Glioneuronal Tumours-WHO Grade1 tumours; includes Gangliogliomas, Desmoplastic Infantile Gangliogliomas, Dysembryoplastic Neuroepithelial Tumours, Papillary Glioneuronal Tumours, Rosette forming Glioneuronal Tumours of the fourth ventricle

1. Glioneuronal Tumours
Presented by: Dr. Mayurakshi Das
Moderated by: Dr. Amrita Ghosh Kar

3. Four principal types:
• Oligodendrocytes: responsible for the formation of
myelin sheaths in the CNS.
• Astrocytes: form part of the blood-brain barrier and
also play an important role in repair of CNS tissue.
• Microglia: defence and immunological functions.
• Ependymal: specialised epithelium which lines the
ventricles and spinal canal.

6. Immunohistochemistry
Neuronal Markers:
1. Synaptophysin
2. NeuN
3. NF-H
4. Class-111 ß
tubulin
5. MAP-2
Others: Anti HuC/HuD,
DCX, PGP 9.5, NSE
Glial Markers:
1. GFAP
2. Olig1
3. Olig 2
4. S 100
5. MBP
6. SOX10
7. MAP-2
8. CD57
9. Vimentin
•Ki-67: Proliferation marker

7. 2007 WHO Classification of Central Nervous System Tumours
Astrocytic Tumours
Oligodendroglial Tumours
Ependymal Tumours
Choroid Plexus Tumours
Other Neuroepithelial Tumours
Neuronal and Mixed Neuronal-glial tumours
Tumours of the pineal region
Embryonal Tumours
Tumours of Cranial and Peripheral Nerves
Meningeal Tumours
Tumours of Hematopoietic System
Germ Cell Tumours
Familiar Tumour Syndromes
Tumours of Sellar Region
Metastatic Tumours

8. Neuronal and Mixed Neuronal-Glial
Tumours and WHO Grading
•Glioneuronal tumors are more common than the purely
neuronal tumors.
•Usually associated with seizure disorders, particularly
gangliogliomas.
•Most tumours are low grade.

9. History
 Ganglioglioma has been a recognized entity for
most of 20th century.
 In 1987, VandenBerg et al described the
desmoplastic infantile ganglioglioma.
 In 1988, the first series of dysembryoplastic
neuroepithelial tumors was published.
 In the 2007 WHO classfication, 2 new glioneuronal
tumors have been added:
 Papillary glioneuronal tumor
Rosette-forming glioneuronal tumor (RGNT) of
the fourth ventricle

10. Why differentiation of
glioneuronal tumors is crucial?
Glioneuronal tumors have favorable
clinical outcomes and are generally
curable with total surgical resection
alone, whereas gliomas typically
require further chemoradiotherapy
depending on their histologic grade
and have poor prognosis.

11. Ganglioglioma
Well differentiated, slowly growing
neuroepithelial tumour, composed of
neoplastic, mature ganglion cells in
combination with neoplastic glial cells;
the most frequent entity observed in
patients with long-term epilepsy.
•WHO grade I.
•Anaplastic ganglioglioma-WHO grade III

12. Incidence
•1.3% of all brain tumours.
Age and Sex Distrbution
•2 months-70 years.
•Male:female ratio-equal distribution or 1.9:1
•In children, mean age at diagnosis was10.3 years.
Localization
•Occur throughout the CNS, especially temporal lobe.
Clinical Features
•Tumours in the cerebrum- Seizures
• Tumours involving brain stem/spinal cord- Crossed
paresis and sphincteric disorder after a mean of
1.5years.
•Most common tumours associated with chronic
temporal lobe epilepsy.

13. Neuroimaging
CT scan-
circumscribed
solid mass or
cyst with a
mural nodule.
Calcification
Contrast
enhancement.
MRI-
T1-weighted
image-
hypointense
T2-weighted
image-
hyperintense

14. Macroscopy
•Solid or cystic lesions, usually with little mass effect.
•Calcification
•Haemorrhage and necrosis are rare.

