Age-Related Clinicopathologic Patterns in Ewing Sarcoma (FET::ETS Family): A Comparative Analysis of Pediatric and...

Background: Ewing sarcoma (ES) is a rare, aggressive small round cell sarcoma (SRCS) that peaks in adolescence. Given its rarity, atypical age or site presentations increase the risk of misclassification. This study examines age-related clinicopathological patterns in molecularly confirmed canonical ES (FET::ETS-fused). Methods: Between 2016 and 2025, 90 tumors diagnosed as ES or Ewing-like SRCSs underwent targeted RNA sequencing and/or EWSR1 break-apart fluorescence in situ hybridization. Patients were stratified into three age groups: 0-18, 19-39, and ≥40 years. Clinical, anatomical, pathological, molecular, and treatment/outcome variables were compared across strata. Results: Canonical ES accounted for 84% (76/90) of SRCSs, dominated by EWSR1::FLI1 (89%). ES comprised 91% of SRCSs in children but declined to 75% in older adults. Tumors arose mainly in bone (63%), with a significant age association (p = 0.016): children and young adults were primarily skeletal (73% and 62%), whereas older adults were predominantly extraskeletal (78%). Renal ES clustered in adults ≥40 years (p = 0.003). Classic histology predominated; atypical patterns were more common in extraskeletal tumors but lacked age specificity. Ewing-like SRCSs (n = 14), with heterogeneous or absent fusions, displayed a broader age distribution-including infants and older adults-and a marked extraskeletal predominance (86%, p = 0.001). Metastatic presentation strongly predicted inferior survival (p = 0.025). Treatment was multimodal, with neoadjuvant chemotherapy more frequent in children (90%, p = 0.029). Conclusions: Age significantly influences anatomic presentation and certain treatment choices in ES, whereas histology and survival remain broadly similar across groups. Age-linked extraskeletal trends reinforce the importance of routine molecular testing, particularly in underreported Middle Eastern populations.