Glioneuronal and neuronal tumors: A perspective.

Glioneuronal and neuronal tumors (GNTs) are slow-growing, lower-grade neuroepithelial tumors characterized by mature neuronal differentiation and, less consistently, glial differentiation. Their identification has traditionally relied on histological proof of neuronal differentiation, reflecting the well-differentiated nature of GNTs. However, after discovering genetic alterations in GNTs, particularly those in the MAP-kinase pathway, it became evident that histological diagnoses do not always correlate with genetic alterations and vice versa. Therefore, molecular-based classification is now warranted since several inhibitors targeting the MAP-kinase pathway are available. The World Health Organization classification published in 2021 applied DNA methylation profiling to segregate low-grade neuroepithelial tumors. As GNTs are essentially indolent, radical resection and unnecessary chemoradiotherapy may be more harmful than beneficial for patients. Preserving tumor tissue for potential future treatments is more important for patients with GNTs.

Extra-temporal pediatric low-grade gliomas and epilepsy.

Low-grade gliomas, especially glioneuronal tumors, are a common cause of epilepsy in children. Seizures associated with low-grade pediatric tumors are medically refractory and present a significant burden to patients. Often, morbidity and patients´ quality of life are determined rather by the control of seizures than the oncological process itself and the resolution of epilepsy represents an important part in the treatment of LGGs. The pathogenesis of tumor-related seizures in focal LGG tumors is multifactorial, and mechanisms differ probably among patients and tumor types. Pediatric low-grade tumors associated with epilepsy include a series of neoplasms that have a pure astrocytic or glioneuronal lineage. They are usually benign tumors with a neocortical localization typically in the temporal lobes, but also in other supratentorial locations. Gangliogliomas and dysembryoplastic neuroepithelial tumors (DNET) are the most common entities together with astrocytic gliomas (pilocytic astrocytomas and pleomorphic xanthoastrocytoma) and angiocentric gliomas, and dual pathology is found in up to 40% of glioneuronal tumors. The treatment of low-grade gliomas and associated epilepsy is based mainly on resection and the extent of surgery is the main predictor of postoperative seizure control in patients with a LGG. Long-term epilepsy-associated tumors (LEATs) tend to be well-circumscribed, and therefore, the chances for a complete resection and epilepsy control with a safe approach are very high. New treatments have emerged as alternatives to open microsurgical approaches, including laser thermal ablation or the use of BRAF inhibitors. Future advances in identifying seizure-related biomarkers and molecular tumor pathways will facilitate targeted treatment strategies that will have a deep impact both in oncologic and epilepsy outcomes.

Role of sodium fluorescein in pediatric low-grade glioma surgery: an update.

PURPOSE: Complete surgical resection is still the mainstay in the treatment of central nervous system low-grade tumors, eventually resulting curative. The complete surgical removal of these lesions, however, may be difficult in some cases because of their infiltrative nature. Intraoperative adjuncts may be a game changer. Sodium fluorescein (SF) is among the ideal candidates as intraoperative tools to favor the actual recognition of the tumor extension, since it accumulates in areas of altered blood-brain barrier, a typical characteristic of pediatric gliomas, and has a low rate of adverse events. This work proposes an update of previous works about the evaluation of the feasibility and usefulness of a systematic use of SF in a low-grade lesion group of pediatric patients. METHODS: Pediatric patients operated on for a resection or a biopsy of a low-grade glial or glioneuronal lesion (WHO grade I and II) at our Institution between September 2021 and December 2023, with the intraoperative use of sodium fluorescein (SF), were enrolled in the study. We collected pre-operative and postoperative clinical and radiological data, intraoperative findings, and post-operative pathological diagnoses. RESULTS: No adverse events were registered related to the intraoperative use of SF. SF appeared useful for the localization of boundaries of tumors, especially when characterized by a high degree of infiltration or by a deep-seated location, and for the checking of possible tumor remnants at the end of surgery. A good tumor-to-healthy tissue contrast was registered when tumor visualization was in a range between 1 to 2 h and 30 min after SF injection. Possible "false positives" due to intraoperative vascular wall injury and clearance of SF from both tumor and healthy tissue were observed in some cases and still remain open issues. CONCLUSIONS: SF is a feasible and safe intraoperative adjunct tool in the surgical removal of pediatric low-grade tumors. SF may show its usefulness especially in selected cases, such as deep-seated lesions and infiltrating tumors. Its safety profile, user-friendly management, and potential utility in both tumor resections and neuronavigated biopsies favor its wider use in the surgical treatment of pediatric low-grade tumors.

