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This article describes a case of a glioneuronal tumor with ATRX alteration, kinase fusion, and anaplastic features (GTAKA) in an adolescent patient. The tumor initially presented as a supratentorial ependymoma but rapidly disseminated to the leptomeninges within three months of surgery. The tumor exhibited specific genetic and epigenetic features of GTAKA, including loss of ATRX expression, a ZMIZ1::RET fusion, and a DNA methylation signature consistent with GTAKA. The case adds to the limited literature on this rare group of tumors and highlights the need for further research on their biological behavior and treatment options. [Extracted from the article]

Aims: Glioneuronal tumours (GNTs) are poorly distinguished by their histology and lack robust diagnostic indicators. Previously, we showed that common GNTs comprise two molecularly distinct groups, correlating poorly with histology. To refine diagnosis, we constructed a methylation-based model for GNT classification, subsequently evaluating standards for molecular stratification by methylation, histology and radiology. Methods: We comprehensively analysed methylation, radiology and histology for 83 GNT samples: a training cohort of 49, previously classified into molecularly defined groups by genomic profiles, plus a validation cohort of 34. We identified histological and radiological correlates to molecular classification and constructed a methylation-based support vector machine (SVM) model for prediction. Subsequently, we contrasted methylation, radiological and histological classifications in validation GNTs. Results: By methylation clustering, all training and 23/34 validation GNTs segregated into two groups, the remaining 11 clustering alongside control cortex. Histological review identified prominent astrocytic/oligodendrocyte-like components, dysplastic neurons and a specific glioneuronal element as discriminators between groups. However, these were present in only a subset of tumours. Radiological review identified location, margin definition, enhancement and T2 FLAIR-rim sign as discriminators. When validation GNTs were classified by SVM, 22/23 classified correctly, comparing favourably against histology and radiology that resolved 17/22 and 15/21, respectively, where data were available for comparison. Conclusions: Diagnostic criteria inadequately reflect glioneuronal tumour biology, leaving a proportion unresolvable. In the largest cohort of molecularly defined glioneuronal tumours, we develop molecular, histological and radiological approaches for biologically meaningful classification and demonstrate almost all cases are resolvable, emphasising the importance of an integrated diagnostic approach. [ABSTRACT FROM AUTHOR]

Pediatric spinal low-grade glioma (LGG) and glioneuronal tumours are rare, accounting for less 2.8–5.2% of pediatric LGG. New tumour types frequently found in spinal location such as diffuse leptomeningeal glioneuronal tumours (DLGNT) have been added to the World Health Organization (WHO) classification of tumours of the central nervous system since 2016, but their distinction from others gliomas and particularly from pilocytic astrocytoma (PA) are poorly defined. Most large studies on this subject were published before the era of the molecular diagnosis and did not address the differential diagnosis between PAs and DLGNTs in this peculiar location. Our study retrospectively examined a cohort of 28 children with LGGs and glioneuronal intramedullary tumours using detailed radiological, clinico-pathological and molecular analysis. 25% of spinal PAs were reclassified as DLGNTs. PA and DLGNT are nearly indistinguishable in histopathology or neuroradiology. 83% of spinal DLGNTs presented first without leptomeningeal contrast enhancement. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that spinal PAs formed a unique methylation cluster distinct from reference midline and posterior fossa PAs, whereas spinal DLGNTs clustered with reference DLGNT cohort. FGFR1 alterations were found in 36% of spinal tumours and were restricted to PAs. Spinal PAs affected significantly younger patients (median age 2 years old) than DLGNTs (median age 8.2 years old). Progression-free survival was similar among the two groups. In this location, histopathology and radiology are of limited interest, but molecular data (methyloma, 1p and FGFR1 status) represent important tools differentiating these two mitogen-activated protein kinase (MAPK) altered tumour types, PA and DLGNT. Thus, these molecular alterations should systematically be explored in this type of tumour in a spinal location. [ABSTRACT FROM AUTHOR]

