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Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
that begin within the
brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
. Initially, signs and symptoms of glioblastoma are nonspecific. They may include
headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...
s, personality changes,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...
, and symptoms similar to those of a
stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
. Symptoms often worsen rapidly and may progress to
unconsciousness Unconsciousness is a state in which a living individual exhibits a complete, or near-complete, inability to maintain an awareness of self and environment or to respond to any human or environmental stimulus. Unconsciousness may occur as the r ...
. The cause of most cases of glioblastoma is not known. Uncommon risk factors include
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
s, such as
neurofibromatosis Neurofibromatosis (NF) is a group of three conditions in which tumors grow in the nervous system. The three types are neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis. In NF1 symptoms include light brown ...
and
Li–Fraumeni syndrome Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder that predisposes carriers to cancer development. It was named after two American physicians, Frederick Pei Li and Joseph F. Fraumeni, Jr., who first recognized the syndro ...
, and previous
radiation therapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Rad ...
. Glioblastomas represent 15% of all
brain tumor A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and seco ...
s. They can either start from normal brain cells or develop from an existing
low-grade astrocytoma Fibrillary astrocytomas are a group of primary slow-growing brain tumors that typically occur in adults between the ages of 20 and 50. Symptoms Seizures, frequent mood changes, and headaches are among the earliest symptoms of the tumor. Hemipa ...
. The diagnosis typically is made by a combination of a CT scan,
MRI scan Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
, and
tissue biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a disea ...
. There is no known method of preventing the cancer. Treatment usually involves
surgery Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pa ...
, after which
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
and
radiation therapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Rad ...
are used. The medication
temozolomide Temozolomide (TMZ), sold under the brand name Temodar among others, is a medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. Text was copied from this source which is © European Medicines Agency. Reproduction ...
is frequently used as part of chemotherapy. High-dose
steroids A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
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 Meningioma, also known as meningeal tumor, is typically a slow-growing tumor that forms from the meninges, the membranous layers surrounding the brain and spinal cord. Symptoms depend on the location and occur as a result of the tumor pressing ...
. 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 An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...
, headaches, nausea and
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenter ...
, 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 Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combination ...
, 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 Smoking is a practice in which a substance is burned and the resulting smoke is typically breathed in to be tasted and absorbed into the bloodstream. Most commonly, the substance used is the dried leaves of the tobacco plant, which have b ...
,
pesticide Pesticides are substances that are meant to control pests. This includes herbicide, insecticide, nematicide, molluscicide, piscicide, avicide, rodenticide, bactericide, insect repellent, animal repellent, microbicide, fungicide, and ...
s, and working in
petroleum refining An oil refinery or petroleum refinery is an industrial process plant where petroleum (crude oil) is transformed and refined into useful products such as gasoline (petrol), diesel fuel, asphalt base, fuel oils, heating oil, kerosene, liquefi ...
or rubber manufacturing. Glioblastoma has been associated with the viruses
SV40 SV40 is an abbreviation for simian vacuolating virus 40 or simian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that has the potential to cause tumors in animals, but most often ...
,
HHV-6 Human herpesvirus 6 (HHV-6) is the common collective name for ''human betaherpesvirus 6A'' (HHV-6A) and ''human betaherpesvirus 6B'' (HHV-6B). These closely related viruses are two of the nine known herpesviruses that have humans as their primar ...
, and
cytomegalovirus ''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order '' Herpesvirales'', in the family '' Herpesviridae'', in the subfamily '' Betah ...
.


