Glioneuronal and Neuronal Tumors
2023-07-27 Scott Ryall, PhD Affiliation1.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)
Classification
Definition
The 2021 WHO guidelines for CNS tumor classification recognizes glioneuronal and neuronal tumors as those with a neuronal component. 1 This includes 14 entities: i) Ganglioglioma, ii) Gangliocytoma, iii) Desmoplastic infantile ganglioglioma/desmoplastic infantile astrocytoma (DIG/DIA), iv) Dysembryoplastic neuroepithelial tumor (DNET), v) Papillary glioneuronal tumor, vi) Rosette-forming glioneuronal tumor, vii) Diffuse leptomeningeal glioneuronal tumor, viii) Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease), vx) Central neurocytoma, x) Extraventricular neurocytoma, xi) Cerebellar liponeurocytoma, xii) Myxoid glioneuronal tumor, xiii) Multinodular and vacuolating neuronal tumor (MVNT), and xiv) Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC). 2 The former 3 are newly recognized entities, with DGONC currently considered provisional.
| Glioneuronal and Neuronal Tumors | Genetic Event(s) |
|---|---|
| Ganglioglioma | Gangliogliomas are caused by molecular alterations that result in up-regulation of the MAPK signaling pathway. The most common of these are BRAF p.V600E which occur in up to 60% of gangligliomas. 3-8 Gangliogliomas lacking BRAF p.V600E harbor other genetic alterations responsible for activating MAPK signaling which include non-canonical BRAF mutations, BRAF fusions, RAF1 fusions, KRAS mutations, FGFR1/FGFR2 mutations/fusions and NF1 alterations. 7 Most often, ganglioglioma harbor a single MAPK-activating event and are absent of secondary alterations, however a small subset has been reported with dual BRAF p.V600E and CDKN2A homozygous deletion, which may be indicative of a worsened prognosis. 7 Likewise, rare midline ganglioglioma have been reported with dual BRAF p.V600E and H3 p.K27M. 8-10 DNA methylation analysis identifies a distinct epigenetic signature for ganglioglioma, which may aid in diagnsotically challenging tumors, assuming the tumor cell content of the specimen is sufficient. 11 |
| Gangliocytoma | Currently, no defining molecular events are associated with gangliocytoma. Histologically related entities such as ganglioglioma frequently harbor MAPK pathway activating alterations and likely constitute a close genetic relationship to gangliocytoma. DNA methylation analysis has not uncovered a specific epigenetic signature associated with gangliocytoma that segregates them from other tumor entities. 11 |
| Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma | Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma (DIA/DIG) are characterized by alterations that activate the MAPK signaling pathway. Most commonly, these alterations manifest as mutations or fusions in BRAF or RAF1, including the canonical BRAF p.V600E mutation and KIAA1549::BRAF fusion, but also other non-canonical events involving these genes. 8,12-16 These alterations do not appear to co-occurr with other oncogenic events, including CDKN2A homozygous deletions. DNA methylation analysis has shown DIA/DIG to have a distinct epigenetic signature that classifies them separately them from other similar tumor entities. 11,15. |
| Dysembryoplastic neuroepithelial tumor | The most common genetic alterations in dysembryoplastic neuroepithelial tumors (DNET) are those involving FGFR1, which include internal tandem duplications of the tyrosine kinase domain, hotspot missense mutations (both familial and sporadic cases, with multiple mutations often present in cis), FGFR1::TACC1 fusions, and complete duplication of FGFR1 in order of prevalence. 8,17-20 These alterations have been shown to induce autophosphorylation of FGFR1 resulting in up-regulation the MAPK and PI3K signaling pathways. 18,21,22 BRAF p.V600E is also common in DNETs 3,17,22,23, although their presence may suggest an alternative diagnoses. Rarely, PDGFRA and NF1 mutations have been observed 17,22. DNA methylation analysis shows that DNET have a distinct methylation profile. 11 |
| Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters | Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC) is a provisional tumor type that can, at this time, only be reliably identified via DNA methylation analysis. 11 The unifying genetic event in these tumors is monosomy 14, which has been reported in 30/31 cases. No other specific recurrent alterations have been uncovered. 2,24 |
