Glioma: what is it, causes, symptoms, treatment, prognosis

What is glioma?

Glioma Is a tumor of the central nervous system that arises from glial stem cells or progenitor cells. Glial cells are a type of cell that is abundant in the nervous system. Gliomas are found primarily in the brain and, rarely, in the spinal cord. Tumors develop in about 6.6 cases per 100,000 people per year. They occur at different ages, depending on the subtype.

Developing gliomas can compress the areas of the brain where they occur and cause a variety of symptoms, including headaches, nausea, vomiting, cognitive impairment, seizures, gait imbalance, tongue disorder (aphasia), numbness or weakness on one side of the body (hemiparesis), vision changes, and personality.

Treatment for gliomas often requires a combination of neurosurgery, radiation therapy, and chemotherapy.

Classification

The classification of gliomas is complex and is based partly on the microscopic appearance of the tumor (histological classification) and partly on gene changes (mutations) that are associated with tumor development. Differentiation is an important concept in the histological classification of gliomas and refers to the "specialization" of the cell. For example, some brain cells may show neuronal or glial differentiation, while embryonic stem cells do not differentiate. Histological classification of gliomas depends on the microscopic similarity of tumor cells with different subtypes of glial cells (such as astrocytes and ependymal cells), the growth and behavior of the tumor, and the degree of cell differentiation in the tumor (degree).

Gliomas can have four different degrees 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. The loss of differentiation is known as anaplasia, hence the name for several grade 3 gliomas. Grade 1 and 2 gliomas are often referred to as low-grade gliomas, and grade 3 and 4 gliomas are often referred to as malignant gliomas. Further classification is possible depending on the genetic changes that have occurred in the affected cells. The 5 types of gliomas are discussed below.

- Diffuse gliomas.

Diffuse gliomas are by far the most common glial tumors in adults. They grow diffusely and penetrate the functional tissues of the central nervous system (CNS parenchyma). They can be further subdivided according to the type of glial cell from which they arise: astrocytic tumors arise from astrocytes, a type of glial cell that is involved in the maintenance of neurons, in the process of tissue repair in the brain and spinal cord, and in the formation of the blood-brain barrier. Diffuse astrocytic tumors additionally characterized by whether 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, the main tumor suppressor gene) and the gene ATRXinvolved in the remodeling of chromatin, a complex of DNA-RNA-protein. Glioblastoma is the most common and malignant subtype of diffuse glioma. Diffuse midline glioma Is another type of malignant astrocytic glioma (grade IV) associated with the H3-K27M mutation. This mutation affects histones, which are part of a protein complex involved in DNA folding within the cell.

Olidendrogliomas 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" through which the electrical current generated by the neuron travels. IHD1 mutations and IDH2 also characteristic of diffuse oligodendroglial tumors. Removal of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), known as joint removal of 1p / 19q, is also a feature of these glial tumors. Telomerase reverse transcriptase (TERT) gene encodes an important subunit of telomerase. Telomeres are located at the end of the chromosome and shorten with each cell division. Telomerase is a protein that can lengthen telomeres. Mutations in the promoter region TERT may be present in diffuse oligodendrogliomas and lead to overexpression of telomerase, which can lead to uncontrolled lengthening of telomeres and infinite replication potential in tumor cells.

- Other astrocytic tumors.

As with most other nondiffuse gliomas, other astrocytic tumors tend to grow slowly and are considered more encapsulated. They are most commonly seen in children and young adults. Known tumors in this category include pilocytic astrocytoma (grade I) and subependymal giant cell astrocytoma. Pilocytic astrocytomas are the most common childhood gliomas and are associated with numerous genetic abnormalities, the most common of which is gene fusion KIAA1549 and BRAF. This leads to gene overexpression BRAFwhich, in turn, leads to unregulated cell growth. Subependymal giant cell astrocytomas are closely related to a syndrome known as tuberous sclerosis, and, therefore, are associated with mutations in the genes of the complex of tuberous sclerosis types 1 and 2 (TSC1 and TSC2).

— Ependymaltumors.

