Background: Papanicolaou (Pap) smears have a relatively low sensitivity. Therefore, current recommendations require rescreening for cervical cancer every one to three years. DNA testing for high-risk strains of human papillomavirus (HPV) is used in patients who have Pap smear results showing atypical squamous cells of undetermined significance (ASCUS). Mayrand and associates conducted a double-blind, randomized controlled trial to determine if HPV testing is superior to Pap smear in screening for cervical cancer.

The Study: The study included 10,154 women 30 to 69 years of age who had no known cervical disease and who sought screening for cervical cancer at 30 clinics in Canada. All participants had a conventional Pap smear and Hybrid Capture 2 test for HPV, but were randomized to receive one or the other first. Women who had a positive Pap smear result (defined as showing ASCUS, atypical glandular cells, or worse) and those with a positive HPV test were referred for colposcopy. A random sample of women with normal tests was also referred. The end point of the study was the detection of high-grade cervical intraepithelial neoplasia (CIN) grade 2 or higher (i.e., CIN 2, CIN 3, adenocarcinoma in situ, and cervical cancer). These findings were confirmed via loop electrosurgical excision procedure or by biopsy with ablative treatment.

Results: Close to 100 percent of eligible participants received the assigned intervention. More than 90 percent of those who had abnormal results underwent colpos-copy. There were no adverse events in the study. Pap smear had a sensitivity of 55.4 percent and the HPV test had a sensitivity of 94.6 percent. Pap smear had a specificity of 96.8 percent compared with 94.1 percent for the HPV test. The negative predictive value of both tests was higher than 99 percent.

Conclusion: Cervical cancer screening with Pap smear and HPV testing reached 100 percent sensitivity; however, the improvement in sensitivity compared with HPV testing alone is marginal. Performing both tests doubles the number of tests and increases referrals for colposcopy. The authors conclude that, because of the higher sensitivity of HPV testing alone, prolonging screening intervals is appropriate.

editor's note: Increasing the sensitivity of tests to detect cervical dysplasia raises the question about whether the test would simply be finding lesions that would regress if left untreated. In the same issue of The New England Journal of Medicine, a study of 12,527 women 32 to 38 years of age were randomized to receive combined Pap smear and HPV testing or Pap testing alone (control group). Women with a positive HPV test and normal Pap smear were given another HPV test at least one year later; those who tested positive for the same high-risk strain of HPV were offered colposcopy. A similar number of randomly selected women in the control group had a second Pap smear and colposcopy. The participants were followed for a mean of 4.1 years. The group who received HPV tests and Pap smears had about 50 percent more cases of grade 2 or 3 cervical lesions or cancer found at initial screening compared with the control group. On subsequent screening, cases of grade 2 or 3 cervical lesions or cancer were reduced by 42 percent compared with the control group. This suggests that the improved sensitivity of HPV testing is not merely from overdiagnosing lesions, but it is from finding at least some lesions at earlier stages that, if left untreated, would not regress.—c.c.k.