Treatment of Pediatric Low-Grade Gliomas.

PURPOSE OF REVIEW: Pediatric low-grade gliomas and glioneuronal tumors (pLGG) account for approximately 30% of pediatric CNS neoplasms, encompassing a heterogeneous group of tumors of primarily glial or mixed neuronal-glial histology. This article reviews the treatment of pLGG with emphasis on an individualized approach incorporating multidisciplinary input from surgery, radiation oncology, neuroradiology, neuropathology, and pediatric oncology to carefully weigh the risks and benefits of specific interventions against tumor-related morbidity. Complete surgical resection can be curative for cerebellar and hemispheric lesions, while use of radiotherapy is restricted to older patients or those refractory to medical therapy. Chemotherapy remains the preferred first-line therapy for adjuvant treatment of the majority of recurrent or progressive pLGG. RECENT FINDINGS: Technologic advances offer the potential to limit volume of normal brain exposed to low doses of radiation when treating pLGG with either conformal photon or proton RT. Recent neurosurgical techniques such as laser interstitial thermal therapy offer a "dual" diagnostic and therapeutic treatment modality for pLGG in specific surgically inaccessible anatomical locations. The emergence of novel molecular diagnostic tools has enabled scientific discoveries elucidating driver alterations in mitogen-activated protein kinase (MAPK) pathway components and enhanced our understanding of the natural history (oncogenic senescence). Molecular characterization strongly supplements the clinical risk stratification (age, extent of resection, histological grade) to improve diagnostic precision and accuracy, prognostication, and can lead to the identification of patients who stand to benefit from precision medicine treatment approaches. The success of molecular targeted therapy (BRAF inhibitors and/or MEK inhibitors) in the recurrent setting has led to a gradual and yet significant paradigm shift in the treatment of pLGG. Ongoing randomized trials comparing targeted therapy to standard of care chemotherapy are anticipated to further inform the approach to upfront management of pLGG patients.

Incidentally exploring natural course of a rare entity: representative case for rosette-forming glioneuronal tumors.

Rosette-forming glioneuronal tumors (RGNT) are extremely rare mostly benign tumors of the central nervous system, which are often studied for its histological aspects despite relatively small numbers of clinical especially radiological knowledge.Despite the increasing number of publications on different localizations and treatment protocols, the morphologic and temporal development process of this rare tumor entity is not clear. We were able to coincidentally observe the entire course of the tumor growth of a RGNT on subsequent MRI examinations in a typical case with mild clinical symptoms and no other neurological illnesses, thus possible clinical complications were prevented.

Unusual radiological and histological presentation of a diffuse leptomeningeal glioneuronal tumor (DLGNT) in a 13-year-old girl.

Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are newly recognized as an entity in the 2016 revision of the WHO Classification of tumors of the central nervous system. They typically present as diffuse leptomeningeal infiltrates along the neuraxis with focal and superficial involvement of the parenchyma. Here, we report a DLGNT with unusual radiological and histological features. A 13-year-old girl presented with scoliosis and back pain. Magnetic resonance imaging demonstrated a syrinx from C2 to T11 and an intramedullary mass from T6 to T9-10. No leptomeningeal involvement was recognized. Histological examination of the gross total resection specimen revealed a low-grade neuroepithelial neoplasm predominantly infiltrating the spinal cord and only focally involving the leptomeninges. Chromosome microarray identified co-deletion of the short arm of chromosome 1 and the long arm of chromosome 19 as well as fusion of the KIAA1549 and BRAF genes. Next-generation sequencing demonstrated wild-type alleles at the mutational hotspots of IDH1 (R132) and IDH2 (R140 and R172). In contrast to most reported DLGNTs, the tumor described in this manuscript was characterized by a predominant parenchymal component and only minor leptomeningeal involvement both radiographically and histologically. Our case, therefore, expands the spectrum of radiological and histopathological features of this new entity. It also highlights the critical role of molecular genetic testing in establishing the diagnosis of DLGNT in unusual cases.