Ependymal tumors arise from ependymal cells that line an area of ​​the brain known as the ventricular system, where cerebrospinal fluid (CSF) is created and circulated. CSF has many functions, including transferring nutrients to and from the brain and protecting against shock injury. The most common subtypes of ependymal tumors are low-grade ependymoma (grade II) and anaplastic ependymoma (grade III). The genetic abnormalities present depend on the subtype and location of the tumor. For example, grade II and III ependymal tumors located above the cerebellum (supratentorial tumors) are associated with gene fusion RELA and C11orf95. This gene fusion leads to the activation of many other genes and contributes to the formation of ependymal tumors.

- Other gliomas.

Glial tumors in this category may show signs of other types of gliomas, but with their own unique characteristics that vary by subtype. In most patients, they grow slowly and well-defined.

- Mixed neuronal-glial tumors.

As their name suggests, mixed neuronal-glial tumors contain cells of glial and neuronal differentiation. Diagnosis of these tumors can be challenging as they can be mistaken for diffuse gliomas that surround neurons. As a rule, mixed neuronal-glial tumors are well-defined and slow growing. They also show clear molecular profiles. For example, diffuse leptomeningeal glioneuronal tumors do not have mutations IDH1but usually have mutations BRAF and deletions of the short arm of chromosome 1 (1p) with or without associated deletions of the long arm of chromosome 19 (19q).

Signs and symptoms

Symptoms associated with gliomas are the same for all types, but can vary depending on the patient and the location of the tumor. Epileptic seizures (focal or generalized), tongue disorder (aphasia), weakness of a body part (hemiparesis), sensory changes in a body part, and headaches are common signs of the disease. Other possible symptoms include:

• gait disturbances;
• fatigue;
• dizziness;
• visual changes;
• vomiting;
• changes in urination.

Psychological symptoms may also occur, such as:

• cognitive impairment;
• personality changes;
• depression;
• anxiety;
• memory impairment.

Most of the symptoms are due to the compressive action of the tumor and the surrounding fluid (peritumoral edema) on the brain. Malignant gliomas (grades 3 and 4) are also associated with the development of blood clots in the deep veins, especially in the legs (deep vein thrombosis of the lower extremities), which can shift and migrate, blocking the arteries of the lungs (pulmonary thromboembolism).

Gliomas can develop at any age. The average age at which they occur varies greatly depending on the subtype of glioma. For example, half of pilocytic astrocytomas occur in children under the age of 12, and half of glioblastomas occur in people over 65. The same way, survival highly dependent on the subtype of glioma. Pilocytic astrocytoma has a survival rate of 96.9% after 5 years in children under 14 years old, while in adults over 40 years old with glioblastoma, this figure is 4.3%.

Forecast

In addition to being used for diagnosis and classification, gene mutations present in affected cells are also used to predict course and survival of the disease (prognosis). For example, mutations in the gene IDH1 associated with a higher 5-year survival rate for glioblastoma and other diffuse gliomas. Changes that do not directly affect the genetic code, but rather the way it is read and expressed (epigenetic modifications), also play a role in prognosis. An example of an epigenetic change is a DNA repair gene called MGMT. When this gene is active, it can repair the damaged DNA of tumor cells, thereby promoting their survival and making them more resistant to certain treatments. However, if this gene is silenced by specific chemical modifications (called islet methylation CpG), it is unable to repair DNA damage, making it more susceptible to certain treatment. Epigenetic silence MGMT (via promoter methylation) is observed in about 40% of patients with glioblastoma and is associated with better survival and increased response to treatment.

Over time, gliomas can increase in degree and therefore become more malignant (malignant progression). The rate of malignant progression depends on the subtype of glioma and on the genetic characteristics of the affected cells. Higher levels of tumors are usually associated with lower survival rates.

Causes and risk factors

Gliomas are caused by the accumulation of genetic mutations in glial stem or progenitor cells, causing them to grow out of control. Mutated genes are commonly 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, DNA-RNA-protein complex), TERT (encoding a subunit of telomerase, an enzyme that can lead to infinite fission 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 people is unknown. The only identified risk factor for the environment, associated with gliomas is exposure to ionizing radiation. Malignant gliomas can occur on their own (mutation de novo), or may result from further accumulation of genetic mutations in low-grade gliomas (malignant progression). Malignant glioma cells usually lose their specialized structure and function (dedifferentiation or anaplasia). Initially, all cells in a glioma contain the same genetic code and are identical. Over time, different mutations accumulate in different tumor cells, resulting in different subclones and a genetically heterogeneous tumor. Changes that do not directly affect the genetic code, but rather how it is read and expressed (epigenetic modifications), are also involved in the growth and development of gliomas.