Case DGONC 1 had been diagnosed as a "malignant glioneuronal tumour", while DGONC 2 and 3 had both been called "high-grade neuroepithelial tumour". Keywords: brain tumour; paediatric; DNA methylation classification; glioneuronal tumour; monosomy 14 EN brain tumour paediatric DNA methylation classification glioneuronal tumour monosomy 14 464 467 4 03/24/21 20210401 NES 210401 In this study, we report three paediatric cases of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC). Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC) - a molecularly defined glioneuronal CNS tumour class displaying recurrent monosomy 14. [Extracted from the article]

Aims: DNA methylation‐based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. Patients and methods: DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. Results: Genome‐wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation‐defined variant of low‐grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. Conclusions: DNA methylation‐based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation‐defined class of low‐grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma‐like features and nuclear clusters. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the expression of somatostatin receptors (SSTRs) and markers of mTOR pathway in paediatric glioneuronal tumours and correlate these findings with tumour type, BRAFV600E mutational status and clinical characteristics such as tumour location, seizure frequency and duration, and age.Method: 37 children and adolescents with a neuropathological diagnosis of glioneuronal tumour were identified over a 22-year period. Immunohistochemical analyses for SSTRs type 1, 2A, 3, 5 and ezrin-radixin-moesin (ERM) and phosphorylated S6 (pS6), which are indicators of mTOR pathway activation, were performed in tumour specimens from 33 patients and evaluated using the immunoreactive score (IRS). The IRS were compared to tumour type, BRAFV600E status and clinical characteristics.Results: Ganglioglioma (GG) was the most frequently encountered subgroup (n = 27), followed by dysembryoplastic neuroepithelial tumour (DNET; n = 4). GGs expressed SSTR2A and SSTR3 to a high extent, 56 % and 44 % respectively. Expression of SSTR2A was also found in DNETs. Signs of mTOR pathway activation were abundant in GGs, but only present in one DNET. No correlations with BRAFV600E presence or clinical characteristics were found.Conclusions: Expression of SSTRs and activation of mTOR pathway in paediatric glioneuronal tumour suggest that somatostatin analogues and mTOR inhibitors may have potential therapeutic implications in a subset of inoperable childhood glioneuronal tumours causing medically refractory epilepsy and/or tumour growth. Further clinical studies are warranted to validate these findings. [ABSTRACT FROM AUTHOR]

Rosette-forming glioneuronal tumour (RGNT) of the fourth ventricle is one of the newly described primary tumours of the central nervous system. These tumours have two components of both neurocytic and glial areas but usually the glial component of the tumour predominates. They have biphasic cytoarchitecture with two elements; neurocytic rosettes resembling Homer-Wright rosettes, and astrocytic component resembling a pilocytic astrocytoma. They are low-grade tumours with lack of histopathological signs of malignancy. Here, clinical, magnetic resonance, computed tomography (CT) and pathological features of rosette-forming glioneuronal tumour of posterior fossa are presented. A 29-year-man was admitted with an acute neurological deterioration. A three ventricular hydrocephalus and a hypo-density around vermis in the posterior fossa were seen in his CT scans. He did well after an emergency external ventricular drainage. He had an elective operation and a mass that was reported to be a rosette-forming glioneuronal tumour of the fourth ventricle was excised.

Brain tumours are the second most common cause of seizures identified in epilepsy surgical series. While any tumour involving the brain has the potential to cause seizures, specific subtypes are more frequently associated with epilepsy. Tumour‐related epilepsy (TRE) has a profound impact on patients with brain tumours and these seizures are often refractory to anti‐epileptic treatments, resulting in long‐term disability and patient morbidity. Despite the drastic impact of epilepsy‐associated tumours on patients, they have not traditionally enjoyed as much attention as more malignant neoplasms. However, recently a number of developments have been achieved towards further understanding of the molecular and developmental backgrounds of specific epilepsy‐associated tumours. In addition, the past decade has seen an expansion in the literature on the pathophysiology of TRE. In this review, we aim to summarize the mechanisms by which tumours may cause seizures and detail recent data regarding the pathogenesis of specific developmental epilepsy‐associated tumours. [ABSTRACT FROM AUTHOR]

