Epithelioid mesenchymal neoplasm with FUS::CREM gene fusion in the tongue: report of a rare and challenging diagnosis

FET (encompassing both EWSR1 and FUS) fusions with genes from the CREB family (CREB1, ATF1, and CREM) are involved in a variety of neoplasms. Recently, FET::CREB fusions were recognized in a group of malignant epithelioid neoplasm with a striking predilection to mesothelial-lined cavities and frequent cytokeratin immunoexpression. Herein, we report a rare mesenchymal neoplasm with epithelioid morphology and nonspecific immunoprofile harboring a FUS::CREM fusion arising in the oral tongue of a 53-year-old man. Histology showed a well-circumscribed tumor composed of epithelioid cells with eosinopohilic or clear cytoplasm with sparse stroma, accompanied by peripheral lymphoplasmacytic infiltrates. Immunohistochemically, an extensive panel revealed only patchy expression of synaptophysin and weak-to-moderate nuclear expression of TFE3, and negativity for other markers including cytokeratins, epithelial membrane antigen, p63/p40, vimentin, S100, smooth muscle actin, CD34, des -min, SOX10, glial fibrillary acidic protein, melan-A, HMB45, and CD68. A FUS::CREM gene fusion was detected by next genera-tion sequencing at an outside institution, and subsequent fluorescence in situ hybridization analysis confirmed the presence of FUS gene rearrangement. The identification and analysis of additional cases should help to clarify the nosologic status and the biologic potential of this tumor. (Oral Surg Oral Med Oral Pathol Oral Radiol 2023;135:e108-e113)