Gliomas are the commonest tumor of brain arising from the supportive cells of the brain with diverse form and presentation the treatment of which is surgical and demands adjuvant therapy for most of circumstances.

1. cka
GLIOMA
DR. SURESH BISHOKARMA,
MCH Neurosurgery ®
Upendra Devkota Memorial National Institute of Neurological and Allied
Sciences
BANSBARI, NEPAL

2.  Gliomas are tumors of neuroepithelial origin derived from glial cells or
cell precursors.
 Glioma is a more inclusive classification encompassing two major basic
histopathological subtypes: astrocytoma and oligodendroglioma.
DEFINITION

3.  Grade I: Pilocytic astrocytomas
 Grade II: nuclear atypia alone: Diffuse low-grade astrocytomas
 Grade III: higher degrees of mitosis and nuclear atypia : Anaplastic
astrocytomas (viz. Anaplastic oligodendrogliomas and anaplastic
oligoastrocytomas).
 Grade IV: microvascular proliferation, invasion or necrosis and metastatic
potential: Glioblastomas.
 Malignant tumor : III and IV tumors and grade II astrocytomas with high
rate of malignant degeneration.
Grades of Astrocytoma

4. Pathophysiology
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Fig: Glioma signaling pathway.
Receptor tyrosine kinases (RTKs) are activated in gliomas by epidermal growth factor (EGF), transforming growth factor (TGF)- ,
platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF)-1.
These RTKs can then signal through Ras-/MAPK (Ras-/mitogen activated protein kinase), PLC-PKC (phospholipase C-/protein kinase
C), and PI3K-AKT/PKB (phosphoinosit- ide 3-kinase/AKT-protein kinase B) pathways.
The tyrosine phosphatase/ tensin homolog (PTEN) protein acts as a tumor suppressor by inhibiting the PI3K/AKT-activated signaling
cascade.
Ras and PI3K engage the cell cycle machinery through interaction with different regulators that include cyclin D1, MDM2, and p27,
which promote cell proliferation, differentiation, anti- apoptosis, migration, and metabolism.

8.  Grade I
• Subependymal giant cell astrocytoma (SEGA)
• Pilocytic astrocytoma
 Grade II
• Pilomyxoid astrocytoma
• Diffuse astrocytoma
• Pleomorphic xanthastrocytoma
 Grade III–anaplastic astrocytoma
 Grade IV
• Glioblastoma
• Giant cell glioblastoma
• Gliosarcoma
WHO 2007 Grading of astrocytomas

9.  2007: Based on this system, which relies on histologic features in addition to
immunohistochemical stains, tumors with astrocytic phenotype are classified
differently than tumors with oligodendroglial features.
 2016: final diagnosis is based on a combination of the phenotypic and genotypic
parameters.
 For example, in the 2007 WHO classification of brain tumors, diffuse
astrocytoma was only a single tumor type.
 The 2016 update uses genetic criteria to designate these tumors as either
astrocytoma (IDH mutant, ATRX wild-type, Ip/19q intact) or oligodendroglioma
(IDH mutant, ATRX wild-type, Ip/19q co-deletion)
 WHO grade II astrocytomas: cellularity is moderately increased and nuclear
atypia is occasional, but mitoses, endothelial proliferation, and necrosis are not
present (although rare mitotic activity is permitted in a large specimen).
2007 vs 2016: WHO class
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10.  Tumors with astrocytic phenotype are classified differently than tumors with
oligodendroglial features.
Molecular classification

