LEF1 and IL13RA2 in testicular sex cord–stromal tumors: LEF1 as a potential diagnostic marker for Sertoli cell tumors

Testicular sex cord-stromal tumors (TSCSTs) are rare and heterogeneous neoplasms, most commonly represented by Leydig cell tumors (LCTs) and Sertoli cell tumors (SCTs). While SCTs are characterized by activation of the Wnt/β-catenin pathway, immunohistochemical detection of β-catenin is often limited by variable staining patterns and interpretative challenges. Lymphoid enhancer factor 1 (LEF1), a nuclear transcription factor cooperating with β-catenin, may represent a more reliable surrogate marker. In parallel, the expression of the cancer/testis antigen IL13Rα2 in TSCSTs has not been previously investigated. To the aim, we retrospectively analyzed 17 TSCSTs (12 LCTs and 5 SCTs) diagnosed between 2020 and 2025 at four Italian institutions. All cases were reviewed according to current WHO and GUPS/ISUP TESST criteria. Immunohistochemistry for β-catenin, LEF1, and IL13Rα2 was performed, assessing staining pattern and extent. Non-neoplastic testicular tissue and selected mimickers were included as controls. All SCTs showed strong and diffuse nuclear LEF1 expression (5/5, 100%), associated with nuclear and cytoplasmic β-catenin staining. In contrast, there was no significant LEF1 expression in all LCTs, control cases, and non-neoplastic testicular parenchyma. Focal IL13Rα2 expression was observed in a subset of LCTs (4/12, 33.3%), whereas all SCTs were negative. Therefore, in the differential diagnosis between SCT and LCT, our results suggest LEF1 is a highly sensitive and specific immunohistochemical marker and may represent a robust alternative to β-catenin, offering clearer nuclear staining and easier interpretation. The detection of IL13Rα2 in a subset of LCTs is a novel finding and suggests potential biological and therapeutic relevance, warranting further investigation in larger and clinically aggressive cohorts.