Gliomas

Dr Mukhtar

PG Neurosurgery

HMC, Peshawar

Road Map• Introduction• Classification• Epidemiology• Clinical Presentation• Neuroimaging• Prognostic Factors &

Outcome• Treatment Options• Emerging Modalities• Conclusion

Introduction & Classification

• Central Nervous Systems’ neoplasms derived from

neuroepithelial cell lineages, hence intra-axial

• Differentiation/classification by particular glial cell types i.e. astrocytes, oligodendrocytes, ependymocytes etc.

• 30% of total CNS tumours & >70% of brain tumours

• Divided into two major categories based upon their clinical & biological characteristics;• Low Grade Glioma (LGG)• High Grade Glioma (HGG)

Glioma

Astrocytes

Astrocytomas

Fibrillary

Gemistocytic

Protoplasmic

Mixed

Anaplastic astrocytoma

Glioblastoma multiforme

Giant cell Glioblastoma

Gliosarcoma

More circumscribed lesions

Pleomorphic xanthoastrocytoma

Pilocytic astrocytoma

Subependymal giant cell astrocytoma

Oligodendrocytes

Oligodendroglioma

Mixed Glioma

Oligoastrocytoma

Low Grade Gliomas

• The term ‘low grade glioma’ refers to a series of primary brain tumours characterized by;

• Benign histology (low proliferation, low neoangiogenesis)

• Aggressive behavior• Slowly invade the normal parenchyma

• Majority of these tumours are classified as Grade II by WHO classification (although Grade I could also be included)

LGGs

WHO Grade II infiltrating astrocytoma

Oligodendroglioma

Oligoastrocytomas

Gangliocytomas

Juvenile Pilocytic Astrocytoma

Pleomorphic xanthoastrocytoma

Dysembryoplastic neuroepithelial tumours

Astrocytomas by cell type

Ordinary Astrocytomas•Fibrillary•Gemistocytic•Protoplasmic

Special Astrocytomas

•Pilocytic•Microcystic cerebellar•Subependymal giant cell

Type 1: Solid tumours without

infiltration

Type 3: Infiltrating

without solid component

Low Grade

Gliomas

Type 2: Solid tumours with

infiltration

Grading systems for astrocytomas

• Bailey & Cushing’s• Kernohan’s System• World health organization• St. Anne’s/Mayo system

Kernohan’s system

• Divides astrocytomas into 4 grades on basis of;• Anaplasia• Nuclear pleomorphism• Number of mitoses

• Grade I/II are grouped together as low grade• Grade III/IV are grouped together as high grade• Grade IV is termed as Glioblastoma multiforme• Less commonly used today

Equivalence of Kernohan’s to WHO systemKernohan Grade WHO Designation

(I) Special tumours: e.g., Pilocytic astrocytoma

III (II) Astrocytoma {low grade}

III (III) Anaplastic astrocytoma

Malignant astrocytomaIV (IV) Glioblastoma multiforme

St. Anne/Mayo Criteria & GradingSt. Anne/Mayo Criteria

• Nuclear atypia: Hyperchromasia & obvious variation in size & shape

• Mitoses: Normal or abnormal configuration

• Endothelial proliferation: Vascular lumina are surrounded by piled up endothelial cells. Does not include hypervascularity

• Necrosis: Only when obviously present. Does not include pseudopalisading when seen alone

Grade No. of criteria1 02 13 24 3 or 4

Epidemiology

• 15% of all brain tumours in adults• 25% of all brain tumours in children• No epidemiologic evidence about increased prevalence in

specific ethnic group or nation• Slight male predominance (1.5:1)• Biphasic age distribution (6-12 years and 3rd – 4th decade)• Median age of presentation is 35 years in adults

15%

85%

Percentage of LGGs among other CNS tumours

LGGsOther CNS tumours

Aetiopathology

• Exposure to ionizing radiations is the only definite risk factor• No significant hereditary role although they are common in;

• NF type I (15 – 20% develop LGGs)• Li-Fraumeni syndrome

• Environmental exposure to Nitrites/Nitrates• Allergies/IgE levels association• p53 gene mutation (a consistent finding)• 1p/19q mutations in tumours transforming to high grade

Clinical

Clinical• Seizures are the most frequent presenting symptom (50 – 80%

of patients)

• Other signs symptoms depend upon tumour size & location

• Raised ICP associated symptoms/signs;• Headache, Vomiting, lethargy, papilloedema, ataxia• Focal neurologic deficits, frontal lobe signs

Neuroimaging

Computed Tomography (CT):

• 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 (MRI):

