Understanding the Role of HPV Testing

Cervical cancer is clearly the first human cancer in which a single necessary cause has been identified. Indeed, HPV16 accounts for approximately 50% of all invasive cervical cancers and more than 25% of cancer precursors. The National Cancer Institute (NCI)-sponsored Atypical Squamous Cells of Undetermined Significance-Low-Grade Squamous Intraepithelial Lesion (ASCUS-LSIL) Triage Study (ALTS) has firmly established adjunctive testing for high-risk HPV as the standard of care for the triage of patients with mildly abnormal cervical cytology. High-risk HPV testing is directly correlated with the degree of cytologic interpretive certainty. What this means is that high-risk HPV testing can be used to control the quality of cytologic interpretations for an individual, group or laboratory. More importantly, the ALTS trial clearly demonstrated that HPV testing is the most effective method for the triage of patients who have an equivocal cytologic interpretation.

If one looks at the causes for cervical cancer screening failure in the United States, it is clear that more than 50% of the patients in whom cervical cancer develops have never been screened, and another 10% to 20% of those patients have not been screened in at least 5 years. However, at least 30% of the patients in whom cervical cancer develops have had a "false negative" Pap smear and approximately half of those false-negative results are due to sampling error while the remaining 50% actually are screening or interpretive errors. While society recognizes the success of the "imperfect" Pap smear in reducing the incidence of cervical cancer, the primacy of the Pap smear has been threatened because of the burden on the pathology community inflicted by the problem of false-negative results. Any single cervical cancer screening event may only be 50% sensitive for prevalent disease. Thus, it is only through the repetitive application of independent screening events, at relatively short intervals, that the Pap smear "system" is really efficacious. While it is possible for women who routinely have perfect annual screening attendance to have very low rates of cervical cancer, even with perfect attendance, the system is imperfect and false-negative results will continue to occur.

The primary data supporting the utility of HPV testing in conjunction with cytology for screening consist of several studies that evaluated more than 40,000 women in a variety of clinical settings. All studies demonstrated that HPV testing was more sensitive than cervical cytology regardless of the clinical setting. The combination of HPV plus cytology achieved sensitivities of over 95% in 6 of 8 studies. At such high levels of sensitivity, many have been concerned that too many patients would be referred to colposcopy, and those referred would fail to have identifiable lesions. The inherent advantage of cytology is that cytologic abnormality tends to have very high specificity, particularly when interpretations are adjudicated. Surprisingly, HPV testing achieved specificities that were comparable to or only slightly less than those with cytology alone. This undoubtedly reflects the problem of interpretive variability inherent in morphologic assessment.

The combined test had a specificity of more than 90% in 6 of the 8 studies presented to the US Food and Drug Administration (FDA).These data led to widespread discussion and eventual publication by both The American Cancer Society and The American College of Obstetrics and Gynecology of revised practice guidelines that included the option of HPV testing in conjunction with cytology for the primary screening of patients. Important in the recommendations is the recognition that this form of high-sensitivity screening in patients who have a relatively low prevalence of disease allows for an extension of the interval before repeat testing is required. Specifically, patients who have both a normal Pap smear as well as a negative high-risk HPV test do not need a repeat screening examination for at least 3 years.

So why has HPV testing for primary screening made such a small impact on clinical practice? Clearly, clinicians are concerned about the need for counseling patients, especially regarding the significance of HPV positivity in the setting of a negative cytology. Perhaps a bigger concern is the change in practice surrounding interval extension. However, these concerns have to be balanced by societal and epidemiologic perspectives. The best strategy for preventing cervical cancer is to use the most accurate test at the longest possible interval. The data presented above suggest that the combination of HPV testing and cytology meets this description. Indeed, the recently published ACOG practice bulletin 61 states that HPV testing is more sensitive than cervical cytology in detecting CIN2/3, and women with negative concurrent tests can be reassured that their risk of unidentified CIN2/3 or cervical cancer is approximately 1 in 1000.

In summary, HPV testing has been shown to be more sensitive than cytology, is more reproducible than cytology and, because of the high sensitivity of combined testing, the consequent high negative predictive value in a low prevalence population provides for less frequent screening, which ultimately may increase the compliance of patients with screening recommendations.