Noonan syndrome, PTPN11 mutations, and brain tumors. A clinical report and review of the literature.

Noonan syndrome (NS), an autosomal dominant disorder, is characterized by short stature, congenital heart defects, developmental delay, and facial dysmorphism. PTPN11 mutations are the most common cause of NS. PTPN11 encodes a non-receptor protein tyrosine phosphatase, SHP2. Hematopoietic malignancies and solid tumors are associated with NS. Among solid tumors, brain tumors have been described in children and young adults but remain rather rare. We report a 16-year-old boy with PTPN11-related NS who, at the age of 12, was incidentally found to have a left temporal lobe brain tumor and a cystic lesion in the right thalamus. He developed epilepsy 2 years later. The temporal tumor was surgically resected because of increasing crises and worsening radiological signs. Microscopy showed nodules with specific glioneuronal elements or glial nodules, leading to the diagnosis of dysembryoplastic neuroepithelial tumor (DNT). Immunohistochemistry revealed positive nuclear staining with Olig2 and pERK in small cells. SHP2 plays a key role in RAS/MAPK pathway signaling which controls several developmental cell processes and oncogenesis. An amino-acid substitution in the N-terminal SHP2 domain disrupts the self-locking conformation and leads to ERK activation. Glioneuronal tumors including DNTs and pilocytic astrocytomas have been described in NS. This report provides further support for the relation of DNTs with RASopathies and for the implication of RAS/MAPK pathways in sporadic low-grade glial tumors including DNTs. © 2017 Wiley Periodicals, Inc.

Posterior cortex epilepsy surgery in childhood and adolescence: Predictors of long-term seizure outcome.

OBJECTIVE: We aimed to investigate the long-term seizure outcome of children and adolescents who were undergoing epilepsy surgery in the parietooccipital cortex and determine their predictive factors. METHODS: We retrospectively analyzed the data of 50 consecutive patients aged 11.1 (mean) ± 5.1 (standard deviation) years at surgery. All patients but one had a magnetic resonance imaging (MRI)-visible lesion. Resections were parietal in 40%, occipital in 32%, and parietooccipital in 28% cases; 24% patients additionally underwent a resection of the posterior border of the temporal lobe. Etiology included focal cortical dysplasia in 44%, benign tumors (dysembryoplastic neuroepithelial tumor, ganglioglioma, angiocentric glioma, and pilocystic astrocytoma) in 32%, peri- or postnatal ischemic lesions in 16%, and tuberous sclerosis in 8% cases. RESULTS: At last follow-up (mean 8 years, range 1.5-18 years), 60% patients remained seizure-free (Engel class I): 30% had discontinued and 20% had reduced antiepileptic drugs. Most seizure recurrences (71%) occurred within the first 6 months, and only three patients presented with seizures ≥2 years after surgery. Independent predictors of seizure recurrence included left-sided as well as parietal epileptogenic zones and resections. Longer epilepsy duration to surgery was identified as the only modifiable independent predictor of seizure recurrence. SIGNIFICANCE: Our study demonstrates that posterior cortex epilepsy surgery is highly effective in terms of lasting seizure control and antiepileptic drug cessation in selected pediatric candidates. Most importantly, our data supports the early consideration of surgical intervention in children and adolescents with refractory posterior cortex epilepsy.

Epilepsy surgery of "low grade epilepsy associated neuroepithelial tumors": A retrospective nationwide Italian study.

