Glioblastoma Multiforme

Glioblastoma multiforme is a high-grade astrocytoma, an aggressive brain tumor arising from astrocytes, with an unknown cause and a poorly understood link to risk factors. There are two main types: primary, a more aggressive form seen more commonly in older patients, and secondary, developing from lower-grade astrocytomas and seen more commonly in younger patients. Glioblastomas most commonly present with headache, seizures, and neurologic deficits. MRI is the gold standard diagnostic tool, and surgical resection combined with radiation and chemotherapy is the treatment of choice. Prognosis is extremely poor, with survival of only 1–5 years in patients receiving aggressive treatment and only 3 months in patients who do not undergo treatment.

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Glioblastoma multiforme (GBM) is an aggressive, rapidly progressive type of brain tumor arising from astrocytes:

  • Classified by the WHO as a grade IV astrocytoma (a high-grade malignant glioma)
  • Glial cells are supportive tissues within the brain and nervous system.
  • Neuroepithelial tumors are those involving the brain parenchyma.
  • Astrocytomas, including GBMs, are graded but not staged.

Classification of nervous system tumors

Table: Classification of nervous system tumors
CategoriesSpecific tumors
Neuroepithelial tumors in the CNS
  • Astrocytomas, including GBM
  • Oligodendroglioma
  • Ependymoma and choroid-plexus tumors
  • Medulloblastomas (embryonal tumors)
Meningeal tumors
  • Meningiomas
  • Hemangioblastomas
Sellar region tumors
  • Craniopharyngioma
  • Pituitary adenoma
  • Pinealoma/pinealoblastoma
Primary CNS lymphomaPrimary CNS lymphoma
Metastasis to the brain (5× more common than primary brain tumors)Most commonly arising from:
  • Lung, breast, and renal cell carcinomas
  • Melanoma
Peripheral tumors
  • Schwannomas, including acoustic neuroma
  • Neuroblastoma


  • Most common malignant brain tumor 
  • Incidence: 
    • 3 per 100,000 population
    • Accounts for 23% of all primary brain tumors.
    • 60% of all astrocytomas are grade IV (GBM) at diagnosis.
  • Age:
    • Can occur in any age group 
    • Peak incidence: 45–70 years of age
    • Mean age at diagnosis: approximately 55–60 years
  • Sex: more common in men than in women
  • Race/ethnicity: does not appear to affect incidence
  • Mortality: GBM has a poor survival rate 
    • 40% mortality in the 1st year after diagnosis 
    • 17% in the 2nd year after diagnosis


The 2 main types of glioblastoma are:

  • Primary glioblastoma:
    • A more aggressive form of GBM arising de novo (without progressing from a lower-grade astrocytoma)
    • More common than secondary GBM
    • Typically seen in older patients (> 50 years)
    • Patients present with a short clinical history and no evidence of a preexisting lesion.
  • Secondary glioblastoma:
    • A slower-growing form of GBM that develops from a lower-grade astrocytoma (e.g., grade II or III) over 1–10 years (mean, 5).
    • Typically seen in younger patients (< 45 years)
    • Patients present with longer-term symptoms and evidence of a preexisting lesion.


Risk factors

The cause of glioblastomas is unclear and it is difficult to determine a single cause. The risk factors that appear to contribute to glioblastoma include:

  • Previous exposure to therapeutic radiation
  • Genetic associations:
    • Li-Fraumeni syndrome (p53 germline mutations)
    • Lynch syndrome
    • Constitutional mismatch repair–deficiency syndrome
  • Large studies have not consistently shown that cell phone use is a risk factor.


Several genetic mutations are associated with astrocytomas:

  • Loss of heterozygosity on chromosome 10q:
    • Occurs in 60%–90% of GBMs (in both primary and secondary)
    • Specific for GBM (rarely found in lower-grade astrocytomas) → a diagnostic marker of GBM
    • Loss of heterozygosity plus 1 or 2 additional mutations are likely key players in the development of GBM.
  • Activating mutations in the telomerase reverse transcriptase (TERT) promoter:
    • TERT is a catalytic subunit in telomerase → activating mutations allow tumor cells to become “immortal.”
    • Diagnostic marker for GBM
  • Activating mutations in epidermal growth factor receptor (EGFR):
    • EGFR helps control cell proliferation → activating mutations contribute to ↑ proliferation
    • Diagnostic marker of GBM
  • Mutations in isocitrate dehydrogenase (IDH):
    • IDH:
      • Catalyzes the reversible oxidative decarboxylation of isocitrate → α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle 
      • A primary producer of nicotinamide adenine dinucleotide phosphate (NADPH) in most tissues, especially the brain
      • Also involved in mitigating oxidative damage
    • Mutations lead to production and buildup of a 2-hydroxyglutarate (2-HG):
      • 2-HG inhibits enzymatic function of α-KG–dependent dioxygenases, which are involved in DNA demethylation.
      • ↑ 2-HG causes epigenetic dysregulation → can lead to tumor development
  • Methylation (i.e., silencing) of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter:
    • MGMT is an enzyme involved in DNA repair (including DNA repair after alkylating-agent chemotherapy).
    • MGMT methylation at the promoter region:
      • Silences expression of the gene
      • May occur during tumor development → prevents repair of DNA damage
      • Improves chemotherapy responsiveness and overall survival (independent of other risk factors) 
  • Inactivating p53 mutations 
  • Overexpression of platelet-derived growth factor alpha (PDGF-α): common in secondary GBM