| Papillary glioneuronal tumor | The genetic hallmark of papillary glioneuronal tumors are gene fusions involving PRKCA. These almost exclusively manifest as SLC44A1::PRKCA, with extremely rare instances of NOTCH1::PRKCA. 25-27 These fusions result in the generation of a constitutively expressed oncoprotein thought to cause up-regulation of the MAPK signaling pathway. 25 DNA methylation analysis classifies papillary glioneuronal tumors as a distinct tumor entity with a highly characteristic and diagnostic epigenetic signature. 11,27 |
| Rosette-forming glioneuronal tumor | Rosette-forming glioneuronal tumors are genetically characterized by hotspot FGFR1 mutations at residues p.N546 or p.K656 which occur in combination with either PIK3CA or PIK3R1 mutations. 28-32 Loss-of-function mutations in NF1 can also occur in a subset of cases, but are not diagnostically specific. DNA methylation analysis shows that rosette-forming glioneuronal tumors have an epigenetic profile distinct from other tumor entities which can be a valuable diagnostic tool. 11,31 |
| Myxoid glioneuronal tumour | Myxoid glioneuronal tumors are genetically defined by a hotspot mutation in PDGFRA resulting in either p.K385L or p.K385I. 33-35 These mutations occur in the absence of PDGFRA amplifications and other accompanying genetic events. DNA methylation analysis shows that myxoid glioneuronal tumors have a distinct epigenetic signature closely related to that of DNETs in the cerebral cortex. 11,36 |
| Diffuse leptomeningeal glioneuronal tumor | Diffuse leptomeningeal glioneuronal tumors (DLGNT) frequently harbor alterations in genes of the MAPK signaling pathway, most commonly KIAA1549::BRAF fusions. 37 Other MAPK-related alterations include BRAF p.V600E and other BRAF alterations, NTRK1/NTRK2/NTRK3 fusions, FGFR1 mutations, and RAF1 rearrangements. 38-40 Deletions of chromosome 1p are seen in up to 100% of DLGNT, and in combination with 19q (1p/19q co-deletion) in 20-30% of tumors. 37,39,41 DNA methylation analysis identifies two epigenetic signatures associated with DLGNT that appears to separate tumors based on their age of onset, clinical course, and presence of 1p/19q co-deletions. 11,39 |
| Multinodular and vacuolating neuronal tumour | Multinodular and vacuolating neuronal tumors most commonly harbor small indels or hotspot mutations in MAP2K1, resulting in up-regulation of the MAPK signaling pathway. Less commonly, they may have pathogenic mutations in BRAF, although not the common p.V600E variant which appears to be excluded from this tumor type. Rare cases have been reported to have FGFR2 fusions. 42-45 |
| Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease) | Dysplastic cerebellar gangliocytoma, also called Lhermitte-Duclos disease, is characterized by slowly progressive unilateral hamartomatous cerebellar tumors that may be neoplastic in nature. 46-48 They are caused by germline mutations in PTEN often later accompanied by loss of the wildtype allele. 47,49-51 This results in activation of the PTEN/AKT/mTOR signaling pathway leading to their pathogenesis. 47 |
| Central neurocytoma | Central neurocytoma do not have recurrent mutations nor chromosome abnormalities, and most have a quiet copy number profile. Rare cases of MYCN amplification have been reported. 52,53 Loss of heterozygosity in 1p and/or 19q were noted in one publication 52, but absent from others. 54 DNA methylation analysis successfull classifies histological central neurocytomas as its own entity, but cannot differentiate between a typical or atypical distinctions. 11,55 |
| Extraventricular neurocytoma | Extraventricular neurocytoma are frequently driven by FGFR gene fusions, the most common of which is FGFR1::TACC1. 56. Neither alterations in IDH1/IDH2 or MGMT promoter methylation have been reported in these tumors. 57 DNA methylation analysis has discovered an epigenetic signature unique to extraventricular neurocytoma which provides diagnostic clarity, particularly in cases that have not had a full FGFR molecular workup 11 |
