Essentials of gliomas-and their

mangement.Dr. Parag Moon

Senior resident,Dept. of Neurology

GMC, Kota

Classification of brain tumors

CNS tumors can primarily be divided into Primary -originates in the brain (solitary, nodular) Secondary-made up of cells that have spread

(metastasized) to the brain from somewhere else in the body.

Multiple in number, prior h/o cancer , edema +, located at gray white interface.

May lodge into - Brain parenchyma – most common area of

metastases- Leptomeninges – pia mater & arachnoid mater- Dural space

WHO classification of brain tumors

Tumors of Neuroepithelial Tissue Tumors of Cranial and Spinal Nerves Tumors of Meninges Lymphomas and Hematopoietic

Neoplasm Germ Cell Tumor Tumors of Sellar Regions (pituitary

/craniopharyngioma) Metastatic Tumors

Many grading systems (e.g., Kernohan, St. Anne-Mayo, and Ringertz systems)

Most of these grading systems share an assessment of nuclear abnormalities, mitoses, endothelial proliferation, and necrosis

WHO Grading :

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

Cell of origin can be1. Astrocytes2. Oligodendrocytes3. Ependymal cells4. Mixed Identified by glial fibrillary acidic protein

(GFAP) and S100

Gliomas

Gliomas-Most common (80%) primary malignant brain tumours.

Gliobastoma accounts for 54%. Most common is astrocytoma (including

gliobastoma)-76%. Slight male preponderance. More common in whites.

Epidemiology

Aetiopathology Exposure to ionizing radiations is the only

definite risk factor They are common in;

NF type I (15 – 20% develop LGGs) NF type II Tuberous sclerosis Li-Fraumeni syndrome

Environmental exposure to Nitrites/Nitrates (nitrosamines/amides)

Radiofrequency radiation. Electromagnetic field radiation(EMF)

Allergies/IgE levels association Vit. E and C consumption. Head trauma Tobacco, alcohol consumption p53 gene mutation (a consistent finding) 1p/19q mutations in tumours transforming

to high grade

Genetics

Well circumscribed both grossly and radiologically.

More common in cerebellum, third ventricle, hypothalamus, optic nerve, spinal cord, dorsal brainstem.

Cerebellar-large fluid filled cyst with enhancing nodule.

Hyothalamus, optic nerve- solid tumours. Outcome excellent (80% 20-year survival)

Pilocytic astrocytoma(WHO grade I)

Biphasic pattern- compact pilocytic areas with interspersed microcytic, loose and spongy areas.

Rosenthal fibres Mulberry shaped eosinophilic granular

inclusion Pilomyxoid astrocytoma-variant, more

aggressive, affects children younger than 3 years

Pilocytic astrocytoma(WHO grade I)

Fig 2.4B: Axial T1 Wtd. MRIFig 2.4A: Axial T2 Wtd. MRI Fig 2.4C: Post-Contrast Axial T1 Wtd. MRIA large cystic tumor (yellow arrow) with a mural enhancing nodule (red arrow) is seen within the left cerebellar hemisphere.

DIAGNOSIS: PILOCYTIC ASTROCYTOMA

• Grade I Astrocytoma (WHO Classification)

• Children and young adults

• Imaging Features: cyst within enhancing tumor nodule.

Diffuse astrocytoma (WHO grade II) Well differentiated, low grade, simply

astrocytoma. Median age at diagnosis-35 years. Brainstem gliomas-childhood Ill defined non enhancing cerebral masses. Grossly poorly circumscribed. Lacks mitotic activity, microvascular

proliferation and necrosis Low MIB(Ki-67) proliferative index.

90%-mutation in IDH1 and IDH2 encoding for isocitrate dehydrogenase in citric acid cycle.

IDH1 mutation-prognostic significance 50%- loss of 17p and mutation in TP53.

Diffuse astrocytoma (WHO grade II)

Axial T1 Wtd. MRI Axial Flair MRI Post-Contrast Axial T1 Wtd. MRI

Non-enhancing tumor (arrow) involving the right temporal lobe.

GRADE II ASTROCYTOMA (LOW GRADE)

• Children and young adults

• Imaging Features: Non-enhancing tumors. Calcification can be seen.

