CNS5:Ganglioglioma

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Primary Author(s)*

Dr Leila Moayed Alaei, Royal Prince Alfred Hospital

Cancer Category/Type

Glioneuronal tumour  

Cancer Sub-Classification / Subtype

Ganglioglioma

Definition / Description of Disease

This is a distinct entity in the World Health Organization (WHO) classification system within the section of Gliomas, Glioneuronal and neuronal tumours. This is a well-differentiated glioneuronal tumour with low proliferative activity, comprised of mixed neoplastic neuronal and glial cell components. It is molecularly characterized by genomic aberrations causing MAPK pathway activation (CNS WHO grade 1)[1].

Synonyms / Terminology

None

Epidemiology / Prevalence

Gangliogliomas are generally tumours of adolescent/young adults with a median age of 12 years at the time of diagnosis. However, the tumour has been reported in wider range of age from 0 to 70 years of age[2][3]. The tumour is more prevalent in male patients (59.8%) than in female patients (40.2%)[4].

Clinical Features

The clinical features are dependent on the tumour location and size. If located in the cerebrum, the most common presentation is with focal seizures[1][5], with up to 23.6% of surgical epilepsy specimens harbouring gangliogliomas[6]. The mean duration of symptoms prior to diagnosis is also dependent on location. For tumours located in the cerebrum, the duration of symptoms prior to diagnosis ranges between 5 and 10 years, whereas in the brainstem and spinal cord, the mean duration of symptoms pre-diagnosis ranges between 1.25 years and 1.4 years, respectively[5][7].

The archetypal radiological features are of a circumscribed, solid/cystic mass, although varied appearances are the norm, ranging from presentation as a small cyst to a solid mass[8].  Patterns of contrast enhancement can also vary, including enhancement of the cystic wall to a markedly enhanced nodule[8].

Signs and Symptoms Intracerebral ganglioglioma: Seizure; chronic temporal lobe epilepsy[5]

Brain stem ganglioglioma: blurry vision, loss of memory, syncope spells, cranial nerve deficits, headache, and gait instability[9]

Spinal cord ganglioglioma:  acute onset paraparesis[10]

Imaging Findings Classic imaging features: T1 iso- to hypointense solid component,  T2-hyperintense solid component with varied signal within the cystic component; nodule and cyst wall show variable contrast enhancement[8]

Sites of Involvement

Most common location: temporal lobes (>70%)[5][7][11]

Other locations: cerebrum, brainstem, cerebellum, spinal cord, and optic nerves, lateral ventricle[3][5][7][11][3,5,6,18]

Morphologic Features

Ganglioglioma is a biphasic tumour composed of a neoplastic neuronal and a neoplastic glial component[3][11]. The neoplastic neuronal component is comprised of dysmorphic ganglion cells showing cytomegaly, binucleation and perimembranous aggregation of Nissl substance. Disorganised cytoarchitecture is also observed, with clustering of neurons. The neoplastic glial component can resemble a diffuse glioma or pilocytic astrocytoma; the glial component harbours the proliferative component of the tumour, which can show infiltration on microscopy. Proliferative activity is usually low to absent. The two components can be intermingled or geographically distinct. Other pertinent histological features include Rosenthal fibres, eosinophilic granular bodies and perivascular lymphoid infiltration[3][11][3,18]. An association with focal cortical dysplasia is a commonly reported finding[12].