Glioneuronal tumours are an important cause of treatment-resistant epilepsy. Subtypes of tumour are often poorly discriminated by histological features and may be difficult to diagnose due to a lack of robust diagnostic tools. This is illustrated by marked variability in the reported frequencies across different epilepsy surgical series. To address this, we used DNA methylation arrays and RNA sequencing to assay the methylation and expression profiles within a large cohort of glioneuronal tumours. By adopting a class discovery approach, we were able to identify two distinct groups of glioneuronal tumour, which only partially corresponded to the existing histological classification. Furthermore, by additional molecular analyses, we were able to identify pathogenic mutations in BRAF and FGFR1, specific to each group, in a high proportion of cases. Finally, by interrogating our expression data, we were able to show that each molecular group possessed expression phenotypes suggesting different cellular differentiation: astrocytic in one group and oligodendroglial in the second. Informed by this, we were able to identify CCND1, CSPG4, and PDGFRA as immunohistochemical targets which could distinguish between molecular groups. Our data suggest that the current histological classification of glioneuronal tumours does not adequately represent their underlying biology. Instead, we show that there are two molecular groups within glioneuronal tumours. The first of these displays astrocytic differentiation and is driven by BRAF mutations, while the second displays oligodendroglial differentiation and is driven by FGFR1 mutations. [ABSTRACT FROM AUTHOR]

Rosette-forming glioneuronal tumour (RGNT) of the fourth ventricle is one of the newly described primary tumours of the central nervous system. These tumours have two components of both neurocytic and glial areas but usually the glial component of the tumour predominates. They have biphasic cytoarchitecture with two elements; neurocytic rosettes resembling Homer-Wright rosettes, and astrocytic component resembling a pilocytic astrocytoma. They are low-grade tumours with lack of histopathological signs of malignancy. Here, clinical, magnetic resonance, computed tomography (CT) and pathological features of rosette-forming glioneuronal tumour of posterior fossa are presented. A 29-year-man was admitted with an acute neurological deterioration. A three ventricular hydrocephalus and a hypo-density around vermis in the posterior fossa were seen in his CT scans. He did well after an emergency external ventricular drainage. He had an elective operation and a mass that was reported to be a rosette-forming glioneuronal tumour of the fourth ventricle was excised. [ABSTRACT FROM AUTHOR]

We describe three unusual tumours characterized by a mixture of glial and neuronal differentiation, involvement of the posterior fossa and formation of rosettes. Mixed glial-neuronal tumours of the posterior fossa are rare and poorly described neoplasms. However, several distinctive entities have appeared in the literature over recent years under a variety of different names. Our cases demonstrate the morphological features of the ‘rosette-forming glioneuronal tumour of the fourth ventricle’, a recently identified tumour characterised by its unique location, neurocytic pseudo-rosette formation and the presence of a low grade astrocytoma component. The long term prognosis of these tumours remains unclear. However, the clinical data available including the cases presented here, along with the histological features, suggest that these are low grade tumours with a good prognosis after surgical resection. [ABSTRACT FROM AUTHOR]

We describe four patients, ranging from 26– 40 years of age, who presented with seizures and large, poorly circumscribed cerebral tumours on magnetic resonance imaging. The resected tumours demonstrated a histopathology similar to low-grade glioma, but with admixed mature neurones. Immunohistochemistry demonstrated expression of putative neuronal antigens in the neuronal component as well as in tumour cells which did not show neuronal morphology. These tumours did not have the usual radiological and pathological features typical of gangliogliomas, but demonstrated an infiltrative pattern of growth and subsequent progressive behaviour. The term ganglioglioma, with its implication of good prognosis, is therefore inappropriate for tumours of this type. The expression of “neuronal” antigens by astrocytomas requires further investigation. [ABSTRACT FROM AUTHOR]

