Gangliocytoma and Ganglioglioma

Synonyms: Ganglion Cell Tumors

Ganglioglioma. The neoplastic nature of the ganglion cell tumor's large neurons is readily apparent when abnormal clustering and cytologic abnormalities such as multinucleation are in evidence. Note admixed small lymphocytes, a common feature. Elsewhere this example harbored astrocytic elements.

Definition

Usually low grade (WHO grade I) tumors composed of well differentiated ganglion / neuronal cells, with (ganglioglioma) or without (gangliocytoma) glial component.

Clinical Features

Typically indolent
Ganglioglioma:
- much more prevalent than gangliocytoma
- a significant percentage of pediatric tumors in brainstem and spinal cord1,2
Usually within first three decades 3–7
Often present with protracted partial complex epilepsy

Pathogenesis

Not clear whether represent neoplasms, hamartomatous proliferations, or combinations thereof
Gangliogliomas may represent tumoral forms of cortical dysplasia or benign neoplasms arising in dysembryogenetic tissues because often:
- remarkable clinical stability 8,9
Shared CD34 expression suggest that gangliogliomas and glioneuronal hamartomas are linked by an origin from developmentally dysregulated neural stem cells:
- neoplastic transformation may selectively target glial elements residing within such hamartomas 3

Gross Pathology

Usually supratentorial:
- predilection for temporal lobes
- can be any level of central neuraxis
- even cranial nerve cases10,11

Histopathology

Irregular distribution of variably sized neurons (some ganglion cell-like profile) in delicate fibrillar matrix:
- often contains scattered calcospherules (Fig. 1
  Fig. 1: Ganglioglioma. The neoplastic nature of the ganglion cell tumor's large neurons is readily apparent when abnormal clustering and cytologic abnormalities such as multinucleation are in evidence. Note admixed small lymphocytes, a common feature. Elsewhere this example harbored astrocytic elements.
  )
Microcystic changes common in regions of predominantly glial composition
Obvious architectural disarray
Anomalous clustering
Conspicuous morphologic abnormalities including:
- striking pleomorphism
- multinucleation
- cytoplasmic vacuolization
- sometimes, gigantism
Rarely:
- Alzheimer disease-type neurofibrillary tangles
- other cytoplasmic inclusions of neurodegenerative and neuronal storage disorders12

Gangliocytoma

Composed exclusively of differentiated neurons13

Ganglioglioma

Admixed glial population:
- typically:
  - astrocytic
  - GFAP-positive
  - well differentiated
  - assuming guise of low-grade fibrillary or pilocytic astrocytoma14,15
- may be:
  - pleomorphic xanthoastrocytoma components 16
  - constituents indistinguishable from conventional oligodendroglioma:
    - oligodendrocyte-like clear cells represent ‘neurocytes’ (diminutive neurons)17
- tanycytic ependymal differentiation recorded18
- exceptionally high-grade histologic features – ‘malignant degeneration’:
  - typically astroglial components
  - potentially results in glioblastoma-like picture19
Anaplastic ganglioglioma:
- dense population of mitotically active glial cells
- may be microvascular proliferation and necrosis
- elements exceptionally observed in malignant ganglioglial tumors20

Clues to Diagnosis

Eosinophilic globular bodies of lysosomal derivation (Fig. 2
Fig. 2: Eosinophilic, hyaline globular bodies are typically associated with, although not restricted to, three indolent neuroepithelial tumors: the pilocytic astrocytoma (shown here), pleomorphic xanthoastrocytoma, and ganglioglioma.
):
- presumably degenerative
- often aggregate in matrices
- seen with comparable frequency only in pilocytic astrocytoma and pleomorphic xanthoastrocytoma
Lymphoid infiltration:
- common, ‘pseudoencephalitic’ phenomenon
- florid inflammatory reaction extending into substance of lesion (not confined to perivascular compartment) in:
  - central neuroepithelial tumors only of this entity
  - pleomorphic xanthoastrocytoma
Desmoplasia:
- uncommonly associated
- disfiguring and deceptive spindling and fascicular or vaguely storiform architecture on constituent cellular elements
Stromal blood vessels:
- often:
  - prominent
  - undergo sclerosis
- result in potential masquerade as vascular malformation on angiographic and gross neurosurgical assessment
Ultrastructurally:
- tumoral neurons elaborate cytoplasmic processes that:
  - contain:
    - parallel microtubular arrays
    - clear, synaptic-type vesicles
  - occasionally terminate in well-developed synaptic complexes14
- often dense-core neurosecretory granules:
  - generally not a feature of native cortical neurons14

