Supplementing a human papillomavirus (HPV) test with cytology adds little value in the search for cervical cancers and precancers, a group of researchers reported in the Journal of the National Cancer Institute.

Current guidance largely supports inclusion of HPV testing, which is the more sensitive of the two tests for screening for precancers. Guidance documents have varied in their advice on cervical cancer screening, and not all recommend cotesting. The U.S. Preventive Services Task Force in its latest draft recommendation, for example, calls for Pap tests every 3 years or HPV tests every 5 years for women aged 30 to 64 in lieu of simultaneously using both tests.

Cotesting is expensive. However, the emergence of rare HPV-negative, cytology-positive cancers has been driving physicians to recommend both tests. Researchers sought to compare the efficacy of cotesting versus HPV alone at Kaiser Permanente Northern California. This integrated healthcare organization in 2003 had implemented a 3-year cotesting protocol in women 30 years or older, a few months before the U.S. Food and Drug Administration’s approval of HPV and cytology cotesting.

Since then, the Kaiser facility has conducted triennial cotesting in more than 1.2 million women. According to a statement summarizing the study’s findings, “this remains the most extensive experience of HPV testing incorporated into routine screening in the world.”

To evaluate the relative contribution of Pap and HPV tests in detecting cancer cases, researchers analyzed screening histories preceding cervical cancers (n=623) and precancers (n=5,369). They compared the performance of the two tests and found that HPV testing identified more women subsequently diagnosed with cancer and precancer than did cytology testing. In most instances, HPV was much more likely to yield a positive result for cancer.

Cervical cancer arises from a persistent infection of a clone of cervical cells with one of a dozen carcinogenic HPV types, Mark Schiffman, MD, MPH, senior investigator at the National Cancer Institute and the study’s lead author, told CLN Stat. “The molecular test detects the virus before the clone of cells is large enough to be readily detectable as abnormal cytology on an exfoliated cell sampling. In other words, first the HPV test turns positive, then the cytology test is positive if the infected cells reach a size of lesion large enough to be detected when the cervix is scraped for the Pap test,” he explained.

Just a minority of HPV-positive women have abnormal cytology results, Schiffman continued. The study also confirmed that very few cancers are positive only by cytology and not by HPV testing. Only 3.5% of precancer cases and 5.9% of cancer cases were associated with HPV-negative/cytology-positive results. According to the researchers, these cancers were more likely to be distant or regional, meaning they had metastasized or spread to nearby tissues.

“If a tumor is very advanced, it tends to outgrow its blood supply and parts of the tumor die. The necrotic (dead) tissue, if sampled by the cytology, can look like ‘debris’ rather than living cells. The cytology can show this debris, whereas the HPV test might not capture any viral particles,” Schiffman said, in explaining why HPV testing works best as a screening tool to find precancerous lesions.At most, Pap tests lead to early cancer detection in 5 cases per million women annually. For all of these reasons, they concluded that the additional Pap exam had little impact as far as finding cervical cancers in women.

Pap continues to have value as a screening tool, Schiffman noted. “Cytology has been very successful and works.” What the study findings encourage is to increase reliance on HPV testing, which is more sensitive than Pap. He acknowledges that this won’t happen overnight. “Cervical cytology is a major medical activity; the move to HPV will need to happen in such a way that we do not precipitously destroy a proven valuable public health activity.”