Glioma
A glioma is a type of malignant tumor originating in the glial cells of the brain or spinal cord. Gliomas comprise about 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. Common subtypes include astrocytoma, glioblastoma, oligodendroglioma, and ependymoma.
Signs and symptoms
The presentation of a glioma depends on the part of the central nervous system that the glioma affects.A brain glioma can cause headaches, vomiting, memory loss, seizures, vision problems, speech difficulties, and cranial nerve disorders. These symptoms arise as a result of increased intracranial pressure.
When the glioma is located in or around the optic nerve cognitive impairments such as vision loss can happen.
Spinal cord gliomas can cause pain, weakness, or numbness in the extremities of the body .
Gliomas do not usually metastasize through the bloodstream, but they can spread via the cerebrospinal fluid and cause "drop metastases" to the spinal cord. Complex visual hallucinations have been described as a symptom of low-grade glioma. Children with sub-acute CNS disorders that produce cranial nerve abnormalities, long-tract signs, unsteady gait secondary to spasticity, and behavioral changes are likely to have a pontine glioma, a tumor of the brainstem.
Causes
Hereditary disorders
The exact causes of gliomas are not known. Hereditary disorders such as neurofibromatosis and tuberous sclerosis complex are known to predispose individuals to developing gliomas. Different oncogenes can cooperate in the development of gliomas.Radiation
The best-known risk factor is exposure to ionizing radiation, including the radiation emitted by CT scans. The dose-response for the relationship between low-dose ionizing radiation and glioma risk is a risk increase of 55% per 100 milligray of radiation. A link between gliomas and electromagnetic radiation from cell phones has not been conclusively proven. It was considered possible, though several large studies have found no conclusive evidence, as summarized by the National Institute of Health's National Cancer Institute review of the topic and its numerous citations, and the FCC. However, further research is still being pursued to obtain more robust evidence and verify that there is no relationship.Infection with cytomegalovirus
Some studies have reported that glioblastomas are infected with cytomegalovirus, with suggestions that this may speed the development of tumors. However, this is a controversial opinion, with recent in-depth studies failing to find an association between viral infection and glioma growth. There is also evidence that previous studies may have been impacted by false-positive antibody staining artifacts.Farming
Studies have shown that farmers have higher rates of gliomas compared to the general population. In a 2021 meta-analysis, 40 of 52 studies since 1998 reported positive associations between farming and brain cancer, with effect estimates ranging from 1.03 to 6.53, of which 80% are gliomas. Livestock farming was associated with a greater risk compared with crop farming. Farmers with documented exposure to pesticides had greater than a 20% elevated risk of brain cancer. The TRACTOR project study, including 1,017 brain tumors among 1,036,069 farm managers, published in 2022, showed an increased risk of glioma in pig farming, crop farming and fruit arboricultureOther causes
Data show that architects, surveyors, retail workers, butchers, and engineers have higher rates of gliomas.Inherited polymorphisms of the DNA repair genes
Germ-line polymorphisms of the DNA repair genes ERCC1, ERCC2 and XRCC1 increase the risk of glioma. This indicates that altered or deficient repair of DNA damage contributes to the formation of gliomas. DNA damage is a likely major primary cause of progression to cancer in general. Excess DNA damages can give rise to mutations through translesion synthesis. Furthermore, incomplete DNA repair can give rise to epigenetic alterations or epimutations. Such mutations and epimutations may provide a cell with a proliferative advantage which can then, by a process of natural selection, lead to progression to cancer.Epigenetic repression of DNA repair genes is often found in progression to sporadic glioblastoma. For instance, methylation of the DNA repair gene MGMT promoter was observed in 51% to 66% of glioblastoma specimens. In addition, in some glioblastomas, the MGMT protein is deficient due to another type of epigenetic alteration. MGMT protein expression may also be reduced due to increased levels of a microRNA that inhibits the ability of the MGMT messenger RNA to produce the MGMT protein. Zhang et al. found, in the glioblastomas without methylated MGMT promoters, that the level of microRNA miR-181d is inversely correlated with protein expression of MGMT and that the direct target of miR-181d is the MGMT mRNA 3'UTR.