13. LOW GRADE GLIOMA

14.  Premalignant astrocytic tumors that grow continuously, migrate along the
white matter pathways
INTRODUCTION
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15.  Low-grade glioma (LGG):WHO II
1. Diffuse astrocytomas,
2. Oligodendrogliomas,
3. Oligoastrocytomas.
 Unlike high-grade gliomas, LGGs tend to grow slowly, but persistently,
at roughly 3.5 mm per year.
 LGGs typically occur in younger adults.
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16. 1. Fibrillary Astrocytoma: MC;low cellularity with minimal nuclear atypia;
expresses intermediate GFAP positivity
2. Gemistocytic Astrocytoma: plump, glassy, eosinophilic cell bodies of
angular shape; consistently express GFAP; more prone to malignant
transformation
3. Protoplasmic Astrocytoma: rarest histological subtype; small bodied
astrocytes with few processes; scant GFAP; mucoid degeneration and
microcystic formation common
 The Ki-67/MIB-1 labeling index in diffuse astrocytomas usually is < 4%.
 The best immunohistochemical marker is glial fibrillary acidic protein (GFAP)
DIFFUSE ASTROCYTOMAS
TYPES
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17.  In oligodendrogliomas, the nuclei are round and regular, and clear
perinuclear haloes are present in most paraffin embedded specimens
(fried-eggs) as well as an array of fine, hexagonal capillaries, which are
commonly described as a “chicken wire pattern”.
 They are moderately cellular and have a dense network of capillaries and
frequently contain calcifications.
 Occasional mitoses and a Ki-67/MIB-1 labeling index up to 5% are
compatible with WHO grade II oligodendrogliomas.
 There is no immunohistochemical marker specific for
oligodendrogliomas.
OLIGODENDROGLIOMAS
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18.  LGG – 15% of all primary adult brain tumors
 Typically affects younger age groups (40s-60s)
 Particular predilection for the insula and supplementary motor area
 Most common symptom at presentation: seizure (80%)
 Only definitive risk: exposure to ionizing radiation
 Hereditary factor – no substantial role; though may be associated with
NF-1 and Li-Fraumeni syndrome
EPIDEMIOLOGY

19.  The most frequent molecular alteration is the IDH1/2 mutation :80% of
LGGs.
 Development of an IDH1-R132H mutation-specific antibody (H09)
greatly assists in the diagnosis of astrocytomas, oligodendrogliomas, and
oligoastrocytomas, and distinguishes these diffuse tumors from other
lower grade gliomas.
 The molecular profile of LGG based on IDH1/2 mutations, TP53
mutations, and 1p/19q loss seems to provide a more objective
classification that correlates well with patient survival.
IDH1/2 mutation in LGG
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20.  LGG cannot be considered any more as a “benign” tumor but rather as a
cancerous disease.
 An understanding of the adaptation of the brain in response to growth and spread
of this slow growing glioma, deficit is not pronounced in most cases.
 LGG is not a tumor mass, but is in fact an infiltrating chronic disease
progressively invading the central nervous system, especially the subcortical
connectivity. Such a diffusion of glioma cells may induce cognitive disorders,
probably due (at least partly) to a “disconnection syndrome.
 A study comparing early resection (7.7yrs) versus single biopsy demonstrated
that the OS was 5.8 years in the biopsy group
NATURAL COURSE OF LGG
THERE IS NO STABLE LGG
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21. UNFAVORABLE RISK FACTORS,
 Independent of treatment, for progression to
a higher-grade tumor are:
1. Age older than 40 years
2. Presence of neurologic deficits
3. Poor KPS (<70) at time of diagnosis
4. Tumor: Large, crossing the midline,
and rapid growth rate.
5. Contrast enhancement at the time of
diagnosis (conflicting)
6. Astrocytic histology
7. evidence of high proliferation (MIB-
1>3%)
UNFAVORABLE RISK FACTORS
FAVOURABLE OUTCOME:
* Mutations in the IDH gene and co-
deletion of 1p/l9q have a better
prognosis.
* Low CBV and low uptake of 11C-
MET.

22.  Adverse Factors:
 Age > 40 yrs
 Astrocytic tumor type
 Tumor size > 6cm
 Tumor crossing the midline
 Neurological deficit at diagnosis
 Favorable prognosis: no more than 2 of the adverse factors  median
survival of 7.7 yrs
 3 – 5 adverse factors  median survival of 3.2 yrs
EORTC (European Organization for
Research and Treatment of Cancer)
Prognostic scoring system..

23. Progression of LGG
criteria
In RANO system, criteria for progression go beyond
just signs of radiographic growth (of macdonald)
and include the formation of new lesions, changes in
enhancement pattern, and clinical changes
independent of imaging.
2010; RANO criteria rely on
T2 and FLAIR images
Obsolete: concept of PFS is meaningless in LGG before any treatment or after an
incomplete surgical resection.

24.  Seizures : cortical invasion: most common (80 to 90%) Intractable 50% :
partial or generalized.
 Rolandic, mediotemporal, and insular/paralimbic locations.
 More frequently associated with oligodendroglial tumor.
 Indeed, neurologic deficits are rare, even if these tumors are frequently
located within “eloquent areas,” because of cerebral plasticity
mechanisms.
CLINICAL FEATURES
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25. WORK-UP