Other

Research has been done to see if consumption of cured meat is a risk factor. No risk had been confirmed as of 2013. Similarly, exposure to radiation during
medical imaging Medical imaging is the technique and process of imaging the interior of a body for clinical analysis and medical intervention, as well as visual representation of the function of some organs or tissues (physiology). Medical imaging seeks to re ...
,
formaldehyde Formaldehyde ( , ) ( systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section ...
, and residential
electromagnetic field An electromagnetic field (also EM field or EMF) is a classical (i.e. non-quantum) field produced by (stationary or moving) electric charges. It is the field described by classical electrodynamics (a classical field theory) and is the classical ...
s, 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 In biochemistry, immunostaining is any use of an antibody-based method to detect a specific protein in a sample. The term "immunostaining" was originally used to refer to the immunohistochemical staining of tissue sections, as first described by ...
of
glial cell Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...
s and glioblastoma, gliomas such as glioblastoma have long been assumed to originate from glial-type cells. More recent studies suggest that
astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...
s,
oligodendrocyte progenitor cell Oligodendrocyte progenitor cells (OPCs), also known as oligodendrocyte precursor cells, NG2-glia, O2A cells, or polydendrocytes, are a subtype of glia in the central nervous system named for their essential role as precursors to oligodendrocytes. ...
s, and
neural stem cell Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor ste ...
s could all serve as the cell of origin. Glioblastomas are characterized by the presence of small areas of
necrotizing Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
tissue that are surrounded by
anaplastic Anaplasia (from grc, ἀνά ''ana'', "backward" + πλάσις ''plasis'', "formation") is a condition of cells with poor cellular differentiation, losing the morphological characteristics of mature cells and their orientation with respect to e ...
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. GBMs 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 Fibrillary astrocytomas are a group of primary slow-growing brain tumors that typically occur in adults between the ages of 20 and 50. Symptoms Seizures, frequent mood changes, and headaches are among the earliest symptoms of the tumor. Hemipa ...
or anaplastic astrocytoma. These are called secondary GBMs 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 Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...
(CSF) (> 100 mg/dl), as well as an occasional pleocytosis of 10 to 100 cells, mostly
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic a ...
s.
Malignant Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
cells carried in the CSF may spread (rarely) to the
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
or cause meningeal gliomatosis. However,
metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, the ...
of GBM beyond the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
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 The cerebrum, telencephalon or endbrain is the largest part of the brain containing the cerebral cortex (of the two cerebral hemispheres), as well as several subcortical structures, including the hippocampus, basal ganglia, and olfactory bulb. ...
and may exhibit the classic infiltration across the
corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental m ...
, producing a butterfly (bilateral)
glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...
.


Glioblastoma classification

Brain tumor A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and seco ...
classification has been traditionally based on histopathology at macroscopic level, measured in hematoxylin-eosin sections. The
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...
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
glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...
s changed importantly and glioblastoma was now mainly classified according to the status of isocitrate dehydrogenase (IDH) mutation: IDH-wildtype or IDH-mutant. 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


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 The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor re ...
(''EGFR'') gene, and most have higher than normal expression of ''EGFR'', whereas the gene''
TP53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often ...
'' (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 PDGFRA, i.e. platelet-derived growth factor receptor A, also termed PDGFRα, i.e. platelet-derived growth factor receptor α, or CD140a i.e. Cluster of Differentiation 140a, is a receptor located on the surface of a wide range of cell types. This re ...
'', the gene encoding a-type
platelet-derived growth factor receptor Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular ...
, and in ''
IDH1 Isocitrate dehydrogenase 1 (NADP+), soluble is an enzyme that in humans is encoded by the ''IDH1'' gene on chromosome 2. Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to t ...
'', 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 Neurofibromin 1 (''NF1'') is a gene in humans that is located on chromosome 17. ''NF1'' codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. ' ...
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 MGMT () is an American indie rock band formed in 2002 in Middletown, Connecticut. It was founded by multi-instrumentalists Andrew VanWyngarden and Ben Goldwasser. Alongside VanWyngarden and Goldwasser, MGMT's live lineup currently consists o ...
, 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 Isocitrate dehydrogenase (IDH) () and () is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a s ...
1 and is uncommonly mutated in glioblastoma (primary GBM: 5%, secondary GBM >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 glioblastoma, compared with ''IDH1'' wild-type glioblastoma or healthy astrocytes. Among others, it increases the glioblastoma cells' dependence on
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
or
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
as an energy source. ''IDH1''-mutated glioblastomas 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 glioblastoma 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 glioblastoma.


