Glioneuronal tumours

Glioneuronal Tumours

Presented by: Dr. Mayurakshi Das

Moderated by: Dr. Amrita Ghosh Kar

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.

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

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

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.

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

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.

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

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.

Neuroimaging

CT scan-

circumscribed

solid mass or

cyst with a

mural nodule.

Calcification

Contrast

enhancement.

MRI-

T1-weighted

image-

hypointense

T2-weighted

image-

hyperintense

Macroscopy

•Solid or cystic lesions, usually with little mass effect.

•Calcification

•Haemorrhage and necrosis are rare.

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

astrocytoma.

•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.

Dysplastic Neurons

Dysplastic neurons embedded in a dense

stroma

Silver impregnation demonstrates abnormally oriented

and shaped neuritic processes from ganglion cells

Reticulin-positive stroma maybe quite exuberant

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

Anaplastic Ganglioglioma

Area resembling diffuse

astrocytoma

Neuropil-like islands


•Neuronal component- NF, synaptophysin, MAP2, NeuN.

•Glial element-GFAP

•Others: CD34, MAP-2

GFAP-

Cytoplasmic

positivty in glial

component

Synaptophysin –

Membranous positivty in

neurons

NF-H: Cytoplasmic

staining of neuronal

component

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

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

aggressive behaviour.

• no cyst or compact architecture Cortical dysplasia

• markedly desmoplastic, smaller ganglion cells DIG

• 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, +/- lipidizationPleomorphic

xanthoastrocytoma:

• site specific, associated with tuberous sclerosis Subependymal giant

cell astrocytoma

Differential Diagnosis

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

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

deficit.

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

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.

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.

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

gliomas.

•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

Glial nodule within the

specific glioneuronal elementGlial nodules in DNT

A. Oligodendrogliom

a like glial

component

B. Pilocytic

astrocytoma like

glial component

C.Perivascular

Rosette formation

Mucin Pools stain positive for Alcian

Blue

GFAP staining of glial

element

MAP2 immunostaining of

floating neurons

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.

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

dysplastic cortical

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.

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

• macrocystic component, neoplastic neurons, reticulin-rich stroma, perivascularlymphocytes

Gangliogloma

• non-enhancing, diffusely infiltrative, involves white matter, perineuronal satellitosis, more polymorphic cells

Oligodendroglioma

• biphasic pattern Pilocytic

Astrocytoma

• usually 4th ventricle, well formed, small synaptophysin+ rosettes

Rosette forming glioneuronal tumor


Proliferation

Ki-67 labelling indices- 0% -8%

Genetic susceptibility

•Neurofibromatosis type 1 (NF1)

•XYY syndrome

Histogenesis

Malformative origin


•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

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

Incidence

0.3% of CNS tumours from all ages


•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.

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

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.

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

some nodules being microcystic

•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.

Heterogenous glial and

globoid neurons in a

conspicuous stroma

Poorly differentiated

neuroepithelial component

Tumour invading Virchow

Robin spaces

Masson Trichrome Stain:

Dense collagenous stroma

stains blue

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

•Epithelial markers (CAM 5.2, AE1/AE3, EMA) are

GFAP

Synaptophysin

NeuN

Reticulin

MAP2 immunoreactvty in the poorly differentiated

neuroepithelial cells

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


•Total resection offer local tumour control.

•Subtotal resection or biopsy-stable or re-grow slowly.

• rare in the pediatric age

• uniform round to oval blandnuclei, indistinct cell borders,intranuclear pseudoinclusions,

• psammomma bodies

• no cystic component onimaging

Fibrous Meningioma


Papillary Glioneuronal

TumourRelatively 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

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 affectNeuroimaging:

Demarcated, solid to cystic, contrast-enhancing masses

with little mass effect

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.

•Microvascular proliferation or necrosis- rare.


•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.

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.

• 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

ExtraventrcularNeurocytoma

• Non-enhancing, diffusely infiltrative

Oligodendroglioma

• Dot-like EMA positivty, synaptophysin negative

Astroblastoma


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

Incidence: Rare


•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.

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.

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

•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

adjacent, perilesional cerebellar cortex does not

Glial area in RGNT

Neurocytic rosettes

containing neuropil

Perivascular

pseudorosettes

Biphasic neurocytic and glial components;

neurocytic and perivascular rosettes


•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.

Synaptophysin NeuN

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.


Favourable in terms of survival, but disabling

postoperative deficits present.

• Lipidized cellsCerebellar

liponeurocytoma

• supratentorialDNET

• Perivascular rosettes, GFAP+, Synaptophysin -

Ependymoma

• Rare location, diffusely infiltrative, no neurocyticcomponent

Oligodendroglioma

• Lacks neurocytic rosettes, usually supratentorial

PGNT

• No neurocytic componentPilocytic

astrocytoma


Other tumours that might show

immunoreactivity to both glial and neuronal

markers:

Medulloblastoma

Supratentorial Primitive Neuroectodermal

Tumour

Medulloepithelioma

Oligodendroglioma with neurocytic features.

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.

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

grade lesions

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, CNS Atlas

Health & Medicine

Glioneuronal tumours