Glioblastoma multiforme

Glioblastoma multiforme: Description, Causes and Risk Factors: Glioblastoma multiformeA glioma consisting chiefly of undifferentiated anaplastic cells of astrocytic origin that show marked nuclear pleomorphism, necrosis, and vascular endothelial proliferation; frequently, tumor cells are arranged radially about an irregular focus of necrosis; these neoplasms grow rapidly, invade extensively, and occur most frequently in the cerebrum of adults. Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor. These tumors are often aggressive and infiltrate surrounding brain tissue. GBMs arise from glial cells, which are cells that form the tissue that surrounds and protects other nerve cells found within the brain and spinal cord. GBMs are mainly composed of star-shaped glial cells known as astrocytes. The general term glioma includes any type of brain tumor such as astrocytoma and oligodendroglioma that arise from glial cells. Glioblastoma multiforme is the highest grade glioma (grade 4) tumor and is the most malignant form of astrocytomas. Over the past decade, the concept of different genetic pathways leading to the common phenotypic endpoint (i.e., GBM) 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 over expression of the receptor as well as re-arrangements 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, EGFR VIII, has shown promise as a target for kinase inhibitors, immunotoxins, and peptide vaccines.
  • 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 30% of glioblastomas, more commonly in primary glioblastoma multiformes.
Less frequent but more malignant mutations 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.
Risk factors: Genetic factors.
  • Extensive cell phone use.
  • Head injury, N-nitroso compounds, occupational hazards, electromagnetic field exposure (inconclusive).
Glioblastoma multiforme typically develop in younger patients (< 45 y) through malignant progression from a low-grade astrocytoma or anaplastic astrocytoma. 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. Of the estimated 17,000 primary brain tumors diagnosed in the United States each year, approximately 15-20% are glioblastoma multiforme. Glioblastoma multiformes are slightly more common in the United States, Scandinavia, and Israel. This may reflect differences in genetics, diagnosis and the healthcare system, and reporting practices. Symptoms: Symptoms may include: Neurologic deficit. Diagnosis: A neurologic evaluation should be done if a patient has slowly increasing signs of mental dysfunction, new seizures, persistent headaches or evidence that there is pressure inside the skull, such as vomiting or swelling or protrusion of the blind spot at the back of the eye. A neurologist performs a complete examination, which may include a magnetic resonance imaging (MRI) scan, a computed tomography (CT/CAT) scan or a chest X-ray to determine if the tumor has spread from another part of the body. An MRI usually finds low-grade astrocytomas earlier than CT. Cerebral angiography is rarely used to diagnose a brain tumor, but it may be done before surgery. Depending on the patient's symptoms, specialized tests may be done, including tests of the field of vision, the sharpness of vision and hearing. If the results of other tests are not conclusive, an examination of the fluid that surrounds the brain and spinal cord may be done, although it is usually unnecessary. 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).
Treatment: No current treatment is curative. Standard treatment consists of the following: Maximal surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide. Carmustine wafers increased 6-month survival from 36% to 56% over placebo in one randomized study of 222 patients, though there was a significant association between the treatment group and serious intracranial infections. The anti-angiogenic agent bevacizumab was approved by the U.S. Food and Drug Administration for recurrent glioblastoma in May 2009. When used with irinotecan, bevacizumab improved 6-month survival in recurrent glioma patients to 46% compared with 21% in patients treated with temozolomide. This bevacizumab and irinotecan combination for recurrent glioblastoma multiforme has been shown to improve survival over bevacizumab alone. Anti-angiogenic agents also decrease peritumoral edema, potentially reducing the necessary corticosteroid dose.
  • Patients older than 70 years: Less aggressive therapy is sometimes considered, using radiation or temozolomide alone.
  • Interstitial brachytherapy is of limited use and is rarely used.
  • Radiosensitizers, such as newer chemotherapeutic agents, targeted molecular agents, and antiangiogenic agents may increase the therapeutic effect of radiotherapy.
  • Other therapy modalities under investigation include gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.
NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.

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