Diffuse Gliomas in Adults
Key Takeaways
Diffuse gliomas are tumors that arise within the brain.
Headaches and seizures are common symptoms.
Most gliomas occur in people without risk factors.
Neurological examination, imaging, and tissue sampling are the mainstays of glioma diagnosis.
Surgical resection, radiation therapy, and chemotherapy are the primary treatment options.
What is diffuse glioma, and how is it categorized?
Diffuse glioma is a brain tumor that develops from an abnormal glial cell. Glial cells and neurons (nerve cells) make up brain tissue. While neurons process and relay information, glial cells provide insulation, maintain homeostasis, assist in immune defense, and help neurons communicate with one another.
In 2021, the World Health Organization changed the way gliomas are categorized in response to evolving knowledge in the field. The four general categories are:
Adult-type diffuse gliomas
Pediatric-type diffuse low-grade gliomas
Pediatric-type diffuse high-grade gliomas
Circumscribed astrocytic gliomas
This article is about adult-type diffuse gliomas, which include three subtypes:
Astrocytoma
Oligodendroglioma
Glioblastoma
Each subtype has a unique prognosis (disease course) and treatment. Diagnosis is based on:
Histology: the appearance of the tissues and cells under the microscope
Molecular analysis: laboratory tests that look for certain genes, proteins, and other molecules, called molecular markers, present in the tumor tissue
Histology
Pathologists study the tumor tissue under the microscope and determine the type of glial cell from which the tumor has potentially originated. In diffuse gliomas, the cells typically resemble:
Astrocytes: Star-shaped glial cells that help maintain the appropriate chemical environment for neuron signaling.
Oligodendrocytes: Glial cells that produce myelin, a special coating for neurons that increases the speed at which neurons send signals.
Tumors are also assigned a grade. Grading is a way to predict how the cancer would behave without treatment. Tumor grades range from 1 to 4, with malignancy (aggressiveness) increasing with higher grades. Some tumor malignancy signs as seen under the microscope are:
Irregular cellular appearance
Cells actively multiplying
Formation of new blood vessels
Necrosis (dead tissue)
Molecular Analysis
In molecular analysis, tumor tissue is evaluated for molecular markers. Some molecular markers are genetic mutations, while others suggest a particular gene has been turned off. Examples of relevant molecular markers in glioma are:
Isocitrate dehydrogenase (IDH) mutation
Codeletion (loss) of chromosomal arms 1p and 19q
Methylation of the MGMT gene promoter
The presence of these molecular markers in the glioma tumor is associated with an improved prognosis. Testing for molecular markers helps to define the glioma subtype and grade and allows physicians to individualize the treatment plan.
Glioma Subtypes
Astrocytomas are diffuse gliomas of astrocyte origin that have the IDH mutation. They account for 10% to 15% of all gliomas and tend to occur in younger adults in their thirties and forties.
Astrocytomas infiltrate the healthy brain tissue and generally cannot be cured with surgery. They are assigned grades 2, 3, or 4. Although those with a lower grade grow slowly, most eventually advance to a higher grade.
Oligodendrogliomas are diffuse gliomas of oligodendrocyte origin characterized by both IDH mutations and loss of chromosome 1p and 19q. They comprise about 10% of diffuse glioma diagnoses.
Grade 2 oligodendrogliomas grow slowly, while grade 3 tumors grow more rapidly and can spread within the brain and spinal cord.
Oligodendrogliomas respond better to radiation therapy and chemotherapy than astrocytomas or glioblastomas.
Glioblastoma is the most common malignant primary (non-metastatic) brain cancer in adults. It is a fast-growing and aggressive glioma of astrocyte origin. It does not possess the favorable IDH mutation that slows growth.
Glioblastoma can occur in the brain or spinal cord, infiltrating nearby healthy tissue and destroying it. It is always considered grade 4 but generally does not spread to distant organs.
Glioblastoma tumors that test positive for methylation of the MGMT gene promoter respond better to chemotherapy and are associated with prolonged patient survival.
What are the symptoms of glioma?
