Glioblastoma Multiforme

Updated: Dec 22, 2022
  • Author: Jeffrey N Bruce, MD; Chief Editor: Herbert H Engelhard, III, MD, PhD, FACS, FAANS  more...
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Practice Essentials

Glioblastoma multiforme (GBM) is the most common and most malignant of the glial tumors. [1] See the image below.

Histopathologic slide demonstrating a glioblastoma Histopathologic slide demonstrating a glioblastoma multiforme (GBM).

See Brain Lesions: 9 Cases to Test Your Management Skills, a Critical Images slideshow, to review cases including meningiomas, glioblastomas and craniopharyngiomas, and to determine the best treatment options based on the case history and images.

Signs and symptoms

The clinical history of a patient with glioblastoma multiforme (GBM) is usually short (< 3 months in > 50% of patients). Common presenting symptoms include the following:

  • Slowly progressive neurologic deficit, usually motor weakness
  • Headache
  • Generalized manifestations of increased intracranial pressure, including headaches, nausea and vomiting, and cognitive impairment
  • Seizures

Neurologic symptoms and signs can be either general or focal and reflect the location of the tumor, as follows:

  • General: Headaches, nausea and vomiting, personality changes, and slowing of cognitive function
  • Focal: Hemiparesis, sensory loss, visual loss, aphasia, and others

The etiology of GBM is unknown in most cases. Suggested causes include the following:

  • Genetic factors
  • Cell phone use (controversial)
  • Head injury, N-nitroso compounds, occupational hazards, electromagnetic field exposure (all inconclusive) [2]

See Presentation for more detail.


No specific laboratory studies are helpful in diagnosing GBM. Tumor genetics are useful for predicting response to adjuvant therapy.

Imaging studies of the brain are essential for making the diagnosis, including the following:

  • Computed tomography
  • Magnetic resonance imaging, with and without contrast (study of choice)
  • Positron emission tomography
  • Magnetic resonance spectroscopy
  • Cerebral angiography is not necessary

Other diagnostic measures that may be considered include the following:

  • Electroencephalography: May show suggestive findings, but findings specific for GBM will not be observed
  • Lumbar puncture (generally contraindicated but occasionally necessary for ruling out lymphoma)
  • Cerebrospinal fluid studies do not significantly facilitate specific diagnosis of GBM

In most cases, complete staging is neither practical nor possible. These tumors do not have clearly defined margins; they tend to invade locally and spread along white matter pathways, creating the appearance of multiple GBMs or multicentric gliomas on imaging studies.

See Workup for more detail.


No current treatment is curative. Standard treatment consists of the following:

  • Maximal safe surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide [3, 4]

  • Patients older than 70 years: Less aggressive therapy is sometimes considered, using radiation or temozolomide alone [5, 6, 7]

  • Supportive care for clinical manifestations (eg, headache, seizures, venous thromboembolism) [8, 9]

Surgical options include gross total resection (better survival), subtotal resection, and biopsy. Because GBM cannot be cured surgically, the surgical goals are as follows:

  • To establish a pathologic diagnosis
  • To relieve any mass effect
  • If possible, to achieve a gross total resection to facilitate adjuvant therapy [10]

In some cases, stereotactic biopsy is followed by radiation therapy (eg, for patients with a tumor located in an eloquent area of the brain, patients whose tumors have minimal mass effect, and patients in poor medical condition who cannot undergo general anesthesia). The extent of surgery (biopsy vs resection) has been shown in a number of studies to affect length of survival.

Key points regarding radiotherapy for GBM include the following: [11, 12]

  • The addition of radiotherapy to surgery increases survival. [13, 14]

  • The responsiveness of GBM to radiotherapy varies.

  • Interstitial brachytherapy, in which radioactive seeds are placed intraoperatively, after tumor resection, allows immediate initiation of radiation therapy

  • Radiosensitizers, such as newer chemotherapeutic agents, [15] targeted molecular agents, [16, 17] and antiangiogenic agents [17] may increase the therapeutic effect of radiotherapy. [18]

  • Radiotherapy and/or radiosurgery for recurrent GBM is controversial.

The optimal chemotherapeutic regimen for GBM is not yet defined, but adjuvant chemotherapy appears to yield a significant survival benefit in more than 25% of patients. [19, 2, 20, 21, 22, 23]

Agents used include the following:

  • Temozolomide
  • Nitrosoureas (eg, lomustine, carmustine)
  • Bevacizumab (alone or with irinotecan) for recurrent cases
  • Tyrosine kinase inhibitors (eg, regorafenib, gefitinib, erlotinib)
  • Investigational therapies

See Treatment and Medication for more detail.

