Genitourinary mesenchymal neoplasms with tumor-defining genetic alterations: A clinicopathologic and molecular...

Genitourinary mesenchymal neoplasms (GMNs) encompass diverse tumors with limited research on clinicopathologic and genetic characteristics across different organs and age groups. We investigated 71 GMNs with tumor-defining genetic alterations (GMN-TDGA), categorizing tumors into spindle, round, or epithelioid based on predominant patterns. Pediatric GMN-TDGAs primarily involved the kidney, with six congenital mesoblastic nephromas showing spindly histology, including three cellular variants with ETV6::NTRK3 fusion, two classical variants with EGFR exon 18-25 duplications, and one novel TFG::NTRK3-positive case. Four renal clear cell sarcomas exhibited spindly and round cell patterns, harboring BCOR exon 15 duplications (n = 3) or YWHAE rearrangement (n = 1). Two renal EWSR1::FLI1-positive Ewing sarcomas (EWS) and one vesical ALK-rearranged inflammatory myofibroblastic tumor (IMT) occurred in children. In adults, recurrent histotypes included vesical IMTs (n = 15: 14 ALK-rearranged/positive, 1 RET-rearranged), renal synovial sarcomas (SS, n = 13: 7 poorly differentiated, 5 monophasic, 1 biphasic), renal EWS (n = 4, including one unreported EWSR1::ERG-positive atypical variant), renal sclerosing epithelioid fibrosarcomas (SEF, n = 3, all with EWSR1::CREB3L1), renal and vesical TFE3-rearranged PEComas (n = 3, 1 malignant), renal and preputial CIC-rearranged sarcomas (CICRS, n = 3), and multi-organ NAB2::STAT6-positive solitary fibrous tumors (SFTs, n = 10). Event-free survival varied significantly across adult GMN-TDGAs (P < 0.001), with CICRS (100 %), SS (61.5 %), and EWS (50 %) showing higher event rates compared to SEF (33.3 %), PEComa (33.3 %), SFT (20 %), and IMT (0 %). Ultra-rare GMN-TDGAs included a PTCH1::GLI1-positive renal epithelioid mesenchymal neoplasm, a BRAF-deleted renal spindle cell tumor, and a MYOD1-mutated prostatic spindle cell rhabdomyosarcoma. Conclusively, molecular profiling highlights the histologic and genetic diversity of GMNs, supporting challenging diagnoses and informing personalized therapies.