Prognostic biomarkers associated with the progression of cervical premalignant lesions to cancer: A scoping review

Introduction: Cervical cancer is the fourth most common cancer and the fourth leading cause of cancer-related death in women, worldwide. Advances in understanding the molecular biology of premalignant cervical lesions have shown that not all low-grade squamous intraepithelial lesions progress to high-grade squamous intraepithelial lesions and, nor will all of these progress to invasive carcinoma. Prognostic biomarkers make it possible to predict the evolution of high-grade squamous intraepithelial lesions and to identify patients at risk of progression to cancer. Biomarkers related to cell proliferation, DNA methylation, and immune regulation have been proposed, although the evidence is extensive and heterogeneous.We conducted a scoping review to search possible promising biomarkers for risk stratification of high-grade squamous intraepithelial lesions progression. Methods: We followed the methodological framework proposed by Arksey and O'Malley and the guidelines established by PRISMA-ScR. A systematic literature search was conducted in Web of Science, PubMed, and Embase using terms such as “high-grade squamous intraepithelial lesions,” “uterine cervical neoplasms,” “biomarkers,” and “disease progression,” from the inception of each database through May 30, 2025. Results: A total of 11,795 articles were identified; after removing 4,447 duplicates with Rayyan®, 7,348 records remained for title and abstract screening. Of these, 619 were assessed in full text and 34 were included in the qualitative synthesis. In high-grade squamous intraepithelial lesions, p16, Ki-67, and detection of E6/E7 were associated with a higher risk of progression, whereas FAM19A4/miR124-2 methylation was associated with regression. Overexpression of markers such as RFC4, RIPK4, ATAD2, EZH2, IMP3, ADAR1, AEG-1, TK1, PAK1, aPKCι/λ, tenascin-C, HABP1, CFTR, CPE, and the Np63/TAp63 ratio was linked to greater aggressiveness, lymph node metastasis, and poorer survival. Conclusions: The most promising biomarkers for risk stratification of high-grade squamous intraepithelial lesions progression are p16, Ki-67, FAM19A4/miR124-2 methylation, and E6/E7 mRNA. Their combined use could optimize the identification of patients who require active management and reduce overtreatment in cases with a high probability of regression. Standardization of methods and cut-off values is required for their clinical validation.