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

Our plain-English summary of EWSR1/FUS-CREB fusions define a distinctive malignant epithelioid neoplasm with predilection for mesothelial-lined cavities, by P. Argani, I. Harvey, G.P. Nielsen, et al (Modern Pathology, 2020).

The study

• Authors: P. Argani, I. Harvey, G.P. Nielsen, A. Takano, A.J.H. Suurmeijer, L. Voltaggio, L. Zhang, Y.S. Sung, A. Stenzinger, G. Mechtersheimer, B.C. Dickson, C.R. Antonescu
• Journal: Modern Pathology
• Published: 2020;33(11):2233-2243
• Cited by: 104 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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).

In plain English

This article is a case series by pathologists describing 13 tumors that had not fitted any known tumor type. The authors selected them from their own consultation files. The patients were 7 females and 6 males aged 9 to 63 years. Every tumor carried a gene fusion joining EWSR1 or FUS to a CREB-family gene: 7 EWSR1-CREM, 4 FUS-CREM and 2 EWSR1-ATF1. Eleven tumors involved a mesothelial-lined body cavity, mostly the abdomen. One of these was a pleural-based mass, and two other tumors arose in the soft tissue of a limb. Under the microscope the tumors were mainly epithelioid with cysts, and all but one showed epithelial markers. Some stained for WT1. All tumors tested were negative for calretinin and kept BAP1 expression. Two cases had originally been submitted as localized malignant mesothelioma. Nine patients had follow-up, and 6 of them developed peritoneal or pleural recurrence or metastatic implants. The authors concluded that the tumors likely represent a new malignant entity with features of both angiomatoid fibrous histiocytoma and mesothelioma, though they could not exclude a mixed group. The article does not study asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: case series (pathology study of consultation cases, with immunohistochemistry, RNA sequencing and/or FISH)
• Who was studied: 13 patients (6 males, 7 females) aged 9 to 63 years, mean and median 36 years, from the authors' consultation files; no study dates are given
• Exposure: No asbestos or other environmental exposure was studied; the study characterized tumors defined by EWSR1/FUS-CREB gene fusions
• Main results:
  • Gene fusions: 7 cases had EWSR1-CREM and 4 had FUS-CREM
  • The remaining 2 cases had an EWSR1-ATF1 fusion
  • 11 of the 13 patients had involvement of a mesothelial-lined cavity
  • Ten tumors occurred inside the abdomen
  • One patient had a pleural-based mass
  • Two tumors occurred in the soft tissue of the arms or legs
  • Two cases had been submitted under a diagnosis of localized malignant mesothelioma
  • All but one tumor showed epithelial differentiation on immunohistochemistry
  • All tumors tested were negative for the mesothelial marker calretinin and kept BAP1 and INI1 expression
  • WT1 staining was present in about a third of cases
  • In the one case examined by electron microscopy, there was no evidence of mesothelial differentiation
  • Of 9 patients with follow-up, 6 developed peritoneal or pleural local recurrence or metastatic implants, 4 of them despite extensive resection and/or chemotherapy
  • One patient developed liver metastases one year after diagnosis
  • In gene-expression analysis, 2 study cases grouped together and apart from other tumors with similar fusions and from fusion-positive mesotheliomas
• The authors' conclusion: The authors concluded that these tumors form a unique group of malignant epithelioid neoplasms with a predilection for mesothelial-lined cavities, suggesting a novel entity combining features of angiomatoid fibrous histiocytoma and malignant mesothelioma
• Limitations the authors state:
  • Follow-up was available for only 9 of the 13 patients
  • The authors could not exclude that the cases are a heterogeneous group of tumors rather than one entity
  • Larger studies using other genomic methods are needed for firmer conclusions

Topics

Medical terms in this study, explained in our Lexicon: Epithelioid, Neoplasm, Translocation, Peritoneal Cavity, Pleural Cavity, Mesothelioma, Fluorescence In Situ Hybridization (FISH).

Related studies

• A Subset of Malignant Mesotheliomas in Young Adults Are Associated With Recurrent EWSR1/FUS-ATF1 Fusions — P. Desmeules, P. Joubert, et al. (2017)
• Generation of human embryonic stem cell models to exploit the EWSR1-CREB fusion promiscuity as a common pathway of transformation in human tumors — F. Vanoli, B. Meskauskaite, et al. (2021)
• EWSR1::YY1 fusion positive peritoneal epithelioid mesothelioma harbors mesothelioma epigenetic signature: Report of 3 cases in support of an emerging entity — J.K. Dermawan, D. Torrence, et al. (2022)
• Malignant Mesothelioma With EWSR1-ATF1 Fusion in Two Adolescent Male Patients — H. Ren, S.R. Rassekh, et al. (2021)
• RNA sequencing identifies fusion of the EWSR1 and YY1 genes in mesothelioma with t(14;22)(q32;q12) — I. Panagopoulos, J. Thorsen, et al. (2013)
• Asbestos-mediated CREB phosphorylation is regulated by protein kinase A and extracellular signal-regulated kinases 1/2 — C.A. Barlow, T.F. Barrett, et al. (2007)

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