The cellular origin of<unk>  is unknown. Because of the similarities in immunostaining of<unk> al cells and<unk> ,<unk> omas such as<unk>  have long been assumed to originate from<unk> al-type cells. More recent studies suggest that astrocytes, oligodendrocyte progenitor cells, and neural stem cells could all serve as the cell of origin.<unk> s are characterized by the presence of small areas of necrotizing tissue that are surrounded by anaplastic cells. This characteristic, as well as the presence of hyperplastic blood vessels, differentiates the tumor from grade 3 astrocytomas, which do not have these features.<unk> s usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. Fewer than 10% form more slowly following degeneration of low-grade astrocytoma or anaplastic astrocytoma. These are called secondary<unk> s and are more common in younger patients (mean age 45 versus 62 years). The tumor may extend into the meninges or ventricular wall, leading to high protein content in the cerebrospinal fluid (CSF) (> 100 mg/dl), as well as an occasional pleocytosis of 10 to 100 cells, mostly lymphocytes. Malignant cells carried in the CSF may spread (rarely) to the spinal cord or cause meningeal<unk> omatosis. However, metastasis of<unk>  beyond the central nervous system is extremely unusual. About 50% of<unk> s occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the cerebrum and may exhibit the classic infiltration across the corpus callosum, producing a butterfly (bilateral)<unk> oma.<unk>  classification Brain tumor classification has been traditionally based on histopathology at macroscopic level, measured in hematoxylin-eosin sections. The World Health Organization published the first standard classification in 1979 and has been doing so since. The 2007 WHO Classification of Tumors of the Central Nervous System was the last classification mainly based on microscopy features. The new 2016 WHO Classification of Tumors of the Central Nervous System was a paradigm shift: some of the tumors were defined also by their genetic composition as well as their cell morphology. The grading of<unk> omas changed importantly and<unk>  was now mainly classified according to the status of isocitrate dehydrogenase (IDH) mutation: IDH-wildtype or IDH-mutant. +Features of IDH-wildtype and mutant<unk>  IDH-wildtype<unk>  IDH-mutant<unk>  Synonym Primary<unk>  Secondary<unk>  Precursor lesion Identified de novo Diffuse astrocytoma Anaplastic astrocytoma Proportion of<unk> s ~90% ~10% Median age at diagnosis ~62 years ~44 years Male:Female ratio 1.42:1 1.05:1 Median length of clinical history at diagnosis 4 months 15 months Median overall survival Surgery + radiotherapy 9.9 months 24 months Surgery + radiotherapy + chemotherapy 15 months 31 months Location Supratentorial Preferentially frontal Necrosis Extensive Limited TERT promoter mutations 72% 26% TP53 mutations 27% 81% ATRX mutations Exceptional 71% EGFR amplification 35% Exceptional PTEN mutations 24% Exceptional Molecular alterations Four subtypes of<unk>  have been identified based on gene expression: * Classical: Around 97% of tumors in this subtype carry extra copies of the epidermal growth factor receptor (EGFR) gene, and most have higher than normal expression of EGFR, whereas the gene TP53 (p53), which is often mutated in<unk> , is rarely mutated in this subtype. Loss of heterozygosity in chromosome 10 is also frequently seen in the classical subtype alongside chromosome 7 amplification. * The proneural subtype often has high rates of alterations in TP53 (p53), and in PDGFRA, the gene encoding a-type platelet-derived growth factor receptor, and in IDH1, the gene encoding isocitrate dehydrogenase-1. * The mesenchymal subtype is characterized by high rates of mutations or other alterations in NF1, the gene encoding neurofibromin 1 and fewer alterations in the EGFR gene and less expression of EGFR than other types. * The neural subtype was typified by the expression of neuron markers such as NEFL, GABRA1, SYT1, and SLC12A5, while often presenting themselves as normal cells upon pathological assessment. Many other genetic alterations have been described in<unk> , and the majority of them are clustered in two pathways, the RB and the PI3K/AKT.<unk> s have alterations in 68–78% and 88% of these pathways, respectively. Another important alteration is methylation of MGMT, a "suicide" DNA repair enzyme. Methylation impairs DNA transcription and expression of the MGMT gene. Since the MGMT enzyme can repair only one DNA alkylation due to its suicide repair mechanism, reserve capacity is low and methylation of the MGMT gene promoter greatly affects DNA-repair capacity. MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide. Cancer stem cells<unk>  cells with properties similar to progenitor cells<unk>  cancer stem cells) have been found in<unk> s. Their presence, coupled with the<unk> 's diffuse nature results in difficulty in removing them completely by surgery, and is therefore believed to be the possible cause behind resistance to conventional treatments, and the high recurrence rate.<unk>  cancer stem cells share some resemblance with neural progenitor cells, both expressing the surface receptor CD133. CD44 can also be used as a cancer stem cell marker in a subset of<unk>  tumour cells.<unk>  cancer stem cells appear to exhibit enhanced resistance to radiotherapy and chemotherapy mediated, at least in part, by up-regulation of the DNA damage response. Metabolism The IDH1 gene encodes for the enzyme isocitrate dehydrogenase 1 and is uncommonly mutated in<unk>  (primary<unk> : 5%, secondary<unk>  >80%). By producing very high concentrations of the "oncometabolite" D-2-hydroxyglutarate and dysregulating the function of the wild-type IDH1 enzyme, it induces profound changes to the metabolism of IDH1-mutated<unk> , compared with IDH1 wild-type<unk>  or healthy astrocytes. Among others, it increases the<unk>  cells' dependence on glutamine or glutamate as an energy source. IDH1-mutated<unk> s are thought to have a very high demand for glutamate and use this amino acid and neurotransmitter as a chemotactic signal. Since healthy astrocytes excrete glutamate, IDH1-mutated<unk>  cells do not favor dense tumor structures, but instead migrate, invade, and disperse into healthy parts of the brain where glutamate concentrations are higher. This may explain the invasive behavior of these IDH1-mutated<unk> . Ion channels Furthermore,<unk>  exhibits numerous alterations in genes that encode for ion channels, including upregulation of<unk> K potassium channels and ClC-3 chloride channels. By upregulating these ion channels,<unk>  tumor cells are hypothesized to facilitate increased ion movement over the cell membrane, thereby increasing H2O movement through osmosis, which aids<unk>  cells in changing cellular volume very rapidly. This is helpful in their extremely aggressive invasive behavior because quick adaptations in cellular volume can facilitate movement through the sinuous extracellular matrix of the brain. MicroRNA As of 2012, RNA interference, usually microRNA, was under investigation in tissue culture, pathology specimens, and preclinical animal models of<unk> . Additionally, experimental observations suggest that microRNA-451 is a key regulator of LKB1/AMPK signaling in cultured<unk> oma cells and that miRNA clustering controls epigenetic pathways in the disease. Tumor vasculature<unk>  is characterized by abnormal vessels that present disrupted morphology and functionality. The high permeability and poor perfusion of the vasculature result in a disorganized blood flow within the tumor and can lead to increased hypoxia, which in turn facilitates cancer progression by promoting processes such as immunosuppression.
Glioblastoma
Ameloblastoma
Glioma
Medulloblastoma
Hemangioblastoma
Gliosarcoma
Astrocytoma
Gliosis