Tissue Factor Pathway Inhibitor‐2 ( <scp>TFPI2</scp> ) as a Biomarker in Gynecologic Malignancies: A Narrative Review Focusing on Clear Cell Carcinoma

Tissue factor pathway inhibitor-2 (TFPI2) is a Kunitz-type serine protease inhibitor and a highly specific biomarker for gynecologic clear cell carcinomas, particularly ovarian clear cell carcinoma (CCC). This review summarizes current evidence on its roles in gynecologic malignancies, focusing on clear cell histology. A structured PubMed search was performed. English-language original articles and reviews addressing the diagnostic, prognostic, and functional roles of TFPI2 were included. Although TFPI2 is commonly silenced as a tumor suppressor in many cancers, it is consistently overexpressed in Müllerian clear cell carcinomas. Clinically, circulating TFPI2 shows high specificity for ovarian CCC, distinguishing it from other ovarian tumors and benign conditions. Its combination with cancer antigen 125 improves diagnostic sensitivity, including in early-stage disease. TFPI2 is selectively expressed in tumor cells, supporting its role as a histology-specific marker across the ovary, endometrium, and cervix. Functionally, TFPI2 may contribute to CCC biology by suppressing cell adhesion and promoting a floating dissemination phenotype. Elevated circulating TFPI2 is associated with poor outcomes in ovarian and endometrial cancers and may reflect coagulation abnormalities. It is also linked to venous thromboembolism and may improve risk stratification when combined with D-dimer. TFPI2 is a unique biomarker with diagnostic, prognostic, and biological significance, with potential applications in precision diagnostics, monitoring, and thrombosis risk assessment.