26.  First-line diagnostic imaging modality.
 Because most of these tumors are slow growing, they may
cause expansion, remodeling, or erosion of the calvarium.
 Contrast enhancement: seldom: non/mildly enhancing.
 LGGs rarely cause significant peritumoral edema.
 Oligodendrogliomas.
 Mixed-density masses
 Calcifications: hallmark: 70%-90%.
 Cystic component (20%).
 Hemorrhage: uncommon.
 Low-grade diffuse astrocytomas
 Ill-defined homogenous masses
 Calcifications: rare.
 Contrast enhancement: seldom: Suspect secondary high-
grade glioma. (LGGHGG)
CT scan

27.  Homogeneously isointense to hypointense on
T1-weighted images and hyperintense on T2/
fluid-attenuated inversion recovery (FLAIR)
weighted images
 Calcifications manifest as areas of low-intensity
"blooming" on GRE, SWI, or T2.
 Mostly non-enhancing; When a nodular contrast
enhancement is present, it indicates generally a
focal area of malignant transformation
MRI
Diffuse Astrocytoma
Oligodendroglioma

28.  Proton magnetic resonance spectroscopy
measures major metabolites in tumoral
tissue.
 The typical (but not specific) spectrum of
an LGG
• Elevated choline (+ membrane
turnover)
• Decreased N-acetyl aspartate (neuronal
loss).
 The presence of lactate and lipids is
correlated to a more aggressive tumor
MRS
Diffuse astrocytoma

29.  Dynamic susceptibility
contrast MRI (DSC-MRI)
enables the measurement
of relative cerebral blood
volume (rCBV), which is
associated with vascularity.
 In astrocytoma, increase in
rCBV in LGG predicts
malignant transformation
before contrast
enhancement occurs.
MRI (DSC-MRI)
Figure 1. Is this a low-grade glioma? (a)
Heterogeneous gadoloniumenchanced right parietal rolandic tumor.
On MRS CNI is moderately increased with the presence of lactate
resonance. The rCBV is 1.6. WHO grade II glioma with Ki-
67 index = 4%.
(b) Homogenous frontal lobe tumor on all sequences, no gadolinium
enchancement. The CNI is much higher here with mobile lipids and
lactate resonance and the rCBV is 3.5. WHO grade II glioma, Ki-67
index 12%.

30.  Functional MRI (fMRI), magnetoencephalography, diffusion tensor
imaging (DTI), and, more recently, transcranial magnetic stimulation,
have enabled us to perform a noninvasive mapping of the whole brain.
Mapping
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31.  Diffusion tensor imaging (DTI) enables the identification of the
tractography of the main fiber bundles.
 DTI enables the study of the sole anatomy of the subcortical pathways,
but not of their function.
 DTI indices (mean diffusivity [MD] and fractional anisotropy [FA]) may
be used to distinguish between LGGs and high- grade gliomas.
DTI
GP=BA=RC (RBG)

32.  FDG PET - LGGs are
hypometabolic in contrast
to HGGs, which are
hypermetabolic uptake of
radiolabeled amino acids
is increased in ~2/3 rd of
LGG
 18 F-FET PET (using
tyrosine) – used in LGG
for predicting outcome.
PET (Positron Emission Tomography)

34. THERAPEUTIC STRATEGIES.
London: Springer, 2013Abbr: ICH:intracranial hypertension; IS:intractable seizure ; S: seizure.

35. 1. To obtain histological confirmation/molecular genetic
analysis
2. To improve neurological condition
3. To reduce risk of tumor growth
4. To prevent malignant transformation
OBJECTIVES SURGERY FOR LOW GRADE GLIOMAS

36.  LGGs are premalignant entities, which, given enough time, at some point
in their lifecycle will transform into higher-grade tumors.
 The indications for biopsy are very limited in LGG.
 The main goal of neuropathological examination is to give the actual
grade of the glioma.
 Overgrading of WHO grade I gliomas occurs in approximately 11% of
cases and undergrading of WHO grade III gliomas occurs in 28%.1
LIMITED ROLE OF BIOPSY
1. Muragaki Y, Chernov M, Maruyama T, et al. Low-grade glioma on stereotactic biopsy: how often is the diagnosis accurate?
Minim Invasive Neurosurg 2008;51:275–279

37.  Aggressive tumors grow continuously, migrate along the white matter
pathways, and inevitably progress to a higher grade of malignancy,
leading to neurologic disability and ultimately to death.
 Wait and see  early and maximal resection.
PARADIGM SHIFT
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38. Early and radical surgical resections of smaller size tumor involving
eloquent areas that were operated with awake mapping, the rate of
permanent deficit was zero.
PROPHYLACTIC FUNCTIONAL NEURO-ONCOLOGICAL
SURGERY IN LGG
Duffau H. Awake surgery for incidental WHO grade II gliomas involving eloquent areas. Acta Neurochir
(Wien) 2012b;154:575–584, discussion 584