OBJECTIVE: To analyze the attitude and results of Italian epilepsy surgery centers in the surgical management of "low grade epilepsy associated neuroepithelial tumors" (LEATs). METHODS: We conducted a retrospective study enrolling 339 consecutive patients with LEATs who underwent surgery between January 2009 and June 2015 at eight Italian epilepsy surgery centers. We compared demographic, clinical, pathologic, and surgical features of patients with favorable (Engel class I) and unfavorable (Engel class II, III, and IV) seizure outcome. In addition, we compared patients with tumor-associated focal cortical dysplasia (FCD) and patients with solitary tumors to identify factors correlated with FCD diagnosis. RESULTS: Fifty-five (98.2%) of 56 patients with medically controlled epilepsy were seizure-free after surgery, compared to 249 (88.0%) of 283 patients with refractory epilepsy. At multivariate analysis, three variables independently predict unfavorable seizure outcome in the drug-resistant group. Age at surgery is largely the most significant (p = 0.001), with an odds ratio (OR) of 1.04. This means that the probability of seizure recurrence grows by 4% for every waited year. The resection site is also significant (p = 0.039), with a relative risk (RR) of 1.99 for extratemporal tumors. Finally, the completeness of tumor resection has a trend toward significance (p = 0.092), with an RR of 1.82 for incomplete resection. Among pediatric patients, a longer duration of epilepsy was significantly associated with preoperative neuropsychological deficits (p < 0.001). A statistically significant association was observed between FCD diagnosis and the following variables: tailored surgery (p < 0.001), temporal resection (p = 0.001), and surgical center (p = 0.012). SIGNIFICANCE: Our nationwide LEATs study gives important insights on factors predicting seizure outcome in refractory epilepsy and determining variability in FCD detection. Timely surgery, regardless of pharmacoresistance and oriented to optimize epileptologic, neuropsychological, and oncologic outcomes should be warranted.

Cerebral hemispheric low-grade glial tumors in children: preoperative anatomic assessment with MRI and DTI.

PURPOSE: The aims of this study are to analyze how the nature and the behavior of low-grade glial tumors (LGGT) in children may correlate with the anatomy of the cerebral hemispheres and to evaluate the consequent impact of diffusion tensor imaging (DTI) techniques in the presurgical assessment. METHODS: This is a combined review of a series of 155 cases of LGGT and of the recent literature on the subject. RESULTS: The cases retrieved from our data bank were divided in central hemispheric tumors (basal ganglia and thalami) (36 cases), glioneuronal cortical-based tumors (49 cases), and glial tumors of the cerebral mantle (70 cases). A close correlation was found in the thalamus between the primary location of the tumor (juxta-ventricular, inferior, lateral, bilateral) and its extension (ventricular lumen, midbrain and mesial temporal, globus pallidus, respectively) which may relate to the connectivity. Among the glioneuronal tumors, most gangliogliomas were located in the temporal lobe and especially in the mesial temporal structures. In addition, the morphologic feature of the ganglioglioma was different there from the neocortical areas. As a complementary approach, DTI data may assist in evaluating the structure and the extension of the LGGT, in addition to planning the surgical strategy. CONCLUSIONS: In the cerebral hemispheres like in the rest of the central nervous system, there is some degree of correlation between the anatomy and the nature, appearance, and behavior of the LGGT in children.

RAS/ERK signaling controls proneural genetic programs in cortical development and gliomagenesis.