Cells in gliomas have altered glucose metabolism (the predominant use of aerobic glycolysis, known as the Warburg effect) and are capable of develop their own network of blood vessels (angiogenesis), which allows them to maintain high energy requirements for division and growth cells. Inflammation and accumulation of fluid around the tumor (peritumoral edema) are also signs of glioma. Over time, certain types of gliomas can grow and invade healthy brain tissue.

Affected populations

Excluding metastases from other cancers that affect the central nervous system, gliomas account for 26% of all brain tumors (primary brain tumors) and 81% of all malignant brain tumors. They develop in about 6.6 per 100,000 people per year and 2.94 per 100,000 people under the age of 14. The average age (i.e., half of the affected individuals are younger than this age and the other half are older) for the development of glioma is 12 to 65 years, depending on the subtype. Pilocytic astrocytoma is the most common glioma in people under the age of 14 (34.4% of all gliomas), while glioblastoma is the most common adult glioma (56.6% of all gliomas).

Gliomas are slightly more common in men. They tend to affect older people and are more common in countries with higher levels of development, as these countries tend to have a higher proportion of older people. There are also several syndromes associated with a higher risk of developing glioma.

Diagnostics

Diagnosing glioma requires an extensive history of the patient, as well as a complete physical and neurological examination. Signs that further investigation may be needed include new seizures, severe cognitive decline, and other neurological symptoms. Headaches that suddenly appear or worsen, which begin to occur after 50 years, awakening the patient from sleep even in mild, and which are associated with impaired cognitive functions, are warning signs indicating the presence of a tumor in brain.

The presence of a brain tumor can be suspected using medical imaging. Magnetic resonance imaging (MRI) is the preferred imaging technique for the initial assessment of glioma. The final diagnosis and, therefore, the treatment plan can only be determined after microscopic analysis of a piece of tumor tissue. Further evaluation can be done by testing the DNA of affected cells to determine the presence of mutations in genes associated with certain subtypes of glioma.

Patient age, clinical symptoms, imaging findings, and pathology analysis help determine the best treatment options and prognosis for the patient.

Standard treatments

The therapeutic management of patients with gliomas requires a large multidisciplinary team of medical professionals and healthcare professionals. Patients usually go to the emergency department or are referred by the treating physician for magnetic resonance imaging. An MRI of the patient's brain will then be interpreted by a radiologist or neuroradiologist. 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). 5-aminolevulinic acid (5-ALA) is a drug that can be prescribed during surgery, in as a result of which tumor cells, especially malignant ones, fluoresce and improve the degree of resection. After surgery, a neurologist will examine and characterize the tumor under a microscope.

Therapeutic management depends on the type of glioma, its size and location, and the specific characteristics of the patient. Especially in patients in whom the tumor cannot be completely removed because it invades the brain in critical areas or is inaccessible, the operation will be followed by chemotherapy and radiation therapy. Therefore, the collaboration of radiation oncologists and medical oncologists or neuro-oncologists will be required. Examples of chemotherapy for glioma include temozolomide and lomustine. These two drugs are part of a class of drugs known as alkylating agents. Their therapeutic effect is to damage the DNA of tumor cells, which leads to the death of tumor cells. Well-circumscribed gliomas can only be treated with surgical resection.

In addition to chemotherapy, medications given to people with gliomas may include antiepileptic drugs (if the patient has epilepsy), anticoagulants (if blood clots develop), and corticosteroids to relieve neurologic symptoms caused by fluid buildup around the tumor (peritumoral edema). Neurologists and possibly other medical professionals may be required to write prescriptions and follow up on affected individuals.

Patients may need to undergo rehabilitation after surgery in order to regain the functions affected by the tumor and the surgery. Rehabilitation teams include many healthcare professionals, including physiotherapists, occupational therapists and nurses. Unfortunately, because some subtypes of gliomas are very aggressive, patients suffering from them may be forced to undergo palliative therapy, where they will receive optimal treatment to minimize symptoms and pain, including pain relievers, antiepileptic drugs, and antiemetics funds.