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

Int J Cancer. 2020 Nov 15;147(10):2695-2707. doi: 10.1002/ijc.33035. Epub 2020 May 26.


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.

Keywords: cervical cancer; cervical intraepithelial neoplasia; human papillomavirus; prospective; risk.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Alphapapillomavirus / genetics
  • Alphapapillomavirus / isolation & purification*
  • Cervical Intraepithelial Neoplasia / epidemiology*
  • Cervical Intraepithelial Neoplasia / pathology
  • Cervical Intraepithelial Neoplasia / virology
  • DNA, Viral / genetics
  • Female
  • Humans
  • Neoplasm Grading
  • Observational Studies as Topic
  • Papillomavirus Infections / epidemiology*
  • Prevalence
  • Randomized Controlled Trials as Topic
  • Uterine Cervical Neoplasms / epidemiology*
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology


  • DNA, Viral