title: Intracranial myxoid mesenchymal tumors with EWSR1-CREB family gene fusions: myxoid variant of angiomatoid fibrous histiocytoma or novel entity?
abstract: Intracranial myxoid mesenchymal tumor harboring EWSR1 fusions with CREB family of genes was recently described, and it resembles the myxoid variant of angiomatoid fibrous histiocytoma. We present three pediatric patients with intracranial EWSR1-rearranged myxoid mesenchymal neoplasm and provide a molecular genetic characterization of these tumors. Clinical histories and imaging results were reviewed. Histology, immunohistochemistry, EWSR1, FUS, NR4A3 fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS) were performed. A 12-year-old male (case 1), 14-year-old female (case 2), and 18-year-old male (case 3), presented with headaches, emesis, and seizures, respectively. The magnetic resonance images demonstrated tumors abutting the dura (cases 1 and 3) and in the third ventricle (case 2). All tumors were vascular, with solid sheets of monomorphic oval cells in a prominent myxoid/microcystic matrix. A thin fibrous pseudocapsule was present in all lesions, but definitive lymphocytic cuffing was absent. Morphologically, they closely resembled myxoid variant of angiomatoid fibrous histiocytoma. Mitoses were rare, and necrosis was absent. All tumors expressed desmin and GLUT1, and focal EMA and CD99. The proliferation index was low. FISH and NGS showed EWSR1-CREB1 fusion (cases 1 and 2), and EWSR1-CREM fusion (case 3). There were no FUS (16p11.2) or NR4A3 (9q22.33) rearrangements in case 3. Gains of 5q (including KCNIP1) and 11q (including CCND1) were present in cases 1 and 2. There were no common pathogenic genomic changes other than EWSR1 rearrangements across cases. CNS myxoid mesenchymal neoplasms with histological and immunophenotypic similarities to myxoid variant of AFH are rare, diagnostically challenging, and harbor EWSR1-CREB1 and also a novel EWSR1-CREM fusion not yet described in AFH. Therefore, it is uncertain if these tumors represent variants of AFH or a new entity. The copy number and mutational changes presented here provide support for future studies to further clarify this issue.
authors.affiliation: Department of Pathology, Brigham and Women Hospital, Boston, MA.
authors.forename: Tejus A
authors.initials: TA
authors.lastname: Bale
authors.affiliation: Department of Pathology Laboratory Medicine, IWK Health Center, Halifax, NS.
authors.forename: Angelica
authors.initials: A
authors.lastname: Oviedo
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA.
authors.forename: Harry
authors.initials: H
authors.lastname: Kozakewich
authors.affiliation: Department of Pathology, Mayo Clinic, Rochester, MN.
authors.forename: Caterina
authors.initials: C
authors.lastname: Giannini
authors.affiliation: Department of Pathology, Brigham and Women Hospital, Boston, MA.
authors.forename: Phani K
authors.initials: PK
authors.lastname: Davineni
authors.affiliation: Department of Pathology, Brigham and Women Hospital, Boston, MA.|Department of Pathology, Boston Children's Hospital, Boston, MA.
authors.forename: Keith
authors.initials: K
authors.lastname: Ligon
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA.
authors.forename: Sanda
authors.identifier: 0000-0001-9246-4184
authors.initials: S
authors.lastname: Alexandrescu
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D002648:Child; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D003937:Diagnosis, Differential; D005260:Female; D050939:Gene Fusion; D051677:Histiocytoma, Malignant Fibrous / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D009232:Myxoma / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D034802:RNA-Binding Protein EWS / Q000235:genetics*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C500986:EWSR1 protein, human; C574775:EWSR1-CREB1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D034802:RNA-Binding Protein EWS
keywords: BRAF; CREB1; CREM; EWSR1; myxoid mesenchymal tumor; myxoid variant angiomatoid fibrous histiocytoma; next-generation sequencing