15. Histopathology:
•Neuronal + glial cell elements.
•Dysplastic neurons are characterized by
(i) loss of cytoarchitectural organization
(ii) abnormal (subcortical) localization
(iii) clustered appearance
(iv) cytomegaly
(v) perimembranous aggregated Nissl
substance
(vi) presence of bi- or multinucleated
neurons.
Glial component-proliferative cell population; may
include cell types resembling fibrillary
astrocytoma, oligodendroglioma or pilocytic

16. •Other features:
•Rosenthal fibers and eosinophilic granular bodies
•Fibrillary matrix
•Microcystic cavities and/or mucous substance
•Reticulin fiber network.
•Occasional mitoses.
•Calcifications, either excessive or as
neuronal/capillary incrustation
•Extensive perivascular lymphoid infiltrates
•Prominent capillary network
•In anaplastic gangliogliomas, malignant change
involves the glial component; necrosis maybe
present.
•May display a clear cell morphology.

19. Dysplastic Neurons

20. Dysplastic neurons embedded in a dense

21. Silver impregnation demonstrates abnormally oriented
and shaped neuritic processes from ganglion cells

22. Reticulin-positive stroma maybe quite exuberant

23. Anaplastic ganglioglioma:
WHO grade III
Low grade neuronal component + anaplastic glial
component
Anaplastic glioma with focal neuronal differentiation :
Neuronal differentiation can be seen in:
•Glioblastoma
•Glioneuronal tumour with neuropil-like islands
•Pleomorphic xanthoastrocytoma with anaplastic
features
Neuronal differentiation manifested as:
•Ganglion and ganglioid cells or neurocytic
differentiation
•Neuropil islands/ rosettes
•PNET component (usually in glioblastoma)
•Immunoexpression of neuronal markers

24. Anaplastic Ganglioglioma

25. Area resembling diffuse
astrocytoma
Neuropil-like islands

26. Immunohistochemistry
•Neuronal component- NF, synaptophysin, MAP2, NeuN.
•Glial element-GFAP
•Others: CD34, MAP-2
GFAP-
Cytoplasmic
positivty in glial
component

27. Synaptophysin –
Membranous positivty in
neurons
NF-H: Cytoplasmic
staining of neuronal
component

28. Electron microscopy
•Neurons with dense core granules
Proliferation
•Mitotic figures-rare.
•Ki-67 labellling indices-1.1-2.7%, only in glial
component
Genetic susceptibility
•Neurofibromatosis- type 1 and 2
•Peutz-Jeghers
Genetics
•Gain of chromosome 7
•Partial loss of chromosome 9p
•CDKN2A deletion in anaplastic gangliogliomas
•IDH-1 mutations- greater risk of recurrence, malignant
progression

29. Histogenesis
A dysplastic, malformative glioneuronal precursor
lesion with neoplastic transformation of the glial
element.
Prognostic and predictive factors
•Benign tumours- 94% recurrence-free survival
rate.
•Good prognosis-
temporal localization
complete surgical resection
long-standing epilepsy.
•Anaplastic change in the glial component, high
Ki-67 & TP53 labelling indices: indicate

30. • no cyst or compact architectureCortical dysplasia
• markedly desmoplastic, smaller ganglion cellsDIG
• site specific, associated with Cowden
syndrome
Dysplastic cerebellar
gangliocytoma
• no abnormal clustering, binucleation of the
entrapped neurons
Infiltrating glioma with
entrapped neurons:
• no neoplastic neuronsPilocytic astrocytoma:
• pleomorphic astrocytes, +/- lipidization
Pleomorphic
xanthoastrocytoma:
• site specific, associated with tuberous sclerosis
Subependymal giant
cell astrocytoma
Differential Diagnosis

31. Dysembryoplastic
Neuroepithelial Tumour
Benign, usually supratentorial
glioneuronal neoplasms, occurring in
children or young adults, characterized
by a predominantly cortical location and
by drug-resistant partial seizures;
typically exhibiting a complex columnar
and multinodular architecture and often
associated with cortical dysplasia.
•WHO grade 1

32. Incidence
“Typical” DNTs-12% in adults and 13.5% in children
Age and sex distribution
•In 90% of cases, 1st seizure occurs before 20
years of age.
•Diagnosed in the 2nd or 3rd decade of life.
•Males are more frequently affected.
Localization
•Supratentorial cortex, especially temporal lobe
•Can also be found in third ventricle, basal ganglia
etc.
Clinical Features:
Drug-resistant partial seizures, with or without
secondary generalization and no neurological