  • Location: GBMs usually arise in the cerebral hemispheres (i.e., parenchyma).
    • Common locations:
      • Frontal lobe
      • Temporal lobe
    • Less common locations:
      • Brain stem
      • Cerebellum
      • Spinal cord
  • Regional effects on brain parenchyma include:
    • Compression
    • Invasion
    • Destruction
  • ↑ Intracranial pressure (ICP) may be due to:
    • Direct mass effect
    • Edema in surrounding brain tissue
    • ↑ Blood volume
    • ↑ CSF volume/hydrocephalus
  • Disruptions of normal parenchymal functions are due to:
    • Hypoxia
    • Competition for nutrients
    • Release of metabolic end products:
      • Free radicals
      • Altered electrolytes
      • Neurotransmitters
    • Release and recruitment of cellular mediators (e.g., cytokines)

Clinical Presentation


  • 50% of the cases present with a short clinical history unless they develop from a lower-grade astrocytoma. 
  • The clinical symptoms progress over days to weeks.
  • Signs and symptoms vary according to the location of the tumor. 

Signs and symptoms

Many generalized symptoms are due to increases in ICP. Symptoms may include:

  • General (symptoms that can occur with tumors in any location):
    • Headache, usually in the morning (50%–60% of patients)
    • Nausea and/or vomiting 
    • Cognitive difficulties: 
      • Memory problems
      • Mood or personality changes
    • Papilledema
  • Focal (symptoms that occur because of tumors in specific locations):
    • Seizures (20%–50% of patients) 
    • Aphasia 
    • Visual field deficits
    • Motor weakness
    • Hemiparesis
    • Sensory abnormalities


Diagnosis of glioblastomas is based mainly on imaging after the clinical presentation and a careful history and exam raise suspicion for a brain tumor. A biopsy is required to confirm the diagnosis. Laboratory studies are not helpful in diagnosing GBMs.


  • MRI:
    • Gold standard imaging method for diagnosis
    • Should be ordered with and without contrast
    • T1-weighted images show a hypointense, irregularly shaped, ring-enhancing mass with an area of central clearing (indicating central necrosis).
    • T2-weighted images show a hyperintense, irregularly shaped lesion, with a broad surrounding zone of edema.
  • CT:
    • Indicated in patients with a contraindication to MRI or in the acute setting (e.g., to rule out hemorrhage or stroke)
    • Lesions appear hypointense in comparison to adjacent brain tissue.
    • Midline shift is present because of moderate to severe edema.


A histopathologic specimen obtained through biopsy is required for definitive diagnosis. Findings include:

  • Areas of necrosis (key diagnostic feature differentiating GBM from grade III astrocytomas)
  • Areas of microvascular proliferation
  • Irregular and elongated astrocytic cells with eosinophilic and hyperchromatic nuclei
  • Marked nuclear pleomorphism and atypia
  • Multiple mitotic figures
  • Key molecular tests to perform on biopsy specimen:
    • Immunohistochemical staining for IDH and p53 mutations
    • Methylation assays or PCR to assess MGMT promoter methylation status

Management and Prognosis

The main approach to management is surgical intervention, followed by radiation and chemotherapy. No treatment is curative, and prognosis remains poor, even with aggressive treatment.

Management challenges

Challenges that hinder the management of glioblastomas are:

  • Location of the tumor
  • Poorly defined tumor margins make complete resection complicated.
  • Limited ability of medications to cross the blood–brain barrier
  • Disrupted blood supply within the tumor, making drug delivery even less effective
  • Neurotoxicity of treatments
  • Tumor-induced seizures

Primary management

  • Surgical intervention:
    • Goal is maximal resection.
    • Effects of surgical resection:
      • Reduced tumor burden (which also makes radiation and chemotherapy more effective)
      • Relief of ICP
      • Improvement in both survival and quality of life
    • Preoperative imaging is important to determine the location and extent of the tumor.
  • Radiation therapy:
    • Improves survival rates
    • Starts after surgery
  • Chemotherapy:
    • Primary agent used: temozolomide: 
      • Alkylating agent
      • Given after surgery for 6 cycles
    • Other chemotherapeutic agents include:
      • Carmustine polymer wafers (implanted at the time of surgical resection)
      • Cisplatin
      • Tyrosine kinase inhibitors: erlotinib, gefitinib
      • Bevacizumab + irinotecan (for recurrent GBM)
  • Alternative electric field therapy (the Optune device):
    • Uses low-intensity, intermediate-frequency, alternating electric fields to selectively target actively dividing cells 
    • Indications:
      • Can be used in combination with temozolomide as initial therapy
      • Recurrent GBM