| Cerebellar liponeurocytoma | Cerebellar liponeurocytoma is a cerebellar neoplasm with advanced neuronal or neurocytic differentiation, which have been shown to harbor recurrent losses of chromosomes 2p and 14 via DNA methylation analysis. 55 TP53 mutations have also been reported. 58 Classification via DNA methylation acknowledges cerebellar liponeurocytoma as its own distinct tumor entity, more similar to central neurocytoma than to medulloblastoma. 11,55 An inheritable predisposition for cerebellar liponeurocytoma has been suggested, but requires further evaluation. 59,60 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 34185076 | 2021 | The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. | Louis DN et al |
| 2 | 31867747 | 2020 | Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC) - a molecularly defined glioneuronal CNS tumour class displaying recurrent monosomy 14. | Deng MY et al |
| 3 | 23583981 | 2013 | Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. | Zhang J et al |
| 4 | 23609006 | 2013 | BRAF(V600E) mutation is a negative prognosticator in pediatric ganglioglioma. | Dahiya S et al |
| 5 | 24238153 | 2014 | Pediatric brainstem gangliogliomas show BRAF(V600E) mutation in a high percentage of cases. | Donson AM et al |
| 6 | 28986151 | 2017 | BRAF V600E mutation is a significant prognosticator of the tumour regrowth rate in brainstem gangliogliomas. | Chen X et al |
| 7 | 29880043 | 2018 | The genetic landscape of ganglioglioma. | Pekmezci M et al |
| 8 | 32289278 | 2020 | Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas. | Ryall S et al |
| 9 | 27984673 | 2018 | Co-occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma. | Pagès M et al |
| 10 | 28378357 | 2017 | H3 K27M Mutation in Gangliogliomas can be Associated with Poor Prognosis. | Kleinschmidt-DeMasters BK et al |
| 11 | 29539639 | 2018 | DNA methylation-based classification of central nervous system tumours. | Capper D et al |
| 12 | 23822828 | 2014 | BRAF V600E expression and distribution in desmoplastic infantile astrocytoma/ganglioglioma. | Koelsche C et al |
| 13 | 27860162 | 2017 | Desmoplastic infantile astrocytoma/ganglioglioma with rare BRAF V600D mutation. | Greer A et al |
| 14 | 29902580 | 2018 | Desmoplastic non-infantile astrocytoma/ganglioglioma: rare low-grade tumor with frequent BRAF V600E mutation. | Chatterjee D et al |
| 15 | 30006355 | 2018 | Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations. | Wang AC et al |
| 16 | 31562743 | 2019 | Desmoplastic Infantile Ganglioglioma: A MAPK Pathway-Driven and Microglia/Macrophage-Rich Neuroepithelial Tumor. | Blessing MM et al |
| 17 | 26810070 | 2016 | Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. | Qaddoumi I et al |
| 18 | 26920151 | 2016 | Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. | Rivera B et al |
| 19 | 27791984 | 2017 | Droplet digital PCR is a powerful technique to demonstrate frequent FGFR1 duplication in dysembryoplastic neuroepithelial tumors. | Fina F et al |
| 20 | 30825062 | 2019 | Multiplex ligation-dependent probe amplification analysis is useful for detecting a copy number gain of the FGFR1 tyrosine kinase domain in dysembryoplastic neuroepithelial tumors. | Matsumura N et al |
| 21 | 23941441 | 2014 | BRAF V600E mutation is associated with mTOR signaling activation in glioneuronal tumors. | Prabowo AS et al |
| 22 | 31617914 | 2019 | Genomic Analysis of Dysembryoplastic Neuroepithelial Tumor Spectrum Reveals a Diversity of Molecular Alterations Dysregulating the MAPK and PI3K/mTOR Pathways. | Surrey LF et al |
| 23 | 25346165 | 2015 | BRAF V600E mutations are frequent in dysembryoplastic neuroepithelial tumors and subependymal giant cell astrocytomas. | Lee D et al |
| 24 | 33325069 | 2021 | A case series of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC). | Pickles JC et al |
| 25 | 22725730 | 2013 | Identification of a novel, recurrent SLC44A1-PRKCA fusion in papillary glioneuronal tumor. | Bridge JA et al |
| 26 | 26671581 | 2015 | Papillary glioneuronal tumors: histological and molecular characteristics and diagnostic value of SLC44A1-PRKCA fusion. | Pages M et al |
| 27 | 30759284 | 2019 | Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA. | Hou Y et al |
| 28 | 21997360 | 2012 | Recurrent PIK3CA mutations in rosette-forming glioneuronal tumor. | Ellezam B et al |
| 29 | 24806303 | 2014 | FGFR1 mutations in Rosette-forming glioneuronal tumors of the fourth ventricle. | Gessi M et al |