Immunophenotype

Finding Marker
Positive (universal) CD34 expressed in expressed in ramified tumor cells[13]

Neoplastic neuronal component – MAP2, neurofilament, synaptophysin, chromogranin A

  • No definitive markers for neoplastic neuronal component
  • Typical profile: chromogranin A+, NeuN-, synaptophysin+, neurofilament+, MAP2+ (but MAP2 - in glial component)[1][14]

Neoplastic glial component – GFAP, OLIG2 (MAP2 -)

Positive (subset) BRAF VE1 (+ in BRAF-mutant gangliogliomas)[1]
Negative (universal)  IDH1 R132H, ATRX (normal retained pattern of staining)[1]
Negative (subset) BRAF VE1 (- in BRAF-wildtype gangliogliomas)[1]

Chromosomal Rearrangements (Gene Fusions)

Chromosomal Rearrangement Genes in Fusion

(5’ or 3’ Segments)

Structural variation Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
t(7;7)(q34;q34)[16][17] KIAA1549::BRAF[16][18] duplication   16.7%[18] Yes[1][16] No Yes[19] - also seen in PLNTY, ganglioglioma, and pilocytic astrocytoma; can distinguish by methylation signature[1]

- in-frame fusion[16]

t(8;8)(p11.23;p11.22)[16][17] FGFR1::TACC1[16] inversion 2.5% (1/40)[16] Unknown Unknown Unknown   - in-frame fusion[16]

- no FDA-approved anti-FGFR therapy for ganglioglioma at present

t(10;10)(q26.13;q25.3)[16][17] FGFR2::KIAA1598[16] deletion 2.5% (1/40)[16] Unknown Unknown Unknown - in-frame fusion[16]


t(10;10) (q26.13;q24.3)[16][17] FGFR2::INA[16] inversion 2.5% (1/40)[16] Unknown Unknown Unknown - in-frame fusion[16]


t(3;3)(p14.3;p25.2)[16][17] ERC2::RAF1[16] deletion 2.5%(1/40)[16] Unknown Unknown Yes (potential)[19] - in-frame fusion[16]


t(14;7)(q32.32;7q34)[16][17] CDC42BPB::BRAF[16] translocation 2.5% (1/40)[16] Unknown Unknown Yes (potential)[19] - in-frame fusion[16]


t(7;7)(p15.3;q34)[16][17] KLHL7::BRAF[16] inversion 2.5% (1/40) [16]


Unknown Unknown Yes (potential)[19] - in-frame fusion[16]


t(1;11)(q25.2;q14.1)[16][17] ABL2::GAB2[16] translocation 2.5% (1/40)[16]


Unknown Unknown Yes (potential)[19] - in-frame fusion[16]


Characteristic Chromosomal Aberrations / Patterns

None

Genomic Gain/Loss/LOH[16]

Chr #   Gain/Loss/Amp/LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance

(Yes, No or Unknown)  

Therapeutic Significance

(Yes, No or Unknown)

Notes
1 loss Chr1:1- 248956422


Chr1 Unknown Unknown Unknown This constellation of chromosomal abnormalities was found in a case series of 40 gangliogliomas[8].

It is unknown if the abnormalities are either diagnostic, prognostic or therapeutic.  

3 gain Chr3:1- 198295559


Chr3 Unknown Unknown Unknown
4 gain Chr4:1- 190214555 Chr4 Unknown Unknown Unknown
5 gain Chr5:1- 181538259 Chr5 Unknown Unknown Unknown
6 gain Chr6:1- 170805979 Chr6 Unknown Unknown Unknown
7 gain Chr7:1- 159345973 Chr7 Unknown Unknown Unknown
8 gain Chr8:1- 145138636 Chr8 Unknown Unknown Unknown
9 gain Chr9:1- 138394717 Chr9 Unknown Unknown Unknown
10 loss (segmental) Chr10:1- 133797422 Chr10 Unknown Unknown Unknown
11 gain Chr11:1- 135086622 Chr11 Unknown Unknown Unknown
12 gain Chr12:1- 133275309 Chr12 Unknown Unknown Unknown
15 gain Chr15: 1- 101991189 Chr15 Unknown Unknown Unknown
16 Gain   Chr16:1-90338345


