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Brain tumor
1. PRIMARY NERVOUS SYSTEM TUMORS IN
ADULTS AND MANAGEMENT
Dr. RAVI GOYAL
SR NEUROLOGY
GMC ,KOTA
2. Primary brain tumors are a diverse group of neoplasms arising from
different cells of the central nervous system (CNS).
It account for about 2% of all cancers, with an overall annual
incidence of 22 per 1,00 000 population.
MC brain tumor in adult- Brain metastasis (15-17%).
Meningiomas are the most common non-malignant primary brain
tumours f/b pituitary and nerve sheath tumours.
Gliomas account for 75% of malignant brain tumours, in which more
than half are glioblastomas.
11. Not Established :-
Head trauma
Electro magnetic field radiation
Radiofrequency and cellular phones
N-nitroso compounds
Vitamin C and E
Allergies/infection association
Tea and coffee
Occupational
Tobacco, alcohol consumption
12. Brain tumours are classified according to the WHO CNS
tumours grading system.
Previously , primary CNS tumours were defined on the basis of
histological criteria & assigned a grade (from I to IV).
In 2016, the classification was revised from the 2007
classification to incorporate signature molecular genetic
alterations to the classic histology.
13. WHO grade I – low proliferative potential. Possible cure with
surgery alone
WHO grade II – infiltrating but low in mitotic activity. Can recur
and progress to other grades.
WHO grade III – Histologic evidence of malignancy (mitotic
activity), infiltrative, anaplastic
WHO grade IV – mitotically active, necrosis, rapid pre and post-
surgical progression
14.
15.
16.
17. Generalized Focal
Headaches
Focal motor Weakness
Nausea/vomiting Ataxia
Syncope
Seizures
Mental status and
Behavioral Changes
Aphasia
Seizure Visual dysfunction
18. 50-70% of patients
Bifrontal and tension-like, with constant, dull pressure type
Classic brain tumor headaches occur in the early morning with
nausea and vomiting and improve over the course of the day
(only occur in 5%–17% of all brain tumor patients, 42% of
whom have posterior fossa tumor)
More common in brain metastases and glioblastomas. (90%)
19. MRI Brain with contrast is the investigation of choice .
Diffusion-weighted imaging , diffusion tensor imaging, MR
perfusion & MR spectroscopy are used to better characterise the
tumour cellularity, vascularity and metabolism respectively.
Can distinguish tumour, from non neoplastic processes,
including treatment effect.
Surgical biopsy
20. NECT –
Intra axial tumours – usually low attenuation
(High attenuation areas within a tumour-calcification,
hemorrhage and lymphoma )
Extra axial : Bone erosion and hyperostosis
MRI Brain :-
TIWI: low signal intensity
T2WI / FLAIR : High signal intensity
21. Low signal intensity In T2WI :
CNS Lymphoma
PNET
Metastasis ( melanoma )
GBM (less common )
Meningioma (less common).
Enhancement : almost all tumurs except
low grade glioma (WHO II & III )
Cystic non-tumoral lesions:
◦ Dermoid cyst
◦ Epidermoid cyst
◦ Arachnoid cyst
22. Homogeneous enhancement can be seen in:
Metastases
Lymphoma
Germinoma and other pineal gland tumors
Pituitary macroadenoma
Pilocytic astrocytoma and hemangioblastoma (only solid component)
Ganglioglioma
Meningioma and Schwannoma
Patchy enhancement can be seen in:
Metastases
Glioblastoma multiforme
Radiation necrosis
23. Ring enhancement-
seen in metastases and high-grade glioma
Diffusion Restriction : CNS lymphoma, oligodendroglioma
MR Spectroscopy :
decreased NAA,
increased choline , lipid lactate peak
(Ch/NAA ratio >1.3)
25. Medical (symptomatic) :
For raised ICP –mannitol preferred (1g/kg bolus f/b 0.25 to 0.5g/kg
6 or 8hrly)
vasogenic oedema –dexamethasone (10 mg loading f/b 16mg/d)
Seizure –Levetiracetam is preferred
not used prophylactically but may be used peri operatively.
Surgical intervention
Radiotherapy
Chemotherapy
26. Primary modality of treatment
Goals of surgery:
Establishing a diagnosis
Symptoms alleviation
Decompression
Tumour cyto reduction
28. Complication –
Due to direct injury to the brain or arterial or venous infarction
Factors responsible are :
age >60 years
poor performance status,
eloquent or deep location & prior surgery or radiation
Regional complications –
Hemorrhage, CSF leak, wound infection. Impaired wound
healing
Postoperative seizures (in 1%–7.5% of patients) after craniotomy
Perioperative mortality of 1.5%–3% with craniotomy.
