NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, and Jennie Taylor, MD, MPH, Assistant Professor, Neurology and Neurosurgery, University of California, San Francisco, for assistance in the preparation of this report.
A glioma is a tumor of the central nervous system that arises from glial stem or progenitor cells. Glial cells are a type of cell widely present in the nervous system. Gliomas mostly occur in the brain and, rarely, in the spinal cord. They develop in approximately 6.6 per 100,000 individuals each year. They occur at various ages, depending on the subtype. Developing gliomas can compress areas of the brain where they occur and cause various symptoms including headaches, nausea, vomiting, cognitive impairment, seizures, gait imbalance, language impairment (aphasia), numbness or weakness of one side of the body (hemiparesis), visual changes, and personality changes. The treatment of gliomas often requires a combination of neurosurgical interventions, radiation therapy, and chemotherapy.
Classification of gliomas is complex and based partly on the microscopic appearance of the tumor (histologic classification) and partly on the gene changes (mutations) that are implicated in tumor development. Differentiation is an important concept for the histologic classification of gliomas and refers to the “specialization” of the cell. For instance, some of the cells in the brain can show neuronal or glial differentiation, while embryonic stem cells are undifferentiated. The histologic classification of gliomas depends on the microscopic similarities of the tumor cells with different subtypes of glial cells (such as astrocytes and ependymal cells), the growth pattern and behavior of the tumor, and the degree of differentiation of cells within the tumor (grade).
Gliomas can have four different grades of differentiation. Grade 1 gliomas show the highest level of differentiation and are the least malignant, while grade 4 tumors are the least differentiated and most malignant. Loss of differentiation is known as anaplasia, hence the name of several grade 3 gliomas. Grade 1 and grade 2 gliomas are often referred to as low-grade gliomas, while grade 3 and 4 are referred to as malignant gliomas. Further classification is possible depending on the genetic alterations that occurred in the affected cells. The five types of glioma are discussed below.
Diffuse gliomas are by far the most common glial tumors in adults. They grow diffusively and invade functional tissue of the central nervous system (CNS parenchyma). They can be further divided depending on the type of glial cell they arise from: astrocytic tumors arise from astrocytes, a type of glial cell that is involved in neuron maintenance, in the repair process of brain and spinal cord tissue, and in the formation of the blood-brain barrier. Diffuse astrocytic tumors are further characterized by whether or not they have mutations in IDH1 or IDH2, which are genes involved in cellular metabolism. They can also have mutations in genes such as tumor protein 53 (TP53, a major tumor suppressor gene), and ATRX, a gene involved in the remodeling of chromatin, a DNA-RNA-protein complex. Glioblastoma (GBM) is the most common and malignant subtype of diffuse glioma (for more information on this specific glioma, choose “glioblastoma multiforme” as your search term in the Rare Disease Database). Diffuse midline glioma is another type of malignant astrocytic glioma (grade IV) and is associated with a mutation called H3-K27M. This mutation affects histones, which are part of a protein complex involved in DNA folding inside the cell.
Olidendendrogliomas arise from oligodendrocytes, which are responsible for the formation of the myelin sheath of neurons in the central nervous system. The myelin sheath insulates the axon, the “cable” by which the electrical current generated by a neuron is propagated. IHD1 and IDH2 mutations are also characteristic of diffuse oligodendroglial tumors. The deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), collectively known as 1p/19q co-deletion, is also a feature of these glial tumors. The telomerase reverse transcriptase (TERT) gene encodes an important subunit of telomerase. Telomeres are located at the end of chromosome and shorten with each cell division. Telomerase is a protein that is able to elongate telomeres. Mutations in the promoter region of TERT can be present in diffuse oligodendrogliomas and lead to overexpression of telomerase, which can lead to uncontrolled elongation of telomeres and an infinite replication potential in tumor cells.
Other astrocytic tumor
As it is the case for most other nondiffuse gliomas, other astrocytic tumors tend to grow slowly and are thought to be more encapsulated. They most commonly occur in children and young adults. Notable tumors in this category include pilocytic astrocytoma (grade I) and subependymal giant cell astrocytoma (SEGA). Pilocytic astrocytomas are the most common pediatric gliomas and are associated with numerous genetic abnormalities, the most common being a fusion between the KIAA1549 and BRAF genes. This lead to over-expression of BRAF, which in turns leads to unregulated cell growth. SEGAs are highly associated with a syndrome known as tuberous sclerosis and are therefore associated with mutations in the tuberous sclerosis complex genes 1 and 2 (TSC1 and TSC2, see “related disorders” section for additional information on this disorder).