Chr16 Unknown Unknown Unknown
16 loss Chr16:1-90338345


Chr16 Unknown Unknown Unknown
17 loss Chr17:1- 83257441 Chr17 Unknown Unknown Unknown
18 gain Chr18:1- 80373285 Chr18 Unknown Unknown Unknown
19 gain Chr19:1- 58617616 Chr19 Unknown Unknown Unknown
20 gain Chr20:1- 64444167 Chr20 Unknown Unknown Unknown
21 gain Chr21:1- 46709983 Chr21 Unknown Unknown Unknown
22 gain Chr22:1- 50818468 Chr22 Unknown Unknown Unknown


Gene Mutations (SNV/INDEL)

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene (TSG)/Oncogene/Other) Prevalence (COSMIC/ TCGA/Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance

(Yes, No or Unknown)  

Therapeutic Significance

(Yes, No or Unknown)

Notes
BRAF p.V600E[1][16] oncogene 10-60%[1] Homozygous deletion of CDKN2A[16][8]


H3-3A p.K27M[20]

KRAS, RAF1, NF1, FGFR1, and FGFR2[16] Yes[1][16] Yes[21] Yes[22] FDA-approved therapy includes dabrafenib-trametinib[22]


BRAF indel events: p.L505delinsLEYLS p.R506delinsRVLR p.R506delinsRSTQ p.T599_W604delinsTDG) [16] oncogene 10%[16] KRAS, RAF1, NF1, FGFR1, and FGFR2[16] Yes[1][16] Unknown Unknown  
KRAS p.Q61K[16] oncogene 5%[16] KRAS, RAF1, NF1, FGFR1, and FGFR2[16] Yes[1][16] No[16][21] No
FGFR2 exon 17 splicesite mutation[16] oncogene 2.5%[16]


KRAS, RAF1, NF1, FGFR1, and BRAF[16] Yes[1][16] No[16][21] No - no FDA-approved anti-FGFR therapy for ganglioglioma at present


FGFR1 p.N546K[16] oncogene 2.5%[16]


KRAS, RAF1,

 NF1, BRAF, and FGFR2[16]

Yes[1][16] No[16][21] No - no FDA-approved anti-FGFR therapy for ganglioglioma at present


Epigenomics (Methylation)

Methylation profiling can be used in the diagnosis of ganglioglioma, however low tumour cellularity can impact on feasibility in the diagnostic setting[1].

Genes and Main Pathways Involved

90% of gangliogliomas harbor genetic alterations activating the MAPK signaling pathway, with non-MAPK signaling seen in 10% of cases (e.g. ABL2::GAB2 gene fusion)[16].  

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
BRAF; activating alterations MAPK signaling Increased cell growth and proliferation
RAF1; activating alterations MAPK signaling Increase cell growth and proliferation
KRAS; activating mutations MAPK signaling Increase cell growth and proliferation
NF1; inactivating mutations MAPK signaling   Increase cell growth and proliferation
FGFR1/2/3; activating alterations MAPK signaling Increase cell growth and proliferation

Diagnostic Testing Methods

  • Chromosome microarray  
  • Next generation sequencing  
  • DNA methylation profiling

Familial Forms

Inactivating germline mutations or deletions of NF1, as occurs in neurofibromatosis type 1, can be associated with a minor proportion of gangliogliomas[16][23]

