Glioneuronal and Neuronal Tumors

2024-10-31 Scott Ryall, PhD Affiliation

1.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 as confirmed by histological review. ¹ This classification 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.

Additional details are described in the 2021 WHO Classification of Tumors of the Central Nervous System.

Glioneuronal and Neuronal Tumors	Genetic Event(s)
Ganglioglioma	The median age at diagnosis of ganglioglioma is 12 years (0-70 years). ^3-5 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. ^6-11 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. ¹⁰ 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. ¹⁰ Likewise, rare midline ganglioglioma have been reported with dual BRAF p.V600E and H3 p.K27M. ^11-13 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. ¹⁴
Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma	Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma (DIA/DIG) are exclusively seen in children with a median age at diagnosis of 1 year (0-14 years) with the vast majority being diagnosed within the first 2 years of life. ^15-18. 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. ^11,15-19 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. ^14,17.
Dysembryoplastic neuroepithelial tumor	The median age at diagnosis of dysembryoplastic neuroepithelial tumors (DNET) is 18 years (3-73 years) with the first indication of disease (seizures) occurring before the age of 20 in >90% of patients. ^5,20 The most common genetic alterations in 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. ^11,20-23 These alterations have been shown to induce autophosphorylation of FGFR1 resulting in up-regulation of the MAPK and PI3K signaling pathways. ^20,24,25 BRAF p.V600E is also common in DNETs ^6,21,25,26, although their presence may suggest an alternative diagnoses. Rarely, PDGFRA and NF1 mutations have been observed ^21,25. DNA methylation analysis shows that DNET have a distinct methylation profile. ¹⁴
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters	Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC) is a newly defined methylation-based entity that has a median age of diagnosis of 9 years (2-75 years). ^2,27 DGONC is a provisional tumor type that can, at this time, only be reliably identified via DNA methylation analysis. ¹⁴ 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. ^2,27
Diffuse leptomeningeal glioneuronal tumor	The median age at diagnosis of diffuse leptomeningeal glioneuronal tumors (DLGNT) is 5 years [0-46 years]. This can be further segregated based on the methylation class of DLGNT, with MC-1 occurring in younger patients (Median: 5 years [2-23 years]) and MC-2 in older patients (Median: 14 years [5-47 years]). ^28,29 DLGNT frequently harbor alterations in genes of the MAPK signaling pathway, most commonly KIAA1549::BRAF fusions. ³⁰ Other MAPK-related alterations include BRAF p.V600E and other BRAF alterations, NTRK1/NTRK2/NTRK3 fusions, FGFR1 mutations, and RAF1 rearrangements. ^29,31,32 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. ^28-30 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. ^14,29
Multinodular and vacuolating neuronal tumour	The median age at diagnosis of multinodular and vacuolating neuronal tumors (MVNT) is 42 years (5-71 years) with isolated pediatric cases. ^33-36 MVNT 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. ^33,35-37

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	22120270	2012	Surgical treatment of brain tumors in infants younger than six months of age and review of the literature.	Lang SS et al
4	25603107	2015	Pediatric low-grade ganglioglioma: epidemiology, treatments, and outcome analysis on 348 children from the surveillance, epidemiology, and end results database.	Dudley RW et al
5	29069555	2017	Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery.	Blumcke I et al
6	23583981	2013	Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas.	Zhang J et al
7	23609006	2013	BRAF(V600E) mutation is a negative prognosticator in pediatric ganglioglioma.	Dahiya S et al
8	24238153	2014	Pediatric brainstem gangliogliomas show BRAF(V600E) mutation in a high percentage of cases.	Donson AM et al
9	28986151	2017	BRAF V600E mutation is a significant prognosticator of the tumour regrowth rate in brainstem gangliogliomas.	Chen X et al
10	29880043	2018	The genetic landscape of ganglioglioma.	Pekmezci M et al
11	32289278	2020	Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas.	Ryall S et al
12	27984673	2018	Co-occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma.	Pagès M et al
13	28378357	2017	H3 K27M Mutation in Gangliogliomas can be Associated with Poor Prognosis.	Kleinschmidt-DeMasters BK et al
14	29539639	2018	DNA methylation-based classification of central nervous system tumours.	Capper D et al
15	27860162	2017	Desmoplastic infantile astrocytoma/ganglioglioma with rare BRAF V600D mutation.	Greer A et al
16	29902580	2018	Desmoplastic non-infantile astrocytoma/ganglioglioma: rare low-grade tumor with frequent BRAF V600E mutation.	Chatterjee D et al
17	30006355	2018	Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations.	Wang AC et al
18	31562743	2019	Desmoplastic Infantile Ganglioglioma: A MAPK Pathway-Driven and Microglia/Macrophage-Rich Neuroepithelial Tumor.	Blessing MM et al
19	23822828	2014	BRAF V600E expression and distribution in desmoplastic infantile astrocytoma/ganglioglioma.	Koelsche C et al
20	26920151	2016	Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors.	Rivera B et al
21	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
22	27791984	2017	Droplet digital PCR is a powerful technique to demonstrate frequent FGFR1 duplication in dysembryoplastic neuroepithelial tumors.	Fina F et al
23	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
24	23941441	2014	BRAF V600E mutation is associated with mTOR signaling activation in glioneuronal tumors.	Prabowo AS et al
25	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
26	25346165	2015	BRAF V600E mutations are frequent in dysembryoplastic neuroepithelial tumors and subependymal giant cell astrocytomas.	Lee D et al
27	33325069	2021	A case series of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).	Pickles JC et al
28	22941225	2012	Disseminated oligodendroglial-like leptomeningeal tumor of childhood: a distinctive clinicopathologic entity.	Rodriguez FJ et al
29	29766299	2018	Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features.	Deng MY et al
30	25720745	2015	High rate of concurrent BRAF-KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN).	Rodriguez FJ et al
31	26994902	2016	Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation.	Dodgshun AJ et al
32	32605662	2020	Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases.	Appay R et al
33	23324039	2013	Multinodular and vacuolating neuronal tumors of the cerebrum: 10 cases of a distinctive seizure-associated lesion.	Huse JT et al
34	28833756	2018	Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?	Thom M et al
35	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
36	30550736	2019	Clinicopathological and molecular analysis of multinodular and vacuolating neuronal tumors of the cerebrum.	Choi E et al
37	31229580	2020	Multinodular and Vacuolating Neuronal Tumor of the Cerebrum (MVNT): A case series and review of the literature.	Buffa GB et al

External Links

Citation

Scott Ryall

Glioneuronal and Neuronal Tumors

Atlas Genet Cytogenet Oncol Haematol. 2024-10-31

Online version: http://atlasgeneticsoncology.org/solid-tumor/209286