined Pap plus HPV testing for women over 30. Another 60 percent apparently leave the decision to the gynecologist to order Pap plus HPV for specific patients, without regard to age. This would appear to indicate that about 25 percent of labs do not promulgate the guideline recommendation for HPV testing in combination with a Pap test for women over age 30.

“Practice guidelines” based on “evidence-based medicine” are the rational means of improving health care. The two terms are becoming politically charged, with potential to affect the way physicians are reimbursed for their work. Within the broad field of medicine, the algorithms for testing for cervical cancer are relatively straightforward, yet this important study shows that, in practice, even these simple guidelines are not easily applied. Further work is needed to understand the forces that seem to prevent evidence-based guidelines for HPV testing from being adopted.