Sarcomas With EWSR1::NFATC2 and FUS::NFATC2 Gene Fusions Arising in Soft Tissue and Bone: A Clinicopathologic Study...

Bone and soft tissue sarcomas harboring EWSR1::NFATC2 and FUS::NFATC2 fusions (NFATC2-rearranged sarcomas) are 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 men and 8 women; median age, 40 years; range, 14-78 years), 16 of which arose in soft tissue, while 8 originated in the 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 months) demonstrated local recurrence in 3 patients, while distant metastases occurred in 6 patients. Two patients died of disease, 4 were alive with disease, and 13 were alive without evidence of disease. In contrast, the FUS::NFATC2 fusion was exclusively seen in osseous tumors, which occurred in 7 patients (4 men and 3 women; median age, 32 years; range, 4-62 years). Further, FUS::NFATC2 tumors showed significant morphologic heterogeneity. Follow-up (6 patients; median, 18 months; range, 13-60 months) demonstrated local recurrence in 2 patients and lung metastases in 2 patients. At the last follow-up, 3 patients were alive with disease, while 3 patients were alive without evidence of disease. Using a 2-tiered grading scheme based on cytologic atypia, mitotic rate, and necrosis, patients with low-grade tumors experienced significantly fewer adverse events than those with high-grade tumors (P = .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 are 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.