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EWSR1/FUS–CREB fusions define a distinctive malignant epithelioid neoplasm with predilection for mesothelial-lined cavities

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Abstract

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 seven females and six males, with a mean age of 36 (range 9–63). All except three 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, five 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 four 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 two harbored EWSR1–ATF1 fusion. Clinically, seven 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 and lymphoid cuffing) and mesothelioma (peritoneal/pleural involvement, epithelioid phenotype, and cytokeratin and WT1 co-expression).

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Fig. 1: Microscopic features of peritoneal lesions with EWSR1–CREM fusion and co-expression of cytokeratin and WT1.
Fig. 2: Morphologic spectrum of tumors with EWSR1–CREM fusion including epithelioid, round, and spindle cell components.
Fig. 3: Pathologic findings of peritoneal tumors harboring alternative fusions (FUS–CREM and EWSR1–ATF1 fusions).
Fig. 4: Unsupervised clustering using TruSight RNA Fusion Panel gene expression shows EWSR1–CREM fusion-positive lesions group together but separate from other EWSR1–CREB positive tumor entities.

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Acknowledgements

We thank Norman Barker and Bruce Crilly for expert photographic assistance.

Funding

This study was supported in part by: P50 CA217694 (CRA), P50 CA140146 (CRA), P30 CA008748 (CRA), Cycle for Survival (CRA), Sara’s Cure (CRA), Kristin Ann Carr Foundation (CRA), Dahan Translocation Carcinoma Fund (PA), Joey’s Wings (PA).

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Correspondence to Cristina R. Antonescu.

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Argani, P., Harvey, I., Nielsen, G.P. et al. EWSR1/FUS–CREB fusions define a distinctive malignant epithelioid neoplasm with predilection for mesothelial-lined cavities. Mod Pathol 33, 2233–2243 (2020). https://doi.org/10.1038/s41379-020-0646-5

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