Ganglioglioma is a glioneuronal tumor comprised of a combination of neoplastic ganglion and glial cells and associated with mutations in the MAPK signaling pathway. It is considered a central nervous system (CNS) World Health Organisation grade 1 tumor and is usually seen in a younger age group, particularly in the first two decades of life. The most common location is the temporal lobe, although they can occur anywhere in the central nervous system. They usually have an excellent prognosis, but around 5% of gangliogliomas are associated with aggressive behavior. Recurrence or malignant transformation in gangliogliomas is rare. We report an unusual case of recurrent aggressive ganglioglioma in a 12-year-old child with unexpected novel genotypic expression along with a brief review of literature.

Diffuse leptomeningeal glioneuronal tumor in an adult male without leptomeningeal enhancement: The diagnostic value of integrated molecular profiling.

A dysembryoplastic neuroepithelial tumor (DNET) is a low-grade, slow-growing brain tumor. It is a glioneuronal tumor, which means it contains properties of both glial and neuronal cells. DNETs can manifest as seizures that may be drug-resistant. The initial diagnosis is made by MRI or the radiological appearance is often suggestive. In this work we report the case of a patient in whom the DNET type tumor was revealed by convulsive seizures.

Myxoid glioneuronal tumors can harbor unusual PDGFRA alterations.

IntroductionRosette-forming glioneuronal tumor (RGNT) is characterized by astrocytic components and neurocytic cells forming rosette-like structures. While there have been recent reports of RGNTs arising in supratentorial regions, large tumors with contrast enhancement and hemorrhage remain rare. We report a case of a large cystic tumor in the right frontal lobe initially diagnosed as pilocytic astrocytoma (PA), which later recurred and was suspected to be RGNT.Case PresentationA 12-year-old girl presented with symptoms of increased intracranial pressure. MRI revealed a 6 cm cystic tumor with contrast enhancement and intratumoral hemorrhage in the right frontal lobe. She underwent biopsy, drainage, and subsequent gross total resection. However, local recurrence occurred five years later, and a second surgery was performed at the age of 16.Pathological FindingsThe initial specimen was diagnosed as PA, showing BRAF V600E wild-type, IDH1/2 wild-type, and TERT wild-type. The recurrent tumor showed neurocytic cells with medium-sized round nuclei forming rosettes and perivascular pseudorosettes, positive for synaptophysin and showing EGFR amplification, suggestive of RGNT. However, histology varied by resection site and included features of oligo-like cells (OLC), PA, dysembryoplastic neuroepithelial tumor (DNT), ganglioglioma (GG), and RGNT. DNA methylation profiling of the recurrent tumor indicated a DNT methylation class.DiscussionIt is rare for RGNT, GG, or DNT to present as large hemorrhagic tumors with acute symptoms. The initial specimen showed a single histological pattern without DNT features, whereas the recurrent specimen demonstrated heterogeneous histology depending on the tumor region. Whether this represents a single tumor entity or a collision tumor is currently under investigation with region-specific methylation analysis.ConclusionWe report a rare case of a large cystic tumor with recurrent components suggestive of RGNT, PA, DNT, and GG. Further accumulation of similar cases and detailed pathological analyses are needed.

Methylation of CpG islands plays a crucial role in the regulation of gene expression. The study of DNA methylation profiles offers deep insights into key oncogenic processes and facilitates the differentiation of tumor entities at the epigenetic level. Methylation profiling was performed on 8 CNS tumors (6 children, 1 adolescent, 1 young adult) with inconclusive diagnoses, available frozen tissue, and surgeries dating back over 5 years. Our goal was to correlate the resulting methylation classes with the clinical-radiological data and to evaluate the diagnostic and prognostic power of this analysis. The resulting molecularly defined diagnoses were: pilocytic astrocytoma (3 cases), pilocytic astrocytoma subclass FGFR1 altered (1 case), ganglioglioma (2 cases), diffuse leptomeningeal glioneuronal tumor subtype 1 (1 case), and diffuse midline glioma H3.3K27-altered, subtype H3K27 mutant or EZHIP-expressing (1 case). Clinico-pathological features of each tumor in our series are discussed. The clinical behavior was consistent with the molecular diagnosis in all cases but one that was lost to follow-up. In our series, the initial diagnostic failure in 3 of the 8 cases was due to the fact that the pathological entities-diffuse midline glioma, H3 K27-altered, pilocytic astrocytoma with FGFR1 alteration and diffuse leptomeningeal glioneuronal tumor -had not yet been fully characterized or widely recognized in the literature at the time of diagnosis. In the remaining cases, the lack of distinctive histopathological features hindered a definitive diagnosis. In conclusion, according to our experience, DNA methylation profile analysis represents a very attractive diagnostic tool and provides important support for the diagnosis and classification of CNS tumors.

