Translational Insights into Cervical Cancer Screening: The Role of p16INK4a and Ki-67 in Early Detection

Despite the global coverage of the early detection programs, cervical cancer is still one of the most common causes of death among women worldwide. The integration of Pap test in the healthcare systems worldwide has led to major advances in the diagnosis of premalignant changes in the cervix, although there are limitations regarding the sensitivity of the test. Due to the somewhat lower sensitivity and specificity of the Pap test, the Human Papillomavirus (HPV) (test has been adopted as the first-tier screening method. The further evaluation of the findings is followed by the various complementary techniques and methods to diagnose patients or quantify the risk of developing high-grade cervical intraepithelial lesions. These techniques are increasingly being investigated to provide specific and reliable final diagnosis and instruct the further treatment. This review summarizes the biological basis of p16 and Ki-67 expression, their correlation, and their diagnostic role in the triage of HPV-positive women. The analysis includes results from major clinical trials and meta-analyses, which demonstrate that dual immunostaining of p16/Ki-67 provides higher sensitivity for detecting CIN2+/CIN3+ compared to cytology alone, with an acceptable trade-off in specificity. In conclusion, dual staining represents a reliable complementary tool for the evaluation of abnormal cytological findings, improving early detection of cervical cancer and guiding the appropriate management and treatment of patients.