What does this research mean for the field?

NFATC2-rearranged bone sarcomas exhibit unique radiographic and pathologic features that differ significantly from Ewing sarcoma, characterized by lytic lesions, peripheral sclerosis, and frequent extraosseous extension. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This investigation aims to characterize the radiologic and pathologic features of NFATC2-rearranged bone sarcomas.

March 4, 2026

Does This Imaging Make Me Look NFATC2? The Value of Radiologic-pathologic Correlation in NFATC2-rearranged Sarcomas of Bone

Key Points

This investigation aims to characterize the radiologic and pathologic features of NFATC2-rearranged bone sarcomas.
Examined 16 primary bone sarcomas with NFATC2 fusions.
Conducted histologic and immunohistochemical analysis of tumor samples.
Utilized radiographic and CT imaging to evaluate tumor characteristics.
Performed additional genetic analysis on select cases.
Identified typical histologic features including uniform epithelioid and spindle cells.
Radiographic imaging showed lucent lesions with peripheral sclerosis.
87.5% of tumors demonstrated soft tissue extension and expansile cortical remodeling was noted in 50% of cases.
MRI showed hypointense signals on T1 and avid enhancement after contrast.

Abstract

Radiologic-pathologic correlation is essential for diagnostic accuracy, particularly when dealing with primary bone tumors. This investigation explores the unique radiographic and pathologic features of NFATC2-rearranged bone sarcomas. Inclusion criteria focused on primary bone sarcomas with NFATC2 fusions while excluding soft tissue sarcomas, benign bone cysts, and vascular neoplasms with similar fusions. Our cohort comprised 16 patients (12 males, 4 females) with a mean age of 45.6 years (range: 15 to 77 y). Tumors were located in the femur (n=9), tibia (n=3), humerus (n=2), ulna (n=1), and radius (n=1). Symptoms generally followed a long latency period and several were incidentally discovered for other reasons, with a mean tumor size of 9.7 cm (range: 3.0 to 19.7 cm). Histologic examination revealed typical features of NFATC2-rearranged sarcomas, including uniform epithelioid, round, or spindle cells growing in cords, chains, clusters, and sheets suspended in a richly vascularized fibromyxoid to variably sclerotic stroma. Mitotic activity varied dramatically between and within tumors (from 50 per 10 HPF). By immunohistochemistry, positive stains included CD99 (12/14), NKX2.2 (7/7), AGGRECAN (3/3), SMA (6/7), CAM5.2 (3/4), SATB2 (8/9), and ERG (5/8) with more limited expression of CK AE1/AE3 (3/12) and NKX3.1 (2/8). All had an NFATC2 gene fusion, with 9 harboring FUS and 7 EWSR1 as 5' partners. Additional genetic analysis beyond the targeted fusion panel (n=7) demonstrated that all cases harbored a range of secondary genomic alterations in addition to the driver NFATC2 fusion. On radiography and CT imaging, all showed lucent lesions with peripheral sclerosis and narrow transition zones. Expansile cortical remodeling (n=8; 50%) varied from minimal to extensive. Despite generally indolent-appearing radiographic features, 87.5% (14/16) demonstrated soft tissue extension, ranging from focal to extensive. Internal septations were present in 62.5% (10/16). MRI, performed on 15 tumors, revealed hypointensity on T1-weighted images and heterogeneously hyperintense on fluid-sensitive sequences. After contrast administration, avid enhancement was seen in all tumors with perilesional edema and enhancement in 26.7% (4/15). In summary, the imaging of NFATC2-rearranged bone sarcomas differs significantly from Ewing sarcoma, suggesting a tumor of longer duration characterized by a lytic nature, areas of peripheral sclerosis, expansile cortical remodeling, and frequent extraosseous extension. However, these features may not correlate with prognosis. This study represents the first systematic radiologic evaluation of NFATC2-rearranged bone sarcomas, highlighting distinctive characteristics that may aid pathologists in their initial diagnostic assessments.

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