122 Malignant gliomas anaplastic astrocytoma gb gliosarcoma

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