EWSR1::NFATC2 Rearranged Sarcoma : Distinct Clinicopathological Features From a Series of 5 Rare Cases

Area of Science:

• Oncology
• Molecular Pathology
• Skeletal Tumors

Background:

• Ewing sarcoma (ES) is a pediatric and young adult round cell sarcoma defined by EWSR1-ETS gene fusions.
• Undifferentiated round cell sarcomas with EWSR1-non-ETS fusions, including EWSR1::NFATC2, are emerging entities.

Purpose of the Study:

• To characterize the clinicopathologic features of EWSR1::NFATC2 fusion sarcomas.
• To differentiate EWSR1::NFATC2 fusion sarcomas from classic Ewing sarcoma.

Main Methods:

• Case identification and clinical data review.
• Morphologic assessment and immunohistochemical profiling (MIC2, NKX2.2, NKX3.1, AE1/AE3, SATB2).
• Fluorescence in situ hybridization (FISH) for EWSR1 gene rearrangement and amplification.

Main Results:

• Five cases of EWSR1::NFATC2 fusion sarcoma identified, predominantly in males, with a history of trauma and bone lesions in the femur and tibia.
• Morphologic heterogeneity observed, from myxohyaline to fibrotic stroma, with characteristic immunophenotypic profiles.
• FISH confirmed EWSR1 rearrangement and amplification; two cases showed treatment resistance and relapse.

Conclusions:

• EWSR1::NFATC2 fusion sarcoma is a distinct entity within undifferentiated small round cell sarcomas.
• Despite overlapping features with Ewing sarcoma, its unique fusion partner warrants separate classification.
• Further research is needed to understand treatment strategies for this rare sarcoma.