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Last updated: 8/5/2024
Years published: 2019, 2023
NORD gratefully acknowledges Etienne Leveille, MD, Yale School of Medicine and Jennie Taylor, MD, MPH, Associate Professor, Neurology and Neurological Surgery, University of California, San Francisco, for assistance in the preparation of this report.
Summary
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 occur at various ages depending on the subtype. 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, radiotherapy and chemotherapy.
Introduction
Classification of gliomas is based on the microscopic appearance of the tumor and the molecular characteristics such as gene changes (mutations) in the tumor. Tumors are often graded 1-4 based on severity, with 4 being the most aggressive. Information about specific tumor types is available from the National Brain Tumor Society.
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 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. Similarly, the survival rate greatly depends on the subtype of glioma.
In addition to being used for diagnosis and classification, the gene variants present in tumor cells are also used to predict disease course and survival (prognosis).
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.
Cells in gliomas have an altered glucose metabolism and can develop their own blood vessel network which allows them to sustain the high energy requirements for cell division and growth. Inflammation and accumulation of fluid around the tumor are also features of gliomas. Over time, certain types of gliomas can grow and invade healthy brain tissue extensively.
The diagnosis and classification of brain tumors called gliomas have evolved over time, especially in the way the World Health Organization (WHO) categorizes them.
Previously, gliomas were primarily diagnosed by comparing tumor cells to normal brain cells. The main subtypes included:
Gliomas have been further categorized based on cell appearance, how often the cells divide (mitotic activity) and certain molecular markers. These categories helped determine if a tumor is low-grade (less aggressive), atypical or high-grade (more aggressive).
The latest WHO classification, released in 2021, uses more detailed molecular testing to better understand and categorize gliomas.
The new WHO grading system relies more on these molecular markers to determine the prognosis and the best treatment options for patients. In the new classification, gliomas, along with related tumor types, are categorized into several groups:
Each of these categories can have different subtypes and are sometimes graded from 1 to 4, indicating their aggressiveness, with grade 1 being the least aggressive and grade 4 the most aggressive.
This classification helps doctors provide more precise diagnoses and determine the best treatment for individual patients based on the specific characteristics of their tumors.
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 gliomas 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 IDH (involved in cellular metabolism).
The exact underlying cause of glioma development in most individuals is unknown. The only established environmental risk factor associated with gliomas is exposure to ionizing radiation, such as in 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.
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 glioblastoma is the most common glioma in adults (56.6% of all gliomas) (for more information on these types of gliomas, 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.
Treatment
A large multi-disciplinary team of medical specialists and health professionals is required for the therapeutic management of patients with gliomas. Patients will usually come to the emergency room or be referred by their primary care physician for MRI. The MRI of the patientโs brain will then be interpreted by a radiologist or neuroradiologist and identify a mass. After an initial diagnosis is made, the patient will be considered for neurosurgery to safely remove as much of the tumor as possible (surgical resection. After surgery, a neuropathologist will examine and characterize the tumor under the microscope.
The age of the patient, clinical symptoms, imaging findings and pathology analysis help to determine the best treatment options and the prognosis for the patient. 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 radiotherapy 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). Neurologists and possibly other medical specialists might be required for prescriptions and follow-up of affected individuals.
In 2024, the U.S. Food and Drug Administration (FDA) approved tovorafenib (Ojemda) for patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma with a BRAF gene fusion or rearrangement or BRAF V600 gene variant.
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. Some patients may benefit from 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 patientโs 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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
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Boots-Sprenger SH, Sijben A, Rijntjes J, et al. Significance of complete 1p/19q co-deletion, IDH1 mutation and MGMT promoter methylation in gliomas: use with caution. Mod Pathol. 2013;26:922-9.
Lin ZX. Glioma-related edema: new insight into molecular mechanisms and their clinical implications. Chin J Cancer 2013;32:49-52.
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Wright BL, Lai JT, Sinclair AJ. Cerebrospinal fluid and lumbar puncture: a practical review. J Neurol 2012;259:1530-45.
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INTERNET
Chheda MG, Wen PY. Uncommon brain tumors, UpToDate. Last updated: Apr 24, 2023. https://www.uptodate.com/contents/uncommon-brain-tumors Accessed August 16, 2023.
Brook I. Brain Abscess Differential Diagnoses, Medscape. Last updated: March 2, 2021.
https://reference.medscape.com/article/212946-differential Accessed August 16, 2023.
Glioma. Genetic and Rare Diseases Information Center. Last updated: July 15, 2015.
https://rarediseases.info.nih.gov/diseases/6513/glioma Accessed August 16, 2023.
Glioma. American Brain Tumor Association. May 2018.
https://www.abta.org/tumor_types/glioma/ Accessed August 16, 2023.
Louis DN, Schiff D, Batchelor T Classification and pathologic diagnosis of gliomas, UpToDate. Last updated: Aug 19, 2022.
https://www.uptodate.com/contents/classification-and-pathologic-diagnosis-of-gliomas Accessed August 16, 2023.
Batchelor T, Louis DN, Molecular pathogenesis of diffuse gliomas. UpToDate. Last updated: Mar 16, 2023. https://www.uptodate.com/contents/molecular-pathogenesis-of-diffuse-gliomas Accessed August 16, 2023.
Tumor Types: Understanding Brain Tumors. National Brain Tumor Society. https://braintumor.org/brain-tumors/about-brain-tumors/brain-tumor-types/ Accessed August 16, 2023.
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