EWSR1/FUS-CREB Fusions Define a Distinctive Malignant Epithelioid Neoplasm with Predilection for Mesothelial-Lined Cavities

Gene fusions constitute pivotal driver mutations often encoding aberrant chimeric transcription factors. However, an increasing number of gene fusion events have been shown not to be histotype specific and shared among different tumor types, otherwise completely unrelated clinically or phenotypically. One such remarkable example of chromosomal translocation promiscuity is represented by fusions between EWSR1 or FUS with genes encoding for CREB-transcription factors family (ATF1, CREB1 and CREM), driving the pathogenesis of various tumor types spanning mesenchymal, neuroectodermal, and epithelial lineages. In this study we investigate a group of 13 previously unclassified malignant epithelioid neoplasms, frequently showing an epithelial immunophenotype and marked predilection for the peritoneal cavity, defined by EWSR1/FUS-CREB fusions. There were 7 females and 6 males, with a mean age of 36 (range 9–63). All except 3 cases occurred intra-abdominally, including one each involving the pleural cavity, upper and lower limb soft tissue. All tumors showed a predominantly epithelioid morphology associated with cystic or microcystic changes and variable lymphoid cuffing either intermixed or at the periphery. All except one case expressed EMA and/or CK, 5 were positive for WT1, while being negative for melanocytic and other mesothelioma markers. Nine cases were confirmed by various RNA sequencing platforms, while in the remaining 4 cases the gene rearrangements were detected by FISH. Eleven cases showed the presence of CREM-related fusions (EWSR1-CREM, 7; FUS-CREM, 4), while the remaining 2 harbored EWSR1-ATF1 fusion. Clinically, 7 patients presented with and/or developed metastases, confirming a malignant biologic potential. Our findings expand the spectrum of tumors associated with CREB-related fusions, defining a novel malignant epithelioid neoplasm with an immunophenotype suggesting epithelial differentiation. This entity appears to display hybrid features between angiomatoid fibrous histiocytoma (cystic growth, lymphoid cuffing) and mesothelioma (peritoneal/pleural involvement, epithelioid phenotype, and cytokeratin and WT1 co-expression).