Cumulative risk of cervical intraepithelial neoplasia for women with normal cytology but positive for human papillomavirus: Systematic review and meta‐analysis

Abstract Most women positive for human papillomavirus (HPV) are cytology normal. The optimal screen‐management of these women is unclear given their risk of developing precancer. We performed a systematic review and meta‐analysis of progression rates to precancer and cancer for HPV‐positive, cytology normal women. We searched MEDLINE, EMBASE and Scopus for prospective studies measuring the cumulative incidence of precancer and cervical cancer in HPV‐positive, cytology/histology normal women. Record screening was performed independently by two reviewers. We modeled the cumulative incidence over time using a multilevel random‐effects meta‐regression model. We used the model to predict HPV type‐specific risks of precancer and cancer over follow‐up. Data from 162 unique records were used in our analysis. The average incidence rate of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) in high‐risk HPV positive but cytology/histology normal women was 1.0 per 100 women‐years (95% CI: 1.0‐1.1). This corresponds to an average cumulative risk at 1, 3 and 5 years of 2.1% (95% prediction interval 0.0‐9.5), 4.3% (95% prediction interval 0.0‐11.5) and 6.4% (95% prediction interval 0.0‐13.5). HPV type was a strong predictor of the risk of oncogenic progression. There was substantial heterogeneity in the background precancer risk across studies ( P ‐value < .0001). Our HPV type‐specific progression risk estimates can help inform risk‐based cervical cancer screening guidelines for HPV‐positive women. However, precancer and cervical cancer risks are highly variable and may not be generalizable between populations.