Glioneuronal and neuronal tumors are defined histologically by the presence of mixed glial and neuronal elements in the case of glioneuronal tumors, and by neuronal elements in the case of neuronal tumors. In 2021, the World Health Organization (WHO) published the latest edition of central nervous system tumor classifications and added three new glioneuronal tumors, as well as further delineated histological, immunohistochemical, and molecular markers associated with the diagnosis of these tumors. This review aims to highlight the key updated features of glioneuronal and neuronal tumors in adults based on the 5th edition of the WHO classification of central nervous system tumors by clinical and epidemiological presentation, imaging appearance, and pathology.ABBREVIATIONS: DGONC = diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters; DLGNT = diffuse leptomeningeal glioneuronal tumor; DNET = dysembryoplastic neuroepithelial tumor; LEAT = long term epilepsy associated tumor; MGNT = myxoid glioneuronal tumor; MVNT = multinodular and vacuolating neuronal tumor; PGNT = papillary glioneuronal tumor; RGNT = rosette-forming glioneuronal tumor; WHO = World Health Organization.

SLC44A1::PRKCA fusion-positive glioneuronal tumor without histological and epigenetic features of papillary glioneuronal tumor.

Abstract Glioneuronal tumors with ATRX alteration, kinase fusion, and anaplastic features (GTAKA) are a recently identified, rare subset of glioneuronal tumors characterized by distinct molecular alterations, most notably NTRK gene fusions, ATRX mutations, and CDKN2A/B homozygous deletions. These tumors display more aggressive clinical behavior compared to typical low-grade glioneuronal tumors. We report the case of a 21-year-old male who presented with headaches, nausea, and vomiting. Brain MRI revealed a cystic, enhancing mass in the right basal ganglia extending to the midbrain, with hydrocephalus. Resection was performed, with histopathology and molecular profiling revealed a high-grade glioneuronal tumor with CCDC85::NTRK2 fusion, ATRX mutation, and CDKN2A/B deletion. These characteristics are consistent with the recently classified Glioneuronal tumors with ATRX alteration, kinase fusion, and anaplastic features (GTAKA). The patient completed 6 weeks of IMRT (60 Gy) with concurrent temozolomide and will proceed with adjuvant temozolomide. NTRK inhibitor therapy will be considered upon recurrence. There is a paucity of data in the management of this newly classified and molecularly distinct glioneuronal tumor. The median progression-free survival of 12.5 months is based on a limited series. While current treatment approaches are like any high-grade glioma, NTRK inhibitors may represent a promising option, particularly in the recurrent setting. Optimal timing, including possible use in the newly diagnosed setting, remain to be seen. GTAKA is a rare, high-grade glioneuronal tumor with distinct molecular features. Given its likely aggressive nature and possible actionable targets, molecular profiling is crucial. Further studies are needed to guide targeted treatment strategies.

