EWSR1 Fusions With CREB Family Transcription Factors Define a Novel Myxoid Mesenchymal Tumor With Predilection for Intracranial Location

Abstract

Recurrent gene fusions involving EWSR1 with members of the cAMP response element binding protein (CREB) family (ATF1 and CREB1) have been reported in a diverse group of tumors including angiomatoid fibrous histiocytoma (AFH), soft tissue and gastrointestinal clear cell sarcoma (CCS), primary pulmonary myxoid sarcoma (PPMS) and hyalinizing clear cell carcinoma of salivary gland. We have recently encountered a group of 5 myxoid mesenchymal tumors positive for EWSR1 fusions with one of the CREB family member (ATF1, CREB1 and CREM), with histologic features distinct from any of the previously described pathologic entities. Tumors occurred in children or young adults (12–23 years; mean 18), with equal gender distribution. All except one were intracranial (intra-axial, 2; meningeal, 2) while one was perirectal. Histologically, the tumors were well-circumscribed, often lobulated, composed of uniform ovoid to round cells, and arranged in cord-like or reticular structures in a myxoid background. All except one displayed unique sunburst amianthoid fibers. Immunohistochemically, tumors were positive for EMA (5/5; 4 focal, 1 diffuse) and desmin (3/5). A novel EWSR1-CREM fusion was identified by RNA sequencing in the peri-rectal tumor, which was further confirmed by FISH and RT-PCR. A 2nd case with similar EWSR1-CREM fusion was identified by RT-PCR and FISH in a meningeal tumor. The remaining cases studied by FISH showed the presence of EWSR1-CREB1 fusion in 2 cases and EWSR1-ATF1 in one. In conclusion, we report a distinct group of myxoid mesenchymal neoplasms occurring in children or young adults with a predilection for intracranial locations. Although the immunoprofile (EMA, desmin) and the fusion type raise the possibility of a myxoid AFH, none of the typical histologic findings of AFH were present, suggesting a novel entity.

A Subset of Malignant Mesotheliomas in Young Adults Are Associated With Recurrent EWSR1/FUS-ATF1 Fusions

“…An EWSR1-ATF1 fusion transcript has been described in several tumor types without an unifying cell lineage, morphology or behavior, spanning both benign and malignant tumors of either mesenchymal or epithelial differentiation (19). These include clear cell sarcoma (20), angiomatoid fibrous histiocytoma (21, 22), GI clear cell sarcoma (23), hyalinizing clear cell carcinoma (24), myoepithelial carcinoma (25), primary pulmonary myxoid sarcoma (19) and more recently in a myxoid mesenchymal tumor with intracranial predilection (26). To our knowledge, EWSR1/FUS-ATF1 fusions have not been previously described in a MM case.…”

“…The tumor is typically negative for cytokeratins and harbors the related EWSR1-CREB1 fusion (42); while no example with EWSR1-ATF1 fusion has been yet reported. Finally, a group of unclassified myxoid mesenchymal neoplasms with predilection for the intracranial compartment and characterized by fusions of EWSR1 with members of the CREB gene family, including ATF1 , was recently described (26). From this series of 5 tumors occurring in young patients (range: 12–23 years), one presented in the pelvic soft tissues.…”

Primary myxoid mesenchymal tumour with intracranial location: report of a case with a EWSR1–ATF1 fusion

“…On histology, they were lobulated and myxoid, containing cords or strands of uniform round cells. Based on the unique clinicopathological features, a new entity was suggested, named descriptively as ‘myxoid mesenchymal tumor with predilection for intracranial location’ . In the latest report on three cases, the question was raised as to whether this lesion could be related to the myxoid variant of angiomatoid fibrous histiocytoma …”

“…Cytogenetic analysis by G‐banding using fresh tissue sample from the primary surgical specimen showed 45‐46,XX,‐13,t(12;22)(q13;q12)[cp20] karyotype (Figure A). Two separate break‐apart fluorescence in‐situ hybridisation (FISH) assays were performed on paraffin sections from primary tumour following standard procedure, using either dual‐colour EWSR1 (Abbot Molecular, Des Plaines, IL, USA) or custom‐made ATF1 (combination of BACs RP11‐189H16 and RP11‐407N8 clones) break‐apart probe set, as described previously . By both assays, approximately 80–85% of tumour cells showed one fused (red/green) signal and one green and red split signal per nucleus (Figure B), confirming the rearrangement of both, EWSR1 and ATF1 genes.…”

Intraluminal EWSR1–CREB1 gene rearranged, low‐grade myxoid sarcoma of the pulmonary artery resembling extraskeletal myxoid chondrosarcoma (EMC)

“…At present, the exact topographic distribution of myxoid mesenchymal EWSR1–CREB translocated tumours is not well known, due to the rarity of the entity, as well as the inherent diagnostic challenges. Recent reports have described such tumours as being mainly intrapulmonary (PPMS) or intracranial (iMN), with one perirectal example . Hybrid tumours, with typical AFH areas and a variable myxoid component, have been described in a wide range of locations.…”