Neural cell fate specification is well understood in the embryonic cerebral cortex, where the proneural genes Neurog2 and Ascl1 are key cell fate determinants. What is less well understood is how cellular diversity is generated in brain tumors. Gliomas and glioneuronal tumors, which are often localized in the cerebrum, are both characterized by a neoplastic glial component, but glioneuronal tumors also have an intermixed neuronal component. A core abnormality in both tumor groups is overactive RAS/ERK signaling, a pro-proliferative signal whose contributions to cell differentiation in oncogenesis are largely unexplored. We found that RAS/ERK activation levels differ in two distinct human tumors associated with constitutively active BRAF. Pilocytic astrocytomas, which contain abnormal glial cells, have higher ERK activation levels than gangliogliomas, which contain abnormal neuronal and glial cells. Using in vivo gain of function and loss of function in the mouse embryonic neocortex, we found that RAS/ERK signals control a proneural genetic switch, inhibiting Neurog2 expression while inducing Ascl1, a competing lineage determinant. Furthermore, we found that RAS/ERK levels control Ascl1's fate specification properties in murine cortical progenitors--at higher RAS/ERK levels, Ascl1(+) progenitors are biased toward proliferative glial programs, initiating astrocytomas, while at moderate RAS/ERK levels, Ascl1 promotes GABAergic neuronal and less glial differentiation, generating glioneuronal tumors. Mechanistically, Ascl1 is phosphorylated by ERK, and ERK phosphoacceptor sites are necessary for Ascl1's GABAergic neuronal and gliogenic potential. RAS/ERK signaling thus acts as a rheostat to influence neural cell fate selection in both normal cortical development and gliomagenesis, controlling Neurog2-Ascl1 expression and Ascl1 function.

Focal cortical dysplasias in temporal lobe epilepsy surgery: Challenge in defining unusual variants according to the last ILAE classification.

OBJECTIVE: Focal cortical dysplasias (FCDs) represent a common architectural cortical disorder underlying pharmacoresistant focal epilepsy. The recent ILAE classification defines different types of FCDs based on their histopathological features, MRI imaging, and presumed pathogenesis; however, their clinical features and their prognostic significance are still incompletely defined. In addition, the combination of different histopathological abnormalities can represent "unusual" subtypes that can be difficult to classify. The aim of our study was to analyze the incidence and the significance of these "unusual" subtypes of FCDs in drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: We retrospectively analyzed 133 patients consecutively submitted to tailored anteromesial temporal lobe resection for pharmacoresistant MTLE. Seizure onset, seizure duration, age at surgery, and postoperative seizure outcome were evaluated in relation to the different neuropathological groups defined according to the new ILAE classification. RESULTS: Focal cortical dysplasias were found in 80 out of 133 patients. Six patients were affected by isolated FCD type I, 12 patients by FCD type II, and 44 patients by FCD type III. Furthermore, we found 18 "atypical" cases (20.5% of all FCD cases and 26.6% of FCDs associated with a principal lesion): 10 cases of associated FCD type II-hippocampal sclerosis (HS) and 8 cases associated with FCD II-epilepsy-associated tumors (EATs). CONCLUSION: Our results indicate that "unusual" subtypes of FCDs, in particular associated FCD type II, are not uncommon findings, suggesting that they deserve a classification recognition. Similarities in seizure outcome and immunohistochemical and molecular evidences, shared by FCD type II+EATs and EATs, suggest a common pathogenic link. The choice to create a specific unifying class or, on the contrary, to also include "associated FCD type II" in the definition of the new unifying class FCD type III should be further discussed.

Rare variant of large pediatric glioneuronal tumor with novel MYO5A::NTRK3 fusion: illustrative case.

BACKGROUND: Glioneuronal tumors (GNTs) comprise a rare class of central nervous system (CNS) neoplasms with varying degrees of neuronal and glial differentiation that predominately affect children and young adults. Within the current 2021 World Health Organization (WHO) classification of CNS tumors, GNTs encompass 14 distinct tumor types. Recently, the use of whole-genome DNA methylation profiling has allowed more precise classification of this tumor group. OBSERVATIONS: A 3-year-old male presented with a 3-month history of increasing head circumference, regression of developmental milestones, and speech delay. Magnetic resonance imaging of the brain was notable for a large left hemispheric multiseptated mass with significant mass effect and midline shift that was treated with near-total resection. Histological and molecular assessment demonstrated a glioneuronal tumor harboring an MYO5A::NTRK3 fusion. By DNA methylation profiling, this tumor matched to a provisional methylation class known as "glioneuronal tumor kinase-fused" (GNT kinase-fused). The patient was later started on targeted therapy with larotrectinib. LESSONS: This is the first report of an MYO5A::NTRK3 fusion in a pediatric GNT. GNT kinase-fused is a provisional methylation class not currently included in the WHO classification of CNS tumors. This case highlights the impact of thorough molecular characterization of CNS tumors, especially with the increasing availability of novel gene targeting therapies.