• 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)• Differentials & the imaging characteristics of a lesion

• 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

• Rarely, gliomatosis cerebri

Outcome & Prognostication

• Diversity of opinion & research for prognosis/outcome• Age the most important defining factor for prognosis/outcome

(more or < 40 y)

• LGG preoperative prognostic scoring system• Location of tumour (eloquent/non-eloquent)• KP score (70-80 limit)• Age (40 years limit)• Maximum diameter (4 cm limit)• Grades 1 to 4

• Low risk LGGs => Grades 0 & 1• High risk LGGS => Grade 4

• Median survival for Oligodendrogliomas 15 years

• Median survival for astrocytomas is 10 years

• Large tumours & those crossing midline are more aggressive

• Increased proliferative indices (Ki 67, MIB-1) & contrast enhanced tumours also have poor prognosis

• Bauman et al’, four classes of LGG patients• Younger age (18-40 y) with good KPS has median survival

of 10 y

• Younger age with low KPS or older age & good KPS with NO contrast enhancement has median survival of ≥ 7 y

• Older age with good KPS & contrast enhancement has median survival of ≤ 4 y

• Older age with low KPS has a survival of only 12 months

• EORTC’s prognostic model:• Age > 40 y• Astrocytic tumour• Tumour > 6 cm in diameter• Tumour crossing midline• Neurologic deficit

• Presence of 2 factors median survival of 7.7 y• Presence of 3 to 5 factors survival of 3.2 y

Yawn

Treatment considerations

1. Observation with serial neuro exams & imaging2. Radiation3. Chemotherapy4. Radiation with Chemotherapy5. Surgery

• Factors prompting treatment:

• Extremely young patients or patients > 50 y• Large tumours that enhance• Short clinical history• Evidence of progression on imaging studies

Extent of Resection:

• Recent evidence favouring early extensive resection• Good life expectancy• Influencing malignant transformation • Progression free survival & overall survival both improves

Malignant Transformation:• LGG transformation ranges from 17% to 73% in clinical

studies• Risk of progression increases with tumour burden• growth rate of ≥ 8 mm per year Median survival of 5.16

years• growth rate ≤ 8 mm/year median survival of ≥ 15 years• Residual tumour after surgery is an important determinant

Transformation rates for LGGs

Patients diagnosed at age < 45 y

Patients diagnosed at age > 45 y

Mean time to transformation

44.2 ± 17 months 7.5 ± 5.7 months

Time to death 58 months 14 months

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

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;

• Pilocytic astrocytoma• Threat of herniation• CSF flow obstruction• Seizure control• Delaying adjuvant therapy for smaller children/elderly• Smaller tumours are less aggressive & better surgical candidates

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

Radiation:• No definitive proof of survival benefit• Radiation for Pilocytic astrocytoma after surgery may be

reserved until recurrence or deep lesions• Fractionated radiation of up to 45 Gy (more focussed,

more good)• Malignant transformation may be treated with radiation

Chemotherapy:• No clear benefit in terms of survival• PCV (Procarbazine, Lomustine, Vincristine) may have a

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

astrocytoma

Emerging modalities of treatment

• Recent research points towards more aggressive treatment strategies

• Increasing role of MR modalities such as MR spectroscopy, MR tractography, DWI, DTI, CBV estimation and fMRI

• Role of PET and SPECT in metabolic profiling• Neuronavigation assisted resection of deep/eloquent tumours• Awake brain surgery, language & motor task mapping• Intraop MRI, EEG, ECoG and MEG showing promise in

reducing surgical morbidity & lesser residual tumours

Conclusion

• 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

Thanks!

Gliomas

Dr MukhtarPG NeurosurgeryHMC, Peshawar

Road Map

• Introduction• Classification• Epidemiology• Clinical Presentation• Histopathology• Neuroimaging• Management• Outcome & Survival• Future Directions• Conclusion

Introduction & Classification

• Central Nervous Systems’ neoplasms derived from

neuroepithelial cell lineages, hence intra-axial

• Differentiation/classification by particular glial cell types i.e. astrocytes, oligodendrocytes, ependymocytes etc.

