HPV test is a better long-term predictor of cervical cell abnormalities than pap smear

Nov 1 2006

The best initial cervical cancer screening tool for younger women is still the traditional Pap smear. However, a large Danish study has found that for older women (age 40 and older), a test for human papillomavirus (HPV) is a much more effective way to screen for potential cancer.

The reason, report researchers in the November 1 issue of Cancer Research, is that HPV infection is both frequent and transient in younger women, and they would often test positive for HPV when no actual risk of cervical cancer existed. But, in older women, HPV infection is rarer and more persistent, putting a woman at substantial risk for the disease before changes in cervical cells, detected by Pap smears, are obvious.

“We have documented that a single HPV test can actually predict older women at risk for cervical cancer better than a single Pap smear can,” said the study’s senior author, Susanne Krüger Kjaer, M.D., professor and head of the Department of Virus, Hormones and Cancer at the Danish Cancer Society.

The researchers specifically found that the absolute risk of developing cervical cancer in an older woman who tests positive for HPV is greater than 20 percent within a 10-year period. They also note that most women who test positive for HPV also test negative on a Pap smear given at the same time.

“Based on these results, we feel that an HPV test would benefit older women, whether or not that test is used in conjunction with Pap smears, or used by itself as an initial screen,” Kjaer said.

Pap smears (also known as cervical cytology) look for abnormalities in the appearance of cells lining the cervix and have long been the primary screening tool for cervical cancer. The test has led to significant declines in both the incidence and morbidity of the disease in the U.S. Some strains of HPV (which includes more than 100 different viruses) are now recognized as the major cause of cervical cancer. The federal Food and Drug Administration (FDA) has approved use of the HC2 High-Risk HPV DNA Test for women who had abnormal Pap test results.

In 2003, the FDA allowed the HC2 test, which checks for 13 high-risk HPVs, to be used for screening in conjunction with the Pap smear in women over the age of 30.

Each of the screening tests has its limitations, Kjaer says. Several studies have shown Pap smears to be only modestly accurate, with a sensitivity (ability to correctly identify lesions) that is lower than generally believed, she said. The HPV test is more sensitive than a Pap smear, but has a relatively lower specificity, meaning that it isn’t as able to detect truly negative cases, Kjaer said.

However, the majority of women who test positive for HPV actually has a concurrent negative Pap smear, Kjaer says, and it has been uncertain how truly at risk they are for developing cervical cancer.

To find out how effective the HPV test was at predicting that risk, Kjaer and her colleagues used two Danish population-based prospective cohorts ­− one included 8,656 women aged 22-32, and the other enrolled 1,578 women who were 40-50 years old. At enrollment in the study these women had cytology; cervical samples for HPV testing were also collected. These samples were stored and later tested for HPV using the HC2 test. The women were followed with a number of Pap smears over the course of 10-plus years.

The researchers found that among women 40-50 years old who had a positive HPV test and a negative Pap smear, nearly 25 percent developed cervical abnormalities within 5 years; after 10 years, more than 35 percent experienced an abnormal Pap test. Younger women who were HPV positive and Pap smear negative also had a high absolute risk of subsequent cervical abnormalities − 18 percent after 5 years and 24 percent after 10 years.

Even more important, says Kjaer, was the finding that as many as 21 percent of the older HPV positive women with initially normal cytology subsequently developed histologically confirmed severe changes on the cervix (CIN3 or worse). Conversely, the risk of developing such abnormalities was very low (1.7 percent) among women who tested negative on both screening exams.

“This shows that the HPV test was better than a Pap smear at predicting worrisome changes in the cervix over time,” Kjaer says.

But the researchers also found two other important factors. One is that HPV infection was much more common in the younger women (17 percent) compared to the older women (3.6 percent) and that in the older women, a much higher percentage of the abnormalities were regarded as severe.

“This reflects the phenomenon that HPV infection among younger women is mostly transient, and therefore causes mostly mild changes, whereas in older women a higher proportion of the infections are persistent, and more likely to induce more severe cellular change,” she said.

Given the findings, coupled with the frequency of infection, Kjaer said clinicians may find it beneficial to screen younger women with a Pap smear and follow up on positive results at a given level with an HPV test, and offer HPV testing to older women as a stand-alone screening test, or in conjunction with a Pap smear.

“Since even a single positive HPV test is substantially predictive of future cellular changes in the cervix, it can help stratify women in different risk categories,” she said.