39.  As already mentioned, biopsy samples within and beyond MRI-defined
abnormalities showed that imaging underestimated the spatial extent of
LGG, because tumoral cells were present around the area of MRI signal
abnormalities, up to 20 mm.
 Supratotal resection is resection extending beyond the area of MRI signal
abnormalities.
 The goal of supratotal resection is to delay malignant transformation and
the administration of adjuvant therapy, without claiming to cure LGG
patients.
SUPRATOTAL RESECTION OF LOW
GRADE GLIOMA
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40.  Extent of resection œ to survival.1-3
 The French Glioma Network (2013) 3 published the largest surgical series
of LGG ever reported, 1,097 patients, and found that EOR as well as the
postsurgical residual volume were independent prognostic factors
significantly associated with a longer OS.
EOR AND SURVIVAL
1. Schomas DA, Laack NN, Rao RD, et al. Intracranial low-grade gliomas in adults: 30-year experience with long-term follow-up at Mayo Clinic.
Neuro-oncol 2009;11:437–445
2. 2. Ius T, Isola M, Budai R, et al. Low-grade glioma surgery in eloquent areas: volumetric analysis of extent of resection and its impact on overall
survival. A single-institution experience in 190 patients: clini- cal article. J Neurosurg 2012;117:1039–1052
3. Capelle L, Fontaine D, Mandonnet E, et al. Spontaneous and therapeu- tic prognostic factors in adult hemispheric WHO grade II gliomas: a series
of 1097 cases. J Neurosurg 2013;118:1157–1168

41. • Usually reserved for tumor progression.
• Temozolomide may be effective in progressive WHO grade II astrocytomas (of label use).
• Toxicity profile favors TMZ in terms of better tolerability (reduced myelotoxicity) and
QoL.
• Effectiveness of PCV (procarbazine, CCNU, and vincristine) was assessed by RTOG 9802.
• It showed no significant difference in 5-yr OS rates (RT+PCV versus RT:
72%versus 63%.
• But on post hoc analysis of survival for patients surviving to 2 years,
RT+PCVgroup had higher 5-yr OS than RT alone.
• Adjuvant chemotherapy may also be useful for shrinking a tumor prior to surgery
and enabling a more extensive resection.
• Patients more likely to respond have oligodendroglial tumors, but mixed or astrocytic
tumors may respond as well.
• Chemotherapy may also result in a control of refractory epilepsy.
• When chemotherapy was discontinued in the absence of tumor progression, a majority of
LGGs resumed their progressive growth within 1 year
• 1p/19q deletion: The response rate is higher/longer.
CHEMOTHERAPY
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42.  Significant and concomitant decrease in Cho/Cr and Cho/Naa ratios was
observed in responders, indicating the direct metabolic effect of
temozolomide on tumor anaplasia
TMZ and MRS
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43. • Unlike WHO grade I gliomas, it is clear that surgery alone is not curative
in the treatment of LGGs.
• Timing: uncertain.
 Early radiotherapy (54 Gy in fractions of 1.8 Gy) is recommended as
adjuvant therapy and is shown to prolong median progression free
survival from 3.4 to 5.3 years but does not affect overall survival.
• Most LGGs do not present with significant morbidity at the time of their
diagnosis, it is preferred to delay radiation side effects until absolutely
necessary to ensure better overall outcomes.
• Safe to delay after gross total resection in lower-risk disease*.
RADIOTHERAPY
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44.  Overall 5-year, progression-free survival rates in randomized studies vary
from approximately 40% to 75%, reflecting the heterogeneity in risk
factors.
 Impressive improvements in 5-year, progression-free survival were seen
in oligodendroglioma or LGGs with IDH 1 mutation after chemoradiation
adjuvant therapy.
 Median progression-free survival across all tumor subtypes
 Chemoradiation treatment vs radiation-alone arm : 10.4 years versus 4
 Most recent study:
• 5-year survival: chemoradiation vs Radiation: 72% vs 63%
• median survival: chemoradiation vs Radiation: 13.3 years vs 7.8 years.
SURVIVAL

45. De-differentiation
The major cause of morbidity with low-grade astrocytomas is de-
differentiation to a more malignant grade.
Genetic markers that correlate with a higher degree of malignant
degeneration
Loss of heterozygosity on chromosomes 10 &17
Alteration in tumor suppressor genes at 9p, 13q, 19q &22q .
Changes in epidermal growth factor receptor (EGRF) and platelet-derived
growth factor (PDGF)
Mutation of the TP53 gene located on chromosome 17p.
Transformation of the p53 suppressor gene
Isocitrate dehydrogenase (IDH) mutations – genetic aberrations that lead to
epigenetic machinery dysfunction
LGG  HGG