Long-term monitoring of brain tumors: when is it necessary?

Tumors, particularly low grade glioma and glioneuronal tumors, account for 25-35% of patients who are undergoing epilepsy surgery for intractable seizures. A comprehensive epilepsy evaluation including video-electroencephalography (EEG) monitoring is useful for most of these patients, to determine the optimal extent of resection for the achievement of seizure-free outcome without causing postoperative deficits. Video-EEG monitoring for patients with brain tumor should also be considered in specific situations, such as patients with new postoperative seizures or advanced tumors with unexplained mental status change.

Dysembryoplastic neuroepithelial tumor, a pure glial tumor? Immunohistochemical and morphometric studies.

Dysembryoplastic neuroepithelial tumor (DNT) is a benign glioneuronal tumor, occurring in children and adolescents, typically associated with drug-resistant partial seizures. Pathologically, DNT is characterized by a specific glioneuronal element that is comprised of oligodendroglia-like cells (OLC) and floating neurons. The definition of DNT is currently controversial and the incidence of DNT varies among institutions. In this study we characterize the morphologic profiles of OLC and floating neurons by performing immunohistochemical and morphometric studies on seven cases of a simple form of DNT. While a majority of OLC was positive for oligodendrocyte transcription factor 2 (Olig2), only floating neurons and a few small cells were positive for neuronal nuclear antigens (NeuN). Double immunofluorescence studies revealed co-localization of Olig2 and galectin 3 in OLC, but no co-localization of Olig2 and NeuN. The distribution pattern of NeuN-positive nuclei within the tumor tissue was not different from that in the adjacent neural tissue. A section cut perpendicular to the cortex stained with NeuN showed a continuous laminar arrangement with the adjacent cortex. Densities of NeuN-positive nuclei from tumors embedded in the white matter were significantly lower than those from tumors in the gray matter. Our results suggest that the NeuN-positive small and large cells observed within the specific glioneuronal element are in fact entrapped granular and pyramidal cells within the cortex and that OLCs are essentially glial and not neuronal in nature. DNT is thus a pure glial tumor rather than a glioneuronal tumor, that is, the equivalent of non-infiltrating oligodendroglioma, grade I.

Recurrent TRAK1::RAF1 Fusions in pediatric low-grade gliomas.

Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5' of the kinase domain, while the breakpoints in the 3' partner preserved the N-terminal kinesin-interacting domain and coiled-coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non-classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re-resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.

Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline.

In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types. For those tumors, an integrated, "histomolecular" diagnosis is required. A variety of approaches exists for determining the status of the underlying molecular markers. The present guideline focuses on the methods that can be used for assessment of the currently most informative diagnostic and prognostic molecular markers for the diagnosis of gliomas, glioneuronal and neuronal tumors. The main characteristics of the molecular methods are systematically discussed, followed by recommendations and information on available evidence levels for diagnostic measures. The recommendations cover DNA and RNA next-generation-sequencing, methylome profiling, and select assays for single/limited target analyses, including immunohistochemistry. Additionally, because of its importance as a predictive marker in IDH-wildtype glioblastomas, tools for the analysis of MGMT promoter methylation status are covered. A structured overview of the different assays with their characteristics, especially their advantages and limitations, is provided, and requirements for input material and reporting of results are clarified. General aspects of molecular diagnostic testing regarding clinical relevance, accessibility, cost, implementation, regulatory, and ethical aspects are discussed as well. Finally, we provide an outlook on new developments in the landscape of molecular testing technologies in neuro-oncology.

Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor-like population.