Special Stains and Immunohistochemistry

Synaptophysin:
- glycoprotein component of presynaptic vesicle membrane.
- on assay shows coarsely granular or linear deposition of reaction product about perikarya of large neurons:
  - apparently due to formation of aberrant axosomatic synapses (Fig. 3
    Fig. 3: Ganglioglioma. Surface perikaryal labeling for synaptophysin characterizes the neuronal elements of some ganglion cell tumors on immunohistochemical assay.
    )14,17
  - not observed on antisynaptophysin immunoassessment of normal cerebral cortex, but must be cautiously interpreted:
    - circumperikaryal synaptophysin labeling is recognized attribute of some striatal, cerebellar, bulbar and intramedullary neurons 21,22
    - can be shown by:
      - cerebrocortical neurons entrapped within arteriovenous malformations 21
      - postradiation neuronal gigantism23
        suggesting that chronic, nonspecific neuronal injury may rarely provoke anomalous synaptic remodeling
Chromogranin A:
- intense and diffuse perikaryal labeling (Fig. 4
  Fig. 4: Ganglioglioma. Diffuse and strong cytoplasmic immunoreactivity for chromogranin A, a feature foreign to native cerebrocortical neurons, characterizes the neoplastic neuronal perikarya of some ganglion cell tumors.
  )
  - reflection of dense core granule formation14
  - native CNS neurons outside brainstem and cerebellum:
    - fail to react (as do glia) or
    - display only punctate and relatively weak partial labeling of perikarya
CD34:
- antigen expressed in CNS by neural stem cells and endothelium but apparently not by differentiated neuroepithelial cell types
- matrix and perikaryon-associated immunoreactivity shown by many gangliogliomas (and glioneuronal hamartomas)3,8
- contradictory statements about CD34 expression in glial neoplasms
Neuronal constituents of ganglion cell tumors may exhibit immunoreactivity for:
- neuronal nuclear proteins designated as NeuN 24 and Hu25
- various neuropeptides
- enzymes integral to catecholamine metabolism
- other neuron-associated antigens14,15
Gangliogliomas:
- usually low MIB-1 labeling indices of 1–3%9,14,15
- higher indices for anaplastic variants and recurrent lesions 14
- independent predictive power of proliferation assays not clear
- MIB-1 reactivity typically restricted to cells of glial appearance26,27

Diagnosis

Complement of large and essentially mature neurons unassociated, by definition, with recognizably embryonal elements
Variants:
- Melanotic 28
- ganglion cell tumors associated with:
  - (possibly progenitory) glioneuronal hamartomas3,8
  - other maldevelopmental cerebrocortical anomalies 9
- dysembryoplastic neuroepithelial tumors
‘Intrasellar gangliocytomas’:
- heterogeneous collection of benign lesions
- small minority may represent ganglion cell tumors ab initio or ectopic hypothalamic-type neuronal hamartomas

Other Investigations

Neuroradiology:
- well demarcated
- partially cystic mass
- contrast enhancement of solid components
- foci of calcification

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Gangliocytoma and Ganglioglioma

Cerebral hemispheric lesion presenting as discrete mural nodule within a cyst usually:
- ganglion cell tumor
- pilocytic astrocytoma, or
- pleomorphic xanthoastrocytoma
Tumors of astrocytic lineage:
- may assume ganglion cell-like cytologic profiles
- manifest no specialized neuronal features of ganglion cell tumors
- usually readily unmasked by GFAP expression
High-grade neoplasms of patently astrocytic character:
- may contain ganglion cell-like forms
- can display potentially confusing class III β-tubulin labeling29

Genetics

Most appear to be monoclonal, so support:30
- neoplastic nature
- origin of glioneuronal populations in common, bipotential precursor
Additional genetic events responsible for malignant progression await clarification

