Coronal MRI with contrast of a glioblastoma WHO grade IV in a 15-year-old boy
|Classification and external resources|
Glioblastoma multiforme (GBM), WHO classification name "glioblastoma", also known as Grade IV Astrocytoma, is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells and accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors. GBM is a rare disease, with an incidence of 2–3 cases per 100,000 person life-years in Europe and North America. It presents two variants: giant cell glioblastoma and gliosarcoma. About 50% of the patients diagnosed with GBM die within one year, while 90% within three years.
Treatment can involve chemotherapy, radiation and surgery. Median survival with standard-of-care radiation and chemotherapy with temozolomide is 15 months. Median survival without treatment is 4½ months. Although no randomized controlled trials have been done, surgery remains the standard of care.
- 1 Signs and symptoms
- 2 Risk factors
- 3 Pathogenesis
- 4 Diagnosis
- 5 Treatment
- 6 Prognosis
- 7 History
- 8 Research
- 9 References
- 10 External links
Signs and symptoms
Although common symptoms of the disease include seizure, nausea and vomiting, headache, memory loss, 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.
For unknown reasons, GBM occurs more commonly in males. Most glioblastoma tumors appear to be sporadic, without any genetic predisposition. No links have been found between glioblastoma and smoking, consumption of cured meat, or electromagnetic fields as of yet. Alcohol consumption may be a possible risk factor. Glioblastoma has been associated with the viruses SV40, HHV-6, and cytomegalovirus. There also appears to be a small link between ionizing radiation and glioblastoma. Some also believe that there may be a link between polyvinyl chloride (which is commonly used in construction) and glioblastoma. A 2006 analysis links brain cancer to lead exposure in the work-place. There is an association of brain tumor incidence and malaria, suggesting that the anopheles mosquito, the carrier of malaria, might transmit a virus or other agent that could cause glioblastoma or that the immunosuppression associated with malaria could enhance viral replication. Also HHV-6 reactivates in response to hypersensitivity reactions from drugs and environmental chemicals.
Other risk factors include:
- Sex: male (slightly more common in men than women)
- Age: over 50 years old
- Ethnicity: Caucasians, Hispanics, and Asians
- Having a low-grade astrocytoma (brain tumor), which often, given enough time, develops into a higher-grade tumor
- Having one of the following genetic disorders is associated with an increased incidence of gliomas:
Glioblastoma multiforme tumors are characterized by the presence of small areas of necrotizing tissue that are surrounded by anaplastic cells. This characteristic, as well as the presence of hyperplastic blood vessels, differentiates the tumor from Grade 3 astrocytomas, which do not have these features.
There are four subtypes of glioblastoma. Ninety-seven percent of tumors in the 'classical' subtype carry extra copies of the epidermal growth factor receptor (EGFR) gene, and most have higher than normal expression of epidermal growth factor receptor (EGFR), whereas the gene TP53, which is often mutated in glioblastoma, is rarely mutated in this subtype. In contrast, the proneural subtype often has high rates of alterations in TP53, and in PDGFRA, the gene encoding a-type platelet-derived growth factor receptor, and in IDH1, the gene encoding isocitrate dehydrogenase-1. The mesenchymal subtype is characterized by high rates of mutations or other alterations in NF1, the gene encoding Neurofibromin 1 and fewer alterations in the EGFR gene and less expression of EGFR than other types. Many other genetic alterations have been described in glioblastoma, and the majority of them are clustered in three pathways, the P53, RB, and the PI3K/AKT. Glioblastomas have alterations in 64-87%, 68-78% and 88% of these pathways, respectively. Another important alteration is methylation of MGMT, a "suicide" DNA repair enzyme. Methylation is described to impair DNA transcription and therefore, expression of the MGMT enzyme. Since an MGMT enzyme can only repair one DNA alkylation due its suicide repair mechanism, reverse capacity is low and methylation of the MGMT gene promoter greatly affects DNA-repair capacity. Indeed, MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide.
GBMs usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. Less than 10% form more slowly following degeneration of low-grade astrocytoma or anaplastic astrocytoma. These are called secondary GBMs and are more common in younger patients (mean age 45 versus 62 years). 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 GBMs occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the cerebrum and may rarely 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 an 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.
Glioblastoma stem-like cells
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 recurrence rate). A biomarker for cells in glioblastomas that exhibit cancer stem cell properties, the transcription factor Hes3, has been shown to regulate their number when placed in culture.
The IDH1 gene encodes for the enzyme isocitrate dehydrogenase 1 and is frequently mutated in glioblastoma (primary GBM: 5%, secondary GBM >80%). By producing very high concentrations of the "oncometabolite" D-2-hydroxyglutarate and dysregulating the function of the wild-type IDH1-enzyme it induces profound changes to the metabolism of IDH1-mutated glioblastoma, compared with IDH1 wild-type glioblastoma or healthy astrocytes. Among others, it increases the glioblastoma cells' dependence on glutamine or glutamate as an energy source. It has been hypothesized that IDH1-mutated glioblastoma are in a very high demand for glutamate and use this amino acid and neurotransmitter as a chemotactic signal. Since healthy astrocytes excrete glutamate, IDH1-mutated glioblastoma cells do not favor dense tumor structures but instead migrate, invade and disperse into healthy parts of the brain where glutamate concentrations are higher. This may explain the invasive behaviour of these IDH1-mutated glioblastoma.
