Small Round Cell Tumors of Soft Tissue and Skeleton in Children and Youth: A Narrative and TruSight-Based Illustrative Review of Diagnostic Cases

Small round cell tumors (SRCT) affecting soft tissue and bone are a distinct category of malignancies. These lesions frequently exhibit similar clinical and radiologic features, may harbor overlapping histologic and immunophenotypic features, and generally have distinct prognostic outcomes. Therefore, in some instances, the diagnosis and accurate subclassification require molecular confirmation. We aimed to provide a comprehensive overview of the morphologic, immunohistochemical, and molecular features of SRCTs of soft tissue and bone in pediatric and young adult patients, with an emphasis on both commonly encountered tumors and rare, recently described entities, accompanied by illustrative material from our TruSight platform. The literature data were mined from the PubMed/Medline, Scopus, and Cochrane databases covering the period from January 1, 2014, to December 31, 2024, and the authors' personal experience with diagnostic cases at their institutions. We reviewed tumors that include sarcoma with EWSR1-non-ETS fusion, CIC-rearranged sarcoma, BCOR-rearranged sarcoma, Ewing sarcoma, alveolar rhabdomyosarcoma, desmoplastic small round cell tumor, high-grade/round cell myxoid liposarcoma, poorly differentiated synovial sarcoma, small-cell type osteosarcoma, mesenchymal chondrosarcoma, and extraskeletal myxoid chondrosarcoma. Immunohistochemistry plays a crucial role in interpreting a specific diagnosis or narrowing the differential diagnosis of SRCTs. Molecular genetic investigations are essential, particularly in cases exhibiting atypical or overlapping histologic and immunohistological features.