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.

Keywords: BRAF; CREB1; CREM; EWSR1; myxoid mesenchymal tumor; myxoid variant angiomatoid fibrous histiocytoma; next-generation sequencing.

Figure 1

a. Case 1—axial T2‐hyperintense well‐demarcated tumor in right cerebellar hemisphere with surrounding edema, abutting the dura. b. Axial T1 MRI of case 2 shows well‐demarcated tumor involving left posterior horn of lateral ventricle. c. Case 3—axial T2‐hyperintense tumor in left frontal region, having similar features to those in case 1, but no definitive attachment to dura.

Figure 2

Histological characteristics. a. Hematoxylin–eosin‐stained section representative of the three tumors, showing epithelioid neoplasm composed of round‐to‐oval cells growing in short cords in a prominent myxoid background. b. A vague nodular pattern admixed with hypocellular areas rich in collagen, and occasional prominent vessels. c. Short cords and trabecula of monomorphic cells in a prominent myxoid background with scattered collagen fibers. d. The tumors were surrounded by a thin fibrous capsule. e. Cords and occasional whorls composed of monomorphic oval‐to‐spindle cells with minimal atypia in a prominent myxoid background. f. Focus of rich capillary network (more prominent in case 2). g. Discrete angiocentric pattern (more prominent in case 1). h. Spindle and stellate cells with collagen fibers resembling amianthoid fibers.

Figure 3

Immunohistochemical profile. Desmin (a) and Glut‐1 (b) immunostains diffusely and strongly positive, EMA (c) expressed in subset of tumor cells, CD99 immunostain (d) positive in a membranous pattern in large number of lesional cells.

Figure 4

The EWSR1–CREM fusion in case 3 is supported by discordant read pairs indicating a break in EWSR1 (a) and alignment of split reads to EWSR1 and CREM (b) as predicted by the translocation analysis tool BreaKmer.