Links

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References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 Solomon D.A. et al. (2021). Ganglioglioma, in "World Health Organization Classification of Central Nervous System Tumours" (5th edition). pp.111-115.
  2. ↑ Lang, Shih-Shan; et al. (2012-07). "Surgical treatment of brain tumors in infants younger than six months of age and review of the literature". World Neurosurgery. 78 (1–2): 137–144. doi:10.1016/j.wneu.2011.09.012. ISSN 1878-8769. PMC 3292637. PMID 22120270. Check date values in: |date= (help)
  3. ↑ 3.0 3.1 3.2 3.3 Blumcke, Ingmar; et al. (2017-10-26). "Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery". The New England Journal of Medicine. 377 (17): 1648–1656. doi:10.1056/NEJMoa1703784. ISSN 1533-4406. PMID 29069555.
  4. ↑ Dudley, Roy W. R.; et al. (2015-03). "Pediatric low-grade ganglioglioma: epidemiology, treatments, and outcome analysis on 348 children from the surveillance, epidemiology, and end results database". Neurosurgery. 76 (3): 313–319, discussion 319, quiz 319–320. doi:10.1227/NEU.0000000000000619. ISSN 1524-4040. PMC 4333003. PMID 25603107. Check date values in: |date= (help)
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Prayson, R. A.; et al. (1995-07). "Cortical architectural abnormalities and MIB1 immunoreactivity in gangliogliomas: a study of 60 patients with intracranial tumors". Journal of Neuropathology and Experimental Neurology. 54 (4): 513–520. doi:10.1097/00005072-199507000-00005. ISSN 0022-3069. PMID 7541447. Check date values in: |date= (help)
  6. ↑ Blumcke, Ingmar; et al. (2017-10-26). "Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery". The New England Journal of Medicine. 377 (17): 1648–1656. doi:10.1056/NEJMoa1703784. ISSN 1533-4406. PMID 29069555.
  7. ↑ 7.0 7.1 7.2 Lang, F. F.; et al. (1993-12). "Central nervous system gangliogliomas. Part 2: Clinical outcome". Journal of Neurosurgery. 79 (6): 867–873. doi:10.3171/jns.1993.79.6.0867. ISSN 0022-3085. PMID 8246055. Check date values in: |date= (help)
  8. ↑ 8.0 8.1 8.2 Zhang, D.; et al. (2008-01). "Intracranial ganglioglioma: clinicopathological and MRI findings in 16 patients". Clinical Radiology. 63 (1): 80–91. doi:10.1016/j.crad.2007.06.010. ISSN 0009-9260. PMID 18068794. Check date values in: |date= (help)
  9. ↑ Mpairamidis, Evriviadis; et al. (2008-12). "Brainstem ganglioglioma". Journal of Child Neurology. 23 (12): 1481–1483. doi:10.1177/0883073808319316. ISSN 1708-8283. PMID 19073857. Check date values in: |date= (help)
  10. ↑ Cruz, Thainá Zanon; et al. (2021). "Ganglioglioma of the cervicothoracic spinal cord in a patient with neurofibromatosis type 1: A case report". Surgical Neurology International. 12: 313. doi:10.25259/SNI_192_2021. ISSN 2229-5097. PMC 8326088 Check |pmc= value (help). PMID 34345454 Check |pmid= value (help).
  11. ↑ 11.0 11.1 11.2 11.3 Wolf, H. K.; et al. (1994). "Ganglioglioma: a detailed histopathological and immunohistochemical analysis of 61 cases". Acta Neuropathologica. 88 (2): 166–173. doi:10.1007/BF00294510. ISSN 0001-6322. PMID 7985497.
  12. ↑ Blümcke, Ingmar; et al. (2011-01). "The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission". Epilepsia. 52 (1): 158–174. doi:10.1111/j.1528-1167.2010.02777.x. ISSN 1528-1167. PMC 3058866. PMID 21219302. Check date values in: |date= (help)
  13. ↑ Blümcke, Ingmar; et al. (2002-07). "Gangliogliomas: an intriguing tumor entity associated with focal epilepsies". Journal of Neuropathology and Experimental Neurology. 61 (7): 575–584. doi:10.1093/jnen/61.7.575. ISSN 0022-3069. PMID 12125736. Check date values in: |date= (help)
