Glioblastoma Multiforme

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Glioblastoma multiforme
Classification and external resources
ICD-10 C71.
ICD-9 191
ICD-O: M9440/3
OMIM 137800
DiseasesDB 29448
eMedicine neuro/147 med/2692
MeSH [2]
Image 1a. Coronal MRI with contrast of a glioblastoma WHO grade IV in a 15-year-old boy
Image 1b. Sagittal MRI with contrast of a glioblastoma WHO grade IV in a 15-year-old boy
Glioblastoma (histology slide)

Glioblastoma multiforme (GBM) is the most common and most aggressive type of primary brain tumor in humans, involving glial cells and accounting for 52% of all parenchymal brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBMs occur in only 2–3 cases per 100,000 people in Europe and North America. According to the WHO classification of the tumors of the central nervous system?, the standard name for this brain tumor is “Glioblastoma”; it presents two variants: Giant cell glioblastoma and Gliosarcoma.
Glioblastomas are also an important brain tumor of the canine, and research is ongoing to use this as a model for developing treatments in humans.[1]

Treatment can involve chemotherapy, radiotherapy, and surgery, all of which are acknowledged as palliative measures, meaning that they do not provide a cure. Even with complete surgical resection of the tumor, combined with the best available treatment, the survival rate for GBM remains very low. However, many advances in the understanding of cancer genes, microsurgery techniques, radiotherapy and chemotherapy are slowly increasing the survival time of patients diagnosed with glioblastoma as these new developments become available.




Although common symptoms of the disease include seizure, nausea and vomiting, headache, and hemiparesis, the single most prevalent symptom is a progressive memory, personality, or neurological deficit due to temporal and frontal lobe involvement. The kind of symptoms produced depends highly on the location of the tumor, more so than on its pathological properties. The tumor can start producing symptoms quickly, but occasionally is an asymptomatic condition until it reaches an enormous size.


When viewed with MRI, glioblastomas often appear as ring-enhancing lesions. The appearance is not specific, however, as other lesions such as abscess, metastasis, tumefactive multiple sclerosis, and other entities may have a similar appearance.[2] Definitive diagnosis of a suspected GBM on CT or MRI requires a stereotactic biopsy or a craniotomy with tumor resection. Because the tumor grade is based upon the most malignant portion of the tumor, biopsy or subtotal tumor resection can result in undergrading of the lesion.


GBM is more common in males, although the reason for this is not clear.[3] Most glioblastoma tumors appear to be sporadic, without any genetic predisposition. No links have been found between glioblastoma and smoking,[4]diet,[5]cellular phones,[6] or electromagnetic fields.[7] Recently, evidence for a viral cause has been discovered, possibly SV40[8] or cytomegalovirus.[9] There also appears to be a small link between ionizing radiation and glioblastoma.[10] Some also believe that there may be a link between polyvinyl chloride (which is commonly used in construction) and glioblastoma.[11] A recent link cited in the Lancet medical journal links brain cancer to lead exposure in the work place. [12]

Other risk factors include:[13]


Glioblastomas multiforme are characterized by the presence of small areas of necrotizing tissue that is surrounded by anaplastic cells (pseudopalisading necrosis). This characteristic, as well as the presence of hyperplastic blood vessels, differentiates the tumor from Grade 3 astrocytomas, which do not have these features. Although glioblastoma multiforme can be formed from lower-grade astrocytomas, post-mortem autopsies have revealed that most glioblastomas multiforme are not caused by previous lesions in the brain.

GBM usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. Some GBM form following degeneration of lower grade gliomas. These are called secondary GBM and are more common in younger patients. The tumor may extend into the meninges or ventricular wall, leading to high protein content in the cerebrospinal fluid (CSF) (> 100 mg/dL), as well as an occasional pleocytosis of 10 to 100 cells, mostly lymphocytes. Malignant cells carried in the CSF may spread (rarely) to the spinal cord or cause meningeal gliomatosis. However, metastasis of GBM beyond the central nervous system is extremely unusual. About 50% of GBM occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the cerebrum and may exhibit the classic infiltration across the corpus callosum, producing a butterfly (bilateral) glioma.

The tumor may take on a variety of appearances, depending on the amount of hemorrhage, necrosis, or its age. A CT scan will usually show a inhomogeneous mass with a hypodense center and a variable ring of enhancement surrounded by edema. Mass effect from the tumor and edema may compress the ventricles and cause hydrocephalus.

Cancer cells with stem cell-like properties have been found in glioblastomas (this may be a cause of their resistance to conventional treatments, and high re-occurrence rate)[14].


