The spectrum of rare central nervous system (CNS) tumors with EWSR1‐non‐ETS fusions: experience from three pediatric institutions with review of the literature

Abstract

The group of CNS mesenchymal (non‐meningothelial) and primary glial/neuronal tumors in association with EWSR1‐non‐ETS rearrangements comprises a growing spectrum of entities, mostly reported in isolation with incomplete molecular profiling. Archival files from three pediatric institutions were queried for unusual cases of pediatric (≤21 years) CNS EWSR1‐rearranged tumors confirmed by at least one molecular technique. Extra‐axial tumors and cases with a diagnosis of Ewing sarcoma (EWSR1‐ETS family fusions) were excluded. Additional studies, including anchored multiplex‐PCR with next‐generation sequencing and DNA methylation profiling, were performed as needed to determine fusion partner status and brain tumor methylation class, respectively. Five cases (median 17 years) were identified (M:F of 3:2). Location was parenchymal (n = 3) and undetermined (n = 2) with topographic distributions including posterior fossa (n = 1), frontal (n = 1), temporal (n = 1), parietal (n = 1) and occipital (n = 1) lobes. Final designation with fusion findings included desmoplastic small round cell tumor (EWSR1‐WT1; n = 1) and tumors of uncertain histogenesis (EWSR1‐CREM, n = 1; EWSR1‐CREB1, n = 1; EWSR1‐PLAGL1, n = 1; and EWSR1‐PATZ1, n = 1). Tumors showed a wide spectrum of morphology and biologic behavior. For EWSR1‐CREM, EWSR1‐PLAGL1 and EWSR1‐PATZ1 tumors, no significant methylation scores were reached in the known brain tumor classes. Available outcome (4/5) was reported as favorable (n = 2) and unfavorable (n = 2) with a median follow‐up of 30 months. In conclusion, we describe five primary EWSR1‐non‐ETS fused CNS tumors exhibiting morphologic and biologic heterogeneity and we highlight the clinical importance of determining specific fusion partners to improve diagnostic accuracy, treatment and monitoring. Larger prospective clinicopathological and molecular studies are needed to determine the prognostic implications of histotypes, anatomical location, fusion partners, breakpoints and methylation profiles in patients with these rare tumors.

Expanding the spectrum of EWSR1‐PATZ1 rearranged CNS tumors: An infantile case with leptomeningeal dissemination

“…Beside such similarities, some characteristics of our case are unique, that is the onset in an infant, the occurrence of a high‐grade area and the leptomeningeal involvement. No previous EWSR1‐PATZ1 cerebral tumors have been reported in infants and the median age in this group of patients, in the current literature, is 21 years (range 7‐50) (1–6).…”

“…Expanding the spectrum of EWSR1-PATZ1 rearranged CNS tumors: An infantile case with leptomeningeal dissemination EWSR1-PATZ1 fusions, first described in small round or spindle cell sarcomas (1) have recently been reported in rare low-and high-grade CNS tumors (1)(2)(3)(4)(5)(6). Among the cerebral cases, only three have been provided with a complete clinico-pathological description (4,6).…”

“…EWSR1‐PATZ1 fusions, first described in small round or spindle cell sarcomas (1) have recently been reported in rare low‐ and high‐grade CNS tumors (1–6). Among the cerebral cases, only three have been provided with a complete clinico‐pathological description (4,6). We report a case of EWSR1‐PATZ1 brain tumor displaying unique clinico‐pathological and molecular features.…”

A case of intracranial myxoid mesenchymal tumor with EWSR1:CREM fusion in an adult female: Extensive immunohistochemical evaluation

“…However, CREM fusions have subsequently been found in a variety of tumors, including IMMT/intracranial AFH-like tumor, 11,13,[17][18][19]23,28,31 myxoid variants of extracranial AFH, 9 HCCC of the upper aerodigestive tract and lung, 32 ectomesenchymal chondromyxoid tumor of the tongue, 33 CCS of the soft tissue, 9,34 a clear cell tumor resembling CCS, 35 malignant epithelioid mesothelioma-like tumor, 36 SEF/LGFMS, 37,38 and several other unclassified tumor of intracranial and extracranial sites. 9,11,[39][40][41] This diversity of phenotypes and tumor sites makes it extremely difficult to define the characteristics of tumors with CREM fusions. At least intracranially, however, the majority of tumors appear to exhibit the phenotype of IMMT/AFH-like tumors, with similar frequencies of mucin-rich and mucin-poor cases.…”

Recurrent fusions inPLAGL1define a distinct subset of pediatric-type supratentorial ependymoma

“…Our findings suggest rearrangements involving PLAGL1, particularly EWSR1:PLAGL1 and PLAGL1:FOXO1 fusions, as a molecular hallmark of this novel group of tumors. Gene fusions of PLAGL1 with EWSR1 have been reported exceptionally rarely in neoplasms of the CNS, including single cases of a SMARCB1-deficient atypical teratoid/rhabdoid tumor (AT/RT) 26 and a glioneuronal tumor, not elsewhere classified (NEC) 27 . However, in a very recent report, a PLAGL1:EWSR1 fusion was described in a supratentorial ependymoma of a six-year-old child 11 .…”