46.  Documented incidence of transformation: 17-73% over 15 yrs
 Median interval for transformation: 2.1-10.1 years
 Several recent studies have examined malignant transformation in the context
of extent of resection  risk of progression increases with tumor burden
 Greater preoperative tumor volume significantly associated with shortened
malignant progression free survival
 Larger tumor at presentation have inherent faster growth rate, thus recur
faster
MALIGNANT TRANSFORMATION

47. HIGH GRADE GLIOMA

48. Characteristics Primary Secondary
Type 2 1
Synonym IDH wild type IDH mutant
Development Denovo without evidence (clinical or
histological) of a less malignant
precursor.
Malignant degeneration of WHO II
or III
Age Older Mean 55 Younger Mean 40
Clinical History <3months 15 months
Location Supratentorial Preferentially frontal
Necrosis Extensive Limited
Genetic TERT promotor mutation, EGRF
amplification (40%), PTEN mutation
(30%), CDKN2A (P16) deletion
(40%), TP53 (27%), LOH in Chr10
TP53 (81%),
IDH1 and IDH2
mutation
Rare, 5% 60-90%
ATXR mutation Exceptional 71%
Median Survival 4.7m 7.8m
Sx+Xrt 9.9m 24m
Sx+Xrt+Chemo 15m 31m
LOH: Loss of heterozygosity
Primary vs Secondary GBM

49. Subtype Age Genomic
Mutation
Response to Rx Survival
Classical EGFR Good Longest
Pro-neural Young TP53,
PDGRFR,IDH1
Less Longer
Mesenchymal NF1, TP53,
PTEN
Least Worst
Neural None
PRIMARY GLIOBLASTOMAS
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and
core pathways. The Cancer Genome Atlas (TCGA) project. Nature. 2008.
Large-scale National Institutes of Health (NIH) effort on GBM genomic analysis
Verhaak et al. 2008

50.  Gliomas : 29% of all primary brain tumors
 Glioblastoma : 54% of gliomas (most common)
 Anaplas astrocytomas : 10 to 30% of all the gliomas.
 Anaplastic astrocytoma: 35 to 55 years
 GBM : 45-55 years.
EPIDEMIOLOGY
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51.  Approximately 60% of gliomas are located in one of the cerebral
hemispheres
• Frontal lobe (25.6%) > temporal lobe (19.6%) > parietal lobe (12.6%).
• Glioblastoma multiforme is uncommon in the region of the third
ventricle (< 1%) and rarely occurs in the posterior fossa.
• Although most GBMs are centered in the deep white matter,
• Epicenter at the gray-white junction: 10%.
LOCATION
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52.  Genetic syndromes including neurofibromatosis types 1 and 2 and Li-
Fraumeni and Turcot’s syndromes, are putatively responsible for around
5% of these tumors, and these patients often have a positive family
history.
 Ionizing radiation is the only well-established risk factor
 Inconclusive: head injury, foods, occupational exposures, electromagnetic
fields, and cellular telephones as causative agents is inconclusive.
 Allergic immune phenomenon: protective role of IgE: asthma, eczema,
allergies: decreased risk of glioma.
ASSOCIATION
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53.  Headaches, seizures, focal neurologic deficits, confusion, memory loss,
and personality changes.
 Determinants: anatomic location, mass effect, and growth rate, but not
necessarily histology.
 seizure activity does not correlate with tumor grade
 Tumors in eloquent locations that cause mass effect, regardless of size,
can present with rapid onset of symptoms, whereas very large tumors in
non-eloquent areas (e.g., right frontal lobe) may be clinically silent for a
long time.
CLINICAL FEATURES
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54.  Malignant gliomas tend to spread or recur in adjacent brain regions along
white matter tracts.
 Spread outside the central nervous system (CNS) is extremely rare.
Spread
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55.  (<10% of recurrent gliomas recur away from the original site):
 1. Tracking through white matter
• a) corpus callosum (CC)
 through genu or body of CC→bilateral frontal lobe involvement (“butterfly
glioma”)
 through splenium of CC→bilateral parietal or occipital lobes
• b) cerebral peduncles →midbrain involvement
• c) internal capsule →encroachment of basal ganglion tumors into centrum
semiovale
• d) uncinate fasciculus →simultaneous frontal and temporal lobe tumors
• e) interthalamic adhesion →bilateral thalamic gliomas
 2. CSF pathways (subarachnoid seeding): 10–25%frequency of meningeal and
ventricular seeding by high grade gliomas
 rarely, gliomas may spread systemically
SPREAD OF GLIOMA

