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Glioblastoma

Multiforme
DR.KATTA CHARU GOUTHAM REDDY

Glioblastom
a
Multiforme
Definition
Glioblastoma
multiforme (GBM),
also known as
glioblastoma and
grade IV astrocytoma,
is the most common
and most aggressive
cancer that begins
within the brain.

Objectives
1.Anatomy
2.Physiology
3.Natural History of Disease
4.Diagnostic Work Up
5.Classification
6.Disease Management by Stage
7.Radiation Treatment Techniques
8.Sequelae of Treatment
9.Follow Up
10.Recurrence Management

Anatomy-Cerebrum
The cerebrum is the largest part of the
brain.
The cerebrum is made up of the
1. Two cerebral hemispheres and
their cortices, (the outer layers of
grey matter)
2. Underlying regions of white matter
3. Subcortical structures
(hippocampus, basal ganglia and
olfactory bulb)

Cerebral Cortex
The cerebral cortex, the outer layer
of gray matter of the cerebrum
Surface of folds to create gyri
(ridges) and sulci (furrows) to
increase the surface area.
The cerebral cortex is classified into
four lobes:
Frontal,
Parietal,
Temporal,
Occipital Lobes(Calcirine Sulcus
Divides occipital and Parietal

White Matter Tracts


White matter is composed of bundles
of myelinated nerve cell projections
which connect various grey matter
areas
Myelin acts as an insulator,
increasing the speed of transmission
of all nerve signals
Two important parts of White matter
Tracts are
1. Corona Radiata: cranially where
they connect to Grey matter
Areas
2. Internal Capsule: caudally when
fibers are tightly packed due to
Basal Ganglia

Subcortical Structures-Basal
Ganglia
The basal ganglia (or basal nuclei)
comprise multiple subcortical nuclei
1. dorsal striatum (caudate ,putamen)
2. ventral striatum (nucleus
accumbens . olfactory tubercle),
3. globus pallidus,
4. ventral pallidum,
5. substantia nigra
6. subthalamic nucleus

Microscopic Anatomy
Cell Type

Function

Neuron

Main functional unit of


Nervous system
,responsible for
generation and
conduction of Impulses

Oligodendroc
yte

Myelination of CNS
neuron

Astrocyte

Multiple functions

Microglia

Macrophages of Brain

Ependymal
Cells

movement of CSF,
separate ventricles and
the CSF from the
neuronal environment

Astrocytes
1. Structural Framework For Neuronal
Cells
2. Integrity Of The Bloodbrain Barrier
3. Taking Up, Storing And Releasing
Some Neurotransmitters
4. Neuronal Guidance During
Development
5. Adult Neurogenesis.
6. Presenting Antigen To The Immune
System

Higher Mental Functions


Lobe

Functions

Frontal

1.
2.
3.
4.

Memory Formation
Emotion
Decision Making
Personality

Parietal 1. Senses and integrates


Sensation
2. Spatial Awareness and
Perception
Tempor 1. Hearing
al
2. Organization and
Comprehension of Language
3. Information retreival
Occipit
al

processing, integration,
interpretation, etc. of Vision
and Vision Stimuli

Speech
Area

Function

Defect

Brocas Area
Left Frontal
Lobe

Controls facial
neurons,
speech, and
language
comprehension

ability to
comprehend
speech, but the
decreased r ability
to speak and form
words

Wernicke Area
Left Temporal
Lobe

Language
comprehension.

Words and
sentences are not
understood,
sentence formation
non-sensical

Arcuate
Fasuculus
A white matter
Brocas Area
and Wernickes
Area.

Allows for
coordinated,
comprehensible
speech

Conduction Aphasia
- auditory
comprehension and
speech articulation
are preserved,
difficult to repeat
heard speech

Motor Functions
Area

Functions

Premotor Cortex
(Precentral Gyrus)

Primary Motor Cortex


Cortical site involved with
controlling movements of
the body.