Abstract BACKGROUND Dysembryoplastic neuroepithelial tumor (DNT) is a rare glioneuronal tumor that typically arises in childhood and is strongly associated with drug-resistant epilepsy. Diagnosis is often challenging due to histological heterogeneity. Therefore, DNT may be an ideal candidate for genome-wide DNA methylation profiling. However, integrated analyses combining histopathology and genome-wide DNA methylation profiling remain limited. METHODS We retrospectively analyzed the clinical data, histopathological diagnoses, and molecular findings of patients diagnosed with DNT or low-grade glioneuronal tumors mimicking DNT at the Japan Children’s Cancer Group Central Diagnosis between February 2016 and March 2025. RESULTS Twenty-three patients (12 males and 11 females) were included. The median age at the diagnosis was 11 years (range, 3 to 24 years). The majority were located in the temporal lobes (n=12) and other cortical regions (n=10), but a case was located in the third ventricle. Seizure onset was noted in 15 cases. FGFR1 tyrosine kinase domain internal tandem duplication was identified in 10 cases, and FGFR1 K656E mutation in 5 cases. Genome-wide DNA methylation profiling was available in 16 cases. According to the DKFZ classifier, 14 cases were classified as DNT, one as Pilocytic astrocytoma (PA), hemispheric, and one as Glioneuronal tumour, subtype A (novel). A case of PA, hemispheric was histopathologically diagnosed as DNT complex form and showed focal areas with PA morphology. Interestingly, a case of Glioneuronal tumour, subtype A (novel) showed atypical clinical features such as non-seizure onset and location in the third ventricle. It showed recurrence 5 years after an initial surgery with histopathological changes, including loss of specific glioneuronal elements and growth of multinucleated cells. CONCLUSIONS Discrepancy between histopathological diagnosis and DNA methylation classification may result from varied cellular composition. In addition, atypical DNA methylation classification may be associated with clinical signatures, requiring integrated analyses in larger cohorts.

Abstract OBJECTIVE To investigate the clinicopathological, immunohistochemistry, molecular characteristics, and prognosis of new entity-GTAKA (Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features). METHODS Seven GTAKA cases were collected and analyzed through histomorphological evaluation, immunohistochemistry (IHC), DNA methylation profiling, DNA&RNA sequencing and prognosis. A review of 28 reported cases (including our 7 cases) was conducted to compare clinicopathological and molecular features. RESULTS GTAKA predominantly affected children or young adults (median age: 18), with supratentorial localization. Histopathological patterns were identified: (1)Central neurocytoma-like; (2)Non-neurocytoma-like. IHC character: GFAP positive (7/7,100%), Olig2 positive (7/7,100%), Syn partly positive (7/7,100%), ATRX negative (5/7,71.4%), NKX2.2 positive (7/7,100%) and SOX10 positive (7/7,100%). Molecular profiling revealed all the cases have NTRK fusion and ATRX mutation. Methylation analysis revealed all the 7 cases were classified as “GTAKA” cluster. Survival outcome revealed GTAKA was worse than atypical central neurocytoma in our cohort (median OS: 35 VS. 78 months, P<0.001). CONCLUSION CNS GTAKA tumors exhibit distinct clinicopathological and molecular profiles, with DNA methylation profiling aiding accurate classification. The double strong positivity of NKX2.2 and SOX10 can be used as an immunohistochemical feature to assist in the diagnosis of GTAKA. Targeted NTRK inhibition is a promising therapeutic option. This study underscores the importance of recognizing GTAKA as a unique entity, providing critical insights for classification, prognostication, and personalized treatment.

Pediatric low-grade gliomas (pLGGs) are the most common brain tumors in children with varying degrees of infiltration. Despite having a positive prognosis, if the standard treatment, gross total resection, is impossible due to tumor location or diffuseness, outcomes worsen. Development of targeted therapeutics for diverse subtypes of pLGGs is limited by a lack of genetic models. We generated five fly pLGG models using patient-derived fusion genes to investigate molecular subtype-specific pathology, and found glial overexpression of QKI::RAF1, associated with pilocytic astrocytomas and glioneuronal tumors, induced aberrant glial migration and infiltration. Both repulsive guidance signaling and GPR180/CG9304 mediated glial infiltration, which was suppressed by glial overexpression of Robo2 or PlexA/B, or knockdown of GPR180/CG9304. ROBO2 and GPR180/CG9304 were down and upregulated, respectively, in flies and patients with RAF fusions. Our study provides mechanistic insights into pLGG tumorigenesis and suggests targeting repulsive guidance signaling and GPR180/CG9304 as potential therapeutics for pLGG subtypes.

