Cervical Cancer Screening in the Molecular Era: Integrating Cytology, Human Papillomavirus Testing, and Biomarkers

Cervical cancer screening has evolved immensely with advances in molecular diagnostics and improved understanding of human papillomavirus (HPV)-mediated carcinogenesis. While conventional cervical cytology has historically played a pivotal role in reductions in cervical cancer incidence and mortality, its limitations have led to the development of liquid-based cytology (LBC) and HPV-based testing. LBC offers improved sample adequacy, better preservation of cellular morphology, and permits the use of residual material for ancillary testing. HPV DNA testing, particularly as a primary screening modality, provides high sensitivity for detecting high-grade cervical intraepithelial neoplasia. In addition, emerging biomarkers such as p16INK4a and Ki-67 dual staining enhance risk stratification and triage of HPV-positive women. Despite the growing adoption of primary HPV screening, cytology remains indispensable for morphologic assessment, detection of HPV-independent lesions, and clinical correlation. An integrated approach combining HPV testing, cytology, and biomarkers represents the most effective strategy for cervical cancer screening. Such a balanced model is essential for optimizing diagnostic accuracy, guiding management, and supporting global efforts toward cervical cancer elimination.