A glioma is a type of
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
that starts in the
glial cells
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 mye ...
of the
brain
A brain is an 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 vision. It is the most complex organ in a v ...
or the
spine
Spine or spinal may refer to:
Science Biology
* Vertebral column, also known as the backbone
* Dendritic spine, a small membranous protrusion from a neuron's dendrite
* Thorns, spines, and prickles, needle-like structures in plants
* Spine (zoolog ...
. Gliomas comprise about 30 percent 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 seconda ...
s and central nervous system tumours, and 80 percent of all malignant brain tumours.
Signs and symptoms
Symptoms of gliomas depend on which part of the central nervous system is affected. A brain glioma can cause
headaches
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 of m ...
,
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 Human nose, nose.
Vomiting can be the result of ailments like Food-poisoning, foo ...
,
seizures
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or neural oscillation, synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much o ...
, and
cranial nerve
Cranial nerves are the nerves that emerge directly from the brain (including the brainstem), of which there are conventionally considered twelve pairs. Cranial nerves relay information between the brain and parts of the body, primarily to and ...
disorders as a result of increased intracranial pressure. A glioma of the
optic nerve
In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual system, visual information from the retina to the brain. In humans, the optic nerve i ...
can cause visual loss. Spinal cord gliomas can cause
pain
Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
,
weakness
Weakness is a symptom of a number of different conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, i ...
, or
numbness
Hypoesthesia or numbness is a common side effect of various medical conditions that manifests as a reduced sense of touch or sensation, or a partial loss of sensitivity to sensory stimuli. In everyday speech this is generally referred to as num ...
in the extremities. Gliomas do not usually
metastasize
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, then, ...
by the bloodstream, but they can spread via 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 bra ...
and cause "drop metastases" to the spinal cord. Complex visual hallucinations have been described as a symptom of low-grade glioma.
A child who has a subacute disorder of the central nervous system that produces cranial nerve abnormalities (especially of cranial nerve VII and the lower bulbar nerves), long-tract signs, unsteady gait secondary to spasticity, and some behavioral changes is most likely to have a pontine glioma.
Causes
Hereditary disorders
The exact causes of gliomas are not known.
Hereditary disorders such as
neurofibromatoses
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 Cafe au lait spot ...
(type 1 and type 2) and
tuberous sclerosis complex
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 ...
are known to predispose to their development. Different oncogenes can cooperate in the development of gliomas.
Diet
Some studies of diet and vitamin supplementation appear to point out that dietary
N-nitroso
In organic chemistry, nitrosamines (or more formally ''N''-Nitrosamines) are organic compounds with the chemical structure , where R is usually an alkyl group. They feature a nitroso group () bonded to a deprotonated amine. Most nitrosamin ...
compounds may affect the risk of both childhood and adult brain tumors. Researchers have observed in some studies that brain tumor patients (or their mothers) have generally consumed more cured foods (also known as
Curing) than control groups. Recently, Drs. Lee, Wrensch and others found that adults with glioma were more likely to consume diets high in cured foods and low in vitamin C-rich fruits and vegetables, and to consume diets high in
nitrites
The nitrite ion has the chemical formula . Nitrite (mostly sodium nitrite) is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name nitrite also re ...
and low in
vitamin C
Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) an ...
. The effect was more pronounced in men than women. However, the pattern of increased risk with increased consumption of cured foods, and decreased risk with greater consumption of fruits, vegetables, and antioxidant vitamins is compatible with other cancer studies that show increased consumption of vegetables and possibly of fruits is associated with decreased cancer risk.
Radiation
A link between gliomas and
electromagnetic radiation
In physics, electromagnetic radiation (EMR) consists of waves of the electromagnetic field, electromagnetic (EM) field, which propagate through space and carry momentum and electromagnetic radiant energy. It includes radio waves, microwaves, inf ...
from
cell phones
A mobile phone, cellular phone, cell phone, cellphone, handphone, hand phone or pocket phone, sometimes shortened to simply mobile, cell, or just phone, is a portable telephone that can make and receive calls over a radio frequency link whil ...
has not been conclusively proven. It was considered possible, though several large studies have found no conclusive evidence, as summarized by the NIH's
National Cancer Institute
The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
review of the topic and its numerous citations, and the
FCC
The Federal Communications Commission (FCC) is an independent agency of the United States federal government that regulates communications by radio, television, wire, satellite, and cable across the United States. The FCC maintains jurisdiction ...
. 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
''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 ''Betaherpe ...
, 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.
Other causes
Though some studies have shown that
farmers
A farmer is a person engaged in agriculture, raising living organisms for food or raw materials. The term usually applies to people who do some combination of raising field crops, orchards, vineyards, poultry, or other livestock. A farmer mi ...
have higher rates of gliomas compared to the general population, exposure to farm animals or manure is not associated with glioma. Later studies have not found an association between farming and gliomas; similar conflicting data concerns
teachers
A teacher, also called a schoolteacher or formally an educator, is a person who helps students to acquire knowledge, competence, or virtue, via the practice of teaching.