It is very difficult to treat glioblastoma due to several complicating factors:[15]

  • The tumor cells are very resistant to chemotherapy and other conventional therapies
  • The brain is susceptible to damage due to therapy
  • The brain has a very limited capacity to repair itself
  • Many drugs cannot cross the blood brain barrier to act on the tumor

Treatment of primary brain tumors and brain metastases consists of both symptomatic and palliative therapies.

Symptomatic therapy

Supportive treatment focuses on relieving symptoms and improving the patient’s neurologic function. The primary supportive agents are anticonvulsants and corticosteroids.

  • Historically, around 90% of patients with glioblastoma underwent anticonvulsant treatment, although it has been estimated that only approximately 40% of patients required this treatment. Recently, it has not been recommended that neurosurgeons administer anticonvulsants prophylactically, and should wait until a seizure occurs before prescribing this medication[16]. Those receiving phenytoin concurrent with radiation may have serious skin reactions such as erythema multiforme and Stevens-Johnson syndrome.
  • Corticosteroids, usually dexamethasone given 4 to 10 mg every 4 to 6 h, can reduce peritumoral edema (through rearrangement of the blood-brain barrier), diminishing mass effect and lowering intracranial pressure, with a decrease in headache or drowsiness.

Angiotensin inhibitor drugs have been shown to reduce edema due to leakage of tumor blood vessels in mice with glioblastoma.

Palliative therapy

Palliative treatment usually is conducted to improve quality of life and to achieve a longer survival time. It includes surgery, radiation therapy, and chemotherapy. A maximally feasible resection with maximal tumor-free margins is usually performed along with external beam radiation and chemotherapy. Gross total resection of tumor is associated with a better prognosis.


Surgery is the first stage of treatment of glioblastoma. An average GBM tumor contains 1011 cells, which is on average reduced to 109 cells after surgery. It is used to take a section for a pathological diagnosis, to remove some of the symptoms of a large mass pressing against the brain, to remove disease before secondary resistance to radiotherapy and chemotherapy, and to prolong survival.

The greater the extent of tumor removal, the longer the survival time. Removal of 98% or more of the tumor has been associated with a significantly longer median survival time than if less than 98% of the tumor is removed.[17] The chances of near-complete initial removal of the tumor can be greatly increased if the surgery is guided by a fluorescent dye known as 5-aminolevulinic acid.[18]


On average, radiotherapy after surgery can reduce the tumor size to 107 cells. Whole brain radiotherapy does not improve survival when compared to the more precise and targeted three-dimensional conformal radiotherapy.[19] A total radiation dose of 60–65 Gy has been found to be optimal for treatment.[20]

Boron neutron capture therapy has been tested as an alternative treatment for glioblastoma multiforme but is not in common use.


The standard of care for glioblastoma includes chemotherapy during and after radiotherapy. On average, chemotherapy after surgery and radiotherapy can initially reduce the tumor size to 106 cells. The use of temozolomide both during radiotherapy and for six months post radiotherapy results in a significant increase in median survival with minimal additional toxicity.[21] This treatment regime is now standard for most cases of glioblastoma where the patient is not enrolled in a clinical trial.[22][23] Temozolomide seems to work by sensitizing the tumor cells to radiation. [24] The U.S. Food and Drug Administration approved Avastin (bevacizumab) to treat patients with glioblastoma at progression after standard therapy [25].


Long-term disease-free survival is unlikely but possible, and the tumor will often reappear, usually within 2 cm of the original site, and 10-20% may develop new lesions at distant sites. More extensive surgery and intense local treatment after recurrence has been associated with improved survival.[26].


The median survival time from the time of diagnosis without any treatment is 3 months. Increasing age (> 60 years of age) carries a worse prognostic risk. Death is usually due to cerebral edema or increased intracranial pressure. One in twenty of glioblastoma patients survive for more than three years, and approximately one in 5,000 glioblastoma patients survives for decades.[27]

Survival of more than three years has been associated with younger age at diagnosis, a good initial Karnofsky Performance Score (KPS), and MGMT methylation.[27] A DNA test can be conducted on glioblastomas to determine whether or not the promoter of the MGMT gene is methylated. Patients with a methylated MGMT promoter have been associated with significantly greater long-term survival than patients with an unmethylated MGMT promoter.[28] This DNA characteristic is intrinsic to the patient and currently cannot be altered externally.

Long-term survival has also been associated with those patients who receive surgery, radiotherapy, and temozolomide chemotherapy.[27] However, much remains unknown about why some patients survive longer with glioblastoma.

UCLA Neuro-Oncology publishes real-time survival data for patients with this diagnosis. They are the only institution in the United States that shows how their patients are performing. They also show a listing of chemotherapy agents used to treat GBM tumors.

According to a 2003 study, glioblastoma multiforme prognosis can be divided into three subgroups dependent on KPS, the age of the patient, and treatment:[29]