Ion channels

Furthermore, GBM exhibits numerous alterations in genes that encode for
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...
s, 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 Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the ''STK11'' gene. Expression Testosterone and DHT treatment of murine 3T3-L1 or hu ...
/
AMPK AMPK may refer to: * AMP-activated protein kinase 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate gl ...
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

When viewed with MRI, glioblastomas often appear as ring-enhancing lesions. The appearance is not specific, however, as other lesions such as
abscess An abscess is a collection of pus that has built up within the tissue of the body. Signs and symptoms of abscesses include redness, pain, warmth, and swelling. The swelling may feel fluid-filled when pressed. The area of redness often extends ...
,
metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, the ...
,
tumefactive multiple sclerosis Tumefactive multiple sclerosis is a condition in which the central nervous system of a person has multiple demyelinating lesions with atypical characteristics for those of standard multiple sclerosis (MS). It is called tumefactive as the lesions ...
, and other entities may have a similar appearance. Definitive diagnosis of a suspected GBM on CT or MRI requires a
stereotactic biopsy Stereotactic biopsy, also known as stereotactic core biopsy, is a biopsy procedure that uses a computer and imaging performed in at least two planes to localize a target lesion (such as a tumor or microcalcifications in the breast) in three-dimensio ...
or a
craniotomy A craniotomy is a surgical operation in which a bone flap is temporarily removed from the skull to access the brain. Craniotomies are often critical operations, performed on patients who are suffering from brain lesions, such as tumors, blood clot ...
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 In vivo magnetic resonance spectroscopy (MRS) is a specialized technique associated with magnetic resonance imaging (MRI). Magnetic resonance spectroscopy (MRS), also known as nuclear magnetic resonance (NMR) spectroscopy, is a non-invasive, ion ...
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 primary glioblastoma from secondary glioblastoma is important. These tumors occur spontaneously (''de novo'') or have progressed from a lower-grade glioma, respectively. Primary 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. Over 80% of secondary glioblastomas carry a mutation in ''IDH1'', whereas this mutation is rare in primary glioblastoma (5–10%). Thus, ''IDH1'' mutations are a useful tool to distinguish primary and secondary glioblastomas, since histopathologically they are very similar and the distinction without molecular biomarkers is unreliable. File:Histopathology of glioblastoma, high magnification, annotated.jpg,
Histopathology Histopathology (compound of three Greek words: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία '' -logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Sp ...
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. File:Glioblastoma (1).jpg, 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 The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of the central nervous system where ne ...
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
anticonvulsant Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of ...
s and
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are inv ...
s. * 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 Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The in ...
concurrent with radiation may have serious skin reactions such as
erythema multiforme Erythema multiforme (EM) is a skin condition that appears with red patches evolving into target lesions, typically on both hands. It is a type of erythema possibly mediated by deposition of immune complexes (mostly IgM-bound complexes) in the ...
and
Stevens–Johnson syndrome Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN), it forms a spectrum of disease, with SJS being less severe. Erythema ...
. * Corticosteroids, usually
dexamethasone Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena ...
, can reduce peritumoral edema (through rearrangement of the blood–brain barrier), diminishing mass effect and lowering intracranial pressure, with a decrease in headache or drowsiness.


Surgery

Surgery is the first stage of treatment of glioblastoma. An average GBM tumor contains 1011 cells, which is on average reduced to 109 cells after surgery (a reduction of 99%). Benefits of surgery include resection for a pathological diagnosis, alleviation of symptoms related to mass effect, and potentially removing disease before secondary resistance to radiotherapy and chemotherapy occurs. The greater the extent of tumor removal, the better. In retrospective analyses, removal of 98% or more of the tumor has been associated with a significantly longer healthier time than if less than 98% of the tumor is removed. The chances of near-complete initial removal of the tumor may be increased if the surgery is guided by a fluorescent dye known as
5-aminolevulinic acid δ-Aminolevulinic acid (also dALA, δ-ALA, 5ALA or 5-aminolevulinic acid), an endogenous non-proteinogenic amino acid, is the first compound in the porphyrin synthesis pathway, the pathway that leads to heme in mammals, as well as chlorophyll in p ...
. GBM cells are widely infiltrative through the brain at diagnosis, and despite a "total resection" of all obvious tumor, most people with GBM later develop recurrent tumors either near the original site or at more distant locations within the brain. Other modalities, typically radiation and chemotherapy, are used after surgery in an effort to suppress and slow recurrent disease.


