A global clinicopathologic and molecular portrait of spindle cell/sclerosing rhabdomyosarcoma with emphasis on retroperitoneal cases.

Introduction: Spindle cell and sclerosing rhabdomyosarcoma (Sc/SRMS) are rare histologic subtypes of rhabdomyosarcoma, increasingly recognized for their distinct molecular profiles and aggressive clinical behavior. Retroperitoneal involvement is exceptionally uncommon and poorly characterized. To characterize the clinical, pathological, and molecular features of retroperitoneal Sc/SRMS through a combined institutional case series and individual patient data (IPD) meta-analysis. Methods: We retrospectively analyzed 12 adult patients with retroperitoneal Sc/SRMS treated at Peking University International Hospital between 2014 and 2023. Clinical data, imaging, histopathology, immunohistochemistry, and MYOD1 mutation status were evaluated. In parallel, we conducted a systematic review and IPD meta-analysis of 136 publications, yielding 403 unique Sc/SRMS cases. Data were extracted on demographics, tumor characteristics, treatment, molecular alterations, and outcomes. Results: All institutional cases presented with large, high-grade retroperitoneal tumors, frequently invading adjacent organs. MYOD1 mutations were detected in 33.3% of patients, and MyoD1 immunopositivity exceeded myogenin (92% vs. 42%, P<0.05). All patients experienced local recurrence; 83.3% died of disease. Kaplan-Meier analysis revealed a 2-year survival rate of 40%. The IPD meta-analysis identified six additional retroperitoneal cases, none of which reported molecular data. Across the full dataset, MYOD1 and PIK3CA mutations were observed in 95.5% and 100% of tested cases, respectively. Fusion genes such as FUS::TFCP2 and EWSR1::TFCP2 were also prevalent. Overall, 34.7% of patients died of disease and 41.7% developed local recurrence. Discussion: Retroperitoneal Sc/SRMS exhibits a highly aggressive clinical course, marked by extensive local invasion, high recurrence rates, and poor survival. Our institutional series represents the largest molecularly characterized cohort of retroperitoneal cases to date. Integration with IPD meta-analysis supports the importance of MYOD1 mutation and highlights the frequency of PIK3CA co-mutations. However, these frequency estimates are derived from a subset of tested cases and should be interpreted within the context of variable molecular data reporting across studies. These findings highlight the potential value molecularly guided treatment strategies in this rare and lethal disease subtype.