Adding Human Papillomavirus Testing to Cytology for Primary Cervical Cancer Screening: Shooting First and Asking Questions Later

Annual cervical cancer screening is a well-established and highly effective routine practice in the United States (1), but it is also inefficient and expensive (2). A more streamlined approach would be to stratify women by risk and adjust the frequency of screening accordingly: Screen low-risk women infrequently, thereby minimizing the harms of screening, while focusing attention and resources on those at higher risk. Because oncogenic types of human papillomavirus (HPV) cause cervical neoplasia, HPV testing is a prime candidate to risk-stratify women for screening. Several different HPV tests are used worldwide, but in the United States, the only commercially available test approved by the U.S. Food and Drug Administration is Hybrid Capture 2 (Digene, Gaithersburg, Maryland), an assay that detects DNA from 1 or more of 13 oncogenic HPV types. To perform this test, a cervical specimen is obtained at the time of speculum examination and is either placed in a transport medium or, if liquid-based cytology is used, a vial of liquid preservative. In the laboratory, the specimen is treated with a base solution to release oncogenic HPV DNA, if present. Specific RNA probes are added that combine with DNA to create RNADNA hybrids; these are captured onto a solid phase coated with antibodies specific to the RNADNA hybrid. Captured hybrids are detected with multiple antibodies conjugated with alkaline phosphatase; the resulting signal is amplified and detected by chemiluminescence. In 2003, the U.S. Preventive Services Task Force considered the evidence regarding routine HPV testing to be insufficient to recommend for or against its use as a primary screening test for cervical cancer (3). Both the American Cancer Society (4) and the American College of Obstetricians and Gynecologists (5), however, defined an alternative to cytology screening alone in women older than 30 years of age that incorporates HPV DNA testing: Perform both cytology and HPV DNA testing, and if both tests are negative, do not screen for at least 3 years. Age 30 years was chosen as a cut-point because rates of HPV DNA positivity were thought to be too high in younger women to make such a strategy viable. According to American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines, women should have colposcopy if they have atypical squamous cells of undetermined significance (ASC-US) and a positive HPV DNA test result or if they have higher-grade cytologic abnormalities (6). Compelling evidence about the sensitivity of HPV DNA testing supported this recommendation, but what about women who are HPV DNApositive but have normal cytology? This question is the subject of this editorial. The ASCCP guidelines (6) recommend repeating both cytology and HPV DNA testing 1 year later and, if both yield normal results, resuming routine screening in 3 years; if either result is positive, colposcopy should be performed. Before adopting this strategy, clinicians and policymakersand patientsmay wonder what proportion of women older than 30 years of age who have been screened with HPV DNA testing and cytology will be expected to fall into this new category of uncertainty. Studies in Europe and Canada using Hybrid Capture 2 (7, 8) suggest that this proportion is 5% to 6%, but we have little information from U.S. cohorts. In this issue, Datta and colleagues (9) provide information from a large, U.S.-based cohort derived from various geographical areas. Using Hybrid Capture 2, the prevalence of HPV DNA positivity among women younger than 30 years of age who had normal cytology was 22%. In women older than 30 years of age, the prevalence of HPV DNA positivity was surprisingly high at 9%, similar to the prevalence of abnormal cytology. The authors concluded that on the basis of ASCCP guidelines, many women would need follow-up if HPV testing were added to cytology for primary screening. But what is the evidence to support the current recommendation for this level of heightened surveillance and intervention in Hybrid Capture 2positive women with normal cytology? Although persistence of the same oncogenic HPV type is associated with subsequent development of high-grade precancerous lesions (10), the implications of 2 positive results on Hybrid Capture 2 tests performed 1 year apart are less clear. Continued Hybrid Capture 2 positivity may be explained by persistence of the same oncogenic viral type, but it could also be due to detection of a different oncogenic HPV type at the later time point, detection of nononcogenic HPV types caused by antibody cross-reactivity (11, 12), or false-positive results (up to 17% of women with positive Hybrid Capture 2 tests have no detectable oncogenic HPV types by polymerase chain reaction testing) (11). The likelihood of continued Hybrid Capture 2 positivity at 1 year in Hybrid Capture 2positive women with normal cytologyand the reasons for itare unknown; this constitutes