Radiotherapy

Subsequent to surgery, radiotherapy becomes the mainstay of treatment for people with glioblastoma. It is typically performed along with giving
temozolomide Temozolomide (TMZ), sold under the brand name Temodar among others, is a medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. Text was copied from this source which is © European Medicines Agency. Reproduction ...
. A pivotal clinical trial carried out in the early 1970s showed that among 303 GBM patients randomized to radiation or nonradiation therapy, those who received radiation had a median survival more than double those who did not. Subsequent clinical research has attempted to build on the backbone of surgery followed by radiation. On average,
radiotherapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Rad ...
after surgery can reduce the tumor size to 107 cells. Whole-brain radiotherapy does not improve when compared to the more precise and targeted three-dimensional conformal radiotherapy. A total radiation dose of 60–65 Gy has been found to be optimal for treatment. GBM tumors are well known to contain zones of tissue exhibiting hypoxia, which are highly resistant to radiotherapy. Various approaches to chemotherapy radiosensitizers have been pursued, with limited success . , newer research approaches included preclinical and clinical investigations into the use of an
oxygen diffusion-enhancing compound An oxygen diffusion-enhancing compound is any substance that increases the availability of oxygen in body tissues by influencing the molecular structure of water in blood plasma and thereby promoting the movement (diffusion) of oxygen through plasm ...
such as
trans sodium crocetinate Crocetin is a natural apocarotenoid dicarboxylic acid that is found in the crocus flower together with its glycoside, crocin, and ''Gardenia jasminoides'' fruits. It forms brick red crystals with a melting point of 285°C. The chemical structure ...
as
radiosensitizer A radiosensitizer is an agent that makes tumor cells more sensitive to radiation therapy. It is sometimes also known as a radiation sensitizer or radio-enhancer. Mechanism of action Conventional chemotherapeutics are currently being used in co ...
s, and a clinical trial was underway.
Boron neutron capture therapy Neutron capture therapy (NCT) is a type of radiotherapy for treating locally invasive malignant tumors such as primary brain tumors, recurrent cancers of the head and neck region, and cutaneous and extracutaneous melanomas. It is a two-step pro ...
has been tested as an alternative treatment for glioblastoma, but is not in common use.


Chemotherapy

Most studies show no benefit from the addition of chemotherapy. However, a large clinical trial of 575 participants randomized to standard radiation versus radiation plus temozolomide chemotherapy showed that the group receiving temozolomide survived a median of 14.6 months as opposed to 12.1 months for the group receiving radiation alone. This treatment regimen is now standard for most cases of glioblastoma where the person is not enrolled in a
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
. Temozolomide seems to work by sensitizing the tumor cells to radiation, and appears more effective for tumors with ''MGMT'' promoter methylation. High doses of temozolomide in high-grade gliomas yield low toxicity, but the results are comparable to the standard doses. Antiangiogenic therapy with medications such as
bevacizumab Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, ...
control symptoms, but do not appear to affect overall survival in those with glioblastoma. The overall benefit of anti-angiogenic therapies as of 2019 is unclear. In elderly people with newly diagnosed glioblastoma who are reasonably fit, concurrent and adjuvant chemoradiotherapy gives the best overall survival but is associated with a greater risk of haematological adverse events than radiotherapy alone.


