Paediatric high-grade gliomas (pHGGs) are the most lethal brain tumours in children, characterised by profound epigenetic dysregulation and limited treatment options. The 2021 WHO Classification has established a molecular framework that distinguishes pHGGs as biologically distinct from adult glioblastoma, recognising four major subtypes: H3K27-altered diffuse midline glioma, H3G34-mutant diffuse hemispheric glioma, infant-type hemispheric glioma, and the rare IDH-mutant gliomas. Each subtype exhibits unique epigenetic landscapes, metabolic dependencies, and therapeutic vulnerabilities, necessitating subtype-specific treatment strategies. This review explores the molecular classification of pHGGs and examines the critical role of the tumour microenvironment in disease progression. We focus on glioma stem cells as central drivers of tumour initiation, maintenance, and therapeutic resistance, highlighting their remarkable cellular plasticity and ability to dynamically transition between different states. Particular attention is given to metabolic reprogramming in pHGGs, including alterations in glucose and lipid metabolism, and the exceptional metabolic flexibility of glioma stem cells that enables adaptation to microenvironmental pressures. Importantly, we discuss the intimate crosstalk between metabolism and epigenetic regulation, whereby metabolites serve as essential cofactors for chromatin-modifying enzymes-exemplified by α-ketoglutarate maintaining low H3K27me3 in H3K27M tumours and 2-hydroxyglutarate driving hypermethylation in IDH-mutant gliomas. We review preclinical models that have advanced pHGG research and discuss emerging immunotherapeutic approaches, including CAR T-cell therapies and oncolytic viruses. By synthesising current understanding of pHGG biology, this review aims to identify promising therapeutic avenues that exploit the unique metabolic and epigenetic vulnerabilities of each molecular subtype.

We report a child with an antenatally detected brain tumor that progressed over three years' time despite surgery, chemo- and proton therapy. Retrospective whole-genome and transcriptome sequencing with methylation analysis of primary tumor tissue led to the molecular diagnosis infant-type hemispheric glioma, and identified a novel SNRNP70::ALK fusion, providing a therapeutic target for compassionate-use precision treatment with the ALK tyrosine kinase inhibitor lorlatinib. Functional studies confirmed the fusion protein to be expressed and active in the patient's tumor. After two years of therapy, the child has sustained partial tumor regression on MRI and no new neurological symptoms. We conclude that comprehensive multi-omics analyses are required for correct molecular diagnosis in childhood CNS tumors and can radically impact patient outcome by identifying molecular targets for precision treatment.

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions, although present in fewer than 2 % of gliomas, are recognized oncogenic drivers. With the approval of NTRK-targeted therapies, increasing attention has focused on these tumors, as targeted treatments may substantially enhance outcomes. This study aimed to characterize the pathological features and molecular diversity of pediatric NTRK-rearranged gliomas to inform targeted therapeutic strategies. We analyzed six pediatric gliomas harboring NTRK fusions, identified through next-generation DNA sequencing (n = 5) and fluorescence in situ hybridization (n = 6). All tumors were supratentorial, involving the cerebral hemispheres (n = 3), thalamus (n = 2), and pineal region (n = 1). All infantile cases (n = 3) demonstrated high-grade histology and predominantly involved NTRK1, with one NTRK3 fusion. The three low-grade gliomas included two with NTRK1 and one with NTRK2 rearrangement. Dual gene fusions were identified in one case with intrachromosomal BCAN exon 14-NTRK1 exon 11 and NTRK1 exon 8-ARHGEF11 exon 2 rearrangements. One case harbored triple gene fusions, including interchromosomal ETV6-NTRK3 and PHYH-ETV6 fusions and an intrachromosomal NTRK3 rearrangement. Additional genetic alterations were detected in three cases, involving CDKN2A/B, TP53, ROS1, ABL1, MSH2, ARID4A, and CHEK1. DNA methylation profiling showed no collective methylation class and low-confidence matches to established methylation families. This study expands the clinicopathological and molecular spectrum of pediatric NTRK-rearranged gliomas, including rare entities and complex fusion patterns, and supports routine NTRK testing in pediatric gliomas irrespective of histological grade.

Desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) is a rare, low-grade tumor of infants. They are usually composed of a mixed astrocytic and neuronal component with desmoplastic stroma and embryonal-looking areas. Despite some recent reports, clinical, morphological and molecular features of DIG/DIAs are still not well characterized. Here, we present a series of 8 DIG/DIA cases. Hacettepe University and Koc University Hospital, Departments of Pathology, databases were screened for DIG/DIA. Eight patients were identified. All the slides were reevaluated, and patients' clinical data were obtained. All cases were tested for BRAF V600 mutation and 3 BRAF V600 wild-type cases were sequenced. Median age at the diagnosis was 5.5 months (4-30 months). The female to male ratio was 6:2. Two cases recurred. Four cases showed BRAF p. V600 mutation. Of those BRAF p. V600 wild-type cases, one harbored TMEM106B::BRAF fusion, described for the first time in a DIG/DIA case. DIG/DIA is a low-grade tumor seen in early childhood and characterized by an indolent clinical course. The most common molecular signature of these tumors is BRAF alterations, including rearrangements. The primary differential diagnosis is infant-type hemispheric glioma and given the similarities, pathologists must remain careful to ensure accurate diagnosis.

Infant-type hemispheric glioma is a high-grade cellular astrocytoma that arises in the cerebral hemispheres in early childhood. It is characterized by receptor tyrosine kinase fusions, typically involving genes such as the NTRK family, ROS1, ALK, or MET. This tumor type represents a distinct diagnostic category in the fifth edition of the WHO Classification of Tumors of the Central Nervous System. Here, we present a congenital brain tumor case that developed in the left lateral ventricle with EML4::ALK fusion, and was classified as an infant-type hemispheric glioma. The patient was found to have hydrocephalus and a brain tumor in utero. Central pathologists made a diagnosis of high-grade anaplastic astrocytoma with EML4::ALK fusion. The patient underwent radical tumor resection and a combination of chemotherapies. She is now 7 years old and doing well with no recurrence. To our knowledge, this is the first report of a congenital intraventricular tumor with EML4::ALK fusion.