Cervical Precancer and Cancer Risk by Human Papillomavirus Status and Cytologic Interpretation: Implications for Risk-Based Management

Background: Cervical cancer risks, estimated by using cervical intraepithelial neoplasia grade 3 (CIN3) or more severe diagnoses ({greater than or equal to}CIN3) endpoints, have not been quantified for different combinations of results from currently approved screening methods. Understanding these risks will guide optimal patient management. Methods: Women aged {greater than or equal to}25 years (n=7,823) underwent high-risk human papillomavirus (hrHPV) and liquid-based cytology (LBC) testing. Women with hrHPV-positive results and/or abnormal LBC, plus a random subset of hrHPV and LBC negatives, underwent colposcopy; those without {greater than or equal to}CIN2 at baseline were screened annually by LBC and referred to colposcopy for an abnormal LBC (n=7,392). One- and three-year {greater than or equal to}CIN3 risks with 95% confidence intervals (95%CI) were calculated for paired hrHPV and LBC (hrHPV/LBC) results. Results: One-year {greater than or equal to}CIN3 risks ranged from 81.27% (95%CI:66.02%-90.65%) for HPV16 positive/high-grade to 0.33% (95%CI:0.18%-0.62%) for hrHPV negative/negative for intraepithelial lesion or malignancy (NILM). One-year {greater than or equal to}CIN3 risk for HPV16/NILM (13.95%, 95%CI:10.98%-17.58%) was greater than low-grade squamous intraepithelial lesion (LSIL) (7.90%, 95%CI:5.99%-10.37%) (p=0.002) and similar to hrHPV-positive/LSIL (11.45%, 95%CI:8.61%-15.07%)(p=0.3). Three-year {greater than or equal to}CIN3 risks for HPV16 positive/LSIL and HPV16/ atypical squamous cells of undetermined significance was 24.79% (95%CI:16.44%-35.58%) and 24.36% (95%CI:15.86%-35.50%), respectively, and 0.72% (95%CI:0.45%-1.14%) for hrHPV negative/NILM. Conclusions: hrHPV and LBC results stratify cervical cancer risk by more than two orders of magnitude. HPV16-positive women, regardless of the LBC result, warrant immediate colposcopy. Women with concurrent HPV16 and high-grade LBC might consider treatment without a confirmatory biopsy with informed decision-making with their provider. Impact: These results provide relevant benchmarks for risk-based cervical cancer screening and management.