Furthermore, glioblastoma multiforme exhibits numerous alterations in genes that encode for ion channels, including upregulation of gBK potassium channels and ClC-3 chloride channels. It has been hypothesized that by upregulating these ion channels, glioblastoma tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H2O movement through osmosis, which aids glioblastoma cells in changing cellular volume very rapidly. This is helpful in their extremely aggressive invasive behavior, because quick adaptations in cellular volume can facilitate movement through the sinuous extracellular matrix of the brain.
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. Definitive diagnosis of a suspected GBM on CT or MRI requires a stereotactic biopsy or a craniotomy with tumor resection and pathologic confirmation. 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. Imaging of tumor blood flow using perfusion MRI and measuring tumor metabolite concentration with MR spectroscopy will add value to standard MRI in the diagnosis of glioblastoma by showing increased relative cerebral blood volume and increased choline peak respectively, but pathology remains the gold standard.
In the diagnosis of glioblastoma it is important to distinguish primary glioblastoma from secondary glioblastoma. These tumors occur spontaneously (de novo) or have progressed from a lower-grade glioma, respectively. Primary glioblastomas have a worse prognosis, different tumor biology may have a different response to therapy, which makes this a critical evaluation to determine patient prognosis and therapy. Over 80% of secondary glioblastoma carries a mutation in IDH1, whereas this mutation is rare in primary glioblastoma (5-10%). Thus, IDH1 mutations may become a useful tool to distinguish primary and secondary glioblastomas in the future, since histopathologically they are very similar and the distinction without molecular biomarkers is unreliable.
It is very difficult to treat glioblastoma due to several complicating factors:
- The tumor cells are very resistant to conventional therapies.
- The brain is susceptible to damage due to conventional 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.
- 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 been recommended that neurosurgeons not administer anticonvulsants prophylactically, and should wait until a seizure occurs before prescribing this medication. 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 8 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.
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 (a reduction of 99%). 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 better. Removal of 98% or more of the tumor has been associated with a significantly longer healthier time than if less than 98% of the tumor is removed. 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. GBM cells are widely infiltrative through the brain at diagnosis, and so despite a "total resection" of all obvious tumor, most people with GBM later develop recurrent tumors either near the original site or at more distant "satellite lesions" within the brain. Other modalities, including radiation, are used after surgery in an effort to suppress and slow recurrent disease.
After surgery, radiotherapy is the mainstay of treatment for people with glioblastoma. A pivotal clinical trial carried out in the early 1970s showed that among 303 GBM patients randomized to radiation or nonradiation therapy, those who received radiation had a median survival more than double those who did not. Subsequent clinical research has attempted to build on the backbone of surgery followed by radiation. On average, radiotherapy after surgery can reduce the tumor size to 107 cells. Whole brain radiotherapy does not improve when compared to the more precise and targeted three-dimensional conformal radiotherapy. A total radiation dose of 60–65 Gy has been found to be optimal for treatment.
GBM tumors are well known to contain zones of tissue exhibiting hypoxia which are highly resistant to radiotherapy. Various approaches to chemotherapy radiosensitizers have been pursued with limited success to date. Newer research approaches are currently being studied, including preclinical and clinical investigations into the use of an oxygen diffusion-enhancing compound such as trans sodium crocetinate (TSC) as radiosensitizers and a clinical trial is currently underway.
Boron neutron capture therapy has been tested as an alternative treatment for glioblastoma multiforme but is not in common use.
Most studies show no benefit from the addition of chemotherapy. However, a large clinical trial of 575 participants randomized to standard radiation versus radiation plus temozolomide chemotherapy showed that the group receiving temozolomide survived a median of 14.6 months as opposed to 12.1 months for the group receiving radiation alone. This treatment regime is now standard for most cases of glioblastoma where the person is not enrolled in a clinical trial. Temozolomide seems to work by sensitizing the tumor cells to radiation.
High doses of temozolomide in high-grade gliomas yield low toxicity, but the results are comparable to the standard doses.
Gene transfer is a promising approach for fighting cancers including brain cancer. Unlike current conventional cancer treatments such as chemotherapy and radiation therapy, gene transfer has the potential to selectively kill cancer cells while leaving healthy cells unharmed. Over the past two decades significant advances have been made in gene transfer technology and the field has matured to the point of clinical and commercial feasibility. Advances include vector (gene delivery vehicle) construction, vector producer cell efficiency and scale-up processes, preclinical models for target diseases and regulatory guidance regarding clinical trial design including endpoint definitions and measurements. In one such approach, researchers at UCLA in 2005 reported a long-term survival benefit in an experimental brain tumor animal model. Subsequently, in preparation for human clinical trials, this technology was further developed by Tocagen, and is currently under clinical investigation in a Phase I/II trial for the potential treatment of recurrent high grade glioma including glioblastoma multiforme (GBM) and anaplastic astrocytoma.
