SOX17 and TRPS1 in Müllerian, Breast, and Mesothelial Tumors: Tissue-Based Specificity Profiles and Diagnostic Pitfalls in Malignant Serous Effusions

Background Malignant serous effusions may be the first manifestation of an underlying malignancy, and accurate primary-site attribution is essential. However, distinguishing Müllerian carcinoma, breast carcinoma, and mesothelioma in effusion cytology remains a challenge because of overlapping immunophenotypes. We evaluated SOX17 and TRPS1 in this setting. Materials and Methods A multicenter retrospective cohort including 650 tissue specimens (300 breast carcinomas, 300 Müllerian tumors, and 50 mesothelial lesions) and 150 malignant serous effusion cell blocks was analyzed. SOX17 and TRPS1 expression was assessed by immunohistochemistry and compared with established markers, including PAX8, GATA3, WT1, and calretinin. Sensitivity, specificity, and positive predictive value (PPV) were calculated according to the primary diagnosis. Results In the tissue cohort, SOX17 showed 87% sensitivity and 100% specificity for Müllerian tumors, with no expression in breast carcinomas or mesothelial lesions, including tumors with PAX8/WT1 co-expression. This specificity was retained in cell blocks, yielding a PPV of 100%. TRPS1 showed 98% sensitivity for breast carcinoma and identified 84% of GATA3-negative breast carcinomas. However, TRPS1 expression was also observed in 48% of tubo-ovarian serous carcinomas, limiting its PPV for breast carcinoma in effusions to 55% despite a negative predictive value of 97%. Conclusion SOX17 is a highly specific confirmatory marker for Müllerian origin and may help resolve diagnostic pitfalls related to PAX8-positive mesothelial lesions. TRPS1 is a complementary marker for breast carcinoma, including GATA3-negative tumors, but its stand-alone diagnostic value is limited by cross-reactivity in Müllerian serous carcinomas. These findings support a panel-based approach for accurate primary-site attribution in malignant serous effusions.