Clinicopathological and molecular characterization of a case classified by DNA‑methylation profiling as “CNS embryonal tumor with BRD4–LEUTX fusion”

Abstract

Central Nervous System (CNS) embryonal tumors represent a heterogeneous group of highly aggressive tumors occurring preferentially in children but also described in adolescents and adults. In 2021, the CNS World Health Organization (WHO) classification drastically changed the diagnosis of the other CNS embryonal tumors including new histo-molecular tumor types. Here, we report a pediatric case of a novel tumor type among the other CNS embryonal tumors classified within the methylation class “CNS Embryonal Tumor with BRD4–LEUTX Fusion”. The patient was a 4-year girl with no previous history of disease. For a few weeks, she suffered from headaches, vomiting and mild fever associated with increasing asthenia and loss of weight leading to a global deterioration of health. MRI brain examination revealed a large, grossly well-circumscribed tumoral mass lesion located in the left parietal lobe, contralateral hydrocephalus and midline shift. Microscopic examination showed a highly cellular tumor with a polymorphic aspect. The majority of the tumor harbored neuroectodermal features composed of small cells with scant cytoplasm and hyperchromatic nuclei associated with small “medulloblastoma-like” cells characterized by syncytial arrangement and focally a streaming pattern. Tumor cells were diffusely positive for Synaptophysin, CD56, INI1 and SMARCA4 associated with negativity for GFAP, OLIG-2, EMA, BCOR, LIN28A and MIC-2. Additional IHC features included p53 protein expression in more than 10% of the tumor’s cells and very interestingly, loss of H3K27me3 expression. The Heidelberg DNA-methylation classifier classified this case as “CNS Embryonal Tumor with BRD4:LEUTX Fusion”. RNA-sequencing analyses confirmed the BRD4 (exon 13)–LEUTX (exon 2) fusion with no other molecular alterations found by DNA sequencing. Our case report confirmed that a new subgroup of CNS embryonal tumor with high aggressive potential, loss of H3K27me3 protein expression, BRDA4–LEUTX fusion, named “Embryonal CNS tumor with BRD4–LEUTX fusion”, has to be considered into the new CNS WHO classification.

Molecular and clinicopathologic characteristics of CNS embryonal tumors with BRD4::LEUTX fusion

“…Five previously published cases [ 4 – 8 ] were identified in the following manner. One case presented a dedicated case report for a tumor matching to the methylation class “CNS embryonal tumor with BRD4::LEUTX fusion”, with demonstration of the fusion [ 4 ].…”

“…Five previously published cases [ 4 – 8 ] were identified in the following manner. One case presented a dedicated case report for a tumor matching to the methylation class “CNS embryonal tumor with BRD4::LEUTX fusion”, with demonstration of the fusion [ 4 ]. A second case had been discovered in a large series of pediatric cancers where the BRD4::LEUTX fusion had been identified in one case of the series [ 5 ].…”

“…Of note, cases #1–4 were all described to have been treated in a manner similar to clinical trial NCT00336024, where the chemotherapy regimen included cisplatin, cyclophosphamide, vincristine, and etoposide followed by thiotepa. Case #5 was a 4-year female [ 4 ] presenting with a large left parietal mass with multiple smaller supra- and infra- tentorial tumor nodules, as well as signs of subependymal and leptomeningeal dissemination. The patient died of disease shortly after surgery.…”

“…Recently, two cases of CNS embryonal tumors harboring a BRD4::LEUTX fusion were described [ 4 , 5 ]. One of these reports characterized the fusion in a large series of pediatric cancers [ 5 ], while the other incorporated detailed clinical and pathological data, including methylome analysis matching to the novel Heidelberg version 12 classifier class “CNS embryonal tumor with BRD4::LEUTX fusion” [ 4 ].…”

“…Recently, two cases of CNS embryonal tumors harboring a BRD4::LEUTX fusion were described [ 4 , 5 ]. One of these reports characterized the fusion in a large series of pediatric cancers [ 5 ], while the other incorporated detailed clinical and pathological data, including methylome analysis matching to the novel Heidelberg version 12 classifier class “CNS embryonal tumor with BRD4::LEUTX fusion” [ 4 ]. Three additional cases also exist in the literature, which while not specifically described as such, were initially presented before the version 12 of the Heidelberg classifier was available to interrogate this provisional tumor type [ 6 – 8 ].…”