33. Neuroimaging
•Cortical topography,
absence of mass effect
and no peritumoural
edema
•MRI > CT scan.
•Hyperintense on T2-
weighted and hypointense
on T1-weighted images.
•Deformation of overlying
calvarium
•Ring-shaped contrast
enhancement

34. Macroscopy
•Vary in size.
•Identified at cortical surface, maybe exophytic.
•Leptomeninges are not involved.
•Viscous consistency of the glioneuronal component.
•Maybe associated with multiple/single firmer nodules.

35. Histopathology
•Histological hallmark- ‘Specific glioneuronal
element’, characterized by columns of axons lined
by small oligodendroglia-like cells, oriented
perpendicularly to the cortical surface.
•‘Floating’ neurons with a normal cytology
embedded in a pale, eosinophilic matrix.
•Scattered GFAP-positive stellate astrocytes.
•Fluid extravasation determines if
columnar/alveolar/ compact structure.
•Histological sub-classfication has no clinical or
therapeutic implication.

36. Simple form
•Consists of the unique glioneuronal element.
•Maybe patchy.
Complex form
•Glial nodules + specific glioneuronal element
•Glial components:
•form typical nodules or diffuse pattern
•resemble gliomas or show unusual features
•mimic low-grade gliomas: nuclear atypia,or
necrosis
•microvascular network poor to exuberant.•Frankly hamartomatous, calcified vessels ->
behave as vascular malformations-> haemorrhage.
•Non-specific histological variants (20-50%)-
histologically indistinguishable from low-grade

37. •Adjacent dysplastic
disorganization of the cortex
in 80% cases.
Neuronal populations of
DNTs:
•mature neurons
•may show cytological
anomalies
• no dysplastic ganglion cells
Cortical topography
•Limits of tumour often coincide
with that of the cortex.
•May have disordered neuronal
migration

40. Glial nodule within the
specific glioneuronal element
Glial nodules in DNT

41. A. Oligodendrogliom
a like glial
component
B. Pilocytic
astrocytoma like
glial component
C.Perivascular
Rosette formation

42. Mucin Pools stain positive for Alcian

43. GFAP staining of glial
element
MAP2 immunostaining of
floating neurons

44. Why diagnosis maybe difficult?
•Limited material.
•Inadequate sample orientation
•Semi-liquid consistency->inadvertent surgical
aspiration or fragmentation during fixation->loss of
element
Diagnostic criteria
All of the following criteria must be present:
(i) partial seizures with beginning before 20 years of
age.
(ii) no progressive neurological deficit.
(iii) Cortical topography of a supratentorial lesion.

45. Diagnostic Difficulties
DNT versus low-grade
diffuse gliomas.
(i) Infiltrative microcysts
may mimic a “specific
glioneuronal element”
(ii) May exhibit “floating”
neurons
(iii) Oligodendroglioma
may exhibit a nodular
pattern
(iv) Secondary
architectural changes
caused by the growth
of gliomas vs
DNT versus
ganglioglioma
(i) neoplastic ganglion
cells may not be
present in small
samples
(ii) may show a
multinodular structure
(iii) small gangliogliomas
may show a
predominant cortical
topography
(iv) clinical presentations
are often similar.

46. DNET Low Grade
Oligodendroglioma
Peak Age Children Adults
Location Temporal lobe, cortical
based
Frontal lobe, white
matter based
Architecture Multinodular Uninodular
Infiltration Minmal Common
Cortical dysplasia + -
Calcification +/- + (Most Cases)
Cystic + (Most Cases) +/-
Atypia - +/-
Neuronal Component + -
Mitoses Rare +/-
Necrosis Absent Absent
Cell Proliferation Low Relatively higher
Prognosis Excellent More aggressive
DNET Versus Low Grade
Oligodendroglioma

