Human Papillomavirus and Papanicolaou Tests to Screen for Cervical Cancer

Abstract

Screening for cervical cancer by testing for human papillomavirus (HPV), the major cause of the disease, reportedly increases the sensitivity of detecting high-grade (grade 2 or 3) cervical intraepithelial neoplasia (CIN). It is not clear, however, whether this reflects protection against future high-grade CIN or cervical cancer, or whether it represents over-diagnosis. This Swedish population-based screening program randomly assigned 12,527 women ranging in age from 32 to 38 years to have either an HPV test plus a Pap test (n = 6257, the intervention group) or a Pap test alone (n = 6270, the control group). Those having a positive HPV test and a normal Pap test were offered a second HPV test at least 1 year later, and those persistently infected with the same high-risk type of HPV were offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were done in randomly selected control women to avoid ascertainment bias. The average follow-up interval was 4.1 years. Initially, 51% more women in the intervention group than in the control group had grade 2 or 3 CIN or cancer. On subsequent screening, the proportion of women in the intervention group who had grade 2/3 lesions or cancer was 42% less, and the proportion with grade 3 lesions or cancer was 47% less than the proportion of control women having such lesions. The increased incidence of grade 2 lesions found at initial screening in the intervention group was not followed by a significant reduction of such lesions at later screening. Women with persistent HPV infection remained at high risk of grade 2 or 3 lesions or cancer after being referred for colposcopy. Five women in the control group and one in the intervention group were found to have invasive squamous-cell carcinoma. Four in each group developed adenocarcinoma in situ or adenocarcinoma. All of these women with advanced changes were HPV-positive at baseline. The improved sensitivity of HPV testing in women in their mid-30s who are screened for cervical cancer is not solely a result of over-diagnosis. It can be ascribed—at least in part—to the earlier diagnosis of cervical lesions that do not regress on follow-up screening.