Supportive management

  • Deep vein thrombosis (DVT) prophylaxis: in nonambulatory and hospitalized patients
  • Anticonvulsant therapy: in patients with a history of seizures (prophylactic anticonvulsant therapy remains controversial)
  • Corticosteroids (e.g., dexamethasone): may be used for their antiinflammatory properties to reduce tumor mass effect and swelling


  • Without therapy, patients usually do not survive beyond 3 months.
  • Patients treated with optimal therapy have a median survival of 12‒15 months:
    • 1 year survival rate: 38%–50%
    • 5 year survival rate: 5%–10% 
  • Factors affecting prognosis:
    • Age
    • MGMT methylation and IDH mutation status
    • Level of functional capacity
    • Extent of resection achieved with surgery

Differential Diagnosis

For patients who present with neurologic findings, the following conditions should be considered in the differential diagnosis for glioblastoma multiforme.

Other brain tumors

  • Anaplastic astrocytoma: grade III astrocytomas that typically progress to secondary GBM within 2 years. Clinical presentation is similar to that of GBM. Diagnosis is made on imaging and biopsy, with the key difference being that anaplastic astrocytomas lack necrosis and microvascular proliferation. Management is surgical resection with radiation and chemotherapy. 
  • Oligodendroglioma: CNS tumor arising from oligodendrocytes. Oligodendroglioma most commonly develops in the cerebral hemisphere, usually the frontal lobe, and presents similarly to GBM. A key test differentiating oligodendrogliomas from GBM is testing a biopsy specimen for a 1p/19q codeletion, which will typically be present in oligodendrogliomas but absent in GBMs. Management involves surgical resection possibly accompanied by radiation and/or chemotherapy. 
  • Primary CNS lymphoma: rare variant of non-Hodgkin lymphoma involving the brain, leptomeninges, eyes, or spinal cord, without evidence of systemic disease. Immunodeficiency, including HIV infection, is a primary risk factor. Clinical presentation depends on the location of the tumor and is similar to that of GBM. The diagnosis is made with imaging (typically MRI), biopsy, and potentially CSF evaluation. Management typically involves chemotherapy, potentially whole-brain radiation, and, in patients with HIV/AIDS, antiretroviral therapy.
  • Metastatic tumor: neoplastic cells that have spread to the brain from primary tumors elsewhere in the body. Metastatic tumors are the most common neoplasms in the brain. Neuroimaging often shows multiple foci of the carcinoma, suggesting an origin outside the brain. Clinical presentation depends on the primary tumor and location and extent of brain metastasis. Treatment is directed at the underlying neoplasm and may involve surgical resection, radiation therapy, and chemotherapy.

Nonneoplastic processes

  • Intracranial hemorrhage: life-threatening bleeding within the cranium; second most common cause of stroke. Bleeding may be due to hypertension, ruptured aneurysms, or bleeding vascular malformations. Patients usually present with signs of increased ICP and/or neurologic findings. Diagnosis is by clinical presentation and imaging (often a CT scan in an acute care setting). Management involves urgent medical and surgical treatment.
  • Encephalitis: inflammation of the brain parenchyma due to infection. Encephalitis presents with fever, headache, pain in muscles and joints, fatigue, and seizures. The condition is diagnosed by imaging, CSF analysis, lab tests, and EEG. Management is supportive and involves antiinflammatory drugs and, if the etiology is viral, antivirals.
  • Brain abscess: collection of pus within the brain that develops in response to an infection or trauma that clinically presents with fever, headache, seizures, nausea, and vomiting. Brain abscess is diagnosed by clinical presentation, laboratory testing, and brain imaging. Management includes antibiotic therapy, and surgery to drain the abscess.


  1. Prabhu, V. C. (2021). Glioblastoma multiforme. American Association of Neurological Surgeons. Retrieved May 21, 2021, from
  2. Bruce, J. N., Kennedy, B. C. (2019). Glioblastoma multiforme. Medscape. Retrieved May 21, 2021, from
  3. Hanif, F., et al. (2017). Glioblastoma multiforme: A review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev. 18(1), 3–9.
  4. Dietrich, J. (2021). Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas. In Eichler, A. F. (Ed.), UpToDate. Retrieved May 21, 2021, from
  5. Batchelor, T. (2021). Initial treatment and prognosis of newly diagnosed glioblastoma in adults. In Eichler, A. F. (Ed.), UpToDate. Retrieved May 21, 2021, from 

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