• 30% of total CNS tumours & >70% of brain tumours

• Divided into two major categories based upon their clinical & biological characteristics;• Low Grade Glioma (LGG)• High Grade Glioma (HGG)

Glioma

Astrocytes

Astrocytomas

Fibrillary

Gemistocytic

Protoplasmic

Mixed

Anaplastic astrocytoma

Glioblastoma multiforme

Giant cell Glioblastoma

Gliosarcoma

More circumscribed lesions

Pleomorphic xanthoastrocytoma

Pilocytic astrocytoma

Subependymal giant cell astrocytoma

Oligodendrocytes

Oligodendroglioma

Mixed Glioma

Oligoastrocytoma

High Grade Glioma

• Three most common malignant CNS tumours• Malignant or Anaplastic astrocytoma• Glioblastoma Multiforme• Gliosarcoma

• Highly malignant with low survival rates• Invasive & infiltrative in nature precluding complete resection• Walter Dandy’s description of recurrence in 1930• Conflicts & lack of evidence regarding extent of resection• Primary treatment is still surgery in some form

• The adult nervous system has been discovered to harbour neural stem cells that are capable of self-renewal, proliferation, and differentiation into distinctive mature cell types.

• There is now increasing evidence that these neural stem cells, or related progenitor cells, can be transformed into brain tumour stem cells and give rise to malignant gliomas by escaping the mechanisms that control proliferation, programmed differentiation, and apoptosis

Epidemiology

• Most common primary brain tumours• 2% of total cancer burden• Disproportionate rate of cancer related morbidity/mortality• At least one third of patients dies within the first year after

diagnosis/treatment• Leading cause of death from solid tumours in children• Third leading cause of cancer death between 15-34 y age

• CNS tumours incidence is 14.8 per 100000 person-year• Half being malignant• Average age for anaplastic astrocytoma is 40 years• Average age for GBM is 53 years• Peak incidence of GBM between 65 and 74 years• Male to female ratio is 1.5:1• 2% - 8% of GBMs are gliosarcoma

Clinical manifestations

• Hemispheric occurrence of GBMs & AAs• Two types of GBMs;

• Primary GBM, arising de novo• Secondary GBM, malignant transformation of LGGs

• AA has a tendency to progress to GBM• AA tends to recur locally & at resection margins• Three main features presents clinically;

• High ICP features• Local/mass effects• Seizures in up to 1/3rd

• Gliosarcoma occur at temporal, parietal, frontal, occipital lobes in that order

• It tend to occur close to leptomeninges• Might have a dural tail/base• Spreads through CSF pathways into ventricles, cranial nerves,

spinal cord• Distant (extracranial) metastasis in upto 15% to 30% of

gliosarcoma• Signs/symptoms similar to GBM/AA

Histopathology

• Highly invasive/infiltrative tumours• Spread along subarachnoid space• Microsatellite tumour cell nests remain even after curative

resection• Walter Dandy demonstrated that GBMs recur even after

hemispherectomy• Grading by histologic features, not by TNM status

• Four features for classifying gliomas (as discussed previously)• Nuclear Atypia• Mitoses• Endothelial proliferation• Necrosis

• Combination of these four features results in grading of a particular tumour cell population and a specific WHO grade

• Gliosarcoma in addition to the above features have features of mesenchymal origin (multinucleated giant cells, altered fibroblasts)

St. Anne/Mayo Criteria & GradingSt. Anne/Mayo Criteria

• Nuclear atypia: Hyperchromasia & obvious variation in size & shape

• Mitoses: Normal or abnormal configuration

• Endothelial proliferation: Vascular lumina are surrounded by piled up endothelial cells. Does not include hypervascularity

• Necrosis: Only when obviously present. Does not include pseudopalisading when seen alone

Grade No. of criteria1 02 13 24 3 or 4

• MIB-1/Ki-67 indices are indicators of histological aggressiveness• AA index is usually between 5% to 10%, GBM is 10% to 20%• EGFR amplifications/mutations• Chromosome 10q loss of heterozygosity• Deletion of chromosome p16• tp53 mutations, PDGFR overexpression, p16 and Rb gene

abnormalities

Neuroimaging

• MRI is the preferred modality for all brain tumours• CT is usually used in acute setting, for delineating

haemorrhages or acute infarctions• CT is particularly useful in identifying haemorrhage or

calcification• Once a mass is identified, further characterisation is with the

help of MRI

• HGGs appear irregular hypodense lesion on T1WI• Various degrees of contrast enhancement and oedema• The presence of;

• ring-like enhancement• surrounding irregularly shaped areas of presumed

necrosis suggests glioblastoma• AAs can appear as nonenhancing tumour• Glioblastomas may present as nonenhancing lesions,

especially in older patients

• Functional MRI can be used to define the locations of functionally eloquent cortex

• in up to 40% of cases, MRI in the first month after radiotherapy may show increased enhancement

• the increased enhancement reflects increase in vessel permeability that is a result of radiotherapy, a phenomenon that improves with time and is designated “pseudoprogression”