For patient education resources, see the Cancer Center as well as the patient education article Brain Cancer.



Glioblastoma multiforme (GBM) is by far the most common and most malignant of the glial tumors. Attention has been drawn to this form of brain cancer by the deaths of Senator Ted Kennedy and Senator John McCain from glioblastoma.

Of the estimated 17,000 primary brain tumors diagnosed in the United States each year, approximately 60% are gliomas. Gliomas comprise a heterogeneous group of neoplasms that differ in location within the central nervous system, in age and sex distribution, in growth potential, in extent of invasiveness, in morphological features, in tendency for progression, and in response to treatments.

See images below.

A T1-weighted axial MRI without intravenous contra A T1-weighted axial MRI without intravenous contrast. This image demonstrates a hemorrhagic multicentric tumor (glioblastoma multiforme [GBM]) in the right temporal lobe. Effacement of the ventricular system is present on the right, and mild impingement of the right medial temporal lobe can be observed on the midbrain.
A T1-weighted sagittal MRI with intravenous contra A T1-weighted sagittal MRI with intravenous contrast in a patient with glioblastoma multiforme (GBM).

Composed of a heterogeneous mixture of poorly differentiated neoplastic astrocytes, glioblastomas primarily affect adults, and they are located preferentially in the cerebral hemispheres. Much less commonly, glioblastoma multiforme can affect the brainstem (especially in children) and the spinal cord. These tumors may develop from lower-grade astrocytomas (World Health Organization [WHO] grade II) or anaplastic astrocytomas (WHO grade III), but more frequently they manifest de novo, without any evidence of a less malignant precursor lesion. The treatment of glioblastomas is palliative and includes surgery, radiotherapy, and chemotherapy. [24, 25, 26]



Glioblastomas can be classified as primary or secondary. Primary glioblastoma multiforme accounts for the vast majority of cases (60%) in adults older than 50 years. These tumors manifest de novo (ie, without clinical or histopathologic evidence of a preexisting, less-malignant precursor lesion), and patients presenting after a short clinical history, usually less than 3 months.

Secondary glioblastoma multiformes (40%) typically develop in younger patients (< 45 y) through malignant progression from a low-grade astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III). The time required for this progression varies considerably, ranging from less than 1 year to more than 10 years, with a mean interval of 4-5 years. Increasing evidence indicates that primary and secondary glioblastomas constitute distinct disease entities that evolve through different genetic pathways, affect patients at different ages, and differ in response to some of the present therapies. Of all the astrocytic neoplasms, glioblastomas contain the greatest number of genetic changes, which, in most cases, result from the accumulation of multiple mutations.

Over the past decade, the concept of different genetic pathways leading to the common phenotypic endpoint (ie, glioblastoma multiforme) has gained general acceptance. Genetically, primary and secondary glioblastomas show little overlap and constitute different disease entities. Studies are beginning to assess the prognoses associated with different mutations. Some of the more common genetic abnormalities are described as follows:

  • Loss of heterozygosity (LOH): LOH on chromosome arm 10q is the most frequent gene alteration for both primary and secondary glioblastomas; it occurs in 60-90% of cases. [27] This mutation appears to be specific for glioblastoma multiforme and is found rarely in other tumor grades. This mutation is associated with poor survival. LOH at 10q plus 1 or 2 of the additional gene mutations appear to be frequent alterations and are most likely major players in the development of glioblastomas. [28]

  • p53: Mutations in p53, a tumor suppressor gene, were among the first genetic alterations identified in astrocytic brain tumors. The p53 gene appears to be deleted or altered in approximately 25-40% of all glioblastoma multiformes, more commonly in secondary glioblastoma multiformes. [29] The p53 immunoreactivity also appears to be associated with tumors that arise in younger patients.

  • Epidermal growth factor receptor (EGFR) gene: The EGFR gene is involved in the control of cell proliferation. Multiple genetic mutations are apparent, including both overexpression of the receptor as well as rearrangements that result in truncated isoforms. [30] However, all the clinically relevant mutations appear to contain the same phenotype leading to increased activity. These tumors typically show a simultaneous loss of chromosome 10 but rarely a concurrent p53 mutation. Overexpression or activation mutations in this gene are more common in primary glioblastoma, with mutations appearing in 40-50% of these tumors. One such common variant, EGFRvIII, has shown promise as a target for kinase inhibitors, immunotoxins, and peptide vaccines. [31]

  • MDM2: Amplification or overexpression of MDM2 constitutes an alternative mechanism to escape from p53-regulated control of cell growth by binding to p53 and blunting its activity. Overexpression of MDM2 is the second most common gene mutation in glioblastoma multiformes and is observed in 10-15% of patients. Some studies show that this mutation has been associated with a poor prognosis. [32]

  • Platelet-derived growth factor–alpha (PDGF-alpha) gene: The PDGF gene acts as a major mitogen for glial cells by binding to the PDGF receptor (PDGFR). Amplification or overexpression of PDGFR is typical (60%) in the pathway leading to secondary glioblastomas.