Abstract Somatostatin type-2A receptors (SST2A) regulate cell growth through downstream modulation of proliferation and apoptosis signaling, representing a potential therapeutic target. Membranous SST2A protein expression has been identified immunohistochemically in certain pediatric CNS tumors, but little is known about functional expression by DOTATATE PET. CONNECT2007 (NCT05278208, currently accruing) is a multicenter phase I/II study investigating safety and efficacy of Lutathera (177Lu-DOTATATE), SST2A-targeted radionuclide therapy, in children and adults with recurrent/progressive SST2A-expressing CNS tumors. Eligibility screening consists of 68Ga-DOTATATE PET imaging for functional confirmation of adequate SST2A expression (Krenning score [KS] ≥2 out of 4) by central review. As of 05/2025, 22 patients (progressive meningioma [n=7], relapsed medulloblastoma [n=10], rarer high-grade glioneuronal tumors [n=5]) have undergone screening. Strong DOTATATE uptake was observed across all meningiomas, with mean KS=2.7 (range: 2-4), including two patients with germline predisposition syndromes (CHEK2, BAP1). DOTATATE uptake in medulloblastoma was variable (KS range: 0-3), potentially reflecting molecular heterogeneity: uptake was greater in two group 3 cases (KS=2, 3) and two children with SHH, TP53-mutant disease (KS=2, 3); uptake was less in three adolescent/young adult patients with SHH, TP53-wildtype disease (KS=0-1) and one young adult with WNT medulloblastoma (KS=0). Two patients with group 4 medulloblastoma had KS of 1 and 3. Among rarer entities, strong uptake (KS=3) was observed in high-grade diffuse leptomeningeal glioneuronal tumor and neuroepithelial tumor with suspected BCOR ITD, whereas cases of pineoblastoma, PFA ependymoma, and BCOR-fused high-grade neuro-epithelial tumor had KS of zero. Preliminary CONNECT2007 screening results provide insight into the prevalence and heterogeneity of targetable SST2A expression across high-risk pediatric and young adult CNS tumors. Strong DOTATATE uptake was identified in all patients with progressive meningiomas, some patients with medulloblastoma (particularly group 3 and SHH, TP53-mutant), and rarer high-grade glioneuronal tumors, suggesting a potential role for SST2A-targeted theranostics in these entities.

Abstract Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare, predominantly pediatric tumor, with adult-onset cases being exceedingly uncommon. Symptoms are non-specific, often presenting with headaches or signs of elevated intracranial pressure. Due to the rarity of adult-onset cases and the insidious nature of symptoms, delays in diagnosis and treatment are common. Furthermore, limited data on DLGNT restricts understanding of optimal management strategies. We report a case of a 65-year-old male who presented with isolated headaches. Magnetic resonance imaging (MRI) revealed diffuse leptomeningeal contrast enhancement involving the brain and spinal cord. Lumbar puncture revealed elevated intracranial pressure with elevated protein and a lymphocytic pleocytosis. Cytology was negative for tumor cells. A biopsy was initially deferred, and the patient was treated empirically for neurosarcoidosis, without clinical improvement. Eventually a brain biopsy was performed, which confirmed the diagnosis of DLGNT harboring a BRAF V600E. The patient is managed with BRAF/MEK inhibition with dabrafenib and trametinib. These therapies target this molecular abnormality directly. With this case report, we hope to further the knowledge of adult-onset DLGNTs and to further emphasize the clinical importance of surgical biopsy in establishing a definitive diagnosis.

Abstract High-grade (anaplastic) gangliogliomas are rare malignant glioneuronal tumors characterized by aggressive behavior and poor prognosis. While surgical resection is a mainstay of treatment, limited evidence exists on whether GTR confers a survival advantage over STR. This study evaluates whether gross total resection (GTR) is associated with improved overall survival compared to subtotal resection (STR) in patients with intracranial high-grade gangliogliomas. The National Cancer Database (NCDB) was queried for patients diagnosed with intracranial high-grade gangliogliomas (histology code 9505; behavior code 3) between 2004 and 2019 who underwent surgical resection. Patients were stratified by extent of resection (GTR vs. STR). Multivariable Cox proportional hazards analysis was performed, adjusting for age, sex, ethnicity, race, facility type, comorbidities, tumor size, adjuvant radiotherapy, and systemic therapy. Among 74 patients meeting inclusion criteria, 56.76% were male. Most were under 40 years old (47.30%), followed by those over 60 (28.38%) and those aged 40–60 (24.32%). GTR was achieved in 37 patients (50.00%), and STR in 37 (50.00%). Mean survival following GTR was 43.76 months, compared to 21.72 months for STR. On multivariate analysis, STR was associated with significantly increased mortality risk compared to GTR (hazard ratio [HR]=2.50, p=0.0117). Additional predictors of worse survival included male sex (HR=2.35, p=0.0190) and increasing age (HR=1.04, p=0.0002). Adjuvant radiotherapy and chemotherapy were not significantly associated with survival. GTR is associated with significantly improved overall survival compared to STR in high-grade gangliogliomas. This NCDB analysis suggests that maximal safe resection, alongside consideration of patient-specific factors like age and sex, may confer a survival benefit—underscoring the importance of complete tumor removal when feasible in managing anaplastic ganglioglioma.