Primary
Site involved with
Somatosensory Cortex processing of tactile and
Postcentral Gyrus)
proprioceptive
information.
Somatosensory
Association Cortex

Assists with the


integration and
interpretation of
sensations relative to
body position and
orientation in space. May
assist with visuo-motor
coordination

Limbic System
1. Emotional brain :Emotional and
motivational aspects of behavior.
2. Provides emotional component to
learning process: Especially the
amygdala.
3. Associated with memory
Especially the hippocampus.
4. Associated with pain/pleasure,
rage

Molecular Pathogenesis of
Glioma
Oncogenes
EGFR
(Epidermal Derived
growth Factor
Receptor)
PGDFR
Platelet Derived
Growth Factor
Receptor

Tumour Supressor DNA Stability


Genes
Genes
P53
MGMT
Retinoblastoma
Gene
PTEN
Phosphatase and
Tensin Homologue

Molecular changes in
Glioblastoma
Gene

Function

LOH

Loss of heterozygosity on chromosome arm 10q is the most frequent gene alteration it occurs in
60-90% of cases. specific for glioblastoma multiforme associated with poor survival.

p53

The p53 gene appears to be deleted or altered in approximately 25-40% of all glioblastoma
multiform, more commonly in secondary glioblastoma multiformes.

EGFR

more common in primary glioblastoma, with mutations appearing in 40-50% of these tumours

MDM2

Amplification or overexpression of MDM2 constitutes an alternative mechanism to escape from p53regulated control
Overexpression of MDM2 is the second most common gene mutation in glioblastoma
multiformes and is observed in 10-15% of patients

PDGF

The PDGF gene acts as a major mitogen for glial cells by binding to the PDGF receptor (PDGFR).
Amplification or overexpression of PDGFR is typical (60%) in the pathway leading to secondary
glioblastomas.

PTEN

PTEN (also known as MMAC and TEP1) encodes a tyrosine phosphatase located at band 10q23.3.
cellular phosphatase, turning off signaling pathways, is consistent with possible tumor-suppression
action.
When phosphatase activity is lost because of genetic mutation, signaling pathways can become
activated constitutively, resulting in aberrant proliferation.
PTEN mutations have been found in as many as 20% of glioblastomas, more commonly in primary
glioblastoma multiformes

Natural History of Disease


Embryonal Stage Adult Stem cells wander through the extracellular spaces of the white matter
Some stop wandering, start reproducing resulting in Gliomas
Invades along myelinated axons, vascular basement membranes, and the subependyma, in the
subcortical matter of the cerebrum
The propagation is closely linked to the microvascular proliferation in hypoxic areas of the brain due
to the over-expression VEGF
Once it established itself within the subcortical matter, it extends to the adjacent cerebral cortex
and basal ganglia.
tumor spreads across the corpus callosum, the lesion becomes bilaterally symmetric

Natural History of Disease


1. These primary and secondary GBMs
constitute separate and distinct
disease entities.
2. They affect different epidemiological
groups and carry different prognoses.

Primary

Secondary

Definition

De novo

From LGG

Age

Older

Younger
(<45)

Genetics

EGFR
P53 PGDF
overexpressi IDH1
on
mutation

Clinical

worse

Better

Gliomas Pathways of Spread


Direction of Spread
White Matter
Tracts

Supratentorial : Anterior Posterior


Infratentorial :Craniocaudally

Corpus
Callosum

should be considered for any lesion crossing the


corpus callosum.
display a characteristic bihemispheric involvement,
resulting in a classic butterfly pattern.

Other Pathways
of spread

Ependymal,
Subpial Spinal Cord Metastasis
Intramedullary
Meningeal Spread
Extra neural Metastases

Clinical Presentation
Generalized

Focal

1. Headache

1.
2.
3.
4.

1. Due to increased intraranial pressure or to local


pressure on sensitive intracranial structures (mainly
dura and vessels).
2. Occur in the morning associated with focal neurologic
deficits, behavioral changes, and papilledema.

2.Cushings triad is classically associated with


increased intracranial pressure, but the full triad
(hypertension, bradycardia, respiratory irregularity) is seen
in only one-third of the cases of increased intracranial
pressure.

3.Optic atrophy and blindness


transmission of the pressure to the optic nerves.