29. Are indicated for deep-seated or multiple brain lesions and
for patients with poor prognosis in whom the risks of
resection outweigh the potential outcome benefits.
The main goal of such procedures is not to improve the
resection extent but to safely acquire viable tissue
representative of the lesion for further comprehensive
histological, immunohistochemical, and molecular analyses.
Two type-
Frameless neuro navigation based biopsy
Frame based biopsy
30. Frame based biopsy-
a stereotactic frame to head before obtaining the MRI or CT scan
to be used with the image guidance system .
This technique is cumbersome, restricted to point targeting and
still carries a small, but significant complication rate.
Frameless neuro navigation based biopsy-
A special MRI or CT one or two days before the planned biopsy
↓
image is imported into a computer system that provides a 3-
dimensional image of brain and biopsy target in the operating
room.
By using this image, along with a biopsy guidance arm guides
needle safely into the tumor target.
31. Provides the precision of stereotaxy and practicality of
neuronavigation.
It also has advantages for more safety, less time consuming
and less cost than current gold-standard of frame-based
biopsy.
32. As adjuvant of surgery
Cure or palliation
Photons are the most commonly used particles
usually delivered by a linear accelerator (LINAC),
That uses high-frequency electromagnetic waves to accelerate
electrons to high energies,
For infiltrative tumors, such as malignant gliomas, with a margin of
1–3 cm.
For sharply demarcated cystic astrocytomas, a margin of 0.5 cm
suffices.
33. 1. Whole-brain radiation therapy (WBRT) :-
Used to treat-
multifocal infiltrating tumors seen in gliomatosis cerebri
the multiple masses of recurrent brain lymphoma
I. Conventional Fractionated Radiotherapy : provided in daily
fractions of 1.8 to 2.0 Gy. (Total dose <60Gy)
II. Hyper fractionation” protocol : reduces repopulation of
tumor cells during irradiation.
34. 2. Stereotactic Radiosurgery Techniques :
Three types of facilities are typically used-
LINAC radiosurgery
proton radiosurgery
Gamma knife
3.Brachytherapy :
radiation is delivered by implanting the irradiation source close
to or into the target tissue.
35. Complications :
Radiation damage to the brain can be in form of-
Acute encephalopathy (within days)- Increasd ICP
Early-delayed encephalopathy (1–6 months),
Late-delayed encephalopathy (months to Years – as radiation
necrosis)
36. most patients with malignant brain tumors.
Important for patients with brain lymphoma or anaplastic
oligo dendroglial tumors
Alkylating agents are the major compounds used against brain
tumors.
37. Delivery Strategies.
The BBB is the major anatomical obstacle for chemotherapy of
primary brain tumors.
1. Intrathecal administration of methotrexate, thio-TEPA or
cytosine-arabinoside for leptomeningeal metastases
2. Intracarotid infusion of hypertonic solutions (25% mannitol or
15% glycerol) to produce reversible opening of the BBB.
3. Biodegradable polymers impregnated with BCNU increase
local drug concentration without notable systemic toxicity.
38. Temozolomide - fatigue and thrombocytopenia
Procarbazine or PCV —(procarbazine, CCNU/lomustine,
vincristine) can cause encephalopathy and peripheral
neuropathy.
Nitrosoureas (lomustine and carmustine)- Higher-dose can
cause encephalopathy, seizures and optic neuropathy.
Methotrexate -Acute encephalopathy from intrathecal or high
dose intravenous injection.
Aseptic meningitis or myelopathy can also develop after
intrathecal treatment.
40. Widely used for
Obtaining a diagnostic biopsy,
Performing a concurrent CSF diversion procedure, and
assessment of any residual tumor after debulking by microscopic
techniques.
The ideal tumor for total endoscopic resection is considered to be
soft, less than 2 cm in diameter,
located completely inside the ventricles, has associated hydrocephalus,
is mild to moderately vascular, and should be accessible through a
straight trajectory.
Pure endoscopic neurosurgery has been used mostly for CSF diversion
procedures, cyst fenestrations, and tumor biopsies while
Endoscopic-assisted procedures have been preferred for tumor
debulking and excision.
41. Most common malignant primary brain tumor.
Cell of origin can be
1. Astrocytes
2. Oligodendrocytes
3. Ependymal cells
4. Mixed
Identified by glial fibrillary acidic protein (GFAP) and S100.
44. Pilocytic Astrocytoma:-(WHO I)
Benign tumors, BRAFV600E mutation
85% of infra tentorial astrocytomas,
Location- cerebellum mainly (hypothalamus, the walls of the
third ventricle, the optic pathway (NF type I) and the brainstem.)
occur in the first and second decade .
Present as mural enhancing nodule.
Surgical excision , some cases involved field radiation therapy
with a margin of 0.5 cm .