47. • macrocystic component,
neoplastic neurons, reticulin-
rich stroma, perivascular
lymphocytes
Gangliogloma
• non-enhancing, diffusely
infiltrative, involves white
matter, perineuronal satellitosis,
more polymorphic cells
Oligodendroglioma
• biphasic patternPilocytic
Astrocytoma
• usually 4th ventricle, well
formed, small synaptophysin+
rosettes
Rosette forming
glioneuronal tumor
Differential Diagnosis

48. Proliferation
Ki-67 labelling indices- 0% -8%
Genetic susceptibility
•Neurofibromatosis type 1 (NF1)
•XYY syndrome
Histogenesis
Malformative origin
Prognostic and predictive factors
•Benign.
•No recurrence after surgical removal.
•Risk factors for the development of recurrent seizures after
surgery were: longer pre-operative history of seizures
presence of residual tumour
presence of adjacent cortical dysplasia

49. Desmoplastic Infantile
Ganglioglioma
Large cystic tumours of infants that
involve superficial cerebral cortex and
leptomeninges, often attached to dura,
with good prognosis following surgical
resection; histologically composed of
prominent desmoplastic stroma,
neoplastic astrocytes, a variable
neuronal component and aggregates
of poorly differentiated cells.
•WHO Grade 1

50. Incidence
0.3% of CNS tumours from all ages
Age and sex distribution
•1–24 months
•Male:female ratio of 1.5:1
•Non-infantile cases-5 to 25 years
Localization
•Supratentorial region, involve more than one lobe
•Frontal and parietal>temporal >occipital
Clinical features
•Short duration
•Increasing head circumference, tense and bulging
fontanelles, lethargy, and setting-sun sign.
•May have seizures, focal motor signs or skull bossing
over the tumour.

51. Neuroimaging
•CT scan- Large, hypodense cystic masses with a solid
hyperdense superficial portion that extends to the overlying
meninges. Shows contrast enhancement.
MRI T1-weighted images T2-weghted
images
Solid
component
Isointense, peripheral,
enhancing
Heterogenous
Cystic
component
Hypointense Hyperintense

52. Macroscopy
•Large, measuring up to 13 cm in diameter,
•Deep uni/multiloculated cysts filled with clear or
xanthochromic fluid.
•Solid, superficial portion-primarily extracerebral,
involving leptomeninges and superficial cortex,
commonly attached to the dura, firm or rubbery, and
grey.
•No gross evidence of haemorrhage or necrosis.

53. Histopathology
1. Desmoplastic leptomeningeal component:
•Fibroblast-like spindle-shaped cells arranged
in fascicles/storiform/whorled pattern.
•Reticulin positive network surrounds every
cell.
•Tumour cells- Astrocytes + neoplastic neurons
(atypical ganglionic cells to small polygonal
cells)
2. Poorly differentiated neuroepithelial
component: Cells with small, round, deeply
basophilic nuclei and minimal perikarya.
3. Cortical component: often multinodular, with

54. •Sharp demarcation between the cortical surface
and the desmoplastic tumour.
•Calcifications are common.
•Mononuclear inflammatory cells are not usually
seen.
•Mitotic activity and necrosis are uncommon,
maybe present in poorly differentiated
neuroepithelial cells.
•Microvascular proliferation is not evident.

55. Heterogenous glial and
globoid neurons in a
conspicuous stroma
Poorly differentiated
neuroepithelial component

57. Tumour invading Virchow
Robin spaces
Masson Trichrome Stain:
Dense collagenous stroma
stains blue

58. Immunohistochemistry
•Desmoplastic leptomeningeal component:
Vimentin, GFAP, SMA.
•Neuroepithelial tumour cells: GFAP.
•Antibodies to type IV collagen react in a reticulin-
like pattern around tumour cells.
•Neoplastic neuronal cells: Expression of neuronal
markers (synaptophysin, NF-H, class III ß-
tubulin)
•Poorly differentiated neuroepithelial cells: GFAP,
vimentin, neuronal markers, MAP2

59. GFAP
Synaptophysin
NeuN
Reticulin

60. MAP2 immunoreactvty in the poorly differentiated
neuroepithelial cells

61. Electron microscopy
•Extensive basal lamina surrounds individual tumour
cells.
•Neuronal cells-Dense core secretory granules.
Proliferation
•Mitotic activity-rare; restricted to the undifferentiated,
small cell population.
•Ki-67 labelling indices- <2%.
•May predict aggressive behaviour in subtotally resected
cases.
Histogenesis
Embryonal neoplasms programmed to progressive
maturation
Prognostic and predictive factors
•Total resection offer local tumour control.