Anaplastic astrocytoma (WHO grade III) Mean age- fouth or fifth decade Some contrast enhancement on MRI. More cellular than grade II Presence of mitotic figures. High Ki67/MIB index High incidence of progression to GBM High frequency of TP53, IDH1, IDH2, RB, PTEN EFGR mutation-worse prognosis. Relative survival at 2 years-40% and at 5

years-27%

Fig 2.2B: Axial T1 Wtd. MRIFig 2.2A: Axial Flair MRI Fig 2.2C: Post-Contrast Axial T1 Wtd. MRI Fig 2.2D: Post Contrast Coronal T1 Wtd. MRIAn ill-defined non-enhancing tumor (yellow arrows) is seen in the left parietal lobe with spotty areas of enhancement (red arrows).

DIAGNOSIS: Anaplastic Astrocytoma

• Grade III Astrocytoma (WHO Classification)

• Usually seen between 40 – 60 years of age

• Imaging Features: Ill-defined non-enhancing tumor with or without feeble enhancement.

Glioblastoma (WHO grade IV) Previously known as glioblastoma multiforme Peak age of onset is 50-60yrs. Common in deep white matter, basal

ganglia, thalamus, rarely in cerebellum Grossly may appear circumscribed Microscopic infiltrates widely, often to other

hemisphere via corpus callosum. Multifocal Extracranial metastasis rare. Survival 1-1.5 yrs after treatment.

Central yellow or white zone of necrosis and hemorrhage surrounded by hyperemic ring of endothelial hyperplasia.

Surrounded by edematous brain (mixture of vasogenic edema, tumour infiltrates and gliosis)

TP53, IDH1 and IDH2 mutation less common in primary.

30-40% have EFGR mutation MGMT mutation- favorable prognosis.

Glioblastoma (WHO grade IV)

Primary vs Secondary GBM

Primary GBM◦ Develops de novo from

glial cells◦ Accounts for > 90% of

biopsied or resected cases◦ Clinical history of 6 months◦ Occurs in older patients

(median age: 60 years)◦ EFGR mutation

Secondary GBM◦ Develops from low-grade or

anaplastic astrocytoma ~ 70% of lower grade

gliomas develop into advanced disease within 5-10 years of diagnosis

◦ Comprises < 5% of GBM cases

◦ Occurs in younger patients (median age: 45 years)

◦ TP53, IDH1, IDH2

Fig 2.1B: Axial T1 Weighted (Wtd.) MRI

Fig 2.1A: Axial Flair MRI Fig 2.1C: Post-Contrast Axial T1 Wtd. MRIAn irregular enhancing ring lesion (arrow) is seen involving the left parietal lobe. Tumor is associated with

edema (E) best noticed on FLAIR image (A).

DIAGNOSIS: GLIOBLASTOMA

E

• Grade IV Astrocytoma (WHO Classification)

• Older Patient

•Imaging Features: Tumor with irregular peripheral enhancement with central necrosis.

Pleomorphic Xanthoastrocytoma (WHO grade II or III) Average age of diagnosis-26 yrs. Involve cerebral cortex and overlying

meninges most common in temporal lobe. Bizzare giant cells Xanthomatous cells-foamy lipid filled

astrocytes seen in 1/4th cases. 15-20% have malignant transformation. Survival 81% at 5 yrs and 70% at 10 yrs.

 large well defined cystic mass in right temporo-parieto-occipital region with mild vasogenic oedema and mass effects. Post-contrast rim like enhancement of the cystic mass, with enhancing mural nodule

Associated with tuberous sclerosis Gross- elongated, sausage like or lobulated Candle guttering-identical smaller masses

on walls of ventricle. Rich vascularity Pseudo-rosettes Hydrocephalus TSC1 and TSC2 Inhibitors of mTOR found effective.

Subependymal giant cell astrocytoma (WHO grade I)

Hypo- to isointense to gray matter on T1, heterogeneously hyperintense on FLAIR , T2 punctate hypointensities corresponding to calcium with avid contrast enhancement. 

Seen in young to middle aged adults. Most common in frontal lobe Histopath- uniform round nuclei, bland

chromatin, perinuclear halo-Fried egg Rich branching capillary network-Chicken

wire 50-80%-loss of 1p and 19q Favorable response to chemotherapy IDH1 and IDH2 mutation in grade II (84%)

and grade III (94%).

