A unique epithelioid vascular neoplasm of bone characterized by EWSR1/FUS‐NFATC1/2 fusions

Abstract

An increasing number of epithelioid vascular lesions, in particular tumors from the benign and low‐grade end of the spectrum, have been characterized by recurrent gene fusions. As a result, the detection of these molecular markers have improved the classification of diagnostically challenging cases. However, despite the significant progress, there are occasional lesions that do not fit in known histologic or molecular groups. Herein, we present five such unclassified epithelioid vascular lesions, which occurred in the bone and showed a distinct morphology composed of alternating vasoformative and solid growth and mild to moderate nuclear pleomorphism. The variegated morphologic appearance resembled that of composite hemangioendothelioma, being distinct from both epithelioid hemangioma and epithelioid hemangioendothelioma, and consistently showed cytologic atypia. Due to their unusual morphologic appearance and negative molecular work‐up, targeted transcriptome sequencing was performed in two cases showing the presence of NFATC2 fusions with either EWSR1 or FUS genes. Three additional bone tumors with EWSR1 gene rearrangements were identified by FISH screening of a large cohort of 45 fusion‐negative epithelioid vascular neoplasms, one fused to NFATC2 while two others to NFATC1. There were three females and two males, with a wide age range at presentation, mean of 44 years. The lesions occurred in the pelvis, maxillary sinus, and humerus. Two patients presented with polyostotic disease, both located in the pelvic bones. Two patients had available follow‐up, one developed two local recurrences in the humerus over a 15‐year period, while the other showed no recurrence 4 years subsequent to an en‐bloc resection. Tumors were positive for CD31 and ERG, while negative for EMA, CK, synaptophysin, and chromogranin. FISH confirmed this abnormality in all cases, none of them being associated with gene amplifications. Further studies are needed to establish the pathogenetic relationship of this rare molecular subset with other epithelioid vascular tumors and to determine its clinical behavior.

New molecular entities of soft tissue and bone tumors

“…Of note, identical EWSR1-NFATC2 rearrangements have been recently described in a spectrum of benign vascular lesions of bone, including a hemangioma/vascular malformation-like lesion and an unusual benign epithelioid vascular tumor, as well as in simple bone cyst. The amplification of the fusion product that is characteristic of EWSR1 - NFATC2 -rearranged sarcoma is absent in these benign NFATC2 rearranged lesions and there is no morphological overlap [8–10]. These findings illustrate that molecular findings should always be interpreted within the proper morphological, immunohistochemical, and clinicoradiological context.…”

Vascular Neoplasms With NFATC1/C2 Gene Alterations

“…Subsequently, our group documented 5 cases of a distinct epithelioid vascular neoplasm with variegated architectural patterns and degree of atypia, harboring EWSR1/FUS::NFATC1/2 fusions. 14 As no morphologic overlap was detected between the 2 series, thus raising questions about the pathogenesis and phenotype driven by NFATC-related fusion, we sought to assemble a larger cohort of cases with molecular confirmation to further investigate this entity. Herein, we describe 9 additional new cases with detailed clinical, radiographic, and histologic findings and provide a meta-analysis combining with the previous 5 reported cases for a more in-depth characterization.…”

“…However, in addition to these well-characterized pathologic entities, other unusual epithelioid vascular neoplasms have recently emerged, including the ones harboring EWSR1/ FUS::NFATC1/2 fusions. 14 These lesions, occurring mostly in bone, are characterized by vasoformative and solid growth, mild to moderate cytological atypia, and indolent clinical behavior. Of interest, the same EWSR1:: NFATC2 fusion was also reported in 2, seemingly distinct cases of benign vascular malformations in adults presenting as multifocal lesions mostly in bone.…”

Molecular and immunohistochemical testing of bone tumours: review and update

“…87,88 Fusion between EWSR1 or FUS and NFATC1 or NFATC2 has been identified in a series of unusual epithelioid vascular tumours of bone; they show epithelioid endothelial cells and a variegated pattern, with solid, haemangioma-like, retiform, and/or hobnail features. 89 Data on its behaviour and relationship to other vascular tumours remain limited.…”