Inflammatory and Nested Testicular Sex Cord Tumor: Clinicopathologic and Molecular Features.

Inflammatory and nested testicular sex cord tumor (INTSCT) is a recently recognized malignant testicular neoplasm characterized by distinctive morphologic, immunophenotypic, and molecular features, including frequent EWSR1::ATF1 gene fusions. Although prior series have established INTSCT as a distinct entity with aggressive behavior, its full clinicopathologic and molecular spectrum remains incompletely defined. Thirteen previously unreported INTSCTs from multiple institutions were analyzed. Clinicopathologic features were reviewed, including clinical presentation, outcome, histologic findings, and immunophenotype. Molecular characterization was performed using RNA sequencing and/or fluorescence in situ hybridization for EWSR1 and ATF1 rearrangements. Patients' ages ranged from 22 to 71 years (median, 37 years). All patients presented with testicular masses. Among 8 patients with adequate follow-up, 7 developed metastases to the retroperitoneal lymph nodes and 2 to the lungs. Histologically, tumors consistently exhibited nested architecture, intratumoral and/or peritumoral inflammation, and thick collagenous stroma, with frequent cellular discohesion and vacuolated cytoplasm; 1 case showed a Leydig cell-like phenotype. Immunohistochemistry demonstrated high rates of inhibin-α, CD30, keratin, EMA, and SF1 expression, with the absence of germ cell markers. Molecular studies revealed EWSR1::ATF1 fusion or EWSR1 rearrangement in 12 of 13 tumors. This multi-institutional series corroborates and expands prior observations, confirming INTSCT as a distinctive, aggressive malignant sex cord-stromal tumor with recurrent EWSR1::ATF1 fusion. Awareness of its morphologic spectrum, including features mimicking Leydig cell tumor, is essential to avoid misdiagnosis and ensure appropriate clinical management.