Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation

Abstract

Disseminated glioneuronal tumors of childhood are rare. We present a retrospective IRB-approved review of the clinical course and frequency of BRAF mutations in disseminated glioneuronal tumors at two institutions. Defining features of our cohort include diffuse leptomeningeal-spread, often with a discrete spinal cord nodule and oligodendroglioma-like histologic features. Patients were identified through a pathology database search of all cases with disseminated low-grade neoplasms with an oligodendroglioma-like component. De-identified clinical information was collected by chart review and all imaging was reviewed. We retrieved the results of targeted genomic analyses for alterations in BRAF. Ten patients (aged 2-14 years) were identified from the Dana-Farber/Boston Children's Hospital and the Royal Children's Hospital, Melbourne pathology databases. Nine patients received chemotherapy. Eight patients are alive, although three have had episodes of progressive disease. We identified genomic alterations affecting the MAPK pathway in six patients. One patient had a germline RAF1 mutation and a clinical diagnosis of cardio-facio-cutaneous syndrome. BRAF duplications were identified in four and BRAF V600E mutation was identified in one. These data support the presence of targetable genomic alterations in this disease.

Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features

“…The existence of KIAA1549:BRAF fusions in DLGNT has also been described in recent publications, in conjunction with deletion of chromosomal arm 1p or 1p/19q co-deletion but in the absence of IDH mutation (Table 1) [1,9,12,30,32,33,35].…”

“…Small cystic or nodular T2-hyperintense lesions were frequently encountered along the subpial surface of the brain and spinal cord. Discrete intraparenchymal lesions were also found, especially in the spinal cord [1,12,15,29,31,35]. However, in a recent study by Chiang et al comprising five patients, leptomeningeal dissemination was not seen radiologically in any of the cases, suggesting that DLGNTs do not necessarily present with gross leptomeningeal dissemination on MRI [9].…”

“…A summary of characteristics in previous series is given in Table 1. Although most tumors display a slow progression, aggressive cases were occasionally encountered [12,29,31,36]. The largest series with follow-up data of 24 patients showed 9 deaths within 3-21 years [31].…”

BRAFV600E Expression in Mouse Neuroglial Progenitors Increase Neuronal Excitability, Cause Appearance of Balloon-like cells, Neuronal Mislocalization, and Inflammatory Immune response

“…Inspite of abundant data on occurrence and structural pathological components with shared morphometric features in LNETs and MCDs the mechanisms that cause ictogenesis and subsequently development of epilepsy are not currently well understood. Contribution of cortical structure disruption to seizures and epilepsy may depend on specific case, the size of the affected cortical area, susceptibility of the affected cortical area to such disruptions, the population of progenitor cells involved within the boundaries of affected developmental stages 39,[45][46][47][48] , genetic etiology, epigenetic modulation 49,50 and environmental effects. In some cases it may be malformation independent and originate in adjacent to malformed cortex areas 2,3,[8][9][10][11][12][13] .…”

Diffuse Leptomeningeal Glioneural Tumour Simulating Tuberculous Meningitis in a 13-Year-Old Girl

“…According to Cooper and Kernohan [1], the diagnosis of DLGT requires the fulfilment of 3 diagnostic criteria: (1) no attachment of the tumour to the brain parenchyma, (2) no evidence of intra-axial lesions, and (3) the presence of leptomeningeal encapsulation of the tumour. At the molecular level, these tumours seem to share some of the alterations more typical of low-grade glial tumours (e.g., BRAF tandem duplication, BRAF V600E mutation, or deletion of 1p) [4]. This disseminated form of oligodendroglial tumour should be suspected in cases of unexplained subacute or chronic meningeal processes.…”