HPV16/18 Genotype and Histologic High-Grade Disease in Women with ASC-H Cytology: A Systematic Review of Genotype-Stratified Outcomes

Background/Objectives: Human papillomavirus (HPV) genotyping may stratify histologic risk among women with atypical squamous cells that cannot exclude high-grade squamous intraepithelial lesion (ASC-H). We evaluated genotype-specific high-grade outcomes. Methods: PubMed and Europe PMC were searched on 1 October 2026 and updated on 7 October 2026. Two reviewers independently screened, extracted, and appraised studies in accordance with PRISMA 2020. Eligible English language studies provided ASC-H-specific histologic outcomes for HPV16/18-defined and comparator groups. Risk of bias was appraised with an adapted QUADAS-2 framework (the protocol-specified Joanna Briggs Institute prevalence checklist is reported in an appendix), and certainty was rated with GRADE. An exploratory restricted meta-analysis compared HPV16/18 with other high-risk HPV (hrHPV) for CIN2+/HSIL+ using random effects and modified Hartung–Knapp confidence intervals. Results: Sixteen studies in 17 reports were included; six contributed 1655 women to the restricted comparison. The pooled risk ratio was 1.19 (95% confidence interval, 0.94–1.49), with substantial heterogeneity (I2 = 64.9%) and a prediction interval of 0.70–2.01. The results varied with study selection and genotype definition. In four studies with at least 30 hrHPV-negative women, high-grade outcomes occurred in 6.8–18.4%, and HPV-negative carcinomas were reported. Leave-one-out, screening context, and verification-restricted analyses did not show a consistent difference (histology in all participants: RR 1.01, 0.63–1.62). Incomplete verification, confounding by age and screening context, heterogeneous assays and populations, and inaccessible reports limited confidence; certainty was very low for both outcomes. Conclusions: A modest relative difference between HPV16/18 and other hrHPV types cannot be excluded, but the pooled evidence does not demonstrate a consistent incremental risk difference. Other hrHPV types and negative hrHPV results do not exclude high-grade disease. These findings are consistent with current guidance for colposcopic evaluation of all ASC-H without genotype-based deferral.