Management

Resection:
- generally cures supratentorial examples if accessible
- bulbar and intramedullary variants more prone to symptomatic postoperative regrowth:
  - possibly due to surgical limitations imposed by location
  - protracted clinical course1,2
Gangliogliomas tend to expand in compact, relatively noninvasive fashion that lends itself to the purposes of the neurosurgeon
Anaplastic gangliogliomas:

Prognosis

Remarkably indolent
Only exceptionally:
- spread via CSF
- fatal2–6,7,31
Frankly malignant glial elements do not necessarily indicate poor prognosis 2,17,31
Recorded recurrences of ganglioglioma :
- as high-grade neoplasm composed of cells exhibiting a hybrid neuronal/astrocytic phenotype 27
- with a neuroblastoma-like picture26
Not clear whether outcome following gross surgical extirpation related to:
- proliferative activity
- p53 expression9,14,15

1 Constantini S, Miller DC, Allen JC, Rorke LB, Freed D, Epstein FJ. Radical excision of intramedullary spinal cord tumors. Surgical morbidity and long-term follow-up evaluation in 164 children and young adults. J Neurosurg. 2000;93:183–193.

2 Lang FF, Epstein FJ, Ransohoff J, Allen JC, Wisoff J, Abbott IR, et al. Central nervous system gangliogliomas. Part 2. Clinical outcome. J Neurosurg. 1993;79:867–873.

3 Blümcke I, Wiestler OD. Gangliogliomas: an intriguing tumor entity associated with focal epilepsies. J Neuropathol Exp Neurol. 2002;61:575–584.

4 Johnson JH, Hariharan S, Berman J, Sutton LN, Rorke LB, Molloy P, et al. Clinical outcome of pediatric gangliogliomas. Ninety-nine cases over 20 years. Pediatr Neurosurg. 1997;27:203–207.

5 Selch MT, Goy BW, Lee SP, El-Sadin S, Kincaid P, Park SH, et al. Gangliogliomas. Experience with 34 patients and review of the literature. Am J Clin Oncol. 1998;21:557–564.

6 Zentner J, Wolf HK, Ostertun B, Hufnagel A, Campos MG, Solymosi L, et al. Gangliogliomas. Clinical, radiological, and histopathological findings in 51 patients. J Neurol Neurosurg Psychiatry. 1994;57:1497–1502.

7 Hakim R, Loeffler JS, Anthony DC, Black PM. Gangliogliomas in adults. Cancer. 1997;79:127–131.

8 Blümcke I, Löbach M, Wolf HK, Wiestler OD. Evidence for developmental precursor lesions in epilepsy-associated glioneuronal tumors. Microsc Res Tech. 1999;46:53–58.

9 Prayson RA, Khajavi K, Comair YG. Cortical architectural abnormalities and MIB1 immunoreactivity in gangliogliomas. A study of 60 patients with intracranial tumors. J Neuropathol Exp Neurol. 1995;54:513–520.

10 Athale S, Hallet KK, Jinkins JR. Ganglioglioma of the trigeminal nerve. MRI. Neuroradiology. 1999;41:576–578.

11 Lu WY, Goldman M, Young B, Davis DG. Optic nerve ganglioglioma. Case report. J Neurosurg. 1993;78:979–982.

12 Soffer D, Umansky F, Goldman JE. Ganglioglioma with neurofibrillary tangles (NFTs). Neoplastic NFTs share antigenic determinants with NFTs of Alzheimer's disease. Acta Neuropathol (Berl). 1995;89:451–453.

13 Felix I, Bilbao JM, Asa SL, Tyndel F, Kovacs K, Becker LE. Cerebral and cerebellar gangliocytomas. A morphological study of nine cases. Acta Neuropathol (Berl). 1994;88:246–251.

14 Hirose T, Scheithauer BW, Lopes MB, Gerber HA, Altermatt HJ, VandenBerg SR. Ganglioglioma. An ultrastructural and immunohistochemical study. Cancer. 1997;79:989–1003.

15 Wolf HK, Müller MB, Spänle M, Zentner J, Schramm J, Wiestler OD. Ganglioglioma. A detailed histopathological and immunohistochemical analysis of 61 cases. Acta Neuropathol (Berl). 1994;88:166–173.

