Persistent Low-Grade Squamous Intraepithelial Lesions and the Risk of Overtreatment: Evidence from Long-Term Active Surveillance

Background: Low-grade squamous intraepithelial lesions (LSIL/CIN1) are among the most common abnormalities detected in cervical cancer screening, particularly in the era of primary HPV testing. Despite their low oncogenic potential, persistence of LSIL is still frequently interpreted as a marker of progression risk, often leading to intensified surveillance or excisional treatment and raising concerns about overtreatment. Methods: We conducted a retrospective cohort study including women with persistent LSIL managed through active surveillance in a real-world clinical setting. Time-to-event analyses were performed using Kaplan–Meier estimates to evaluate CIN3-free survival. The association between HPV16 status and progression to CIN3 was assessed using Cox proportional hazards models. The proportional hazards assumption was tested using Schoenfeld residuals, and a prespecified landmark analysis at 24 months was performed to explore potential time-dependent effects. Results: A total of 82 women were included, with a median follow-up of 48 months (range 24–78). Progression to histologically confirmed CIN3 occurred in 7 cases (8.5%). Most CIN3 events (6/7, 85.7%) were diagnosed within the first 24 months of surveillance, followed by a plateau in long-term CIN3-free survival. HPV16-positive women showed a higher incidence of CIN3 compared with non-HPV16 women. In Cox regression analysis, HPV16 positivity showed a higher estimated hazard of CIN3; however, the association did not reach statistical significance and confidence intervals were wide, reflecting the limited number of outcome events. Conclusions: In women with persistent LSIL/managed by active surveillance, progression to CIN3 was uncommon and predominantly occurred early during follow-up. Long-term persistence of LSIL alone did not confer a sustained excess risk of high-grade disease. These findings support a risk-based management approach and suggest that excisional treatment based solely on LSIL persistence may contribute to overtreatment without meaningful oncologic benefit. However, given the limited number of events, the results should be interpreted cautiously and primarily as descriptive evidence.