Shifting High-Risk HPV Genotype Patterns in Histologically Confirmed Cervical HSIL: Temporal Changes and Differential...

High-risk human papillomavirus (HR-HPV) genotypes differ in their oncogenic potential and contribution to cervical precancer and invasive cancer. We investigated temporal changes in HR-HPV genotype patterns in histologically confirmed cervical high-grade squamous intraepithelial lesions (HSIL) and differences between 2022-2025 HSIL and invasive squamous cell carcinoma (SCC) in an opportunistic screening setting in Spain. This retrospective study included 371 patients with HSIL from 2011 to 2016, 411 with HSIL from 2022 to 2025, and 65 with SCC from 2022 to 2025. Among HR-HPV-positive HSIL, HPV16/18 frequency decreased from 65.7% to 50.8% (p = 0.003), accompanied by a lower mean number of detected genotypes. After adjustment for age and cytological diagnosis, the 2022-2025 period was associated with lower odds of HPV16 (OR 0.59) and HPV18 (OR 0.36) detection. Compared with 2022-2025 HSIL, SCC showed higher HPV16/18 frequency (75.0% vs. 50.8%; p = 0.003), fewer multiple infections, and lower representation of other HR-HPV genotypes. Exploratory birth-cohort analysis showed lower HPV16/18 frequency in women born in or after 1994, with higher individual frequencies of HPV52 and HPV58. HR-HPV genotype patterns in histologically confirmed HSIL varied over time and between birth cohorts, while invasive SCC showed greater HPV16/18 representation and lower HPV diversity.