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

Abstract

<p class="first" id="P1">Recurrent gene fusions involving <i>EWSR1</i> with members of the cAMP response element binding protein (CREB) family <i>(ATF1</i> and <i>CREB1)</i> 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 <i>EWSR1</i> fusions with one of the CREB family member ( <i>ATF1, CREB1</i> and <i>CREM</i>), 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 <i>EWSR1-CREM</i> fusion was identified by RNA sequencing in the peri-rectal tumor, which was further confirmed by FISH and RT-PCR. A 2 ^nd case with similar <i>EWSR1-CREM</i> fusion was identified by RT-PCR and FISH in a meningeal tumor. The remaining cases studied by FISH showed the presence of <i>EWSR1-CREB1</i> fusion in 2 cases and <i>EWSR1-ATF1</i> 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. </p>