Genotype–anatomic correlates and survival outcomes in a molecularly validated 90-patient cohort of skeletal and extraskeletal Ewing sarcomas and mimics.

e23501 Background: Ewing sarcoma (ES)—defined by FET::ETS rearrangements—and Ewing-like small round-cell mimics represent a heterogeneous group of aggressive tumors with distinct genotypes and prognostic profiles. Clarifying genotype–anatomic correlations and their relationship to survival outcomes is clinically essential. Methods: Ninety small round-cell sarcomas of bone and soft tissue at a tertiary cancer center (2016–2025) were retrospectively analyzed. All cases underwent molecular confirmation using targeted RNA sequencing (Archer FusionPlex Sarcoma Panel) and/or break-apart FISH for EWSR1 and FUS. Genotypic subsets (Ewing vs Ewing-like) were compared across skeletal and extraskeletal sites. Associations with stage, treatment patterns, and overall survival were evaluated using univariate analysis. Results: Among 90 patients (median age 18.5 years), 76 (84%) harbored classical ES genetics, mainly EWSR1::FLI1 (89%), and 14 (16%) were Ewing-like with alternative (e.g., CIC::DUX4) or no detectable fusions. ES peaked in adolescence and showed a skeletal predilection (63%), particularly axial (p<0.001), whereas Ewing-like tumors spanned a broader age range—including infantile cases—and were significantly enriched at extraskeletal sites (p<0.001). Stage did not differ between ES and Ewing-like tumors or across skeletal and extraskeletal presentations. Most received multimodal therapy; VDC/IE was the predominant regimen. Neoadjuvant chemotherapy was more common in skeletal tumors, while upfront excision predominated in extraskeletal and visceral lesions. Overall survival was comparable across skeletal and extraskeletal tumors and between diagnostic categories; median OS not reached. Metastatic presentation, frequently involving the lungs, remained the dominant adverse prognostic factor (p=0.007). Ewing-like tumors demonstrated higher metastatic rates—particularly to lymph nodes—than ES. Visceral primaries showed a markedly elevated metastatic risk (p=0.004). Conclusions: ES and Ewing-like small round-cell tumors differ markedly in genotype, anatomic distribution, and age profile. Skeletal versus extraskeletal origin does not independently influence survival, underscoring the central prognostic importance of metastatic presentation. Ewing-like sarcomas exhibit more aggressive clinical behavior.