Abstract Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare central nervous system neoplasm first defined in the 2016 WHO classification. Due to its rarity, most available data are limited to case reports or small series, and clinical management remains inconsistent. We conducted a PRISMA-compliant systematic review of DLGNT cases published between 2016 and June 2024 using PubMed, Embase, Scopus, Cochrane Library, and Google Scholar. A total of 76 patients from 42 publications were included. Data on demographics, imaging, pathology, molecular findings, treatment, and survival were extracted. Kaplan–Meier analysis and subgroup comparisons were performed. One institutional case was added. The overall cohort was predominantly pediatric (72%), with frequent spinal dissemination (61%) and hydrocephalus (62%). BRAF fusion was the most common molecular alteration. No significant differences in overall survival were found by age group, BRAF status, or treatment modality (all p > 0.99). In subgroup analysis by surgical extent, patients who underwent surgical resection (n = 19) showed a longer median progression-free survival (PFS; not reached) than those who had biopsy only (n = 57, median PFS = 19 months), though this difference was not statistically significant (p = 1.00). Our institutional case involved a young adult initially misdiagnosed with tuberculous meningitis and later confirmed as DLGNT via biopsy. The patient underwent craniospinal irradiation (36 Gy in 20 fractions) followed by 12 cycles of temozolomide chemotherapy. After 24 months of disease stability, the patient developed peritoneal seeding confirmed as DLGNT and died 29 months after diagnosis. DLGNT displays wide clinical and molecular heterogeneity, often with delayed diagnosis. Although surgical resection may offer longer PFS, current evidence is insufficient to reach statistical significance. This review highlights the need for early recognition, standardized management, and further investigation, especially in atypical disease courses such as extracranial dissemination.

This review consolidates current knowledge on genetic alterations observed in pediatric glial and glioneuronal tumors of the central nervous system (CNS). Some of these alterations serve as diagnostic biomarkers, whereas others may inform the selection of targeted therapeutic strategies. Drawing on both diagnostic and clinical perspectives, the authors aim to facilitate a more comprehensive understanding of the WHO Classification of CNS Tumors and to promote interdisciplinary collaboration. This resource is intended to support accurate tumor classification, guide molecular testing, and aid in identifying actionable genetic targets. The content may be of practical value to pediatric neuro-oncologists, molecular pathologists, neuropathologists, and researchers involved in CNS tumor diagnostics and treatment. For user convenience, selected data are summarized in tables.

BackgroundBrain tumors in low-and middle-income countries are understudied, with limited access to diagnostic tools, treatment, and structured data systems. Since 2019, a multidisciplinary neuro-oncology team has been operating in Abidjan, Côte d’Ivoire, contributing to collaborative care and progressive data collection.ObjectiveTo describe the clinical and histopathological characteristics of brain tumors managed by our multidisciplinary team and highlight patterns of care.MethodsWe retrospectively reviewed 225 histologically confirmed brain tumor cases discussed in neuro-oncology staff meetings between 2019 and 2024. A structured excel-based dataset compiled demographic, clinical, imaging, histological, therapeutic, and survival data. Kaplan-Meier survival analysis was performed using R software.ResultsThe cohort included 110 females and 115 males, with a mean age of 39.7 years (range: 1-82). Most patients (84,9%) had no health insurance, and 89.8% presented more than 3 months after symptom onset. Tumors were supratentorial in 172 cases, infratentorial in 41, sellar in 9, and pineal in 3. The most frequent histological types were meningiomas (n = 109), gliomas or glioneuronal tumors (n = 76) and medulloblastomas (n = 6). Surgery was performed in 98.7% of cases. Postoperative treatments included radiotherapy (n = 34), chemotherapy (n = 3), and concomitant chemoradiotherapy (n = 40). Median follow-up was 12 months, and the estimated overall survival remained above 75% at 20 months.ConclusionThis study provides valuable insight into the clinical and histological landscape of brain tumors in Côte d’Ivoire. The high rate of diagnostic delay underscore health system challenges. Our experience also highlights the importance of clinician-led data collection and supports the need for formal national brain tumor registry to improve research, and regional and international collaborations.