56. WORK UP
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57. GRADING GLIOMA BY CT/MRI
Angiographic appearance:
AAs usually appear as an avascular mass.
Tumor blush and AV-shunting with early draining veins are more characteristic of
GBM

58.  D/D
1. CNS lymphoma,
2. Oligodendroglioma, and
3. Glioblastoma.
 These lesions should be biopsied to avoid misdiagnosis, as CNS
lymphomas and oligodendrogliomas with 1p19 deletions may be more
responsive to adjuvant therapies than glioblastomas and have a
significantly different prognosis.
CONTRAST-ENHANCING BUTTERFLY LESIONS
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59.  Proliferation index (i.e., Ki-67/MIB-1)
 Immunohistochemical staining, and
 Molecular genetic tests.
PROGNOSTICATION
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60.  Glucocorticosteroids: peritumoral edema: neurological symptoms and
survival.
Treatment
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61. 1. Obtain tissue diagnosis
2. Improve symptoms
3. Delay onset of new symptoms
4. Increase survival
5. Allow time for adjuvant treatments
6. Decrease steroid doses
Surgery: Rationale
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62.  Microsurgical resection remains a critical therapeutic modality for HGGs.
 Infiltrative nature of HGG renders complete resection and majority will
recur within 2 cm of their original location.
• However, there remains no general consensus in the literature
regarding the efficacy of extent of resection in improving patient
outcome.
 28 HGG studies strongly suggested an implicit benefit in terms of patient
survival with greater extent of resection.
 Those with 100%, 90%, 80%, and 78% EOR had overall survival times
of 16, 13.8, 12.8, and 12.5 months, respectively. (Difference nearly 3
months).1
EOR
1. Sanai N et al. 2011; An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg.

63.  Surgical excision should be considered when gross total removal is feasible.
• Reduction in mass, postoperative brain swelling.
 Partial resection of glioblastoma carries significant risk of postoperative
hemorrhage or the development of severe cerebral edema termed wounded
glioma syndrome, with risk of herniation.
 The benefit of a subtotal resection is unclear.
 Indication of partial resection.
1. Elderly patients (usually those > 80 years old)
2. KPS scores < 70, and
3. Those whose tumors are multifocal,
4. Involve both hemispheres (e.g., butterfly gliomas), or
5. Eloquency: Extensively involving the dominant hemisphere
Stereotactic needle biopsy of heterogeneous malignant gliomas may misdiagnose
the grade of the tumor in 25% of cases.
Partial resection of glioblastoma
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64. Glioma recurrence vs Radionecrosis
 MRI with gadolinium: Both tumor recurrence and radiation necrosis
show enhancement.
 MR spectroscopy:
In specimens with mixed necrosis and neoplasm, the spectral patterns
are less definitive.
 Cerebral blood volume (CBV) mapping:
Lesions with relative CBV greater than 2.6 mL blood/g of tissue were
indicative of tumor recurrence, and relative CBV of less than 0.6 was
consistent with radiation necrosis. However, there was significant
overlap between the groups.
 Positron emission tomography (PET) scan:
Metabolic activity (glucose uptake) is increased in tumor and
decreased in radiation necrosis.
Recurrent glioma

