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Chapter 122 Malignant Gliomas : Anaplastic AstrocytomaGlioblastoma MultiformeGliosarcoma
Youmans,Neurological surgery15/12/2015
Outline
• Epidemiology• Clinical manifestation• Histopathology• Neuroimaging studies• Management
Epidemiology : Anaplastic Astrocytoma (WHO grade III)Glioblastoma Multiforme(WHO grade IV)
• Most common primary brain tumor in adults• Median age : AAs 40 yrs, GBM 53 yrs• GBM is more common in men, with a male-to-
female ratio of 1.5:1
Epidemiology : Gliosarcoma
• 2% and 8% of cases of GBM (WHO grade IV)• Clinical findings and prognosis are similar in
gliosarcoma and GBM• Mean age of 53 Yrs(40-60 Years)• Male-to-female ratio of 1.8 : 1• May also occur in children
Clinical manifestation : Anaplastic Astrocytoma Glioblastoma Multiforme
• Cerebral hemispheres• Can arise from low-grade astrocytoma (WHO grade II)• AAs can progress to GBM and recur locally,often at
the margins of the tumor resection• Symptoms and signs are nonspecific in patients
with GBM– raised intracranial pressure– extraocular palsies, objective papilledema, pupil
abnormalities, or decreased level of consciousness
Clinical manifestation : Anaplastic Astrocytoma Glioblastoma Multiforme
• Prominent in the morning and improve over the course of the day
• Progressive headaches are a hallmark of the symptomatology of these tumors
• Seizure
Clinical manifestation : Gliosarcoma
• Most common : Temporal lobe, also occur in parietal, frontal, occipital lobes
• Multifocal display of cerebral and cerebellar gliosarcomas
• Can spread into the cerebrospinal fluid pathways and invade the ventricles, cranial nerves, leptomeninges, and spinal cord
• Tendency toward peripheral brain localization and dural attachment
Clinical manifestation : Gliosarcoma
• Metastasis much more frequently than glioblastoma• Most common symptoms : headache, hemiparesis,
nausea, seizures, and personality change• Most common signs : focal weakness, visual field
defects, papilledema, and dysphasia
Clinical manifestation : Gliosarcoma
Histopathology : Anaplastic Astrocytoma Glioblastoma Multiforme
• Morphology is the “gold standard” – Pilocytic astrocytoma (WHO grade I)– Low-grade astrocytoma (WHO grade II)• nuclear atypia, no mitosis
– Anaplastic Astrocytoma (WHO grade III)• mitotic activity and nuclear atypia
– Glioblastoma Multiforme (WHO grade IV)• nuclear atypia, mitoses, and endothelial
proliferation or necrosis
Histopathology : Anaplastic Astrocytoma Glioblastoma Multiforme
• MIB-1 /Ki-67 labeling index increases proportionally with tumor grade– AA (WHO grade III) : 5-10%– GBM (WHO grade IV) : 10-20%
Primary glioblastomas Secondary glioblastomas
> 50 years younger patients as low-grade astrocytoma or AA and then transform over a period of several years into glioblastoma
Mutation or amplification of EGFR overexpression of platelet-derived growth factor receptor (PDGFR)
loss of heterozygosity of chromosome 10q loss of heterozygosity of chromosome 10q
deletion of the phosphatase and tensin homologue on chromosome 10 (PTEN)
mutations in the TP53 tumor suppressor gene
deletion of chromosome p16. abnormalities in the p16
mutation of isocitrate dehydrogenase 1 (IDH1)
Molecular biology
Histopathology : Gliosarcomas
• Characterized by a biphasic tissue pattern with glial and mesenchymal component
• Glial portion : astrocytes with nuclear atypia and mitotic figures
• Sarcomatous region : neoplastic mesenchymal cells with associated reticulin formation
• Glial fibrillary acidic protein (GFAP) immunostaining : distinguishing between gliosarcoma and other tumors such as glioblastoma or pure sarcoma
