The link between human papillomavirus and cervical cancer is well established; HPV is present is almost every single case. The next step in understanding the disease will be to determine how this critical fact fits into screening and diagnosis.
Baseline results from a randomized clinical trial give the first glimpse at an answer for women with an equivocal cervical cytologic diagnosis (see article, p. 293). The studys authors concluded that testing for the presence of HPV in women whose cytologic evaluation finds atypical squamous cells of undetermined significance (ASCUS) can determine if more tests, such as colposcopy, are needed.
"Each year, about 2 million women in the United States receive a Pap test diagnosis of ASCUS," said Diane Solomon, M.D., project officer for the trial and a senior investigator in the Division of Cancer Prevention at the National Cancer Institute. "This study shows that HPV testing can be helpful in determining if further follow-up with colposcopy is warranted."
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The results also show that testing for HPV in women with ASCUS has a negative predictive value of 99.5%, meaning that if an HPV test has a negative result, it is highly unlikely that disease is present.
Overall, 55% of women with ASCUS tested positive for HPV and would be referred to coloscopy using this triage strategy.
Ten to twenty percent of these women will have a high-grade or precursor lesion. However, for the 45% of women who are HPV negative, "the test provides 99.5% reassurance that a significant abnormality is not present, and these women may be spared unnecessary colposcopy and follow-up," Solomon said. "Triage allows us to focus attention on women who are at greater risk of having significant disease versus those who have changes that are likely to go away on their own."
Ultimately, the trial will determine the best management strategies for women whose cytologic evaluations find ASCUS or low-grade squamous intraepithelial lesions (LSIL). There is no consensus on the best way to manage women with abnormal Pap smear results. In the United States, most women with abnormal cytologic results are immediately referred for colposcopy. Other countries, such as Canada and England, have a more conservative approach. Another Pap test is performed 6 months following an abnormal result, and if the second or third analysis is abnormal, then a colposcopy is performed.
Dubbed ALTS (for ASCUS/LSIL Triage Study), the trial randomly assigned about 5,000 women with abnormal cytology to one of three arms: immediate colposcopy, colposcopy only if the cytologic evaluation found high-grade squamous intraepithelial lesions (conservative management), or colposcopy only if the results of an HPV test are positive or missing (HPV triage). Women in all groups had repeat cytology every 6 months.
In the United Kingdom, a demonstration project has begun that will use HPV testing as a way to manage ASCUS. "This is an area where technology provides a chance to streamline and revolutionize a well-accepted screening area, and its an important challenge to figure out how to introduce this into routine practice," said Jack Cuzick, Ph.D., of the Department of Mathematics, Statistics, and Epidemiology at the Imperial Cancer Research Fund, London.
"The ALTS trial has made it very clear that theres a very strong case for using HPV testing in the triage of ASCUS smears," Cuzick added. "The frontiers are evaluating its role as a primary screening test."
Alex Ferenczy, M.D., professor of pathology and of obstetrics and gynecology at McGill University, Montreal, echoed Cuzicks opinion and highlighted the value of HPV testing in women with borderline cytology.
"Most likely, HPV testing will replace cytology in places where cytology is poorly done, or it should be introduced in countries where cytology is not done at all," Ferenczy said.
Solomon stressed that these latest results are only for women with ASCUS. Baseline results from ALTS published last year showed that HPV testing in women with LSIL may not be a useful diagnostic tool. The group found that among women whose Pap test revealed LSIL, about 83% of them tested positive for HPV. These results demonstrated the limited utility of HPV testing for triage because the large majority of women would be referred to colposcopy based on a positive HPV test.
The trial finished accruing patients in December 1998. The last routine exit visits with the patients were finished in mid-January, so data analysis will begin soon. Final results are expected in about 1 year. The ALTS group will also analyze the cost-effectiveness of the various strategies.
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