  • PTEN: PTEN (also known as MMAC and TEP1) encodes a tyrosine phosphatase located at band 10q23.3. The function of PTEN as a cellular phosphatase, turning off signaling pathways, is consistent with possible tumor-suppression action. When phosphatase activity is lost because of genetic mutation, signaling pathways can become activated constitutively, resulting in aberrant proliferation. PTEN mutations have been found in as many as 20% of glioblastomas, more commonly in primary glioblastoma multiformes. [33]

In 2015, Eckel-Passow and colleagues classified gliomas into groups on the basis of three tumor markers: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. Findings included the following [34] :

  • Among patients with a histopathologic diagnosis of glioblastoma, those with both TERT and IDH mutations had poor overall survival
  • Isolated IDH mutations were significantly more frequent in younger patients (mean age at diagnosis, 37 years) and seemed to be associated with tumor evolution along a secondary glioblastoma pathway
  • Mean age at diagnosis was highest (59 years) in patients whose tumors harbored TERT mutations only
  • Patients whose tumors harbored TERT mutations suffered worse overall survival compared with the other molecular subgroups
  • Patients with triple-negative gliomas (IDH-, TERT -, 1p19q intact) had poorer overall survival than patients who had gliomas with TERT or  IDH, or who had triple-positive gliomas

The 2016 World Health Organization Classification of Tumors of the Central Nervous System includes two primary designations of glioblastoma: IDH wild type and IDH mutant. [35] IDH–wild type glioblastomas comprise 71% of all adult gliomas, while IDH–mutant glioblastomas comprise 7%. Patients with IDH-wild type glioblastoma are generally older (median age at diagnosis, 59 years) and have the worst prognosis (median overall survival 1.2 years), while patients with IDH-mutant glioblastoma tend to be younger (median age at diagnosis, 38 years) and have a better prognosis (median overall survival 3.6 years). [36]

Less frequent but more malignant mutations in glioblastomas include the following:

  • MMAC1-E1 - A gene involved in the progression of gliomas to their most malignant form

  • MAGE-E1 - A glioma-specific member of the MAGE family that is expressed at up to 15-fold higher levels in glioblastoma multiformes than in normal astrocytes

  • NRP/B - A nuclear-restricted protein/brain, which is expressed in neurons but not in astrocytes (NRP/B mutants are found in glioblastoma cells.)

Additional genetic alterations in primary glioblastomas include p16 deletions (30-40%), p16INK4A, and retinoblastoma (RB) gene protein alterations. Progression of secondary glioblastomas often includes LOH at chromosome arm 19q (50%), RB protein alterations (25%), PTEN mutations (5%), deleted-in-colorectal-carcinoma gene (DCC) gene loss of expression (50%), and LOH at 10q.

Glioblastoma multiformes occur most often in the subcortical white matter of the cerebral hemispheres. In a series of 987 glioblastomas from University Hospital Zurich, the most frequently affected sites were the temporal (31%), parietal (24%), frontal (23%), and occipital (16%) lobes. [37] Combined frontotemporal location is particularly typical.

Tumor infiltration often extends into the adjacent cortex or the basal ganglia. When a tumor in the frontal cortex spreads across the corpus callosum into the contralateral hemisphere, it creates the appearance of a bilateral symmetric lesion, hence the term butterfly glioma. Sites for glioblastomas that are much less common are the brainstem (which often is found in affected children), the cerebellum, and the spinal cord.

Glioblastoma cells have the ability to migrate and invade healthy brain tissue. Active migration of glioblastoma cells makes curative surgical resection impossible. Hypoxia promotes the migration of glioblastoma cells and increases tumor aggressivenes. Glioblastomas contain extensive hypoxic areas, which distinguishes this tumor from low-grade malignancies. [38]



The etiology of glioblastoma remains unknown in most cases. Familial gliomas account for approximately 5% of malignant gliomas, and less than 1% of gliomas are associated with a known genetic syndrome (eg, neurofibromatosis, Turcot syndrome, or Li-Fraumeni syndrome). [2]

Although concerns have been raised regarding cell phone use as a potential risk factor for development of gliomas, study results have been inconsistent, and this possibility remains controversial. The largest studies have not supported cell phone use as a cancer risk factor. [39, 3, 4, 5, 6, 7]  

Studies of association with head injury, N-nitroso compounds, occupational hazards, and electromagnetic field exposure have been inconclusive. [39]



Overall incidence is very similar among countries. Glioblastoma multiformes are slightly more common in the United States, Scandinavia, and Israel than in Asia. This may reflect differences in genetics, diagnosis and the healthcare system, and reporting practices. Glioblastoma multiforme is the most frequent primary brain tumor, accounting for approximately 12-15% of all intracranial neoplasms and 50-60% of all astrocytic tumors. In most European and North American countries, incidence is approximately 2-3 new cases per 100,000 people per year.

