P16 and CD44 as Biomarkers for Predicting the Progression of Immature Polypoid Squamous Metaplasia of the Cervix

Cervical intraepithelial neoplasia (CIN) is a well-established precursor of cervical cancer, while immature polypoid squamous metaplasia (IPM) has been hypothesized as a possible early lesion in cervical carcinogenesis. However, the mechanisms underlying IPM progression to CIN remain unclear. Therefore, identifying reliable biomarkers to predict progression is crucial. This study evaluates the immunohistochemical expression of P16, CD44, estrogen receptor (ER), and progesterone receptor (PR) in CIN and IPM, focusing on their prognostic significance in IPM-to-CIN progression. A total of 227 cervical tissue samples were analyzed, including CIN1 (N=30), CIN2 (N=30), CIN3 (N=32), IPM (N=60), mature squamous metaplasia (N=45), and reactive ectocervix - control (N=30). P16, CD44, ER, and PR expression were assessed immunohistochemically. Additionally, clinical HPV (human papillomavirus) status was determined via PCR, and marker expression was correlated with lesion grade using a standardized study algorithm. A subgroup of 40 IPM cases that progressed to CIN was analyzed to identify possible markers predictive of progression. Our results demonstrate that higher P16 and CD44 expression levels are significantly associated with higher-grade CIN lesions (p < 0.001). P16 and CD44 expression also strongly predicted IPM progression: P16 showed a 100% positive predictive value (PPV) for progression to CIN2 or CIN3, meaning all IPM cases with moderate or strong P16 expression advanced to high-grade CIN. CD44 had a 90% PPV for CIN progression, suggesting a strong correlation with aggressive epithelial transformation. Although ER and PR expressions were statistically significant (p < 0.05), they were not predictive markers of CIN progression. These findings highlight P16 and CD44 as possible biomarkers for identifying high-risk IPM lesions and assessing the likelihood of progression to CIN2/3.