Ependymal tumors arise from ependymal cells, which line a region of the brain known as the ventricular system, where cerebrospinal fluid (CSF) is created and circulates. The CSF has many functions, including nutrient transfer to and from brain and protection against shock injuries. The most common subtypes of ependymal tumors are low-grade (grade II) and anaplastic (grade III) ependymoma. Genetic abnormalities present depend on the subtype and location of the tumor. For instance, grade II and III ependymal tumors located above the cerebellum (supratentorial tumors) are associated with a gene fusion of RELA and C11orf95. This gene fusion leads to the activation of multiple other genes and drives ependymal tumor formation.
Glial tumors in this category can show features from other types of glioma, but show unique features that vary depending on the subtype. In most patiensts, they grow slowly and are well circumscribed.
Mixed neuronal-glial tumor
As their name indicates, mixed neuronal-glial tumors contain cells of glial and neuronal differentiation. Diagnosis of such tumors can be difficult, as they might be mistaken for diffuse gliomas surrounding neurons. Typically, mixed neuronal-glial tumors are well circumscribed and slowly-growing. They also show distinct molecular profiles. For instance, diffuse leptomeningeal glioneuronal tumors do not have IDH1 mutations, but commonly have BRAF mutations and deletions of the short arm of chromosome 1 (1p), with or without associated deletions of the long arm of chromosome 19 (19q).
The symptoms associated with gliomas are similar among all types, but can vary depending on the individual and the location of the tumor. Seizures (focal or generalized), language impairment (aphasia), weakness of part of the body (hemiparesis), sensory changes on part of the body, and headaches are common. Other possible symptoms include gait disturbances, fatigue, dizziness, visual changes, vomiting, and changes in urination. Psychological symptoms such as cognitive impairment, personality changes, depression, anxiety, and memory impairment can also occur. Most of the symptoms are a consequence of the compressive effect of the tumor and fluid that surrounds it (peritumoral edema) on the brain. Malignant gliomas (grade 3 and 4) are also associated with the development of blood clots in the deep veins, notably of the legs, (deep vein thrombosis) that can dislodge and migrate to occlude the arteries of the lungs (pulmonary embolism).
Gliomas can develop at any age. The average age at which they occur greatly varies depending on the subtype of glioma. For instance, half of pilocytic astrocytomas occur in children less than 12 years of age, while half of glioblastomas occur in individuals aged over 65. Similarly, the survival rate greatly depends on the subtype of glioma. Pilocytic astrocytomas have a 96.9% survival rate after 5 years in children under 14, while this rate is 4.3% for adults over 40 with a glioblastoma.
In addition to being used for diagnosis and classification, the gene mutations present in affected cells are also used to predict disease course and survival (prognosis). For example, mutations in the IDH1 gene are associated with a higher 5-year survival rate in GBM and other diffuse gliomas. Changes not affecting the genetic code directly, but rather how it is read and expressed (epigenetic modifications) also play a role in prognosis. An example of epigenetic change is in a DNA-repair gene named MGMT. When this gene is active, it can repair the damaged DNA of tumor cells, thus promoting their survival and making them more resistant to certain treatments. However, if this gene is silenced by specific chemical modifications (called CpG islands methylation), it is unable to repair DNA damage, therefore making it more susceptible to certain treatment. Epigenetic silencing of MGMT (via promoter methylation) is seen in about 40% of GBM and is associated with better survival and increased response to treatment.
Over time, gliomas can increase in grade and therefore become more malignant (malignant progression). The rate of malignant progression depends on the subtype of glioma and on the genetic characteristics of affected cells. Higher grade tumors are typically associated with lower survival rates.
Gliomas are caused by the accumulation of genetic mutations in glial stem or progenitor cells, leading to their uncontrolled growth. Mutated genes are typically involved in functions such as tumor suppression, DNA repair, and regulation of cell growth. Examples of mutated genes in certain types of glioma include TP53, PTEN (tumor suppressor genes), ATRX (involved in the remodeling of chromatin, a DNA-RNA-protein complex), TERT (encoding a subunit of telomerase, an enzyme that can lead to an infinite division potential in cells) BRAF (involved in cell growth), and IDH1 (involved in cellular metabolism).
The exact underlying cause of glioma development in the vast majority of individuals is unknown. The only established environmental risk factor associated with gliomas is exposure to ionizing radiation, such as atomic bomb survivors. Malignant gliomas can arise on their own (de novo), or can result from further accumulation of genetic mutations in low-grade gliomas (malignant progression). Cells from malignant gliomas have typically lost their specialized structure and function (de-differentiation or anaplasia). Initially, all cells in a glioma contain the same genetic code and are identical. Over time, different mutations accumulate in different cells of the tumor, thus leading to different subclones and a genetically heterogeneous tumor. Changes not affecting the genetic code directly, but rather how it is read and expressed (epigenetic modifications) are also involved in the growth and development of gliomas.