Other procedures

Alternating electric field therapy is an FDA-approved therapy for newly diagnosed and recurrent glioblastoma. In 2015, initial results from a phase-III randomized clinical trial of alternating electric field therapy plus temozolomide in newly diagnosed glioblastoma reported a three-month improvement in progression-free survival, and a five-month improvement in overall survival compared to temozolomide therapy alone, representing the first large trial in a decade to show a survival improvement in this setting. Despite these results, the efficacy of this approach remains controversial among medical experts. However, increasing understanding of the mechanistic basis through which alternating electric field therapy exerts anti-cancer effects and results from ongoing phase-III clinical trials in extracranial cancers may help facilitate increased clinical acceptance to treat glioblastoma in the future. A
Tel Aviv University Tel Aviv University (TAU) ( he, אוּנִיבֶרְסִיטַת תֵּל אָבִיב, ''Universitat Tel Aviv'') is a public research university in Tel Aviv, Israel. With over 30,000 students, it is the largest university in the country. Locate ...
study showed that pharmacological and molecular inhibition of the
P-selectin P-selectin is a type-1 transmembrane protein that in humans is encoded by the SELP gene. P-selectin functions as a cell adhesion molecule (CAM) on the surfaces of activated endothelial cells, which line the inner surface of blood vessels, and act ...
protein leads to reduced tumor growth and increased survival in mouse models of glioblastoma. The results of this research could open to possible therapies with drugs that inhibit this protein, such as crizanlizumab.


Prognosis

The most common length of survival following diagnosis is 10 to 13 months, with fewer than 1 to 3% of people surviving longer than five years. In the United States between 2012 and 2016 five-year survival was 6.8%. Without treatment, survival is typically 3 months. Complete cures are extremely rare, but have been reported. Increasing age (> 60 years) carries a worse prognostic risk. Death is usually due to widespread tumor infiltration with
cerebral edema Cerebral edema is excess accumulation of fluid ( edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compres ...
and increased
intracranial pressure Intracranial pressure (ICP) is the pressure exerted by fluids such as cerebrospinal fluid (CSF) inside the skull and on the brain tissue. ICP is measured in millimeters of mercury ( mmHg) and at rest, is normally 7–15 mmHg for a supine adul ...
. A good initial Karnofsky performance score (KPS) and
MGMT MGMT () is an American indie rock band formed in 2002 in Middletown, Connecticut. It was founded by multi-instrumentalists Andrew VanWyngarden and Ben Goldwasser. Alongside VanWyngarden and Goldwasser, MGMT's live lineup currently consists o ...
methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...
are associated with longer survival. A DNA test can be conducted on glioblastomas to determine whether or not the promoter of the ''MGMT''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
is methylated. Patients with a methylated MGMT promoter have longer survival than those with an unmethylated MGMT promoter, due in part to increased sensitivity to temozolomide. Another positive prognostic marker for glioblastoma patients is mutation of the ''IDH1'' gene, which can be tested by DNA-based methods or by immunohistochemistry using an antibody against the most common mutation, namely IDH1-R132H. More prognostic power can be obtained by combining the mutational status of ''IDH1'' and the methylation status of ''MGMT'' into a two-gene predictor. Patients with both ''IDH1'' mutations and ''MGMT'' methylation have the longest survival, patients with an ''IDH1'' mutation or ''MGMT'' methylation an intermediate survival, and patients without either genetic event have the shortest survival. Long-term benefits have also been associated with those patients who receive surgery, radiotherapy, and temozolomide chemotherapy. However, much remains unknown about why some patients survive longer with glioblastoma. Age under 50 is linked to longer survival in GBM, as is 98%+ resection and use of temozolomide chemotherapy and better KPSs. A recent study confirms that younger age is associated with a much better prognosis, with a small fraction of patients under 40 years of age achieving a population-based cure. Cure is thought to occur when a person's risk of death returns to that of the normal population, and in GBM, this is thought to occur after 10 years. UCLA Neuro-oncology publishes real-time survival data for patients with this diagnosis. According to a 2003 study, GBM prognosis can be divided into three subgroups dependent on KPS, the age of the patient, and treatment.