62. • rare in the pediatric age
• uniform round to oval bland
nuclei, indistinct cell borders,
intranuclear pseudoinclusions,
• psammomma bodies
• no cystic component on
imaging
Fibrous
Meningioma
Differential Diagnosis

63. Papillary Glioneuronal
Tumour
Relatively circumscribed, clinically
indolent and histologically biphasic
cerebral neoplasm composed of flat to
cuboidal, GFAP-positive astrocytes
lining hyalinized vascular
pseudopapillae and synaptophysin-
positive interpapillary collections of
sheets of neurocytes, large neurons and
intermediate-sized “ganglioid” cells.
WHO Grade 1

64. Incidence: Rare neoplasms;
only several dozen reported.
Age and sex distribution:
Any age. No gender
predilection
Localization: Cerebral
hemispheres; esp temporal
lobe.
Clinical features:
•Headache
•Seizures
•Disturbances of vision,
gait, sensation, cognition,
emotional affect
Neuroimaging:
Demarcated, solid to cystic, contrast-enhancing masses
with little mass effect

65. Macroscopy
May be solid/cystic lesions that exert variable mass
effect.
Calcification may be seen. Haemorrhage and necrosis-
rare.
Histopathology
•Prominent pseudopapillary architecture
•Single/pseudostratified layer of small glial cells with
round nuclei and scant cytoplasm covers hyalinized
blood vessels.
•Interpapillary collections of neurocytes, ganglion cells,
“ganglioid cells” with accompanying neuropil.
•Minigemistocytes in the interpapillary spaces.

68. Immunohistochemistry
•Glial cells-GFAP-positive or Olig2-positive, GFAP-
negative
•Neuronal cells- synaptophysin, NSE and class III b-
tubulin, NeuN, membranous immunoreactivity for
NCAM.
•NFP expression is mostly confined to larger ganglioid
and ganglion cells.
•Chromogranin-A expression is lacking.

70. Electron Microscopy
•Astrocytes-bundles of intermediate filaments; basal
lamina separates it from vessels with thick collagen-rich
adventitiae.
•Neurons: parallel microtubules, dense core granules.
Proliferation: Ki-67 labelling indices-1–2%.
Histogenesis: Multipotent precursors capable of
divergent glioneuronal differentiation.
Prognostic and predictive factors: Gross total
resection without adjuvant therapy results in recurrence
free, long-term survival.

71. • 4th ventricle, neurocytic rosettes
with synaptophysin +ve cores
RGNT
• Intracortical, Specific
glioneuronal elements, floating
neurons
DNET
• Synaptophysin negativeClear cell
ependymoma
• No pseudopapillae lined by glial
cells
Extraventrcular
Neurocytoma
• Non-enhancing, diffusely
infiltrative
Oligodendroglioma
• Dot-like EMA positivty,
synaptophysin negative
Astroblastoma
Differential Diagnosis

72. Rosette-forming Glioneuronal
Tumour Of The Fourth Ventricle
Rare, slowly growing neoplasm of the fourth
ventricular region, preferentially affecting
young adults and composed of two distinct
histological components, one with uniform
neurocytes forming rosettes and/or
perivascular pseudorosettes, the other being
astrocytic in nature and resembling pilocytic
astrocytoma.
•WHO Grade 1

73. Incidence: Rare
Age and sex distribution
•12–59 years (mean, 33 years)
•Slight female predilection
Localization
•Arise in the midline, occupy the 4th ventricle and/or
aqueduct
•May involve adjacent brain stem, cerebellar vermis etc
Clinical features
•Headache
•Ataxia
•Cervical pain
•Asymptomatic; incidental imaging findings.

74. Neuromaging
•Relatively circumscribed, solid tumour of the 4th
ventricular region.
•High intensity on T2-weighted images.
•Low intensity on T1-weighted images.
•Focal/multifocal gadolinium enhancement.
•Secondary hydrocephalus may be seen.

