- Author: Jeffrey N Bruce, MD; Chief Editor: Jules E Harris, MD, FACP, FRCPC more...
Glioblastoma multiforme (GBM) is the most common and most malignant of the glial tumors. See the image below.
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
Generalized symptoms of increased intracranial pressure, including headaches, nausea and vomiting, and cognitive impairment
Neurologic symptoms and signs can be either general or focal and reflect the location of the tumor, as follows:
General symptoms: Headaches, nausea and vomiting, personality changes, and slowing of cognitive function International
Focal signs: Hemiparesis, sensory loss, visual loss, aphasia, and others
The etiology of GBM is unknown in most cases. Suggested causes include the following:
Cell phone use (controversial)
Head injury, N-nitroso compounds, occupational hazards, electromagnetic field exposure (inconclusive) 
See Clinical 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:
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 surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide [2, 3]
Patients older than 70 years: Less aggressive therapy is sometimes considered, using radiation or temozolomide alone [4, 5, 6]
Key points regarding radiotherapy for GBM include the following:[7, 8, 9]
The addition of radiotherapy to surgery increases survival. [10, 11]
The responsiveness of GBM to radiotherapy varies.
Interstitial brachytherapy is of limited use and is rarely used.
Radiotherapy for recurrent GBM is controversial.
The optimal chemotherapeutic regimen for glioblastoma is not yet defined, but adjuvant chemotherapy appears to yield a significant survival benefit in more than 25% of patients.[16, 1, 17, 18, 19, 20]
Agents used include the following:
Nitrosoureas (eg, carmustine [BCNU])
Inhibitors of MGMT (eg, O6-benzylguanine)
Bevacizumab (alone or with irinotecan) for recurrent glioma
Tyrosine kinase inhibitors (eg, gefitinib, erlotinib)
Investigational therapies (eg, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, radiolabeled drugs and antibodies [21, 22, 23, 24, 25, 26]
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 
The extent of surgery (biopsy vs resection) has been shown in a number of studies to affect length of survival. Surgical options include the following:
Gross total resection (better survival)
In some cases, stereotactic biopsy 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)
See Treatment and Medication for more detail.
Glioblastoma multiforme (GBM) is by far the most common and most malignant of the glial tumors. Attention was drawn to this form of brain cancer when Senator Ted Kennedy was diagnosed with glioblastoma and ultimately died from it.
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.
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.[28, 29, 30]
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), 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.  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. 
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.  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.  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. [35, 2, 36]
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. 
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. 
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 :
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
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. 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.
Overall incidence is very similar among countries (see International). 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.
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. Mean survival is inversely correlated with age, which may reflect exclusion of older patients from clinical trials. 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.
Race-, Sex-, and Age-related Demographics
Within the United States, glioblastoma multiforme is slightly more common in whites.
In a review of 1003 glioblastoma biopsies from the University Hospital Zurich, 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. In a series reported by Dohrman (1976), only 8.8% of glioblastoma multiformes occurred in children.
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