| 30 | 27893178 | 2018 | Comprehensive genetic characterization of rosette-forming glioneuronal tumors: independent component analysis by tissue microdissection. | Kitamura Y et al |
| 31 | 31250151 | 2019 | Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. | Sievers P et al |
| 32 | 32859279 | 2020 | Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor. | Lucas CG et al |
| 33 | 30006677 | 2018 | Myxoid glioneuronal tumor of the septum pellucidum and lateral ventricle is defined by a recurrent PDGFRA p.K385 mutation and DNT-like methylation profile. | Solomon DA et al |
| 34 | 30726976 | 2019 | Septal dysembryoplastic neuroepithelial tumor: a comprehensive clinical, imaging, histopathologic, and molecular analysis. | Chiang JCH et al |
| 35 | 31609499 | 2020 | Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features. | Lucas CG et al |
| 36 | 32326973 | 2020 | Clinical, imaging, and molecular analysis of pediatric pontine tumors lacking characteristic imaging features of DIPG. | Chiang J et al |
| 37 | 25720745 | 2015 | High rate of concurrent BRAF-KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN). | Rodriguez FJ et al |
| 38 | 26994902 | 2016 | Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation. | Dodgshun AJ et al |
| 39 | 29766299 | 2018 | Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features. | Deng MY et al |
| 40 | 32605662 | 2020 | Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases. | Appay R et al |
| 41 | 22941225 | 2012 | Disseminated oligodendroglial-like leptomeningeal tumor of childhood: a distinctive clinicopathologic entity. | Rodriguez FJ et al |
| 42 | 23324039 | 2013 | Multinodular and vacuolating neuronal tumors of the cerebrum: 10 cases of a distinctive seizure-associated lesion. | Huse JT et al |
| 43 | 29428973 | 2018 | Multinodular and vacuolating neuronal tumor of the cerebrum is a clonal neoplasm defined by genetic alterations that activate the MAP kinase signaling pathway. | Pekmezci M et al |
| 44 | 30550736 | 2019 | Clinicopathological and molecular analysis of multinodular and vacuolating neuronal tumors of the cerebrum. | Choi E et al |
| 45 | 31229580 | 2020 | Multinodular and Vacuolating Neuronal Tumor of the Cerebrum (MVNT): A case series and review of the literature. | Buffa GB et al |
| 46 | 1462769 | 1992 | Immunohistochemistry and proliferative activity in Lhermitte-Duclos disease. | Hair LS et al |
| 47 | 15835270 | 2005 | Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway. | Abel TW et al |
| 48 | 3418394 | 1988 | Recurrent Lhermitte-Duclos disease in a child. Case report. | Marano SR et al |
| 49 | 10051160 | 1999 | Severe Lhermitte-Duclos disease with unique germline mutation of PTEN. | Sutphen R et al |
| 50 | 11726927 | 2001 | Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. | Kwon CH et al |
| 51 | 24355184 | 2013 | Lhermitte-Duclos disease. A case report. | Giorgianni A et al |
| 52 | 10931240 | 2000 | Central neurocytomas are genetically distinct from oligodendrogliomas and neuroblastomas. | Tong CY et al |
| 53 | 17123091 | 2007 | Recurrent cytogenetic aberrations in central neurocytomas and their biological relevance. | Korshunov A et al |
| 54 | 12507133 | 2002 | Genetic differences between neurocytoma and dysembryoplastic neuroepithelial tumor and oligodendroglial tumors. | Fujisawa H et al |
| 55 | 29967940 | 2018 | Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience. | Capper D et al |
| 56 | 29978331 | 2018 | FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma. | Sievers P et al |
| 57 | 22672632 | 2013 | Clinicopathological and genetic characteristics of extraventricular neurocytomas. | Myung JK et al |
| 58 | 15446583 | 2004 | Genetic and expression profiles of cerebellar liponeurocytomas. | Horstmann S et al |
| 59 | 27349466 | 2016 | Cerebellar liponeurocytoma in two siblings suggests a possible familial predisposition. | Pikis S et al |
| 60 | 26613167 | 2016 | Cerebellar liponeurocytoma: a rare intracranial tumor with possible familial predisposition. Case report. | Wolf A et al |
Citation
Scott Ryall, PhD
Glioneuronal and Neuronal Tumors
Atlas Genet Cytogenet Oncol Haematol. 2023-07-27
Online version: http://atlasgeneticsoncology.org/solid-tumor/209194/glioneuronal-and-neuronal-tumors
