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Expanding the Phenotypic Spectrum of Mesenchymal Tumors Harboring the EWSR1-CREM Fusion

Yoshida, Akihiko MD, PhD*,†; Wakai, Susumu CT*; Ryo, Eijitsu PhD; Miyata, Kazuyuki MD, PhD§; Miyazawa, Masahisa MD, PhD; Yoshida, Ken-ichi MD*; Motoi, Toru MD, PhD; Ogawa, Chitose MD#; Iwata, Shintaro MD, PhD†,**; Kobayashi, Eisuke MD, PhD†,**; Watanabe, Shun-ichi MD††; Kawai, Akira MD, PhD†,**; Mori, Taisuke DMD, PhD*,‡

The American Journal of Surgical Pathology: December 2019 - Volume 43 - Issue 12 - p 1622–1630
doi: 10.1097/PAS.0000000000001331
Original Articles
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ATF1, CREB1, and CREM constitute the CREB family of transcription factors. The genes encoding these factors are involved in gene fusion events in human tumors. EWSR1-ATF1 and EWSR1-CREB1 are the 2 most characterized fusions, whereas EWSR1-CREM has been less studied. To better understand the phenotypic spectrum of mesenchymal tumors associated with the EWSR1-CREM fusion, we investigated archival cases using fluorescence in situ hybridization and/or RNA sequencing. Among 33 clear cell sarcomas of soft tissue tested, we found 1 specimen, a hand tumor bearing the rearrangements of EWSR1 and CREM, with classic histology and immunophenotype. None of 6 clear cell sarcoma-like tumors of the gastrointestinal tract tested harbored the EWSR1-CREM fusion. Among 11 angiomatoid fibrous histiocytomas, we found that 3 tumors of myxoid variant harbored the rearrangements of EWSR1 and CREM. All 3 tumors occurred in middle-aged men and involved the distal extremities (N=2) and the lung (N=1). Prominent lymphoid cuff, fibrous pseudocapsule, and amianthoid fiber were present in 3, 2, and 2 tumors, respectively, whereas none showed pseudoangiomatoid spaces. All 3 tumors were immunohistochemically positive for epithelial membrane antigen and desmin. These cases suggested a closer relationship between angiomatoid fibrous histiocytoma and a recently proposed novel group of myxoid tumors with CREB family fusions. Our cohort also included 2 unclassifiable sarcomas positive for EWSR1-CREM. One of these was an aggressive pediatric tumor of the abdominal cavity characterized by proliferation of swirling spindle cells immunopositive for cytokeratin and CD34. The other tumor derived from the chest wall of an adult and exhibited a MUC4-positive sclerosing epithelioid fibrosarcoma-like histology. Our study demonstrates that a wider phenotypic spectrum is associated with the EWSR1-CREM fusion than previously reported.

Departments of *Diagnostic Pathology

#Pediatric Oncology

**Musculoskeletal Oncology

††Thoracic Surgery, National Cancer Center Hospital

Rare Cancer Center, National Cancer Center Hospital

Division of Molecular Pathology, National Cancer Center Research Institute

Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo

§Department of Pathology, Kofu Municipal Hospital

Department of Thoracic Surgery, Kofu Municipal Hospital, Yamanashi, Japan

Conflicts of Interest and Source of Funding: Supported in part by the National Cancer Center Research and Development Fund (30-A-2) and JSPS Grant-in-Aid for Young Scientists (18K15108). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Akihiko Yoshida, MD, PhD, Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan (e-mail: akyoshid@ncc.go.jp).

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