Epidemiology

About three per 100,000 people develop the disease a year, although regional frequency may be much higher. The frequency in England doubled between 1995 and 2015. It is the second-most common
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
cancer after
meningioma Meningioma, also known as meningeal tumor, is typically a slow-growing tumor that forms from the meninges, the membranous layers surrounding the brain and spinal cord. Symptoms depend on the location and occur as a result of the tumor pressing ...
. It occurs more commonly in males than females. Although the average age at diagnosis is 64, in 2014, the broad category of brain cancers was second only to leukemia in people in the United States under 20 years of age.


History

The term glioblastoma multiforme was introduced in 1926 by
Percival Bailey Percival Sylvester Bailey (May 9, 1892 – August 10, 1973) was an American neuropathologist, neurosurgeon and psychiatrist who was a native of rural southern Illinois. He originally studied to become a teacher at Southern Illinois University Car ...
and
Harvey Cushing Harvey Williams Cushing (April 8, 1869 – October 7, 1939) was an American neurosurgeon, pathologist, writer, and draftsman. A pioneer of brain surgery, he was the first exclusive neurosurgeon and the first person to describe Cushing's disease ...
, based on the idea that the tumor originates from primitive precursors of
glial cell Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...
s ( glioblasts), and the highly variable appearance due to the presence of necrosis, hemorrhage, and cysts (multiform).


Research


Gene therapy

Gene therapy Gene therapy is a Medicine, medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying ...
has been explored as a method to treat glioblastoma, and while animal models and early-phase clinical trials have been successful, as of 2017, all gene-therapy drugs that had been tested in phase-III clinical trials for glioblastoma had failed. Scientists have developed the core–shell nanostructured LPLNP-PPT (long persistent luminescence nanoparticles. PPT refers to polyetherimide, PEG and trans-activator of transcription, and TRAIL is the human tumor necrosis factor-related apoptosis-induced ligand) for effective gene delivery and tracking, with positive results. This is a TRAIL ligand that has been encoded to induce apoptosis of cancer cells, more specifically glioblastomas. Although this study was still in clinical trials in 2017, it has shown diagnostic and therapeutic functionalities, and will open great interest for clinical applications in stem-cell-based therapy.


Oncolytic virotherapy

Oncolytic virotherapy is an emerging novel treatment that is under investigation both at preclinical and clinical stages. Several viruses including herpes simplex virus, adenovirus, poliovirus, and reovirus are currently being tested in phases I and II of clinical trials for glioblastoma therapy and have shown to improve overall survival.


Intranasal drug delivery

Direct nose-to-brain drug delivery is being explored as a means to achieve higher, and hopefully more effective, drug concentrations in the brain. A clinical phase-I/II study with glioblastoma patients in Brazil investigated the natural compound perillyl alcohol for intranasal delivery as an
aerosol An aerosol is a suspension of fine solid particles or liquid droplets in air or another gas. Aerosols can be natural or anthropogenic. Examples of natural aerosols are fog or mist, dust, forest exudates, and geyser steam. Examples of anthropogen ...
. The results were encouraging and, as of 2016, a similar trial has been initiated in the United States.


Cannabinoids

The efficacy of
cannabinoid Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
s (cannabis derivatives) is known in oncology (through capsules of tetrahydrocannabinol (THC) or the synthetic analogue nabilone), on the one hand to combat nausea and vomiting induced by chemotherapy, on the other to stimulate appetite and lessen the sense of anguish or the actual pain. Their ability to inhibit growth and angiogenesis in malignant gliomas in mouse models has been demonstrated. The results of a pilot study on the use of THC in end-stage patients with recurrent glioblastoma appeared worthy of further study. A potential avenue for future research rests on the discovery that cannabinoids are able to attack the neoplastic stem cells of glioblastoma in mouse models, with the result on the one hand of inducing their differentiation into more mature, possibly more "treatable" cells, and on the other hand to inhibit tumorigenesis.


See also

* Adegramotide * List of people with brain tumors


References


External links


Information about Glioblastoma Multiforme (GBM)
from the American Brain Tumor Association
AFIP Course Syllabus
nbsp;– Astrocytoma WHO Grading Lecture Handout {{Authority control Brain tumor Wikipedia medicine articles ready to translate Cancer Oncology Aging-associated diseases