PRAME Immunohistochemical Expression as a Diagnostic Tool to Distinguish Between Endocervical and Endometrial Adenocarcinomas

Preferentially expressed antigen of melanoma (PRAME) is a cancer antigen with limited expression in normal tissues and has emerged as a diagnostic and immunotherapeutic target for certain types of cancer. While originally utilized in the evaluation of melanocytic neoplasms, PRAME immunohistochemistry (IHC) has since shown diagnostic utility in a wide range of epithelial and mesenchymal tumors. In gynecologic pathology, PRAME expression has been reported in endometrial and tubo-ovarian carcinomas, with more limited expression in cervical tumors. Data from The Cancer Genome Atlas (TCGA) has shown increased PRAME mRNA expression in gynecologic malignancies, with the highest frequency observed in uterine corpus endometrial carcinoma (UCEC), uterine carcinosarcoma (UCS), and ovarian serous cystadenocarcinoma (OV), and lower levels in cervical tumors. Based on these preliminary data, we evaluated PRAME nuclear expression by IHC in endocervical, endometrial, and tubo-ovarian precursor lesions and carcinomas. We assessed PRAME mRNA expression across 33 TCGA tumor types using the Broad GDAC and TIMER2.0 databases. Expression levels in UCEC, UCS, OV, and cervical and endocervical cancers (CESC) were evaluated using predefined specificity filters. PRAME IHC was performed on 158 gynecologic lesions, including 90 endometrial lesions [84 carcinomas and 6 endometrial intraepithelial neoplasia (EIN)], 34 endocervical adenocarcinomas, and 34 tubo-ovarian carcinomas. PRAME positivity was defined as moderate to strong nuclear staining in >25% of tumor cells. In-depth mRNA analysis from TCGA revealed significantly higher PRAME expression in UCEC, UCS, and OV compared with cervical and other solid tumors (P<0.001). By IHC, PRAME was positive in all endometrial lesions (90/90; 100%) and most tubo-ovarian carcinomas (28/34; 82%), while negative in 94% (32/34) of endocervical adenocarcinomas (P<0.001). PRAME was mostly negative in squamous lesions and benign cervical tissue, but strongly and diffusely positive in benign endometrium. Sensitivity and specificity for distinguishing endometrial versus endocervical adenocarcinoma were 100% and 94%, respectively. In conclusion, PRAME demonstrates strong concordance between protein and mRNA expression in endometrial and tubo-ovarian carcinomas, showing minimal expression in endocervical adenocarcinomas. PRAME nuclear expression is highly sensitive and specific for carcinomas of endometrial and tubo-ovarian origin, with minimal expression in endocervical adenocarcinomas and ovarian mucinous carcinomas. PRAME IHC may be an adjunct tool to determine the site of origin in gynecologic carcinomas of uncertain primary.