Protein therapeutics - APG101
APG101 is a soluble CD95-Fc fusion protein that blocks the CD95 ligand from binding to the CD95 receptor. As demonstrated by Kleber et al., the binding of the CD95 ligand to its cognate receptor stimulates the invasive growth of glioblastoma cells. Thus, the inhibition of this interaction through APG101 reduces tumor cell growth and migration. A randomized, double-blind, placebo-controlled phase I study with 34 healthy volunteers to examine the safety and tolerability of APG101 has shown that it is well tolerated. The efficacy of APG101 was tested in a randomized controlled phase II trial with patients suffering from GBM. The study was initiated at the end of 2009 and first results were released in 2012. A total of 83 patients with first or second relapse of GBM were enrolled in the successful trial. The primary goal of doubling the number of patients reaching progression-free survival at six months (PFS6) was substantially exceeded. No drug-related serious adverse events were observed during treatment with APG101 for up to two years.
Relapse of glioblastoma is attributed to the recurrence and persistence of tumor stem cells. In a small trial, a tumor B-cell hybridoma vaccine against tumor stem cells elicited a specific tumor immune reaction thus enhancing immune response to the disease. Larger trials, including tests of different EGFR signaling patterns and their relationship to tumor stem cells being conducted by John A. Boockvar's lab at Weill Cornell Medical College, are in progress to further assess this approach to treating glioblastoma.
The median survival time from the time of diagnosis without any treatment is 3 months, but with treatment survival of 1–2 years is common. Increasing age (> 60 years of age) carries a worse prognostic risk. Death is usually due to cerebral edema or increased intracranial pressure.
A good initial Karnofsky Performance Score (KPS) and MGMT methylation are associated with longer survival. 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 benefit than patients with an unmethylated MGMT promoter. This DNA characteristic is intrinsic to the patient and currently cannot be altered externally. Another positive prognostic marker for glioblastoma patients is mutation of the IDH1 gene, which can be tested by DNA-based methods or by immunohistochemistry using an antibody against the most common mutation, namely IDH1-R132H.
More prognostic power can be obtained by combining the mutational status of IDH1 and the methylation status of MGMT into a two-gene predictor. Patients with both IDH1 mutations and MGMT methylation have the longest survival, patients with an IDH1 mutation or MGMT methylation an intermediate survival and patients without either genetic event have the shortest survival.
Long-term benefits have also been associated with those patients who receive surgery, radiotherapy, and temozolomide chemotherapy. However, much remains unknown about why some patients survive longer with glioblastoma. Age of under 50 is linked to longer survival in glioblastoma multiforme, as is 98%+ resection and use of temozolomide chemotherapy and better Karnofsky performance scores. A recent study confirms that younger age is associated with a much better prognosis, with a small fraction of patients under 40 years of age achieving a population-based cure. The population-based cure is thought to occur when a population's risk of death returns to that of the normal population, and in GBM, this is thought to occur after 10 years.
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. Despite a poor prognosis, there is a small number of survivors who have been GBM free for more than 10–20 years.
According to a 2003 study, glioblastoma multiforme prognosis can be divided into three subgroups dependent on KPS, the age of the patient, and treatment.
|Recursive partitioning analysis
|Definition||Historical Median Survival Time||Historical 1-Year Survival||Historical 3-Year Survival||Historical 5-Year Survival|
|III||Age < 50, KPS ≥ 90||17.1 months||70%||20%||14%|
|IV||Age < 50, KPS < 90||11.2 months||46%||7%||4%|
|Age > 50, KPS ≥ 70, surgical removal with good neurologic function|
|V + VI||Age ≥ 50, KPS ≥ 70, surgical removal with poor neurologic function||7.5 months||28%||1%||0%|
|Age ≥ 50, KPS ≥ 70, no surgical removal|
|Age ≥ 50, KPS < 70|
The term glioblastoma multiforme was introduced in 1926 by Percival Bailey and Harvey Cushing, based on the idea that the tumor originates from primitive precursors of glial cells (glioblasts), and the highly variable appearance due to the presence of necrosis, hemorrhage and cysts (multiform).
A 2014 investigation made a screening of various drugs for anti-glioblastoma activity and identified 22 drugs with potent anti-glioblastoma activity, including the combination of irinotecan and statins.
A Tumor Treating Fields device was approved by the U.S. Food and Drug Administration (FDA) in April 2011 on the basis of clinical trials that appeared to demonstrate efficacy in the treatment of recurring glioblastoma multiforme (GBM).
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Glioblastoma or glioblastoma multiforme (“multiforme” is no longer part of the WHO designation, though glioblastoma is still often abbreviated “GBM”) is the highest grade glioma (grade IV) tumor, is the most malignant form of astrocytoma, and is synonymous with a grade IV glioma.
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|Wikimedia Commons has media related to Glioblastoma multiforme.|
- Information about Glioblastoma Multiforme (GBM) from the American Brain Tumor Association
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