Sarcomas With EWSR1::NFATC2 and FUS::NFATC2 Gene Fusions Arising in Soft Tissue and Bone: A Clinicopathologic Study of 32 Cases Emphasizing Their Wide Morphologic and Clinical Spectrum.

Abstract

Bone and soft tissue sarcomas harboring EWSR1::NFATC2 and FUS::NFATC2 fusions (NFATC2-rearranged sarcomas) is a recently defined entity with a morphologic spectrum and clinical behavior that are not fully elucidated. We studied 32 such sarcomas that occurred in 21 male and 11 female patients. The EWSR1::NFATC2 fusion was found in tumors of 25 patients (17 M, 8 F; median age: 40, range: 14-78), 16 of which arose in soft tissue, while 8 originated in bone. Morphologically, they showed relatively consistent morphologic features yet variable degrees of cytologic atypia, mitotic rates and necrosis. Follow-up (19 patients; median: 22 months, range: 1-70) demonstrated local recurrence in 3 patients, while distant metastases occurred in 6 patients. Two patients died of disease (DOD), 4 were alive with disease (AWD) and 13 were without evidence of disease (AWOD). In contrast, the FUS::NFATC2 fusion was exclusively seen in osseous tumors, which occurred in 7 patients (4 M, 3 F; median age: 32, range: 4-62). Further, FUS::NFATC2 tumors showed significant morphologic heterogeneity. Follow-up (6 patients; median: 18 months, range: 13-60) demonstrated local recurrence in 2 patients, and lung metastases in 2 patients. At last follow-up, 3 patients were AWD, while 3 patients were AWOD. Using a two-tiered grading scheme based on cytologic atypia, mitotic rate, and necrosis, patients with low-grade tumors experienced significantly fewer adverse events than those classified as high-grade (p=0.026); however, estimated metastasis-free survival was not statistically significant due to our limited sample size. Overall, our study expands on the morphologic spectrum of NFATC2-rearranged sarcomas and highlights the clinicopathologic, molecular, and genetic differences between the EWSR1- and FUS-rearranged tumors. Although additional long-term follow-up data is required, our study further suggests that a subset of these sarcomas have a protracted clinical course while high-grade morphologic features such as atypia, mitotic activity and necrosis may correlate with worse behavior.