Diffuse glioma grows within the normal brain tissue. Symptoms depend on:
Tumor location
Tumor size
Presence of swelling around the tumor
Degree of injury to nearby brain tissue
Presence of increased intracranial pressure (pressure within the skull)
Glioma symptoms may be generalized or specific to the location of the tumor. They can be subtle. Some common symptoms include:
Headaches
Vomiting
Seizures
Memory problems
Blurred vision
Mood disturbances
Personality changes
Fatigue
Headaches caused by brain tumors are often associated with nausea and vomiting, are worse in the morning, and tend to increase in intensity over time. They may wake a person up at night and get worse with coughing, straining, or bending over.
Other symptoms may be specific to the glioma’s location within the brain, such as vision loss or difficulty with hand coordination.
What are the risk factors for glioma?
Most gliomas develop in people without known risk factors, but some patients will have a history of radiation exposure or genetic susceptibility.
Exposure to Ionizing Radiation
People who have had ionizing radiation therapy to treat cancer have an increased risk of developing glioma, especially those who received radiation treatment to their head and neck during childhood.
Other forms of radiation, such as those from power lines, cellular phones, and microwave ovens, have not been shown to increase the risk of glioma.
Family History
Glioma rarely runs in families, but some diagnosed cases have a genetic component. This is an area of active research.
Some rare hereditary cancer syndromes, like Li-Fraumeni syndrome and neurofibromatosis, cause the growth of multiple tumors, including glioma.
How is glioma diagnosed?
Since the symptoms caused by glioma can be present with other illnesses, a careful evaluation is necessary to make a diagnosis.
Neurological Examination
A thorough evaluation of the nervous system includes assessment of:
Mental status: attentiveness, memory, speech, and reasoning
Cranial nerves: nerves in the head and neck responsible for such things as vision, hearing, taste, and facial expressions
Muscle strength and grip
Sense of touch, vibration, and temperature
Balance and coordination
Reflexes
Imaging
If a brain tumor is suspected, a brain scan will be done. Magnetic resonance imaging (MRI) with contrast is the optimal study for this purpose.
Other imaging tests may be used to evaluate the tumor or help plan treatment, including computed tomography (CT), positron emission tomography (PET), functional MRI, perfusion MRI, and magnetic resonance spectroscopy.
When the history, neurological examination, and images are consistent with glioma, the next step is to biopsy the tumor.
Biopsy
A tissue sample is required to establish the diagnosis and accurately classify the glioma. Tissue can be obtained during open surgery or by stereotactic biopsy. Both procedures are performed in the operating room, usually under general anesthesia.
Procedure selection is individualized to the patient and what is known about the tumor. In stereotactic biopsy, the surgeon drills a small hole in the skull, and a needle is inserted into the precise area of the tumor under CT or MRI guidance. Tissue is removed through the needle.
A pathologist analyzes the tissue under a microscope to provide a preliminary diagnosis. Special tissue staining techniques and molecular analysis take a few more days and contribute to the final diagnosis.
What treatments are available for glioma?
A cure has not yet been identified for diffuse glioma. Surgical resection, radiation therapy, and chemotherapy are the primary treatment options.
Surgical Resection
Surgical resection is the removal of part, or all, of a tumor. Diffuse glioma tumors grow into the surrounding brain tissue. A distinct boundary between the tumor and the healthy brain does not exist. Because the tumor cells and normal brain cells are intertwined, the benefit of removing tumor tissue must be balanced with the risk of removing healthy brain tissue.
Surgical resection is beneficial because it:
Reduces the amount of tumor tissue within the brain
Improves the response to radiation and chemotherapy
Relieves symptoms
Lowers intracranial pressure
Surgical resection of a glioma aims to remove as much tumor as possible while preserving brain function. Special intraoperative techniques help achieve this goal, including intraoperative MRI and fluorescent dyes to highlight the tumor.
Unfortunately, some tumor cells inevitably remain following surgical resection. These continue to grow and eventually lead to a recurrence of the tumor. Although not curative, surgical resection may prolong survival and improve the quality of remaining life.
Surgical intervention may not be recommended for some people with glioma. If the tumor is in a critical area of the brain, the risk of damage may outweigh the benefit of tumor resection.