Epigenetic reductions in expression of another DNA repair protein, ERCC1, were found in an assortment of 32 gliomas. For 17 of the 32 of the gliomas tested, ERCC1 protein expression was reduced or absent. In the case of 12 gliomas this reduction was due to methylation of the ERCC1 promoter. For the other 5 gliomas with reduced ERCC1 protein expression, the reduction could have been due to epigenetic alterations in microRNAs that affect ERCC1 expression.
When expression of DNA repair genes is reduced, DNA damages accumulate in cells at a higher than normal level, and such excess damages cause increased frequencies of mutation. Mutations in gliomas frequently occur in either isocitrate dehydrogenase ''1 or 2'' genes. One of these mutations occurs in about 80% of low-grade gliomas and secondary high-grade gliomas. Wang et al. pointed out that IDH1 and IDH2 mutant cells produce an excess metabolic intermediate, 2-hydroxyglutarate, which binds to catalytic sites in key enzymes that are important in altering histone and DNA promoter methylation. Thus, mutations in IDH1 and IDH2 generate a "DNA CpG island methylator phenotype or CIMP" that causes promoter hypermethylation and concomitant silencing of tumor suppressor genes such as DNA repair genes MGMT and ERCC1. On the other hand, Cohen et al. and Molenaar et al. pointed out that mutations in IDH1 or IDH2 can cause increased oxidative stress. Increased oxidative damage to DNA could be mutagenic. This is supported by an increased number of DNA double-strand breaks in IDH1-mutated glioma cells. Thus, IDH1 or IDH2 mutations act as driver mutations in glioma carcinogenesis, though it is not clear by which role they are primarily acting. A study, involving 51 patients with brain gliomas who had two or more biopsies over time, showed that mutation in the IDH1 gene occurred prior to the occurrence of a p53 mutation or a 1p/19q loss of heterozygosity, indicating that an IDH1 mutation is an early driver mutation.
Pathophysiology
High-grade gliomas are highly vascular tumors and have a tendency to infiltrate diffusely. They have extensive areas of necrosis and hypoxia. Often, tumor growth causes a breakdown of the blood–brain barrier in the vicinity of the tumor. As a rule, high-grade gliomas almost always grow back even after complete surgical excision, so they are commonly called recurrent cancer of the brain.Conversely, low-grade gliomas grow slowly, often over many years, and can be followed without treatment unless they grow and cause symptoms.
Several acquired genetic mutations have been found in gliomas. Tumor suppressor protein 53 is mutated early in the disease. p53 is the "guardian of the genome", which, during DNA and cell duplication, makes sure the DNA is copied correctly and destroys the cell if the DNA is mutated and cannot be fixed. When p53 itself is mutated, other mutations can survive. Phosphatase and tensin homolog, another tumor suppressor gene, is itself lost or mutated. Epidermal growth factor receptor, a growth factor that normally stimulates cells to divide, is amplified and stimulates cells to divide too much. Together, these mutations lead to cells dividing uncontrollably, a hallmark of cancer. In 2009, mutations in IDH1 and IDH2 were found to be part of the mechanism and associated with a less favorable prognosis.
Diagnosis
Classification
By type of cell
Gliomas are named according to the specific type of cell with which they share histological features, but not necessarily from which they originate. The main types of glioma are:- Ependymomas: ependymal cells
- Astrocytomas: astrocytes.
- Oligodendrogliomas: oligodendrocytes
- Brainstem glioma: develop in the brain stem
- Optic nerve glioma: develop in or around the optic nerve
- Chordoid glioma, a rare low-grade tumor of the third ventricle
- Mixed gliomas, such as oligoastrocytomas, contain cells from different types of glia
By grade
Image:MRI glioma 28 yr old male.JPG|thumb|right|Low-grade brain glioma in a 28-year-old male
- Biologically benign gliomas are comparatively low risk and can be removed surgically depending on their location
- Low-grade gliomas are well-differentiated ; these tend to exhibit benign tendencies and portend a better prognosis for the patient. However, they have a uniform rate of recurrence and increase in grade over time so should be classified as malignant.
- High-grade gliomas are undifferentiated or anaplastic; these are malignant and carry a worse prognosis. Despite being classified as a high-grade glioma, infant-type hemispheric gliomas have relatively good clinical outcomes, yet they endure significant deficits, making them good candidates for therapy de-escalation and trials of molecular targeted therapy.