Gangliogliomas are brain tumors composed of neuron-like and macroglia-like components that occur in children and young adults. Gangliogliomas are often characterized by a rare population of immature astrocyte-appearing cells expressing CD34, a marker expressed in the neuroectoderm (neural precursor cells) during embryogenesis. New insights are needed to refine tumor classification and to identify therapeutic approaches. We evaluated five gangliogliomas with single nucleus RNA-seq, cellular indexing of transcriptomes and epitopes by sequencing, and/or spatially-resolved RNA-seq. We uncovered a population of CD34+ neoplastic cells with mixed neuroectodermal, immature astrocyte, and neuronal markers. Gene regulatory network interrogation in these neuroectoderm-like cells revealed control of transcriptional programming by TCF7L2/MEIS1-PAX6 and SOX2, similar to that found during neuroectodermal/neural development. Developmental trajectory analyses place neuroectoderm-like tumor cells as precursor cells that give rise to neuron-like and macroglia-like neoplastic cells. Spatially-resolved transcriptomics revealed a neuroectoderm-like tumor cell niche with relative lack of vascular and immune cells. We used these high resolution results to deconvolute clinically-annotated transcriptomic data, confirming that CD34+ cell-associated gene programs associate with gangliogliomas compared to other glial brain tumors. Together, these deep transcriptomic approaches characterized a ganglioglioma cellular hierarchy-confirming CD34+ neuroectoderm-like tumor precursor cells, controlling transcription programs, cell signaling, and associated immune cell states. These findings may guide tumor classification, diagnosis, prognostication, and therapeutic investigations.

EANO - EURACAN - SNO Guidelines on circumscribed astrocytic gliomas, glioneuronal, and neuronal tumors.

In the new WHO 2021 Classification of CNS Tumors the chapter "Circumscribed astrocytic gliomas, glioneuronal and neuronal tumors" encompasses several different rare tumor entities, which occur more frequently in children, adolescents, and young adults. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is low particularly for adult patients, and draw recommendations accordingly. Tumor diagnosis, based on WHO 2021, is primarily performed using conventional histological techniques; however, a molecular workup is important for differential diagnosis, in particular, DNA methylation profiling for the definitive classification of histologically unresolved cases. Molecular factors are increasing of prognostic and predictive importance. MRI finding are non-specific, but for some tumors are characteristic and suggestive. Gross total resection, when feasible, is the most important treatment in terms of prolonging survival and achieving long-term seizure control. Conformal radiotherapy should be considered in grade 3 and incompletely resected grade 2 tumors. In recurrent tumors reoperation and radiotherapy, including stereotactic radiotherapy, can be useful. Targeted therapies may be used in selected patients: BRAF and MEK inhibitors in pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas when BRAF altered, and mTOR inhibitor everolimus in subependymal giant cells astrocytomas. Sequencing to identify molecular targets is advocated for diagnostic clarification and to direct potential targeted therapies.

The 2021 WHO Classification of Tumors of the Central Nervous System: An update on pediatric low-grade gliomas and glioneuronal tumors.

The 2021 5th edition of the WHO Classification of Tumors of the Central Nervous System reflects the discovery of genetic alterations underlying many central nervous system (CNS) neoplasms. Insights gained from technologic advances and novel applications in molecular diagnostics, including next-generation sequencing and DNA methylation-based profiling, coupled with the recognition of clinicopathologic correlates, have prompted substantial changes to CNS tumor classification; this is particularly true for pediatric low-grade gliomas and glioneuronal tumors (pLGG/GNTs). The 2021 WHO now classifies gliomas, glioneuronal tumors and neuronal tumors into 6 families, three of which encompass pLGG/LGNTs: "Pediatric type diffuse low-grade gliomas," "circumscribed astrocytic gliomas," and "glioneuronal and neuronal tumors." Among these are six newly recognized tumor types: "diffuse astrocytoma, MYB or MYBL1-altered"; "polymorphous low grade neuroepithelial tumor of the young (PLNTY)"; "diffuse low-grade glioma-MAPK altered"; "Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)"; "myxoid glioneuronal tumor (MGT)"; and "multinodular and vacuolating neuronal tumor (MVNT)." We review these newly recognized entities in the context of general changes to the WHO schema, discuss implications of the new classification for treatment of pLGG/LGNT, and consider strategies for molecular testing and interpretation.