Oligodendroglioma (WHO grade II or III)

Hypointense on T1 hyperintense on T2 with no contrast enhancement mass in rt. Frontal lobe.

Most difficult to define Survival between astrocytoma and

oligodendroglioma. Usually grade and treated as

oligodendroglioma.

Oligoastrocytoma (WHO grade II or III)

Most common in first decade. Age<3 years have worse prognosis Children-infratentorial Adult-spinal Well circumscribed mass that compresses

and not infiltrates surrounding parenchyma May seed subarachnoid space in 5% Perivascular rosettes 22q deletion in NF2 mutation-spinal

ependymoma.

Ependymoma (WHO grade II or III)

Seen in filum terminale More common in adults Thin collagenous capsule Prognosis excellent if capsule intact May metastasize to lungs

Myxopapillary ependymoma WHO grade I)

Hypointense mass on T1 and hyperintense with some hypointense signal within due to hemorrhage within on T2

Seen in adults Small and incidental Glistening pearly white lobulated

intraventricular proteburance Most often in fourth ventricle May cause hydrocephalus Low proliferative index

Subependymoma (WHO grade I)

Presenting symptoms determined by Tumour’s size, Location Rate of growth

Symptoms

Classically (17%) starts in early morning and disappears soon after pt. gets up

Initially mild, becomes progressively more severe, frequent and of longer duration

Worse with Valsalva manoeuvre Associated with nausea,vomiting Forsyth, Posner(1993) showed tension-

type headache(77%), migraine-like headache (9%),14% had mixture of headaches could not be easily classified

Headache

Forsyth (1993)- commonest headache site was frontal region (68%) seen primarily in supratentorial tumours or with raised ICT.

73% of patients with infratentorial tumours had frontal, temporal or parietal headaches and 24% had nuchal and occipital.

Related to size of tumour and amount of midline shift.

Produced due to traction on pain-sensitive structures such as blood vessels, dura or obstruction of CSF pathways

Headache

Recommendation Level

A patient with new onset or recurrent headache uncharacteristic for that patient should also be imaged, particularly if there are focal neurological symptoms and signs.

III

Neuro-imaging in headache

Other symptoms Limb weakness Language disturbances Apraxia, agnosia Amnesia Depression Seizures- most common partial motor

often with secondary generalization Plateau waves- paroxysmal neurological

symptoms on standing

Proportion of cases presenting with specific symptoms

Computed Tomography (LGG)

◦ A discrete or diffuse hypodense to isodense mass lesion

◦ Minimal or no enhancement (except in 15 – 30% patients)

◦ Calcifications (Oligodendrogliomas/Oligoastrocytomas)

◦ Cystic changes (any histologic type)

Magnetic Resonance Imaging (LGG)

◦ Hypo- to Iso-intense on T1WI

◦ Hyperintense on T2WI

◦ Minimal- to NO gadolinium enhancement

(25 – 50% oligodendrogliomas are somewhat

enhanced)

◦ No significant mass effect

◦ Tendency to invade & reside in white matter

Oligodendrogliomas expands along gyri◦ Calcifications (20% lesions)

MRI (contnd) T1-weighted MRI with contrast may

underestimate the extent of an LGG The true extent is shown on the T2-

weighted sequences, Diffusion tensor MRI used as a marker

of glioma infiltration

Reduced NAA peaks Increased choline peak Increased choline/creatinine ratio Choline/creatinine peak>3:1 predicts high

grade tumour.

MR spectroscopy

Malignant Transformation:LGG transformation ranges from 17% to 73% in clinical studiesRisk of progression increases with tumour burdenGrowth rate of ≥ 8 mm per year Median survival of 5.16 yearsGrowth rate ≤ 8 mm/year median survival of ≥ 15 yearsResidual tumour after surgery is an important determinant

Treatment

Observation: Advantages:

No surgical morbidity Lesser cost of follow up treatment

Disadvantages: Loss of histological diagnosis Loss to follow up (quite frequent than reported) Risk of increased malignant transformation Risk of increasing tumour burden/neurodeficits

Supportive treatment Antiepileptics- leviteracetam preferred.

Prophylactic antiepileptics not recommended.