Cells in gliomas have an altered glucose metabolism (predominant use of aerobic glycolysis, known as the Warburg effect) and are able to develop their own blood vessel network (angiogenesis), which allow them to sustain the high energy requirements for cell division and growth. Inflammation and accumulation of fluid around the tumor (peritumoral edema) are also features of gliomas. Over time, certain types of gliomas can grow and invade healthy brain tissue extensively.
Excluding metastases from other cancers that reach the central nervous system, gliomas make up 26% of all brain tumors, (primary brain tumors) and 81% of all malignant brain tumors. They develop in approximately 6.6 per 100,000 individuals each year and 2.94 per 100,000 individuals under age 14. The median age (meaning that half of affected individuals are younger than this age and the other half are older) for the development of glioma is between 12 and 65 years, depending on the subtype. Pilocytic astrocytoma is the most common glioma in individuals under age 14 (34.4% of all gliomas) whereas GBM is the most common glioma in adults (56.6% of all gliomas) (for more information on these types of glioma, choose the specific glioma name as your search term in the Rare Disease Database).
Gliomas are slightly more common in males. They tend to affect older individuals and are more common in countries with a higher level of development, as these countries generally have a larger proportion of older individuals. There are also several syndromes associated with a higher risk of glioma.
A diagnosis of glioma requires an extensive patient history, as well as a complete physical and neurological examination. Signs that further investigation might be required include a new onset of seizures, abrupt onset of cognitive decline, and presence of other neurological symptoms. Headaches that develop or worsen abruptly, that begin to occur after age 50, that awaken the affected person from sleep even when they are mild, and that are associated with cognitive impairment are warning signs that could indicate a brain mass.
The presence of a brain tumor can be suspected with medical imaging. Magnetic resonance imaging (MRI) is the imaging modality of choice for initial evaluation of glioma. The final diagnosis, and therefore plan for treatment, can only be determined after a piece of tumor tissue is analyzed microscopically. Further characterization can be done by testing the DNA of the affected cells to determine if mutations in genes associated with certain subtypes of glioma are present.
The age of the patient, clinical symptoms, imaging findings and pathology analysis helps to determine the best treatment options and the prognosis for the patient.
A large multi-disciplinary team of medical specialists and health professionals is required for the therapeutic management of patients with gliomas. Patients will usually present to the emergency room or be referred by their primary care physician for magnetic resonance imaging. The MRI of the patient’s brain will then be interpreted by a radiologist or neuroradiologist and identify a mass. After an initial diagnosis is made, patient will be considered for neurosurgery to safely remove as much of the tumor as possible (surgical resection). 5-aminolevulinic acid (5-ALA) is a medication that can be administered during surgery that causes tumor cells, particularly malignant ones, to fluoresce, and improve extent of resection. After surgery, a neuropathologist will examine and characterize of the tumor under the microscope.
Therapeutic management depends on the type of glioma, its size and location, and the specific characteristics of the patient. Especially in patients where the tumor cannot be entirely removed because it is invading the brain in crucial areas or is not accessible, chemotherapy and radiation therapy will follow surgery. The collaboration of radiation oncologists and medical oncologists or neuro-oncologists will therefore be required. Examples of chemotherapy for glioma include temozolomide and lomustine. These two medications are part of a drug class known as alkylating agents. Their therapeutic effect is to damage DNA of tumor cells that leads to tumor cell death. Well circumscribed gliomas might be managed by surgical resection only. MRI will usually be performed at certain intervals to assess the progression of the tumor and the effects of treatment.
In addition to chemotherapy, medication prescribed to individuals with gliomas might include anti-epileptic medication (if the patient has seizures), anti-coagulation medication (if blood clots develop), and corticosteroids, to alleviate neurological symptoms caused by the accumulation of fluid around the tumor (peritumoral edema). Neurologists and possibly other medical specialists might be required for prescriptions and follow-up of affected individuals.
Patients might have to undergo rehabilitation after surgery to recover function affected by the tumor and surgery. Rehabilitation teams comprise many health professionals, including physiotherapists, occupational therapists, and nurses. Unfortunately, as some subtypes of gliomas are very aggressive, affected individuals might have to be admitted to palliative care, where they will receive optimal treatment to minimize their symptoms and pain, including analgesic medication, anti-epileptic medication, and medication to prevent vomiting (antiemetics).
The development of potential new treatments for gliomas is a very active field of medical research. Investigational therapies for gliomas include new ways to deliver anticancer drugs, innovations in chemotherapy and radiotherapy, utilization of factors to slow (inhibit) tumor growth or to destroy the tumor, stimulation of the patient’s own immune system to fight cancer cells (immunotherapy), and gene therapy.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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