Differential Expression of TLE1 in Small Round Cell Tumors: A Proposed Solution for Challenging Differentials Impacting Treatment Strategies

<i>Introduction.</i> Small round cell tumors (SRCTs) represent a heterogeneous group of neoplasms with overlapping histological features but varying origins, prognoses, and treatments. TLE1 is a well-established marker for synovial sarcoma (SS). However, TLE1's diagnostic utility is limited by its expression in a broad range of tumor types, reducing its specificity for SS. This study explores TLE1 expression across SRCTs and proposes an immunohistochemical algorithm to enhance diagnostic accuracy. <i>Methods.</i> This retrospective, single-center observational study, conducted from 2019 to 2024, reviewed pathology records for SRCTs. TLE1 staining was evaluated using the immunoreactive score system, categorized as follows: 0 (negative), 1+ (weak), 2+ (moderate), and 3+ (strong). <i>Results.</i> A total of 301 SRCTs were evaluated with diverse distribution: neuroendocrine neoplasms (21%, n = 63), extraskeletal Ewing sarcoma (15%, n = 45), lymphoblastic lymphoma (11%, n = 34), and poorly differentiated synovial sarcoma (PDSS) (8%, n = 24). TLE1 expression of 3 + was most frequently observed in PDSS (75%, 18/24). Other tumors with TLE1 3 + included extraskeletal Ewing sarcoma, extracutaneous malignant melanoma, neuroendocrine neoplasms, rhabdomyosarcoma, and endometrial stromal sarcoma. TLE1 2 + was noted in lymphoblastic lymphoma and desmoplastic SRCT, while TLE1 1 + was seen in some gastrointestinal stromal tumors. The remaining specimens were negative for TLE1. These findings led to a diagnostic framework for SRCTs based on TLE1 expression patterns. <i>Conclusions.</i> Although TLE1 is a key marker for SS, its expression in other tumors can present diagnostic challenges. Integrating clinical features, histological assessment, and a panel of immunohistochemistry markers is essential for accurate diagnosis and effective management of SRCTs.