Enzyme inducers avoided. Steroids- Dexamethasone most commonly

used. Usual dose 8-16mg daily dose.

Surgical intervention: Open resection Open/stereotactic biopsy

Guided by patient’s clinical status, location of tumour & surgeon’s preference

Goals of surgery: Establishing a diagnosis Symptoms alleviation Decompression Tumour cytoreduction

Biopsy: Open/Image guided or stereotactic (if available) Indicated in high risk patients or when open surgery is

declined/deferred

Advantages: Minimally invasive Early identification of histologic type

Disadvantages: Morbidity/mortality with open biopsy Image guided biopsy may sample wrong site Stereotactic biopsy may be too small for a diagnosis

Surgical Resection: It is the principle mode of treatment in the following;

Whenever possible Mass effect Raised ICT Steroid resistant edema Threat of herniation CSF flow obstruction Seizure control Smaller tumours are less aggressive & better surgical

candidates

Surgery has limited role in following; Disseminated tumours Multifocal tumours Eloquent location

Extent of Resection:

◦ Recent evidence favouring early extensive resection

◦ Good life expectancy◦ Influencing malignant transformation ◦ Progression free survival & overall survival both

improves

Radiation:

Radiation for Pilocytic astrocytoma after surgery may be reserved until recurrence or deep lesions

Fractionated radiation of up to 45-60 Gy (more focussed, more good)

Hyperfraction protocol Provided to T2 abnormality and margin of 1.5 to 2 cm In sharply demarcated tumour 0.5cm margin suffice Adjvunt to surgery Malignant transformation may be treated with

radiation Steriotactic radiosurgery-useful in well circumscribed

tumour. Brachytherapy

Chemotherapy: PCV (Procarbazine, Lomustine, Vincristine) may have

a role in stabilising tumour growth Temozolomide may have a role for progressive

astrocytoma Oligodendroglioma- chemosensitive Recurrence of anaplastic astrocytoma and

glioblastoma multiforme

Temozolomide(Temodal)

Methylating agent Principal mechanism is causing damage to

DNA of tumour cell, leading to cell death Taken orally, rapidly absorbed Penetrates the blood-brain barrier TMZ 75 mg/m2 PO QD for 6 weeks, then 150-

200 mg/m2 PO QD on Days 1-5 every 28 days for 6 cycles

Used with radiotherapy

2nd line Chemotherapy for recurrence No consensus Low dose temozolomide (+/- procarbazine) Carboplatin BCNU/CCNU Bevacizumab (+/- Irinotecan) EFGR inhibitors (geftinib) PDGFR inhibitors (imatinib) Clinical trials if possible

Surgical Implantation of Chemotherapy Wafers: Gliadel®

BCNU(carmustine)-infused wafers

Implanted to tumour bed at time of surgery

Chemotherapy released to surrounding brain tissue over a period of 2 to 3 weeks

Clinical trials showed survival benefit

Prognosis

◦ Extremely young patients<3yrs or patients > 50 y◦ Large tumours that enhance◦ Short clinical history◦ Absent of mental changes◦ Cerebellar location◦ High grade◦ Completeness of surgical lesion◦ Evidence of progression on imaging studies

Clinical course is by no means benign as is manifested by histology & radiologic appearance

Aggressive early resection advised but NOT on the expense of patient’s quality of life

Diagnosis purely on the basis of radiology has a failure rate of up to 50%

Early histologic evidence of the diagnosis is paramount both for the surgeon & the patient

Chemo-radiotherapy can be delayed until recurrence or progression in low grade gliomas.

Conclusion

Thanks

Clinical practice guidelines for management of gliomas: Clinical oncological society of Australia; Aug2009.

Malignant Gliomas in Adults;Patrick Y. Wen, Santosh Kesari:N Engl J Med 2008; 359:492-507

Guidelines on management of low-grade gliomas: report of an EFNS–EANO* Task Force; European Journal of Neurology 2010, 17: 1124–1133

References

High Grade Gliomas: Pathogenesis, Management And Prognosis;ACNR :VOLUME 12 NUMBER 4 ;SEPTEMBER/OCTOBER 2012

Practical Guidelines for the Treatment of Malignant Gliomas;Marc C., Patty A., WJM, February 1998-Vol 168, No. 2