75. Macroscopy
•Involves cerebellum and wall or floor of the
fourth ventricle; occasionally with aqueductal
extension.
Histopathology
•Demarcated; may have some peri-lesional
infiltration.
•Neurocytic + glial architecture.
•Low cellularity
•Mitoses and necrosis- absent.
•Vessels may be thin-walled and dilated or
hyalinized.
•Neurocytic rosettes
•Perivascular pseudorosettes

76. •Glial component: (1) dominates, resembles
pilocytic astrocytoma.
(2) May be microcystic,
containing round,
oligodendroglia-like cells
(3) Rosenthal fibers, eosinophilic
granular bodies,
microcalcifications, and
hemosiderin deposits.
•Neurocytic tumour cells: Spherical nuclei with
finely granular chromatin, inconspicuous nucleoli,
scant cytoplasm and delicate cytoplasmic
processes.
•Ganglion cells are occasionally present, but

77. Glial area in RGNT

78. Neurocytic rosettes
containing neuropil
Perivascular
pseudorosettes

79. Biphasic neurocytic and glial components;
neurocytic and perivascular rosettes

80. Immunohistochemistry
•Synaptophysin: centers of neurocytic
rosettes and in the neuropil of
perivascular pseudorosettes.
•MAP-2 and NSE: both cytoplasm and
processes of neurocytic tumour cells.
•GFAP and S-100: glial component,
absent in rosettes and pseudorosettes.

81. Synaptophysin NeuN

82. Electron microscopy
•Rosette-forming neurocytic cells: Cytoplasmic
processes form the centres of rosettes and contain
aligned microtubules and dense core granules.
Proliferation: Ki-67 labelling indices less than 3%.
Histogenesis
Arise from brain tissue surrounding the
infratentorial ventricular system.
Prognostic and predictive factors
Favourable in terms of survival, but disabling
postoperative deficits present.

83. • Lipidized cellsCerebellar
liponeurocytoma
• supratentorialDNET
• Perivascular rosettes, GFAP+,
Synaptophysin -
Ependymoma
• Rare location, diffusely
infiltrative, no neurocytic
component
Oligodendroglioma
• Lacks neurocytic rosettes,
usually supratentorial
PGNT
• No neurocytic componentPilocytic
astrocytoma
Differential Diagnosis

84. Other tumours that might show
immunoreactivity to both glial and neuronal
markers:
Medulloblastoma
Supratentorial Primitive Neuroectodermal
Tumour
Medulloepithelioma
Oligodendroglioma with neurocytic features.

85. Practical Problems Of Classifying
Mixed Glioneuronal Tumours:
•Recognition of distinctive examples.
•Histologically typical glioblastoma which
show limited immunostaining for a single
neuronal marker, usually synaptophysin: In
such settings, there is no convincing
evidence to suggest that such tumors will
behave differently from conventional
glioblastoma, and designation of such
lesions as mixed glioneuronal neoplasms
is not justified.

86. Conclusion
•Glioneuronal tumours are usually benign and slow
growing neoplasms with WHO grade I.
•Relatively rare neoplasms and may affect any part of the
CNS.
•Tend to cause intractable epilepsy when affecting the
cerebral cortex.
• Along with clinical presentation and neuroimaging; the
histopathology and immunohistochemistry confirms the
diagnosis.
•Surgical resectioning is the treatment of choice with
favorable prognosis and long term cure; adjuvant
treatment is preserved to recurrent tumours or to high

87. References:
 WHO Classification of Central Nervous System
Tumours, 2007 edition
 Diagnostic Histopathology of Tumours, C. Fletcher
 Practical Differential Diagnosis in Neurosurgical
Practice
 Mixed Glioneuronal Tumors-Recently Described
Entities byMark A. Edgar; Marc K. Rosenblum; Arch
Pathol Lab Med. 2007;131:228–233
 The Expanding Family of Glioneuronal Tumors,
Daniela S. Allende and Richard A. Prayson; Adv
Anat Pathol 2009;16:33–39
 Websites: Web Pathology, Pathology Outlines,