Prognosis - excellent , the 25-year survival rates b/t 50% and
94%.
45.
46. Two-thirds of cases are diagnosed before age 25.
BRAF V600E mutation
Location- temporal lobes and extend into the leptomeninges
& Virchow–Robin spaces.
Well demarcated from surrounding tissue and may contain cysts.
Complete resection is feasible in most patients.
Radiation or chemotherapy for aggressive or recurrent tumors.
survival rate is > 80% after 5 years & 70% after 10 years, with
well-resected lesions
Anaplastic transformation occurs in 15-20% cases
47.
48. Occurs in patients with tuberous sclerosis and may be unique
to that disease
Hydrocephalus emerges before the third decade as clog CSF
outflow.
Surgery is curative and required when CSF flow is obstructed.
Rapamycin and everolimus at standard immunosuppressive
can induce regression of tumur.
49.
50. Tumor of young adulthood (during the first or between the
third and fourth decade).
Commonly afflicted are the frontal and temporal lobe of the
cerebral hemispheres.
Non enhancement after contrast
Early and maximal safe resection is the initial treatment.
IDH mutant :
1. Low risk- a watch-and wait policy with MRI every 3–6 months is
accepted.
2. High risk - older than 40 years, have neurological symptoms,
large tumour (>5 cm) or subtotal resection
51. Post-surgical standard of care is focal radiotherapy to 50-54gy
followed by 6 cycles of adjuvant procarbazine, lomustine and
vincristine (PCV).
IDH- wild type astrocytomas are often treated like
glioblastomas.
52.
53. In the past, diffuse gliomas with a unique pattern of
widespread brain invasion were designated as gliomatosis
cerebri (GC).
Definition -three or more lobes with frequent bi hemispheric,
basal ganglionic and/or infra tentorial extension .
These are IDH-wild type anaplastic astrocytomas .
Does not represent a distinct molecular entity and is no
longer considered a separate diagnosis.
54.
55. Most common neuro-epithelial tumor (50%) and 2nd mc primary nervous
system tumor.
Supra tentorial & older adult.
Highly aggressive.
Gross total resection is recommended whenever feasible .
Radiation therapy doubles the median survival of GBM.
Standard therapy combines irradiation with concomitant and adjuvant
temozolomide.(stupp protocol)
low dose (75 mg/m2/day) during the 6 weeks of RT f/b six 4-week cycles
(150–200 mg/m2 on days 1–5)
The efficacy of temozolomide is particularly pronounced in patients whose
tumors lack expression of MGMT.
56.
57.
58.
59. Supra tentorial (mc-frontal lobe)
Older adults
Low grade & high grade (Anaplastic)
IDH mutant and 1p/19q co-deleted tumours hold the best
prognosis f/b IDH-mutant with 1p/19q intact tumours > IDH wild
type tumours .
Heterogeneous enhancement is seen in approximately half of all
case.
Maximal safe surgical resection followed by chemo radiation
(same as Difuse astrocytoma)
60.
61. Comprises 6% of newly diagnosed neuro epithelial neoplasms
(2% of all nervous system tumors) .
Ependymomas occur along the neuraxis, usually in proximity to
the ventricles or subarachnoid space.
Intracranial ependymoma is more common in children (infra
tentorial > supratentorial) & spinal ependymoma in adults.
C11orf95 and RELA gene fusion is found in > 70% of supra-
tentorial ependymomas and confers a poor prognosis .
62. It is the most common intramedullary spinal cord tumor in adults
and is typically in proximity to the conus medullaris. (myxo-
papillary subtype)
Surgery is the mainstay of treatment .
Gross total resection is the most important independent
prognostic factor among all grades (WHO I–II–III).
Postoperative radiotherapy is usually employed in adult patients:
Intracranial grade III ependymomas (irrespective of the extent of
resection)
in subtotally resected intracranial grade II ependymoma.
63.
64.
65. Seizures are the most common manifestations.
MC location- supratentorial (tempral >frontal lobe)
Children and young adult
30-50% calcification
Present as cyst- mural enhancing nodule .
Gross total resection results in survival ranging from 7 to 17
years.
Adjuvant irradiation for incompletely resected or anaplastic
progression. ( survival of 3 years or less)
66.
67.
68. Includes papilloma and carcinoma.
Tumor of childhood.
In adults they account for only 0.2% of all intracranial
neoplasms.
Located in the fourth ventricle, the cerebello-pontine angle, or
lateral ventricles (mc)
Total resection is accomplished in fewer than half of cases.
At progression or recurrence, treatment with conventional
external beam radiation or SRS is of benefit.
69.