Histopathology : Gliosarcomas
• Vimentin : marker for mesenchymal cells, occurs mostly in sarcomatous areas with scarce staining in glial regions
• Gross– tough, well-circumscribed lobular mass often attached to
the dura and at surgery may resemble a meningioma– contain areas of necrosis– The sarcomatous component of these tumors is firm and
well circumscribed
Neuroimaging studies : Anaplastic Astrocytoma Glioblastoma Multiforme
• MRI– T1 : irregular hyposignal with various degrees of
contrast enhancement– Ring-like enhancement surrounding irregularly
shaped areas : suggests glioblastoma– However, AAs can appear as nonenhancing
tumors, and even glioblastomas may initially be manifested as a nonenhancing lesions, especially in older patients
Neuroimaging studies : Anaplastic Astrocytoma Glioblastoma Multiforme
• fMRI– locations of functionally eloquent cortex, such as
the motor cortex, Broca’s area, Wernicke’s area, and the visual cortex
• Pseudoprogression : increased enhancement reflects a transient increase in vessel permeability that is a result of radiotherapy
• Magnetic resonance spectroscopy(MRS) : differentiate tumors from stroke, old trauma, radionecrosis, infection, and multiple sclerosis
Neuroimaging studies : Anaplastic Astrocytoma Glioblastoma Multiforme
• Fluorodeoxyglucose positron emission tomography (FDG-PET)– effective in demonstrating hypermetabolism in high-
grade tumors– distinguishing tumor or tumor recurrence from
radionecrosis
Neuroimaging studies : Gliosarcomas
• MRI– T1 : well demarcated hyperdense mass with
heterogeneous or irregular ring enhancement– T2 : isosignal with surrounding edema– Intraaxial superficial with a dural base– Vasogenic edema– Central hypodensity, as a result of necrosis, is less
common in gliosarcomas
Management : General Medical Management
• Seizure– Selecting antiepileptic drugs to prevent drug
interactions(phenytoin,carbamazepine)– Prefer levetiracetam– AAN : advises against the routine use of antiepileptic
drugs in patients who have never had a seizure• Venous thromboembolism– anticoagulation therapy– LMWH may be more effective and safer than warfarin
Management : General Medical Management
• Peritumoral edema– Corticosteroid(dexamethasone)– Side effect : Cushing’s syndrome, corticosteroid
myopathy, Pneumocystis jiroveci pneumonitis– New therapy : corticotropin releasing factor,
bevacizumab (VEGF monoclonal antibody), VEGF receptor inhibitors
• Fatigue– Methylphenidate for abulia– Donepezil and memantine may reduce memory loss
Management : Surgery
• Goal– obtain a tissue diagnosis– decrease the mass effect– reduce the tumor burden
ManagementRadiation TherapyChemotherapy
• Carmustine-loaded biodegradable polymers• RCT• Improve survival : 23 weeks to 31 weeks after revision resection• Surgery time to death : 58 weeks vs 39 weeks placebo• Median survival time : 13.8 months vs 11.6 months placebo
ManagementRadiation TherapyChemotherapy
• Most effective treatment
• Resection• Carmustine-loaded
biodegradable wafers • Temodar• Radiation therapy
• 20 Months
ManagementRadiation TherapyChemotherapy
• O6-Methylguanine-DNA methyltransferase (MGMT)
• Repair enzyme that contributes to resistance of tumors to alkylating agents such as carmustine or Temodar
Management : Gliosarcoma
• Surgery– firm, well demarcated, and vascular– can be excised to achieve gross macroscopic
clearance• Chemotherapy• Radiotherapy• All patient• Increase survival 8-15 wks
Patient outcome and survival
• Median survival is less than 2 years• Anaplastic glioma : 2-5 years• Age and KPS score are the most significant
prognostic factors
• Gliosarcoma : 6 - 14.8 months