CIN2 in the Era of Risk-Based Management and HPV Vaccination: Epidemiology, Natural History and Guidelines

Background: Cervical intraepithelial neoplasia grade 2 (CIN2) represents a controversial lesion in cervical cancer prevention. Traditionally included in the aggregate CIN2+ endpoint for reasons of diagnostic stability and statistical power, isolated CIN2 has unique biological characteristics: greater interobserver variability, a high probability of spontaneous regression and a lower risk of progression compared to CIN3. Objectives: To critically describe the epidemiology, natural history and management strategies of CIN2, integrating data from clinical and population-based studies and comparing the recommendations of the main international guidelines. Methods: A narrative review was conducted using a search of PubMed and Scopus (1990–January 2025). Prospective and retrospective studies on isolated CIN2, screening and vaccination trials with CIN2+ endpoints, biomarker research, and consensus documents (ASCCP, ESGO, GISCi, Ministry of Health, WHO) were included. Results: Clinical studies have shown a high probability of CIN2 regression (50–70% within two years, >70% in those <25 years), compared to a 10–15% risk of progression, especially in the presence of persistent HPV16. Screening trials and vaccine evaluations with CIN2+ endpoints have documented the efficacy of the HPV test and a dramatic reduction in lesions in vaccinated cohorts, which was also confirmed for isolated CIN2. The most recent guidelines have progressively adopted a risk-based approach, which allows for active surveillance in young women or those seeking to conceive, while the WHO maintains a screen-and-treat model in resource-limited countries. Conclusions: CIN2 is not a lesion to be treated automatically, but rather a paradigmatic model for personalized management. Integrating epidemiological and clinical data, supported by biomarkers, allows for reducing overtreatment without compromising oncological safety.