Within the United States, glioblastoma multiforme is slightly more common in whites.

In a review of 1003 glioblastoma biopsies from the University Hospital Zurich, [40]  males had a slight preponderance over females, with a male-to-female ratio of 3:2.

Glioblastoma multiforme may manifest in persons of any age, but it affects adults preferentially, with a peak incidence at 45-70 years. In the series from University Hospital Zurich (a review of 1003 glioblastoma biopsies), 70% of patients were in this age group, with a mean age of 53 years. [40]  In a series reported by Dohrman (1976), only 8.8% of glioblastoma multiformes occurred in children. [41]



Only modest advancements in the treatment of glioblastoma have occurred in the past 25 years. Although current therapies remain palliative, they have been shown to prolong quality survival. Without therapy, patients with glioblastoma multiformes uniformly die within 3 months. Patients treated with optimal therapy, including surgical resection, radiation therapy, and chemotherapy, have a median survival of approximately 12 months, with fewer than 25% of patients surviving up to 2 years and fewer than 10% of patients surviving up to 5 years. Whether the prognosis of patients with secondary glioblastoma is better than or similar to the prognosis for those patients with primary glioblastoma remains controversial.

Brain tumor resection has an overall mortality rate of 1-2%.  Approximately 40% of patients have no or minimal deficits after surgery, 30% manifest no postoperative change relative to preoperative deficits, and 25% sustain an increased postoperative deficit that usually improves.

Despite extensive clinical trials, individual prediction of clinical outcome has remained an elusive goal. Glioblastomas are among the most malignant human neoplasms, with a median survival despite optimal treatment of less than 1 year. In a series of 279 patients receiving aggressive radiation and chemotherapy, only 5 of 279 patients (1.8%) survived longer than 3 years. [42]

Patient survival depends on a variety of clinical parameters. Younger age, higher Karnofsky performance scale (a standard measure of the ability of patients with cancer to perform daily tasks) score at presentation, radiotherapy, and chemotherapy all correlate with improved outcome. Clinical evidence also suggests that a greater extent of resection favors longer survival. [43, 44, 45, 46] Tumors that are deemed unresectable due to location (eg, in the brainstem) also portend a poorer prognosis. [47]

A review by Perrini et al of 48 patients with recurrent glioblastoma found that preoperative performance status at recurrence and subtotal versus gross-total repeat resection were independent predictors of survival. These authors concluded that gross-total resection at repeat craniotomy is associated with longer overall survival and should be performed whenever possible in patients with recurrent glioblastoma who have good performance status. [48]

Survival has not been shown to correlate with p53, EGFR, or MDM2 mutations. [49]

Two separate reviews of outcomes in elderly patients have been published. One found that although elderly patients have a poor prognosis, gross-total resection confers a modest survival benefit and treatment with bevacizumab significantly increased overall survival. Older age and preoperative Karnofsky Performance Scale score also were significant prognostic factors. [50]

The results of the second study concurred that there is a survival advantage for those who undergo maximal safe resection. The review also found that radiotherapy extends survival in selected patients and temozolomide chemotherapy is safe and extends the survival of patients with tumors that harbor O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation. [51]

A study by Li et al used an updated Radiation Therapy Oncology Group (RTOG) GBM database to produce a simplified original recursive partitioning analysis (RPA) model combining classes V and VI. This resulted in 3 distinct prognostic groups defined by performance status, age, neurologic function, and extent of resection. This classification will be used in future RTOG GBM trials. [52]

Clearly, new approaches for the management of glioblastomas are necessary. Enrollment of patients into clinical trials will generate new information regarding investigational therapies. Novel approaches, such as the use of gene therapy and immunotherapy, as well as improved methods for the delivery of antiproliferative, antiangiogenic, and noninvasive therapies, provide hope for the future.

A study by Kaur et al determined that the presence of a large cyst in patients with GBM does not affect overall survival compared with those who do not have a cyst. [53]


Patient Education

For patient education information, see the Brain Cancer Health Center. In addition, information about glioblastoma (and other brain tumors) is available from the American Brain Tumor Association (ABTA) at Brain Tumor Information.