From the Guidelines
Ewing sarcoma pathogenesis is driven by a characteristic chromosomal translocation, most commonly t(11;22) (q24;q12), which creates the EWS-FLI1 fusion gene, as detected by cytogenetics or PCR in over 90% of cases 1. The pathogenesis of Ewing sarcoma involves the expression of the MIC2 gene, which distinguishes it immunohistochemically from other pediatric 'blue tumors' 1.
- The cell of origin is thought to be a primitive neural element, with the tumor arising in the bone marrow 1.
- The disease is characterized by a complex interplay between genetic alterations, including the EWS gene translocation, and epigenetic modifications.
- Additional mutations in genes such as STAG2, TP53, and CDKN2A may occur, contributing to disease progression and treatment resistance.
- Microenvironmental factors, including interactions with immune cells and growth factors, support tumor growth and metastasis, which commonly occurs in lungs, bones, and bone marrow.
- Understanding the pathogenesis of Ewing sarcoma has led to targeted therapeutic approaches, focusing on disrupting the EWS-FLI1 fusion protein function and its downstream pathways, although the current standard of care involves a multidisciplinary approach with combination chemotherapy, surgery, and radiotherapy 1.
From the Research
Pathogenesis of Ewing Sarcoma
- Ewing sarcoma is a rare tumor that exhibits unique clinical, genetic, and molecular features, making it an excellent paradigm for understanding tumorigenesis 2
- The (11;22)(q24;q12) chromosomal translocation that encodes the EWS/FLI oncoprotein is present in nearly all cases of Ewing's sarcoma, suggesting that EWS/FLI is the primary mutation that drives the development of this tumor 2
- The pathogenesis of Ewing sarcoma involves the interplay between mutations in oncogenes and tumor suppressors, host susceptibility factors, and cellular context 2
Molecular Pathogenesis
- Recent advances in understanding the molecular pathogenesis of Ewing's sarcoma have highlighted the importance of the EWS/FLI oncoprotein in driving tumor development 2
- The EWS/FLI oncoprotein has been shown to play a crucial role in the regulation of gene expression, cell proliferation, and apoptosis in Ewing sarcoma cells 2
Treatment Outcomes
- Treatment outcomes for adults with Ewing sarcoma have been shown to be improved with the use of multimodality therapy, including chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide (VDC/IE) 3, 4, 5, 6
- The use of interval-compressed VDC/IE chemotherapy has been shown to be feasible and effective in adults with Ewing sarcoma, with improved event-free survival compared to historical controls 4
- The addition of ifosfamide and etoposide to cyclophosphamide, doxorubicin, and vincristine (VDC/IE) has been shown to improve 5-year overall survival in children with localized Ewing sarcoma, and similar outcomes have been reported in adults 3