glioblastoma glioblastoma glioblastoma, previously known as glioblastoma multiforme (gbm), is the most aggressive and most common type of cancer that originates in the brain, and has very poor prognosis for survival. initial signs and symptoms of glioblastoma are nonspecific. they may include headaches, personality changes, nausea, and symptoms similar to those of a stroke. symptoms often worsen rapidly and may progress to unconsciousness. glioblastomaother namesglioblastoma multiformecoronal mri with contrast of a glioblastoma in a 15-year-old malespecialtyneuro-oncology, neurosurgerysymptomsinitially nonspecific, headaches, personality changes, nausea, symptoms similar to a strokeusual onset~ 64 years oldcausesusually unclearrisk factorsgenetic disorders (neurofibromatosis, li–fraumeni syndrome), previous radiation therapydiagnostic methodct scan, mri scan, tissue biopsypreventionunknowntreatmentsurgery, chemotherapy, radiationmedicationtemozolomide, steroidsprognosislife expectancy ~ 12 months with treatment (5 year survival <10%)frequency3 per 100,000 per year the cause of most cases of glioblastoma is not known. uncommon risk factors include genetic disorders, such as neurofibromatosis and li–fraumeni syndrome, and previous radiation therapy. glioblastomas represent 15% of all brain tumors. they are thought to arise from astrocytes. the diagnosis typically is made by a combination of a ct scan, mri scan, and tissue biopsy. there is no known method of preventing the cancer. treatment usually involves surgery, after which chemotherapy and radiation therapy are used. the medication temozolomide is frequently used as part of chemotherapy. high-dose steroids may be used to help reduce swelling and decrease symptoms. surgical removal (decompression) of the tumor is linked to increased survival, but only by some months. despite maximum treatment, the cancer almost always recurs. the typical duration of survival following diagnosis is 10–13 months, with fewer than 5–10% of people surviving longer than five years. without treatment, survival is typically three months. it is the most common cancer that begins within the brain and the second-most common brain tumor, after meningioma. about 3 in 100,000 people develop the disease per year. the average age at diagnosis is 64, and the disease occurs more commonly in males than females. signs and symptoms common symptoms include seizures, headaches, nausea and vomiting, memory loss, changes to personality, mood or concentration, and localized neurological problems. the kind of symptoms produced depends more on the location of the tumor than on its pathological properties. the tumor can start producing symptoms quickly, but occasionally is an asymptomatic condition until it reaches an enormous size. risk factors the cause of most cases is unclear. about 5% develop from certain hereditary syndromes. genetics uncommon risk factors include genetic disorders such as neurofibromatosis, li–fraumeni syndrome, tuberous sclerosis, or turcot syndrome. previous radiation therapy is also a risk. for unknown reasons, it occurs more commonly in males. environmental other associations include exposure to smoking, pesticides, and working in petroleum refining or rubber manufacturing. glioblastoma has been associated with the viruses sv40, hhv-6, and cytomegalovirus. other research has been done to see if consumption of cured meat is a risk factor. no risk had been confirmed as of 2023. similarly, exposure to radiation during medical imaging, formaldehyde, and residential electromagnetic fields, such as from cell phones and electrical wiring within homes, have been studied as risk factors. as of 2015, they had not been shown to cause gbm. pathogenesis the cellular origin of glioblastoma is unknown. because of the similarities in immunostaining of glial cells and glioblastoma, gliomas such as glioblastoma have long been assumed to originate from glial-type stem cells found in the subventricular zone. more recent studies suggest that astrocytes, oligodendrocyte progenitor cells, and neural stem cells could all serve as the cell of origin. gbms usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. 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 gliomatosis. however, metastasis of gbm beyond the central nervous system is extremely unusual. about 50% of gbms 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) glioma. glioblastoma 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. in 2021, the fifth edition of the who classification of tumors of the central nervous system was released. this update eliminated the classification of secondary glioblastoma and reclassified those tumors as astrocytoma, idh mutant, grade 4. only tumors that are idh wild type are now classified as glioblastoma. features of glioblastoma, idh wildtype, who 4 synonyms glioblastoma, gbm cell of origin astrocyte median age at diagnosis ~62 years male:female ratio 1.42:1 median length of clinical history at diagnosis 4 months median overall survival surgery + radiotherapy 9.9 months surgery + radiotherapy + chemotherapy 15 months location usually supratentorial, rarely cerebellum or spine necrosis and microvascular proliferation extensive associated molecular/genetic mutations tert promoter mutation, combined gain of chromosome 7 and loss of chromosome 10; egfr amplification molecular