Clinical, Cytological, and Virological Factors Associated with Histological Severity and Recurrence in Vaginal Intraepithelial Neoplasia: A Retrospective Observational Study

Background Vaginal intraepithelial neoplasia (VAIN) is a rare HPV-related condition with heterogeneous behavior and a relevant recurrence risk. Factors associated with severity and recurrence remain incompletely defined.Objective To explore clinical, cytological, virological, and colposcopic features associated with high-grade VAIN and recurrence.Methods This retrospective study included 42 women with histologically confirmed VAIN at a tertiary center between January 2020 and January 2026. All underwent vaginal cytology, high-risk HPV (HR-HPV) genotyping, colposcopy, and biopsy. Histology was classified as VAIN1 or VAIN2-3. Recurrence was defined as a histologically confirmed lesion after treatment and documented disease-free assessment. Associations were assessed using bivariate and exact analyses.Results VAIN2-3 was diagnosed in 31 women (73.8%). Among HR-HPV-positive women, HPV16-related infection was more frequent in VAIN2-3 than VAIN1 (65.4% vs 18.2%; OR 8.50, 95% CI 1.27–91.56; p = 0.013). Cytology was associated with histological grade (p = 0.024); all women with HSIL/ASC-H had VAIN2-3, although sensitivity was limited. Over a median follow-up of 24 months, eight women (19.0%) recurred after a median of 11.5 months. HPV16-related infection was more frequent with recurrence (75.0% vs 38.2%; OR 4.85, 95% CI 0.70–54.01; p = 0.112), but the evidence was not definitive. HPV16-only infection showed borderline evidence of association (p = 0.050), while no clear outcome pattern emerged for multiple-genotype infection. No other significant associations with recurrence were observed.Conclusion HPV16-related infection was associated with high-grade histology among HR-HPV-positive women, while its prognostic relevance for recurrence remains uncertain. The limited sensitivity of cytology underscores the value of multimodal assessment. These exploratory signals warrant prospective validation.