  14. ↑ Blümcke, Ingmar; et al. (2002-07). "Gangliogliomas: an intriguing tumor entity associated with focal epilepsies". Journal of Neuropathology and Experimental Neurology. 61 (7): 575–584. doi:10.1093/jnen/61.7.575. ISSN 0022-3069. PMID 12125736. Check date values in: |date= (help)
  15. ↑ Prayson, R. A.; et al. (1995-07). "Cortical architectural abnormalities and MIB1 immunoreactivity in gangliogliomas: a study of 60 patients with intracranial tumors". Journal of Neuropathology and Experimental Neurology. 54 (4): 513–520. doi:10.1097/00005072-199507000-00005. ISSN 0022-3069. PMID 7541447. Check date values in: |date= (help)
  16. ↑ 16.00 16.01 16.02 16.03 16.04 16.05 16.06 16.07 16.08 16.09 16.10 16.11 16.12 16.13 16.14 16.15 16.16 16.17 16.18 16.19 16.20 16.21 16.22 16.23 16.24 16.25 16.26 16.27 16.28 16.29 16.30 16.31 16.32 16.33 16.34 16.35 16.36 16.37 16.38 16.39 16.40 16.41 16.42 16.43 16.44 16.45 16.46 16.47 16.48 16.49 16.50 16.51 16.52 16.53 16.54 16.55 16.56 16.57 Pekmezci, Melike; et al. (2018-06-07). "The genetic landscape of ganglioglioma". Acta Neuropathologica Communications. 6: 47. doi:10.1186/s40478-018-0551-z. ISSN 2051-5960. PMC 5992851. PMID 29880043.
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 Kim, Pora; et al. (2018-11-08). "FusionGDB: fusion gene annotation DataBase". Nucleic Acids Research. 47 (D1): D994–D1004. doi:10.1093/nar/gky1067. ISSN 0305-1048.
  18. ↑ 18.0 18.1 Appay, Romain; et al. (2018-10). "Duplications of KIAA1549 and BRAF screening by Droplet Digital PCR from formalin-fixed paraffin-embedded DNA is an accurate alternative for KIAA1549-BRAF fusion detection in pilocytic astrocytomas". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 31 (10): 1490–1501. doi:10.1038/s41379-018-0050-6. ISSN 1530-0285. PMID 29802359. Check date values in: |date= (help)
  19. ↑ 19.0 19.1 19.2 19.3 19.4 Schreck, Karisa C.; et al. (2019-08-28). "BRAF Mutations and the Utility of RAF and MEK Inhibitors in Primary Brain Tumors". Cancers. 11 (9): E1262. doi:10.3390/cancers11091262. ISSN 2072-6694. PMC 6769482. PMID 31466300.
  20. ↑ Pagès, Mélanie; et al. (2018-01). "Co-occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma". Brain Pathology (Zurich, Switzerland). 28 (1): 103–111. doi:10.1111/bpa.12473. ISSN 1750-3639. PMC 8028391 Check |pmc= value (help). PMID 27984673. Check date values in: |date= (help)
  21. ↑ 21.0 21.1 21.2 21.3 Ryall, Scott; et al. (2020-04-13). "Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas". Cancer Cell. 37 (4): 569–583.e5. doi:10.1016/j.ccell.2020.03.011. ISSN 1878-3686. PMC 7169997 Check |pmc= value (help). PMID 32289278 Check |pmid= value (help).
  22. ↑ 22.0 22.1 Kowalewski, Adam; et al. (2020-08). "Clinical Relevance of BRAF V600E Mutation Status in Brain Tumors with a Focus on a Novel Management Algorithm". Targeted Oncology. 15 (4): 531–540. doi:10.1007/s11523-020-00735-9. ISSN 1776-260X. PMC 7434793 Check |pmc= value (help). PMID 32648041 Check |pmid= value (help). Check date values in: |date= (help)
  23. ↑ Rodriguez, Fausto J.; et al. (2008-03). "Gliomas in neurofibromatosis type 1: a clinicopathologic study of 100 patients". Journal of Neuropathology and Experimental Neurology. 67 (3): 240–249. doi:10.1097/NEN.0b013e318165eb75. ISSN 0022-3069. PMC 3417064. PMID 18344915. Check date values in: |date= (help)
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