65.  Gross tumor debulking can reduce mass effect and thereby improve
symptoms and quality of life for patients, and add the associated benefits
of reduced steroid doses.
 Reoperation may increase overall survival in patients with recurrent
malignant gliomas by 2 to 5 months.
 Reduced disease burden also theoretically could improve the efficacy of
additional adjuvant therapies being considered.
Surgery for recurrent GBM
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66.  MRI should be obtained within 24 to 48 hours of surgery to more
accurately assess the extent of resection.
Post op imaging
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67.  Patients with tumors harboring methylguanine methyltransferase
(MGMT) methylation, IDH mutation, and 1p19 deletion may have a
significantly better prognosis than those without these genetic alterations
 1p/19 Chromosomal Co-Deletion
 The 1p/19q co-deletion seen in tumors with an oligodendroglial
component appears to confer a significant survival advantage and
improved response to chemotherapy.
 EGFR amplification: Indicates aggressive malignancy, especially in
younger patients and associated with a poorer response to radiation and
chemotherapy.
Consideration
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68. Newly Diagnosed Malignant Glioma
Standard radiotherapy (RT) for malignant glioma utilizes
1. Three- dimensional conformal external-beam radiation
2. For up to a total of 60 Gy in 30 fractions of 200 cGy each, given 5 days
a week.
RT is administered to the area encompassing the tumor plus an extra margin,
which usually involves areas of T2/FLAIR hyperintensity thought to
represent nonenhancing locations of tumor infiltration.
This margin may be limited in eloquent brain areas.
Radiotherapy
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69.  PCV chemo- therapy: Benefit in GBM. (HR [hazard ratio] 0.85 CI
[confidence interval] 0.78 to 0.92, P < 0.0001) with an overall
improvement of 2 months in median survival to 12 months.
 In grade III gliomas two recent randomized controlled trials did not
demonstrate an increase in survival with PCV.
 Temozolomide is also effective as therapy for recurrent disease, where it
increases time to progression without an increase in adverse events.
PCV chemotherapy
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70.  Temozolomide is an atypical alkylating chemotherapeutic agent that was
approved by the Food and Drug Administration (FDA) for the treatment of
newly diagnosed glioblastoma in 2005. A landmark phase 3 study published
in 2005 led to this approval and established TMZ as the current standard of
care.
 For Temozolomide, early data suggest that the best responders, if any, appear
to be patients with oligodendrogliomas and mixed oligoastrocytomas.
 MGMT methylation and Combined 1p/19q loss of heterozygosity is
significantly associated with a higher rate of and longer response to the
methylating agent temozolomide.
 Standard dosing for concomitant TMZ therapy is 75 mg/m2/d given daily
during RT followed by 150 to 200 mg/m2/d for 5 days every 28 days for a
total of six cycles
 Toxicity: myelosuppression.
TEMOZOLOMIDE
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71. TEMOZOLOMIDE IN GLIOMA
IN LGG
The EORTC study 26971 on first-line
temozolomide chemotherapy
demonstrated this with a reported 50%
response rate for recurrent
oligodendroglioma patients.
Using a prolonged temozolomide
schedule, patients with progressive or
recurrent LGGs also have an overall
response rate of 30% and a progression-
free rate of 56.7%
IN GLIOBLASTOMA
Patients were randomized to either post-
resection RT alone or postresection RT with
TMZ.
Median survival of 14.6 versus 12.1 months
Improved 2-year survival rates of 26.5%
versus 10.4%.
In the 5-year follow-up analysis of the trial,
the benefit of TMZ was confirmed in all
clinical prognostic subgroups receiving the
drug.
Overall survival RT vs RT+TMZ:
1.9%/9.8%.
Cohen MH et al. Food and Drug Administration Drug approval summary: temozolomide plus radiation therapy for the treatment of
newly diagnosed glioblastoma multiforme. Clin Cancer Res 2005.

72. METHODS
85 centers, 573 patients from Randomization.
Radiotherapy alone group
Daily fractions of 2 Gy given 5 days per week for 6
weeks, for a total of 60 Gy)
Radiotherapy plus continuous daily temozolomide group
RT+ TMX (75mg/m2 per day, 7 days per week from the
first to the last day of radiotherapy), followed by six
cycles of adjuvant temozolomide (150 to 200 mg per
square meter for 5 days during each 28-day cycle).
The primary end point was overall survival
STUPP PROTOCOL
“Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma”
RESULTS
573 glioblastoma patients Median age was 56 years, and
84% of patients had undergone debulking surgery.
Median follow-up of 28 months,
Median survival: 12.1 vs 14.6 months
Two-year survival rate :10.4% vs 26.5%
CONCLUSIONS
The addition of temozolomide to
radiotherapy for newly diagnosed
glioblastoma result- ed in a clinically
meaningful and statistically significant
survival benefit with minimal additional
toxicity.
STUPP ET AL . NEJM; Randomized study. 2005