• MRI has poor specificity in identifying viable recurrent tumours in brain treated with surgery/radiotherapy/chemotherapy

• MR Spectroscopy may be used to differentiate tumours from stroke, old trauma, radionecrosis, infection and MS

• FDG-PET effectively demonstrate hypermetabolism in high-grade tumours

• FDG uptake also has prognostic value• High FDG uptake in previously low grade tumours means

malignant transformation

• Gliosarcoma on CT is similar to infiltrating glioblastoma• well-demarcated hyperdense mass with heterogeneous or

irregular ring enhancement• Majority of gliosarcomas are superficial with a dural base• Vasogenic oedema in almost all cases of gliosarcoma,

irrespective of tumour size• Central hypodensity, as a result of necrosis, is less common in

gliosarcomas• Osteosarcomatous differentiation often demonstrate

calcification, which appears intensely hyperdense

Left top, Contrast-enhanced, T1-weighted image.

Kato T et al. AJNR Am J Neuroradiol 2008;29:1176-1182

©2008 by American Society of Neuroradiology

• T1WI+C MRI of gliosarcomas shows diffuse, inhomogeneous enhancement or irregular ring-like enhancement

• Gliosarcomas is well-defined lesions with either an inhomogeneous or cystic appearance and surrounding vasogenic oedema

• T2WI these tumours are of intermediate intensity with surrounding oedema

• gliosarcoma should be included in the differentials of any tumour that appears to be intra-axial but abutting a dural surface and is much less hypointense on T2-weighted images than other glial neoplasms

Management

General Medical Management:• Most of the signs/symptoms of HGGs require general

medical management• it is important to keep in mind most common

problems;• peritumoral oedema, seizures, fatigue,• venous thromboembolism & cognitive dysfunction

• Antiepileptics selection need care, keeping in mind drug-drug interactions

• Phenytoin & Carbamazepine induce cytochrome p-450 enzymes & may increase metabolism of chemotherapeutics

• Drugs such as levetiracetam are favoured• Use of prophylactic AEDs is controversial• The American Academy of Neurology recommend against the

use of prophylactic AEDs

• Peritumoral oedema is treated with corticosteroids• Cushing’s syndrome & corticosteroid myopathy• Increased risk for Pneumocystis jiroveci pneumonitis• Vitamin D, calcium supplements, & bisphosphonates

• 20% to 30% cumulative risk of VTE• Anticoagulation is safe, unless known risk of haemorrhage• LMWHs are safer than warfarin

• Malignant glioma patients experience severe fatigue• Methylphenidate & modafinil are indicated for it• Donepezil/memantine may help reduce memory dysfunction• Major depression is common & needs proper management

Surgery:• Three main goals;

i. Tissue diagnosisii. Reduce mass effectiii. Reduce tumour burden

• Imaging cannot accurately diagnose the tumour type or grade• Need for tissue diagnosis in order to

• make treatment recommendations• Assessment & formulation of prognosis

• Tumour mass reduction results in• Improvement of signs & symptoms• Decrease steroid requirement• Prevent early death resulting from mass effect

• Effect of extensive resection on prolonging survival is questionable

• Extensive resection of HGGs is difficult because;• They are invasive & infiltrative, and• They are usually located in eloquent areas

• The effect of gross total resection (GTR), near total resection (NTR) or subtotal resection is unclear

• However, extensive resection may help chemo-/radiotherapy to have their maximal effect by reducing tumour mass

• Radiation & Chemotherapy:• Carmustine-loaded biodegradable polymers (Gliadel

wafers) placement in tumour cavity after resection• Improved survival by 2 to 5 months• Temodar (radiotherapy with Temozolomide

chemotherapy) also has improved survival in RCTs

Outcome & Survival

• Overall the prognosis & outcome for patients with HGGs is poor• Median survival of less than 2 years for GBM & 2 to 5 years for

AA• Even extensive resection leaves nests of tumour cells behind

which acts as havens for recurrence• Currently age & KPS score are the most significant prognostic

factors• Gliosarcoma has worse prognosis than Glioblastoma and AA

Recent Developments & Future Directions

• Functional mapping for eloquence has had a tremendous effect upon safe resection without incurring major disabilities

• Neuronavigation (CT or MR based) assisted resection• Neuronal stem cells identification & their use as

targets/vectors for immunomodulatory/cytotoxic therapy• Advances in molecular/biologic understanding of the glioma

development is guiding future therapies for receptor/gene targeted interventions

• Recent approval of Gliadel wafers, Temodar regimen & MGMT promoter methylation is improving survival

• Development of glioma treatment response criteria for clinical trials such as McDonald & RANO criteria