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).
Subscribe to Journal
Get full journal access for 1 year
only $33.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Thway K, Fisher C. Tumors with EWSR1-CREB1 and EWSR1-ATF1 fusions: the current status. Am J Surg Pathol. 2012;36:e1–e11.
Desmeules P, Joubert P, Zhang L, Al-Ahmadie HA, Fletcher CD, et al. A subset of malignant mesotheliomas in young adults are associated with recurrent EWSR1/FUS-ATF1 fusions. Am J Surg Pathol. 2017;41:980–8.
Antonescu CR, Dal Cin P, Nafa K, Teot LA, Surti U, et al. EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosom Cancer. 2007;46:1051–60.
Antonescu CR, Tschernyavsky SJ, Woodruff JM, Jungbluth AA, Brennan MF, et al. Molecular diagnosis of clear cell sarcoma: detection of EWS-ATF1 and MITF-M transcripts and histopathological and ultrastructural analysis of 12 cases. J Mol Diagn. 2002;4:44–52.
Wang WL, Mayordomo E, Zhang W, Hernandez VS, Tuvin D, et al. Detection and characterization of EWSR1/ATF1 and EWSR1/CREB1 chimeric transcripts in clear cell sarcoma (melanoma of soft parts). Mod Pathol. 2009;22:1201–9.
Antonescu CR, Nafa K, Segal NH, Dal Cin P, Ladanyi M. EWS-CREB1: a recurrent variant fusion in clear cell sarcoma-association with gastrointestinal location and absence of melanocytic differentiation. Clin Cancer Res. 2006;12:5356–62.
Thway K, Nicholson AG, Lawson K, Gonzalez D, Rice A, et al. Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion: a new tumor entity. Am J Surg Pathol. 2011;35:1722–32.
Antonescu CR, Katabi N, Zhang L, Sung YS, Seethala RR, et al. EWSR1-ATF1 fusion is a novel and consistent finding in hyalinizing clear-cell carcinoma of salivary gland. Genes Chromosom Cancer. 2011;50:559–70.
Chapman E, Skalova A, Ptakova N, Martinek P, Goytain A, et al. Molecular profiling of hyalinizing clear cell carcinomas revealed a subset of tumors harboring a novel EWSR1-CREM fusion: report of 3 cases. Am J Surg Pathol. 2018;42:1182–9.
Yoshida A, Wakai S, Ryo E, Miyata K, Miyazawa M, et al. Expanding the phenotypic spectrum of mesenchymal tumors harboring the EWSR1-CREM fusion. Am J Surg Pathol. 2019;43:1622–30.
Kao YC, Sung YS, Zhang L, Chen CL, Vaiyapuri S, et al. EWSR1 fusions with CREB family transcription factors define a novel myxoid mesenchymal tumor with predilection for intracranial location. Am J Surg Pathol. 2017;41:482–90.
Suurmeijer AJH, Dickson BC, Swanson D, Zhang L, Sung YS, et al. A morphologic and molecular reappraisal of myoepithelial tumors of soft tissue, bone, and viscera with EWSR1 and FUS gene rearrangements. Genes Chromosom Cancer. 2020;59:348–56.
Zheng Z, Liebers M, Zhelyazkova B, Cao Y, Panditi D, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med. 2014;20:1479–84.
Flucke U, Mentzel T, Verdijk MA, Slootweg PJ, Creytens DH, et al. EWSR1-ATF1 chimeric transcript in a myoepithelial tumor of soft tissue: a case report. Hum Pathol. 2012;43:764–8.
Sciot R, Jacobs S, Calenbergh FV, Demaerel P, Wozniak A, et al. Primary myxoid mesenchymal tumour with intracranial location: report of a case with a EWSR1-ATF1 fusion. Histopathology. 2018;72:880–3.
Gareton A, Pierron G, Mokhtari K, Tran S, Tauziede-Espariat A, et al. ESWR1-CREM fusion in an intracranial myxoid angiomatoid fibrous histiocytoma-like tumor: a case report and literature review. J Neuropathol Exp Neurol. 2018;77:537–41.
Bale TA, Oviedo A, Kozakewich H, Giannini C, Davineni PK, et al. Intracranial myxoid mesenchymal tumors with EWSR1-CREB family gene fusions: myxoid variant of angiomatoid fibrous histiocytoma or novel entity? Brain Pathol. 2018;28:183–91.
Le Loarer F, Cleven AHG, Bouvier C, Castex MP, Romagosa C, et al. A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation. Mod Pathol. 2020;33:404–19.
Agaram NP, Zhang L, Sung YS, Cavalcanti MS, Torrence D, et al. Expanding the spectrum of intraosseous rhabdomyosarcoma: correlation between 2 distinct gene fusions and phenotype. Am J Surg Pathol. 2019;43:695–702.
Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol cell Biol. 2001;2:599–609.
Lonze BE, Ginty DD. Function and regulation of CREB family transcription factors in the nervous system. Neuron. 2002;35:605–23.
Shaywitz AJ, Greenberg ME. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem. 1999;68:821–61.
Don J, Stelzer G. The expanding family of CREB/CREM transcription factors that are involved with spermatogenesis. Mol Cell Endocrinol. 2002;187:115–24.
Rauen T, Hedrich CM, Tenbrock K, Tsokos GC. cAMP responsive element modulator: a critical regulator of cytokine production. Trends Mol Med. 2013;19:262–9.
We thank Norman Barker and Bruce Crilly for expert photographic assistance.
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).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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