Tissue Factor Pathway Inhibitor-2 Expression in Uterine Cervical Clear Cell Carcinoma: A Potential Biomarker for Clinical Diagnosis

Cervical clear cell carcinoma (CCCC) is an extremely rare histologic type of uterine cancer. Tissue factor pathway inhibitor-2 (TFPI2) is a serine protease inhibitor that was recently shown to be expressed in ovarian clear cell carcinoma and endometrial clear cell carcinomas using immunohistological analyses. In this exploratory study, we conducted an immunohistochemical investigation to determine whether TFPI2 is expressed in cervical cancers, especially CCCC. Further, we examined the expression of hepatocyte nuclear factor 1 homeobox B (HNF-1β), a useful marker for immunohistological diagnosis of ovarian clear cell carcinoma. As a control group, we included 22 patients with cervical intraepithelial neoplasia grade 3 (CIN 3) and 40 patients with non-CCCC (21 with squamous cell carcinoma and 19 with adenocarcinoma). Immunohistochemical staining was positive for TFPI2 in all 3 CCCC cases (100%), whereas in non-CCCC, we observed only weak TFPI2 staining in 7 squamous cell carcinoma cases (33.3%), absence of staining in adenocarcinoma (0%), and staining in one CIN 3 case (4.5%). The histoscore for TFPI2 in CCCC was 166.7 ± 13.2 (mean ± SD), which was significantly higher than that in non-CCCC (3.3 ± 8.3) or CIN 3 (1.4 ± 6.4) ( P <0.001). Similarly, HNF-1β staining was noted in all 3 CCCC cases and in 63.2% of the adenocarcinomas, whereas it was absent in CCCC and CIN 3. In conclusion, examination of TFPI2 expression, similar to that of HNF-1β, is useful for validating the immunohistological diagnosis of CCCC.