Radiation Therapy
Radiation therapy (RT) uses high doses of radiation to kill tumor cells. RT is frequently used to kill remaining tumor cells two to four weeks following surgery. It can also be used when surgical resection is unsafe or to relieve symptoms later in the disease course.
RT kills tumor cells by damaging DNA, the genetic material inside the cell. RT also damages normal brain cells, but they usually recover. The amount of radiation delivered to normal cells is minimized by carefully selecting the radiation field (area to receive the radiation), the total radiation dose, the timing of treatment, and the delivery method.
In external beam radiation therapy (EBRT), radiation directed at the tumor is delivered from outside the body using a special machine. Radiation oncologists use CT and MRI scans and sophisticated software to develop a treatment plan and target the glioma. Treatment is usually delivered in a series of treatments called fractions over several weeks.
Stereotactic radiosurgery is another form of RT suitable for small tumors. This technique is not surgical, despite its name, but delivers radiation to the tumor from outside the body. It uses many small beams of radiation directed at a point within the tumor. Treatment usually takes place in a single session.
Proton therapy is a radiation technique that uses protons instead of traditional x-rays. Proton therapy may be used in critical brain areas where damage to nearby tissues would not be tolerated.
Short-term side effects of RT usually occur within six weeks of treatment and include fatigue, hair loss, rash, and decreased appetite. Headaches, nausea, and a worsening of neurologic symptoms, such as seizures or weakness, may also occur.
Months later, some people complain of mild memory loss, confusion, a decreased ability to perform complex tasks, and poor concentration. These cognitive (thinking) impairments may be caused by the RT, the chemotherapy, or the glioma itself.
Other long-term side effects are cataracts, and rarely, hearing loss, hormonal changes, new tumors, and radiation necrosis (dead tissue formed at the site of radiation).
RT is not curative but helps contain tumor growth and prolongs survival compared with surgery or chemotherapy alone.
Chemotherapy
Glioma tumors are often treated with the chemotherapy drugs: temozolomide or PCV (procarbazine, lomustine, vincristine). The drugs are taken orally (as a pill) or intravenously (through a vein).
Chemotherapy targets cells that are multiplying. Because cancer cells form new cells faster than most normal cells, these drugs cause greater harm to cancer cells.
Some normal cells in the body continue to multiply throughout life, such as hair follicles, cells that line the gastrointestinal tract, and blood cells. These cells are sensitive to the effects of chemotherapy, and their injury may result in:
An increased risk of infection
Bruising and bleeding
Shortness of breath and fatigue
Nausea and vomiting, constipation, and abdominal pain
Hair loss
Chemotherapy is often started at the same time as RT. Sometimes it is used as the primary treatment when the glioma cannot be surgically resected.
Symptom Management
Treatment also includes managing symptoms caused by the glioma.
People who experience seizures are treated with an antiseizure drug, typically levetiracetam. Tumor-induced seizures can be challenging to treat, and surgical resection may be recommended to reduce seizure activity.
Steroids can improve headaches and other neurologic symptoms caused by swelling. Dexamethasone is frequently prescribed for this purpose but is associated with significant side effects and may shorten survival.
Bevacizumab (Avastin) is another drug that is used to reduce swelling. It works by stopping new blood vessel growth and decreasing blood flow to the tumor.
Palliative medicine is a medical specialty focused on relieving the symptoms that people with serious illnesses endure. The goal of palliative therapy is to reduce the suffering caused by cancer and ensure the quality of life is maximized during cancer treatment. Palliative therapy may be given with other treatments from diagnosis until the end of life.
Treatment Innovations and Clinical Trials
Treatment for glioma is an area of active research. Some treatment innovations are:
Convention-enhanced delivery: Chemotherapy is slowly and continuously delivered to the tumor via a pump.
Implanted chemotherapy wafer therapy (Gliadel): Chemotherapy is released directly into the remaining tumor from a disc placed during surgery.
Nanoparticle therapy: Special particles improve the ability of chemotherapy drugs to move into brain tissue and reach the tumor.
Patients may also be eligible to participate in clinical trials to access new treatments under investigation.
