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.