16 Perry A, Giannini C, Scheithauer BW, Rojiani AM, Yachnis AT, Seo IS, et al. Composite pleomorphic xanthoastrocytoma and ganglioglioma. Report of four cases and review of the literature. Am J Surg Pathol. 1997;21:763–771.

17 Miller DC, Lang FF, Epstein FJ. Central nervous system gangliogliomas. Part 1. Pathology. J Neurosurg. 1993;79:859–866.

18 Hayashi S, Kameyama S, Fukuda M, Takahashi H. Ganglioglioma with a tanycytic ependymoma as the glial component. Acta Neuropathol (Berl). 2000;99:310–316.

19 Dash RC, Provenzale JM, McComb RD, Perry DA, Longee DC, McLendon RE. Malignant supratentorial ganglioglioma (ganglion cell-giant cell glioblastoma). A case report and review of the literature. Arch Pathol Lab Med. 1999;123:342–345.

20 Allegranza A, Pileri S, Frank G, Ferracini R. Cerebral ganglioglioma with anaplastic oligodendroglial component. Histopathology. 1990;17:439–441.

21 Quinn B. Synaptophysin staining in normal brain. Importance for diagnosis of ganglioglioma. Am J Surg Pathol. 1998;22:550–556.

22 Zhang PJ, Rosenblum MK. Synaptophysin expression in the human spinal cord. Diagnostic implications of an immunohistochemical study. Am J Surg Pathol. 1996;20:273–276.

23 Caccamo D, Herman MM, Urich H, Rubinstein LJ. Focal neuronal gigantism and cerebral cortical thickening after therapeutic irradiation of the central nervous system. Arch Pathol Lab Med. 1989;113:880–885.

24 Wolf HK, Buslei R, Schmidt-Kastner R, Schmidt-Kastner PK, Pietsch T, Wiestler OD, et al. NeuN. A useful neuronal marker for diagnostic histopathology. J Histochem Cytochem. 1996;44:1167–1171.

25 Gultekin SH, Dalmau J, Graus Y, Posner JB, Rosenblum MK. Anti-Hu immunolabeling as an index of neuronal differentiation in human brain tumors. A study of 112 central neuroepithelial neoplasms. Am J Surg Pathol. 1998;22:195–200.

26 David KM, de Sanctis S, Lewis PD, Noury AM, Edwards JM. Neuroblastomatous recurrence of ganglioglioma. Case report. J Neurosurg. 2000;93:698–700.

27 Jay V, Squire J, Becker LE, Humphreys R. Malignant transformation in a ganglioglioma with anaplastic neuronal and astrocytic components. Report of a case with flow cytometric and cytogenetic analysis. Cancer. 1994;73:2862–2868.

28 Soffer D, Lach B, Constantini S. Melanotic cerebral ganglioglioma. Evidence for melanogenesis in neoplastic astrocytes. Acta Neuropathol (Berl). 1992;83:315–323.

29 Katsetos CD, Del Valle L, Geddes JF, Assimakopoulou M, Legido A, Boyd JC, et al. Aberrant localization of the neuronal class III beta-tubulin in astrocytomas. Arch Pathol Lab Med. 2001;125:613–624.

30 Zhu JJ, Leon SP, Folkerth RD, Guo SZ, Wu JK, Black PM. Evidence for clonal origin of neoplastic neuronal and glial cells in gangliogliomas. Am J Pathol. 1997;151:565–571.

31 Krouwer HG, Davis RL, McDermott MW, Hoshino T, Prados MD. Gangliogliomas. A clinicopathological study of 25 cases and review of the literature. J Neurooncol. 1993;17:139–154.

Last updated: 13 Feb 2006

Gangliocytoma and Ganglioglioma

Definition

Clinical Features

Pathogenesis

Gross Pathology

Histopathology

Gangliocytoma

Ganglioglioma

Clues to Diagnosis

Special Stains and Immunohistochemistry

Diagnosis

Other Investigations

Differential Diagnosis

Genetics

Management

Prognosis

References

Gangliocytoma and Ganglioglioma