4.Unilateral Weakness
5.Mental changes

because of

Weakness
Language dysfunction,
Sensory loss
Hemorrhage

Physical Examination
Aspect

Points to be noted

Consciousness

Digress of Alertness
Symptoms of raised of intracranial
pressure

Visual Symptoms

Field of Vision

Higher Mental Functions

Normal

Speech

Speech deficit type of speech deficit

Cranial Nerve Examination

Note for any cranial nerve Deficits

Sensory Examination

Localization of the sensory deficit

Motor Examination

Localization of motor deficit-power and


tone

Imaging
Objectives
Initial diagnosis of neoplasia
Characterization of cell type
Anatomical localization
Staging tumor extent
Assistance in planning treatment
Biopsy guidance
Monitoring response to
treatment

CT Scan
1. Histological heterogeneity of these
lesions is reflected in the CT
appearances.
2. The typical finding is of a mass with a
thick ring of contrast enhancement
with surrounding low-density
edematous change.
3. Central low density indicates necrosis
and is seen in 95% of tumors.
4. Inhomogeneous patchy
enhancement throughout the mass
may be observed

Magnetic Resonance Imaging


Mixed signal intensity mass lesions
are seen on both T1- and T2weighted images
Heterogeneity of the signal intensity
reflects the presence of central
necrosis which may or may not be
hemorrhagic, as well as multiple
cysts which may show fluiddebris
levels.
Frank hemorrhage may also be
present, with signal intensities
reflecting hemorrhage of different
ages.

Magnetic Resonance Imaging


Irregular signal intensity flow voids
consistent with the development of
increased vascularity may also be
seen.
Around the main tumor component,
extensive signal intensity
abnormality, low on T1 weighting and
high on T2 weighting, is seen
extending through the adjacent brain
parenchyma
This, although described as
representing edema, will also contain
tumor cells

Magnetic Resonance Imaging


Tumor commonly extends across the
corpus callosum, the posterior and
anterior commissures and along the
internal and external capsules

Magnetic Resonance Imaging


Multiple areas of irregular
enhancement separate from the main
mass does not indicate isolated foci of
abnormal cells, as tumor cells will be
found throughout the intervening areas
of non-enhancement.
Patches of enhancement are seen
where the cells are of sufficient number
to create an area of neovascularity and
breakdown of the bloodbrain barrier

Classification
Nonparametric recursive partitioning
analysis classified of patients into groups
with similar outcomes in malignant gliomas.
Age : Patients <50 years fare best
KPS 70
Normal Mental Status
Abnormal Mental Status

Molecular Classification of
Glioma

Treatment
Algorithm of
Glioblastoma
Multiforme

General Management-Cerebral
Edema
Glucocorticoids are used to control neurologic signs and symptoms caused by
cerebral edema.
Lower doses of steroids (e.g., 2 to 4 mg dexamethasone) twice daily have
been shown to be as effective as higher doses. Prolonged steroid use is
associated with multiple medical problems, and therefore steroids should be
discontinued or tapered to the lowest dose necessary, as soon as possible.
Dexamethasone is the most common corticosteroid used for historical
reasons and because of minimal mineral-corticoid effects.
As with all corticosteroids, a slow taper is necessary to prevent a rebound in
cerebral edema and also to allow the pituitaryadrenal axis to recover

General Management-Seizures
Patients with seizures require
anticonvulsants.
Prophylactic anticonvulsant use (in
patients who have never experienced a
seizure) remains controversial,
although practice guidelines from the
American Academy of Neurology
recommended against their use
because of lack of data.

Surgery
Goal is the safe removal of the largest possible
volume of tumor to establish a diagnosis and
relieve mass effect.
Frameless image-guided neuronavigation
systems are employed to localize subcortical
tumors along with intraoperative ultrasound
and MRI.
tumors may be removed en bloc via
circumferential dissection, but more frequently,
resection is effected in piecemeal fashion
Patients are routinely monitored in an intensive
care unit following a craniotomy. The first MRI is
obtained within 24 to 48 hours after surgery
before postoperative changes set in. The extent
of resection can be determined in this manner.