Among the mixed glioneuronal tumours, a new variant called papillary glioneuronal tumour has recently been delineated. A case occurring in a 23-year-old man is reported. The tumour was cystic with a mural nodule enhanced by gadolinium injection. It was located within the left parieto-occipital lobe. Surgical excision showed a greyish friable tumour with cystic areas. Histopathological examination revealed a pseudopapillary component comprising a single layer of regular cells, arranged around hyalinised vessels. These cells were immunoreactive with anti-glial fibrillary acidic protein and HNK1 antibodies. A neurocytoma-like component coexisted with round blind cells and focal fibrillary rosettes. These cells were immunostained by anti-neuron-specific enolase and anti-synaptophysin antibodies. Neither mitoses nor ganglioid cells were seen. HNK1, the three isoforms of NCAM, and the L1 adhesion molecule were detected by Western blot analysis. Ultrastructural study showed three different types of cells. The first contained gliofilaments, the second showed long processes with true synapses, and the third was poorly differentiated. However, all had identical nuclei and contained dense bodies. These findings suggest a common origin for the tumour cells derived from a bipotential neuroglial progenitor. As for other mature mixed neuroglial tumours, the prognosis is good. Our patient is free of disease 7 years after complete surgical treatment. [ABSTRACT FROM AUTHOR]

Glioneuronal tumours, although rare, are an important cause of treatment-resistant epilepsy. Differential diagnosis of glioneuronal tumour subtypes is complicated by their variable histological appearance and the lack of pathognomonic histological or molecular biomarkers. In this study we have applied techniques available in a diagnostic laboratory setting to characterise molecular and cytogenetic abnormalities in a single institution cohort of glioneuronal tumours. A cohort of 29 glioneuronal tumours that included 21 gangliogliomas and 5 dysembryoplastic neuroepithelial tumours (DNETs) was analysed using low pass whole genome sequencing (WGS) and 2 multiplex ligation-dependent probe amplification (MLPA) central nervous system (CNS) tumour probesets. Low pass WGS identified chromosomal or subchromosomal alterations in 15 specimens. The most common chromosomal alterations were gains of chromosome 7 (n = 8) and chromosome 16 (n = 3). The BRAFV600E mutation was detected by MLPA in 9/21 (42.9%) gangliogliomas and 2/2 pleomorphic xanthoastrocytomas (PXAs). Chromosome 7 gains detected by WGS were reflected in MLPAs by overall gains of chromosome 7 gene probes, including those for BRAF , KIAA1549 and EGFR , while an internal BRAF/MKRN1 duplication was detected in a single ganglioglioma. Homozygous CDKN2A/B loss was detected by MLPA in 3 gangliogliomas, with p16 immunohistochemistry supporting these results. The combination of low pass WGS and MLPA identifies multiple, diverse genetic and chromosomal alterations in glioneuronal tumours, irrespective of histological tumour grade. Differential diagnosis of glioneuronal tumour subtypes is complicated by their variable histological appearance and the lack of pathognomonic histological or molecular biomarkers. In this study we demonstrate the utility of methods practicable in diagnostic laboratory settings, low coverage whole genome sequencing and multiplexed ligand-dependent probe amplification (MLPA), to strengthen the molecular characterisation of glioneuronal tumour subtypes. [Display omitted] • Epilepsy-associated glioneuronal tumours contain glial and neuronal lesional cells. • Differential diagnosis is hindered by overlapping tumour features. • Limited biomarker availability further restricts diagnostic pathology. • Low pass WGS and MLPA identify diverse chromosomal and genetic abnormalities. • Chromosomal and genetic changes do not correlate with histological tumour grade. [ABSTRACT FROM AUTHOR]

Abstract: Pleomorphic xanthoastrocytoma (PXA) is a rare primary astrocytic tumour of the nervous system usually involving the superficial temporal cortex of children and young adults. Although the tumour may exhibit histological features of pleomorphism or cellular atypia, the overall prognosis is good compared with other glial tumours, with only 30% of PXA recurring and 20% undergoing anaplastic transformation. Increased mitotic activity, high MIB-1 and proliferating cell nuclear antigen labelling indices and necrosis are poor prognostic factors, whereas abundant lymphocytic infiltration is associated with more benign biological behaviour. Rarely, in older patients, PXA may have a poor prognosis as these patients tend to have intracranial hypertension and focal deficits, as well as histological features of mitosis, increased cellularity and necrosis. We report the case of a 76-year-old woman who presented with dysphasia and right hemiparesis. A left fronto-temporal lobe PXA was misdiagnosed as glioblastoma multiforme. Although a rare and benign tumour type, PXA in the elderly tend to be more malignant, may have the radiological appearance of a malignant tumour and have poor prognosis. [Copyright &y& Elsevier]