Background and AimsPediatric brain tumors (PBT) are a major cause of cancer-related mortality in children and display wide variation in histopathology, molecular characteristics, and prognosis. Although low-grade gliomas and glioneuronal tumors are relatively rare, they represent approximately 30% of pediatric central nervous system (CNS) tumors. Most data on PBT originate from high-income countries, resulting in limited epidemiologic information from low- and middle-income countries (LMICs). This study aims to describe the incidence and treatment modalities of pediatric low-grade gliomas at the Kilimanjaro Christian Medical Center (KCMC) Cancer Care Center in Northern Tanzania between December 2016 and October 2024.MethodsData on pediatric patients treated at the Cancer Care Center (CCC) between December 2016 and October 2024 were analyzed. Inclusion criteria were a diagnosis of a pediatric low-grade glioma and patients aged 0-19 at the time of diagnosis. All patients were previously diagnosed by computed tomography (CT)/magnetic resonance (MR) imaging. Variables were retrospectively collected from the patients’ medical records, which were: demographic characteristics (age, gender, Place of residence, and insurance status), previous history of malignant diseases, incidence date, and treatment modality.ResultsBetween 2016 and 2024, 35 pediatric brain tumor cases (4.6% of pediatric cancers) were diagnosed at CCC; low-grade gliomas comprised 20%, mostly males (57.1%). At diagnosis, 42.8% received curative care, 28.6% palliative care, 14.3% observation, and 14.3% died. All underwent surgery (VP shunt insertion and/or tumor resection), 57.1% had chemotherapy, 42.9% had radiotherapy, and 28.6% received all three treatments.ConclusionImproving access to screening, accurate diagnosis by specifically addressing challenges in histopathology, and treatment modalities are essential in identifying and managing pediatric low-grade glioma patients in our setting.

After leukemia, pediatric brain tumors are the second most common childhood malignancies and are associated with significant neurologic and developmental sequelae, rendering accurate and early diagnosis critical. The 2021 World Health Organization classification for central nervous system tumors emphasizes the utility of molecular pathology in distinguishing between pediatric and adult brain tumors. Imaging studies, including magnetic resonance imaging (T1-, T2-, diffusion-, and perfusion-weighted imaging, diffusion tensor imaging, and magnetic resonance spectroscopy) and positron emission tomography using fluorodeoxyglucose or amino acid tracers, integrate structural assessment with functional and quantitative techniques, enabling the evaluation of cellularity, perfusion, and metabolism. Characteristic imaging patterns support diagnosis and prognosis across tumor types, including diffuse gliomas (adult- and pediatric-type, low- and high-grade subtypes), circumscribed astrocytic gliomas, ependymomas, glioneuronal tumors, choroid plexus tumors, embryonal tumors (e.g., medulloblastoma), pineal region tumors, craniopharyngiomas, nerve sheath tumors, germ cell tumors, meningiomas, Langerhans cell histiocytosis, hamartomas, and cavernous malformations. Molecular features increasingly guide treatment strategies. Emerging technologies, such as radiomics and artificial intelligence (AI), are improving tumor classification, segmentation, and recurrence prediction, with advances such as federated learning and explainable AI supporting privacy-preserving and interpretable models. Imaging also plays roles beyond detection, including surgical planning, treatment monitoring, and prognostication. Future integration of multimodal imaging and AI is expected to improve precision, standardization, and individualized pediatric neuro-oncology care through rapid, noninvasive diagnostics.