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 (cancer of astrocytes), glioblastoma (an aggressive form of astrocytoma), oligodendroglioma (cancer of oligodendrocytes), and ependymoma (cancer of ependymal cells).
Signs and symptoms The presentation of a glioma depends on the part of the central nervous system (CNS) 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 (arms, legs, hands, feet).
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 (especially of cranial nerve VII and the lower bulbar nerves), long-tract signs, unsteady gait secondary to spasticity, and behavioral changes are likely to have a pontine glioma, a tumor of the brainstem.PRETEST pediatrics p. 224
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.Smoll NR, Brady Z, Scurrah K, Mathews JD. Exposure to ionizing radiation and brain cancer incidence: The Life Span Study cohort. Cancer Epidemiology. 2016 Jun;42:60–5. 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 (the NIH's National Institute of Environmental Health Sciences most recent press release discussed an ongoing study showing mildly positive results, although it appears there may have been issues with the control group dying prematurely).
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 to crop farming. Farmers with documented exposure to pesticides had a more than 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 (HR = 2.28), crop farming (HR = 1.28) and fruit arboriculture (HR = 1.72).
Other 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 (inherited) polymorphisms of the DNA repair genes ERCC1, ERCC2 (XPD) 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 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 (the three prime untranslated region of MGMT messenger RNA).
Epigenetic reductions in expression of another DNA repair protein, ERCC1, were found in an assortment of 32 gliomas. For 17 of the 32 (53%) of the gliomas tested, ERCC1 protein expression was reduced or absent. In the case of 12 gliomas (37.5%) 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 (IDH) 1 or 2 genes. One of these mutations (mostly in IDH1) 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 often grow slowly, and the management of these cases typically involves early-removal or debulking of the tumor followed by monitoring; although it is often possible to safely manage low-grade gliomas with 'watch-and-wait' surveillance alone, particularly in younger patients, most literature supports early removal, with or without chemotherapy and/or radiotherapy, to reduce the risk of progression to a higher-grade glioma.
Several acquired (not inherited) genetic mutations have been found in gliomas. Tumor suppressor protein 53 (p53) 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 (apoptosis) if the DNA is mutated and cannot be fixed. When p53 itself is mutated, other mutations can survive. Phosphatase and tensin homolog (PTEN), 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 excessively. 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 (glioblastoma multiforme is a malignant astrocytoma and the most common primary brain tumor among adults). 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 Gliomas are further categorised according to their grade, which is determined by pathologic evaluation of the tumor. The neuropathological evaluation and diagnostics of brain tumor specimens is performed according to WHO Classification of tumors of the Central Nervous System.
Biologically benign gliomas [WHO grade I] are comparatively low risk and can be removed surgically depending on their location Low-grade gliomas [WHO grade II] are well-differentiated (not anaplastic); 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 [WHO grades III–IV] 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.Neuro-Oncology, Volume 25, Issue Supplement_1, June 2023, Pages i38–i39, https://doi.org/10.1093/neuonc/noad073.152
Of numerous grading systems in use, the most common is the World Health Organization (WHO) grading system for astrocytoma, under which tumors are graded from I (least advanced disease—best prognosis) to IV (most advanced disease—worst prognosis).
By location Gliomas can be classified according to whether they are above or below a membrane in the brain called the tentorium. The tentorium separates the cerebrum (above) from the cerebellum (below). The supratentorial is above the tentorium, in the cerebrum, and mostly found in adults (70%). The infratentorial is below the tentorium, in the cerebellum, and mostly found in children (70%).