73.  Bevacizumab is a monoclonal antibody that inhibits vascular endothelial
growth factor A (VEGF-A), a growth factor that is involved in
angiogenesis.
 A meta-analysis of 548 patients in 15 studies reviewed the efficacy of
bevacizumab treatment in patients with recurrent glioblastoma.
• Median OS: 9.3m, 6-month PFS: 45%, and 6-month OS: 76%
 TMZ-based chemoradiation with or without bevacizumab:
• Median OS: 15.7 vs 16.1 months.
 Side effects: Intracranial hemorrhage and thrombotic events (deep venous
thrombosis, pulmonary embolus, and ischemic stroke).
Bevacizumab
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74.  Implantation of biodegradable carmustine (BCNU) wafers (Gliadel®)
 FDA- approved: New and recurrent malignant gliomas.
 Implanted into the resection cavity at the time of surgery.
 Agent diffuses into surrounding, tumor-infiltrated, brain tissue over the
subsequent weeks at over 100-fold the concentration that could be
achieved with systemic administration.
 Their use in malignant gliomas was established by a multi- center,
placebo-controlled trial for recurrent GBMs, which showed survival
improvements.
 In phase 3 clinical trials including 240 patients, Gliadel improved the
overall survival (OS): 13.9 vs 11.6 months; p <0.005)
 However, subgroup analysis failed to show significant benefit in
glioblastoma patients.
GLIADEL BCNU WAFERS
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75.  Median survival is
1. GBM : around 1 year
2. Anaplastic astrocytoma : 2 years
3. Anaplastic oligodendroglioma : 5 years
Survival
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76. RECENT ADVANCES

77. • Chemotherapy, including both new and standard medications
• Immunotherapy (Peptide vaccines, dendritic cell vaccines):
personalized vaccine created with a patient’s own tumor cells to
stimulate a tumor-specific response.
• Angiogenesis inhibitors
• Targeted therapies, designed to attack specific molecular
abnormalities in the tumor
• Antimitotic therapy: tumor treating fields (TTFs):
• Electrical current of 100 – 300 kHz: scalp transducer: least 18 hours
per day.
• Immunomodulatory molecules, such as the PD-1 and CTLA-4
inhibitors
• 19, and Chimeric Antigen Receptor T-cell (CAR T-Cell) strategies
Recent advances in Glioma treament

78. 1. Cortical mapping for awake craniotomies
2. Tumor-brain interface:
A. Confocal Intraoperative Microscopy: Near infrared (NIR) confocal endomicroscopy, which can
facilitate spatial selection of highly heterogeneous tissue for molecular and tissue diagnosis.
B. Fluorescence Guided Surgery: Moore et al. in 1948: selective uptake of 5-ALA by tumor cells
i. 5-ALA is a photosensitive substance precursor of protoporphyrin IX (PpIX) (mainly visible with a
wavelength of 375–475 nm) that turns into a red fluorescent emission signal after mitochondrial
metabolization.
ii. 100% specificity and 85% sensitivity in brain tumor removal using 5-aminolevulinic acid-induced
porphyrin fluorescence.
3. Laser Interstitial Therapy (LIT): Thermocoagulative therapy: percutaneous: optical fiber: heat-
generated necrosis of the tissue. Superior to SRS.
4. Intraoperative mass Spectrometry (IMS): identifies and characterizes molecules by taking into account
their masses and fragmentation patterns
5. Optical coherence tomography (OCT): Future: intraoperative identification of cancer samples without
processing of the sample (fixation or freezing) will enhance tumor resection: interaction of light
emission
6. Nanotechnology
Advances in Brain Tumor Surgery for
Glioblastoma in Adults

80. Take home message
1. WHO 2016: Final diagnosis is based on a combination of the phenotypic and genotypic parameters while 2007 classification
was relied on histologic features in addition to immunohistochemical stains
2. LGG: Focal neurologic deficits rare: cerebral plasticity mechanisms
3. <10% of recurrent gliomas recur away from the original site tracking through white matter or CSF pathway or rarely
systemically.
4. LGG: Favourable outcome are mutations in the IDH-gene and co-deletion of 1p/l9q and low CBV and low uptake of 11c-
met.
5. Rano’s and McDonald criteria are tools for assessment of progression of LGG.
6. LGG: Early and radical surgical resections of smaller size tumor involving eloquent areas that were operated with awake
mapping, the rate of permanent deficit was zero.
7. Supratotal resection is resection (>2cm) extending beyond the area of MRI signal abnormalities.
8. Unlike WHO grade I gliomas, it is clear that surgery alone is not curative in the treatment of LGGs.
9. The major cause of morbidity with low-grade astrocytomas is de-differentiation to a more malignant grade ( EGRF, PDGF,
TP53, P53, IDH mutation, LOH
10.Primary GBM ( Denovo, wild type/type 2- EGRF, PTEN) has worst prognosis.
11.Proliferation index include Ki-67/MIB-1. Higher suggest aggressive behaviour and hence recurrence.
12.When possible plan is GTR, Partial resection GBM—> wounded glioma syndrome, with risk of herniation.
13.STUPP protocol for GBM.
Thank you
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GLIOMAS

81. Thank you

GLIOMAS