CNS5:Ganglioglioma

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).

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. The tumour is more prevalent in male patients (59.8%) than in female patients (40.2%).

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, with up to 23.6% of surgical epilepsy specimens harbouring gangliogliomas. 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.

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.  Patterns of contrast enhancement can also vary, including enhancement of the cystic wall to a markedly enhanced nodule.

Signs and Symptoms	Intracerebral ganglioglioma: Seizure; chronic temporal lobe epilepsy Brain stem ganglioglioma: blurry vision, loss of memory, syncope spells, cranial nerve deficits, headache, and gait instability Spinal cord ganglioglioma:  acute onset paraparesis
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

Sites of Involvement

Most common location: temporal lobes (>70%)[5,6,18]

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

Morphologic Features

Ganglioglioma is a biphasic tumour composed of a neoplastic neuronal and a neoplastic glial component [3,18]. 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[3,18]. An association with focal cortical dysplasia is a commonly reported finding[19].

Immunophenotype

Finding	Marker
Positive (universal)	CD34 expressed in expressed in ramified tumor cells[21] 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, 20] Neoplastic glial component – GFAP, OLIG2 (MAP2 -) Ki-67 <5%[5]
Positive (subset)	BRAF VE1 (+ in BRAF-mutant gangliogliomas)
Negative (universal)	IDH1 R132H, ATRX (normal retained pattern of staining)
Negative (subset)	BRAF VE1 (- in BRAF-wildtype gangliogliomas)

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)[8,13]	KIAA1549::BRAF [8, 9]	duplication	16.7 % [9]	Yes[1,8]	No	Yes[22]	- also seen in PLNTY, ganglioglioma, and pilocytic astrocytoma; can distinguish by methylation signature[1] - in-frame fusion[8]
t(8;8)(p11.23;p11.22)	FGFR1::TACC1 [8]	inversion	2.5% (1/40)[8]	Unknown	Unknown	Unknown	- in-frame fusion[8] - no FDA-approved anti-FGFR therapy for ganglioglioma at present
t(10;10)(q26.13;q25.3) [8,13]	FGFR2::KIAA1598 [8]	deletion	2.5% (1/40)[8]	Unknown	Unknown	Unknown	- in-frame fusion[8]
t(10;10) (q26.13;q24.3)[8,13]	FGFR2::INA[8]	inversion	2.5% (1/40) [8]	Unknown	Unknown	Unknown	- in-frame fusion[8]
t(3;3)(p14.3;p25.2) [8,13]	ERC2::RAF1[8]	deletion	2.5%(1/40) [8]	Unknown	Unknown	Yes (potential) [22]	- in-frame fusion[8]
t(14;7)(q32.32;7q34) [8,13]	CDC42BPB::BRAF [8]	translocation	2.5% (1/40) [8]	Unknown	Unknown	Yes (potential) [22]	- in-frame fusion[8]
t(7;7)(p15.3;q34) [8,13]	KLHL7::BRAF[8]	inversion	2.5% (1/40) [8]	Unknown	Unknown	Yes (potential) [22]	- in-frame fusion[8]
t(1;11)(q25.2;q14.1) [8,13]	ABL2::GAB2[8]	translocation	2.5% (1/40) [8]	Unknown	Unknown	Yes (potential) [22]	- in-frame fusion[8]

Characteristic Chromosomal Aberrations / Patterns

None

Genomic Gain/Loss/LOH

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Chromosome Number	Gain/Loss/Amp/LOH	Region
EXAMPLE 8	EXAMPLE Gain	EXAMPLE chr8:0-1000000
EXAMPLE 7	EXAMPLE Loss	EXAMPLE chr7:0-1000000

Gene Mutations (SNV/INDEL)

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Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
EXAMPLE TP53	EXAMPLE R273H	EXAMPLE Tumor Suppressor	EXAMPLE LOF	EXAMPLE 20%

Other Mutations

Type	Gene/Region/Other
Concomitant Mutations	EXAMPLE IDH1 R123H
Secondary Mutations	EXAMPLE Trisomy 7
Mutually Exclusive	EXAMPLE EGFR Amplification

Epigenomics (Methylation)

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Genes and Main Pathways Involved

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Diagnostic Testing Methods

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Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

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Familial Forms

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Other Information

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Links

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References

EXAMPLE Book

1. Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4thedition.Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.

EXAMPLE Journal Article

1. Li Y, et al., (2001). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28:220-221, PMID 11431691.

Notes

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