an important knowledge gap when we counsel patients. Because the prevalence of high-grade lesions among women with normal cytology and continued Hybrid Capture 2 positivity (and those with ASC-US and a negative second Hybrid Capture 2 test) is also unknown, it is difficult to judge whether colposcopy is justified. The cross-sectional design of Datta and colleagues' study does not shed light on these issues; we need data from a prospectively defined cohort followed over time. Do other proposed advantages argue for adding HPV DNA testing to cytology despite these uncertainties? As stated, a major goal of concurrent HPV DNA testing is to identify women who are at low enough risk to safely extend screening intervals to every 3 years. However, many women in the United States can safely extend screening intervals now without HPV DNA testing. For several years, both American Cancer Society and American College of Obstetricians and Gynecologists guidelines have recommended doing cytology screening every 1 to 2 years for women between 21 and 30 years of age, followed by screening every 2 to 3 years in women with at least 3 consecutive normal cytology results. A great number of women in the United States will have met these criteria by age 30 years. Their excess risk for cervical cancer if they extend the screening interval to 3 years, compared with annual screening during the same 3-year interval, is estimated at 3 to 5 per 100000 women, similar to the risk for breast cancer in men (13, 14). Given this extremely low risk, it is difficult to imagine why a clinician or patient would want an additional negative testbe it a fourth annual Pap test or an HPV DNA testbefore extending the screening interval to 3 years. Of note, the U.S. Preventive Services Task Force endorses screening every 1 to 3 years; triennial screening can therefore be recommended for sexually active women regardless of previous cytology testing or negative HPV DNA testing (3). For HPV DNA testing with cytology to offer unique benefits, extending the screening interval well beyond 3 years must be seriously considered but may be met with strong resistance. What more information is needed? We need validation of the proposed management protocols using prospective data in screened populations, or we need new protocols altogether. Several ongoing, large, randomized trials using Hybrid Capture 2 and other HPV testing methods are in progress, and their findings will be valuable (8, 15, 16). Many novel and intriguing strategies are possible, including performing HPV testing first and then cytology if HPV testing is positive (17). Some may feel uncomfortable using Hybrid Capture 2 testing as a standalone test because it lacks a laboratory control for specimen adequacy, an unusual feature for a cancer screening test (the laboratory will report tests as negative even if they contain no human material). Although HPV DNA testing is not recommended for primary screening for women younger than age 30 years, we must also determine the age above which to discourage HPV DNA testing; several studies report high rates of Hybrid Capture 2 positivity in women older than age 50 years (18), and the benefits of cervical cancer screening diminish with advancing age (2). The age range within which current HPV tests are appropriate may ultimately be quite narrow. Once data from trials are known, we would need decision analyses and cost-effectiveness studies to explore various screening strategies (including screening intervals and ages to begin and end screening) to determine the strategies with the best trade-off among benefits, harms, and costs. Enthusiasm for new screening technologies often leads clinicians to shoot first and ask questions later; however, we do a disservice to our patients with such a cavalier approach. For example, previous ASCCP guidelines recommended HPV DNA testing as the preferred management of ASC-US among all women screened with liquid-based cytology (19). Testing for HPV DNA is now actively discouraged in those age 20 years or younger with ASC-US, regardless of the cytology method, because such a strategy leads to high numbers of needless colposcopies (20); in Datta and colleagues' study, 62% of participants age 14 to 20 years who had ASC-US also had a positive Hybrid Capture 2 test. Adverse consequences of poorly conceived guidelines are easily forgotten, but they should serve as cautionary tales. Recognizing that dual testing is not recommended for women younger than age 30 years, what should clinicians do about dual testing in women older than age 30 years? Clinicians who choose this strategy should not perform Hybrid Capture 2 testing without a patient's knowledge and permission and, if doing primary screening, only after discussing the major goal of dual testing (extending screening intervals) and the expected added reassurance of adding HPV testing beyond those achievable with cytology alone. They must be prepared to discuss the implications of a positive HPV test result and understand that such info