Clinicopathologic correlates of Ewing (FET::ETS-rearranged) sarcoma and non-Ewing undifferentiated small round cell sarcomas across skeletal and extraskeletal sites

Background FET::ETS-rearranged Ewing sarcoma (ES) and non-Ewing undifferentiated small round-cell sarcomas (SRCSs) comprise a morphologically overlapping yet molecularly diverse group of aggressive sarcomas. They differ in genotype, anatomic distribution, age profile, and clinical behavior. Clarifying genotype–anatomic correlations—particularly distinctions between ES and non-Ewing SRCSs, as well as between skeletal and extraskeletal presentations within the Ewing group—is essential for accurate diagnosis and treatment planning, especially in morphologically ambiguous cases. Methods Ninety undifferentiated SRCSs of bone and soft tissue diagnosed between 2016 and 2025 at a tertiary cancer center were retrospectively reviewed. Clinical, histopathologic, and molecular data were analyzed using targeted RNA next-generation sequencing (Archer FusionPlex Sarcoma Panel) and break-apart fluorescence in situ hybridization (FISH) for EWSR1 and FUS rearrangements. ES (FET::ETS-rearranged SRCSs) and non-Ewing SRCSs were compared across skeletal and extraskeletal sites using univariate analysis, and survival outcomes were assessed. Results Among 90 cases (47 males, 43 females; median age 18.5 years), 76 (84%) harbored FET::ETS fusions and/or EWSR1/FUS rearrangements on FISH, consistent with the ES family in the appropriate morphologic context. Of 44 fusion-confirmed tumors, EWSR1::FLI1 predominated (39/44; 89%), followed by EWSR1::ERG (4/44; 9%) and FUS::ERG (1/44; 2%). Fourteen tumors (16%) were classified as non-Ewing SRCSs, including CIC::DUX4 (n=5), BCOR -altered (n=1), EWSR1::ATF1 (n=1), EWSR1::CREB1 (n=1), YWHAE::NUTM2B (n=1), and five fusion-negative SRCSs. ESs peaked during adolescence and showed a strong osseous predilection (48/76; 63%), particularly within the axial skeleton ( p < 0.001). Extraskeletal and visceral ESs occurred in relatively older patients. Although ES still represented most extraskeletal tumors (28/40; 70%), non-Ewing SRCSs were significantly more often extraskeletal ( p < 0.001) and demonstrated a broader age distribution, including infantile cases. Skeletal versus extraskeletal presentation had no significant impact on stage, progression, or overall survival. In contrast, metastatic disease at presentation was the strongest adverse prognostic factor ( p = 0.007). Conclusion ES and non-Ewing SRCSs exhibit morphologic overlap but differ in genotype, anatomic distribution, and age pattern. Within the Ewing group, skeletal versus extraskeletal presentation did not influence outcome, despite clear age differences. Integrating molecular diagnostics with site-specific and histopathologic assessment enhances diagnostic accuracy and guides management of these biologically diverse tumors.