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

<b>Background:</b> 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). <b>Methods:</b> Between 2016 and 2025, 90 tumors diagnosed as ES or Ewing-like SRCSs underwent targeted RNA sequencing and/or <i>EWSR1</i> 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. <b>Results:</b> Canonical ES accounted for 84% (76/90) of SRCSs, dominated by <i>EWSR1::FLI1</i> (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 (<i>p</i> = 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 (<i>p</i> = 0.003). Classic histology predominated; atypical patterns were more common in extraskeletal tumors but lacked age specificity. Ewing-like SRCSs (<i>n</i> = 14), with heterogeneous or absent fusions, displayed a broader age distribution-including infants and older adults-and a marked extraskeletal predominance (86%, <i>p</i> = 0.001). Metastatic presentation strongly predicted inferior survival (<i>p</i> = 0.025). Treatment was multimodal, with neoadjuvant chemotherapy more frequent in children (90%, <i>p</i> = 0.029). <b>Conclusions:</b> 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.