70. Most common primary intracranial tumors.
Older adult
Incidentally found asymptomatic meningiomas ( lacking mass
effect or compression of a venous sinus) - conservatively with
serial MRI evaluation.
when seizures occur, tumors grow or focal signs emerge -
surgical resection can be curative, especially in meningiomas
overlying the hemisphere.
Atypical (6%) and malignant meningiomas (2%) account in small
fraction & recur despite surgical resection and irradiation.
Non-NF2 meningiomas are nearly always benign whereas
mutant NF2 are atypical.
71.
72.
73.
74. An uncommon variant of extranodal non-Hodgkin lymphoma .
Involves the brain (periventricular), leptomeninges, eyes or
spinal cord without evidence of systemic disease.
Most cases are diagnosed in patients between 45 and 65 years
of age, median age (fifth decade) (non-HIV-related PCNSL )
Homogenous enhancement and diffusion restriction.
The most notable risk factor is immunodeficiency.
Highly aggressive tumor
Left untreated, most patients succumb within 6 months.
75.
76. Methotrexate-based chemotherapy given in high doses
(HDMTX, above 3.5 g/m2)
f/b leucovorin rescue has been shown to be the single most
effective treatment for PCNSL.
For PCNSL in AIDS patients, WBRT has been the standard
treatment resulting in poor and nondurable responses
77. Initial treatment of primary central nervous system lymphoma (PCNSL) in adults <70
years of age
78. Initial treatment of primary central nervous system lymphoma (PCNSL) in older
adults
83. Immunotherapy :-
Stimulation of a patient’s immune system to activate specific immune
cells to attack cancer cells. currently studied are-
Cancer vaccines
Oncolytic viro therapeutic,
Monoclonal antibodies (check point inhibitors)
Adoptive t-cell therapies (CAR t-cell).
Phase 3 vaccine trials include tumour lysate and peptide dendritic cell
vaccine (nct0045968 and nct02546102)
Phase 2 and 3 trials of nivolumab in newly diagnosed glioblastoma,
with enrolment based on MGMTp methylation status (NCT02667587
and NCT02617589)
84. Targeted therapy :-
Inhibit aberrant signalling pathways.
Tumour growth factor pathways (such as PDGF/PDGFR,
EGF/EGFR,VEGF/VEGFR),
The only ongoing phase 3 targeted therapy trial in glioma-
Addition of PARP inhibitor veliparib in MGMTp methylated
glioblastoma patients (NCT02152982).
85. Gene therapy:-
uses viruses, cellular carriers (stem cells), and nano
molecules as vectors to deliver genes into the target cells .
To modify known oncogenic mutations or sensitise tumour
cells to treatment.
On going trials in recurrent high-grade gliomas include the
phase 2/3 Toca 5 trial using a replication-competent
Retrovirus vector .
phase I trials using genetically modified neural stem cells.
86. Convection-enhanced delivery:-
Delivers larger molecules directly to the CNS via stereotactically
placed catheters, bypassing systemic toxicity.
By using a pressure gradient rather than a concentration
gradient, more effective concentrations of agents can reach the
tumour.
Compounds are delivered includes a recombinant fusion toxin
composed of IL-13, a modified form of the Pseudomonas
exotoxin (NCT02858895) and nano liposomal-irinotecan .
87. The Cancer Cell Map Initiative-
New effort focusing on mapping the cancer gene network to
identify key tumour drivers and the genetic influences on
treatment responses.
Leads to the development of biomarker-based trials where
treatment is based on molecular drivers rather than histology
alone.
Such biomarker-driven trials for primary brain tumours
patients include INSIGHT (NCT02977780), N2M2
(NCT03158389), AND GBM AGILE
88. Primary brain tumours remain difficult and challenging diseases to
manage despite substantial progress in understanding their
genesis.
Treatments and better outcomes for primary brain tumours have
long lagged behind those of other tumours.
Combinatorial regimens will be required to achieve a broad and
durable antitumour benefit .
New advances in cell engineering technologies and infusion of ex-
vivo prepared immune cells are promising strategies
The present challenge is to translate this better understanding of
the pathophysiology into effective therapies.
89. Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report:
Primary brain and other central nervous system tumors diagnosed in
the United States in 2010–2014. Neuro Oncol 2017; 19: 1–8
Louis DN, Ohgaki H, Wiestler OD CW. (2016) WHO classification of
Tumours of the central nervous system (revised 4th edition). WHO
Lyon, 2016
Weller M, van den Bent M, Tonn JC, et al. European Association for
Neuro-Oncology (EANO) guideline on the diagnosis and treatment of
adult astrocytic and oligodendroglial gliomas. Rev Lancet Oncol 2017;
18: 315–29.
Bradley’s Neurology in Clinical Practice, 7th edition
Osborn’s brain, second edition
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