alterations four subtypes of glioblastoma 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 glioblastoma, 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 glioblastoma, and the majority of them are clustered in two pathways, the rb and the pi3k/akt. glioblastomas 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 glioblastoma cells with properties similar to progenitor cells (glioblastoma cancer stem cells) have been found in glioblastomas. their presence, coupled with the glioblastoma'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. glioblastoma 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 glioblastoma tumour cells. glioblastoma 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 not mutated in glioblastoma. as such, these tumors behave more aggressively compared to idh1-mutated astrocytomas. ion channels furthermore, gbm exhibits numerous alterations in genes that encode for ion channels, including upregulation of gbk potassium channels and clc-3 chloride channels. by upregulating these ion channels, glioblastoma tumor cells are hypothesized to facilitate increased ion movement over the cell membrane, thereby increasing h2o movement through osmosis, which aids glioblastoma 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 glioblastoma. additionally, experimental observations suggest that microrna-451 is a key regulator of lkb1/ampk signaling in cultured glioma cells and that mirna clustering controls epigenetic pathways in the disease. tumor vasculature gbm 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. diagnosis gbm in the frontal right lobe as seen on ct scan sagittal mri with contrast of a glioblastoma who grade 4 in a 15-year-old boy when viewed with mri, glioblastomas often appear as ring-enhancing lesions. the appearance is not specific, however, as other lesions such as abscess, metastasis, tumefactive multiple sclerosis, and other entities may have a similar appearance. definitive diagnosis of a suspected gbm on ct or mri requires a stereotactic biopsy or a craniotomy with tumor resection and pathologic confirmation. because the tumor grade is based upon the most malignant portion of the tumor, biopsy or subtotal tumor resection can result in undergrading of the lesion. imaging of tumor blood flow using perfusion mri and measuring tumor metabolite concentration with mr spectroscopy may add diagnostic value to standard mri in select cases by showing increased relative cerebral blood volume and increased choline peak, respectively, but pathology remains the gold standard for diagnosis and molecular characterization. distinguishing glioblastoma from high-grade astrocytoma is important. these tumors occur spontaneously (de novo) and have not progressed from a lower-grade glioma, as in high-grade astrocytomas glioblastomas have a worse prognosis and different tumor biology, and may have a different response to therapy, which makes this a critical evaluation to determine patient prognosis and therapy. astrocytomas carry a mutation in idh1 or idh2, whereas this mutation is not present in glioblastoma. thus, idh1 and idh2 mutations are a useful tool to distinguish glioblastomas from astrocytomas, since histopathologically they are similar and the distinction without molecular biomarkers is unreliable. idh-wildtype glioblastomas usually have lower olig2 expression compared with idh-mutant lower grade astrocytomas. histopathology of glioblastoma, showing high grade astrocytoma features of marked nuclear pleomorphism, multiple mitoses (one at white arrow) and multinucleated cells (one at black arrow), with cells having a patternless arrangement in a pink fibrillary background on h&e stain. lower magnification histopathology, showing necrosis surrounded by pseudopalisades of tumor cells, conferring a diagnosis of glioblastoma rather than anaplastic astrocytoma prevention there are no known methods to prevent glioblastoma. it is the case for most gliomas, unlike for some other forms of cancer, that they happen without previous warning and there are no known ways to prevent them. treatment treating glioblastoma is difficult due to several complicating factors: the tumor cells are resistant to conventional therapies. the brain is susceptible to damage from conventional therapy. the brain has a limited capacity to repair itself. many drugs cannot cross the blood–brain barrier to act on the tumor. treatment of primary brain tumors consists of palliative (symptomatic) care and therapies intended to improve survival. symptomatic therapy supportive treatment focuses on relieving symptoms and improving the patient's neurologic function. the primary supportive agents are anticonvulsants and corticosteroids. historically, around 90% of patients with glioblastoma underwent anticonvulsant treatment, although only an estimated 40% of patients required this treatment. recently, neurosurgeons have been recommended that anticonvulsants not be administered prophylactically, and should wait until a seizure occurs before prescribing this medication. those receiving phenytoin concurrent with radiation may have serious skin reactions such as erythema multiforme and stevens–johnson syndrome. corticosteroids, usually dexamethasone, can reduce peritumoral edema (through rearrangement of the blood–brain barrier), diminishing mass effect and lowering intracranial pressure, with