''Informally'' the role of teacher may be taken on by anyone (e.g. whe ...
and glioma. More consistent data show that architects, surveyors, retail workers, butchers, and engineers have higher rates of gliomas.
Most studies have found that pesticide exposure is probably not a cause of glioma, though a minority of studies have found an association.
Inherited polymorphisms of the DNA repair genes
Germ-line (inherited) polymorphisms of the DNA repair genes ''
ERCC1
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ''ERCC1'' gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
Many aspects of these two gene ...
'', ''
ERCC2
__NOTOC__
ERCC2, or XPD is a protein involved in transcription-coupled nucleotide excision repair.
The XPD (ERCC2) gene encodes for a 2.3-kb mRNA containing 22 exons and 21 introns. The XPD protein contains 760 amino acids and is a polypeptide w ...
'' (''XPD'') and ''
XRCC1
DNA repair protein XRCC1, also known as X-ray repair cross-complementing protein 1, is a protein that in humans is encoded by the ''XRCC1'' gene. XRCC1 is involved in DNA repair, where it complexes with DNA ligase III.
Function
XRCC1 is invol ...
'' increase the risk of glioma.
This indicates that altered or deficient repair of DNA damage contributes to the formation of gliomas. DNA damages are a likely major primary cause of progression to cancer in general.
Excess DNA damages can give rise to mutations through
translesion synthesis
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
. Furthermore, incomplete DNA repair can give rise to
epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
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
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
repression of DNA repair genes is often found in progression to
sporadic glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...
. For instance,
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 t ...
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
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
that inhibits the ability of the ''MGMT''
messenger RNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the p ...
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
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ''ERCC1'' gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
Many aspects of these two gene ...
'', 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
microRNA
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
s 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
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 ...
'' (''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
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
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 tumor
A vascular tumor is a tumor of vascular origin; a soft tissue growth that can be either benign or malignant, formed from blood vessels or lymph vessels. Examples of vascular tumors include hemangiomas, lymphangiomas, hemangioendotheliomas, Kapos ...
s and have a tendency to infiltrate diffusely.
They have extensive areas of
necrosis
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 ...
and
hypoxia
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
. Often, tumor growth causes a breakdown of the
blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
in the vicinity of the tumor. As a rule, high-grade gliomas almost always grow back even after complete surgical excision, so 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 (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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
) if the DNA is mutated and cannot be fixed. When p53 itself is mutated, other mutations can survive.
Phosphatase and tensin homolog
Phosphatase and tensin homolog (PTEN) is a phosphatase in humans and is encoded by the ''PTEN'' gene. Mutations of this gene are a step in the development of many cancers, specifically glioblastoma, lung cancer, breast cancer, and prostate ca ...
(PTEN), another tumor suppressor gene, is itself lost or mutated.
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 recept ...
, 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
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 two ...
'' and''
IDH2
Isocitrate dehydrogenase ADP mitochondrial is an enzyme that in humans is encoded by the ''IDH2'' gene.
Isocitrate dehydrogenases are enzymes that catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to tw ...
'' were found to be part of the mechanism and associated with a less favorable prognosis.
Diagnosis
Classification
Gliomas are classified by cell type, by grade, and by location.
By type of cell
Gliomas are named according to the specific type of cell with which they share
histological
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
features, but not necessarily from which they originate. The main types of glioma are:
*
Ependymoma
An ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymomas is the fourth ...
s:
ependymal cell
The ependyma is the thin neuroepithelial ( simple columnar ciliated epithelium) lining of the ventricular system of the brain and the central canal of the spinal cord. The ependyma is one of the four types of neuroglia in the central nervous syst ...
s
*
Astrocytoma
Astrocytomas are a type of brain tumor. They originate in a particular kind of glial cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usu ...
s:
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 endo ...
s (
glioblastoma multiforme
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...
is a malignant astrocytoma and the most common primary brain tumor among adults).
*
Oligodendroglioma
Oligodendrogliomas are a type of glioma that are believed to originate from the oligodendrocytes of the brain or from a glial precursor cell. They occur primarily in adults (9.4% of all primary brain and central nervous system tumors) but are also ...
s:
oligodendrocyte
Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...
s
*
Brainstem glioma
A brainstem glioma is a cancerous glioma tumor in the brainstem. Around 75% are diagnosed in children and young adults under the age of twenty, but have been known to affect older adults as well. Brainstem gliomas start in the brain or spinal ...
: develop in the
brain stem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...
*
Optic nerve glioma
Optic nerve glioma (or optic glioma), a form of glioma which affects the optic nerve, is often one of the central nervous system manifestations of neurofibromatosis 1.
Optic gliomas are usually pilocytic tumors, and can involve the optic nerve o ...
: develop in or around the
optic nerve
In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual system, visual information from the retina to the brain. In humans, the optic nerve i ...
* Mixed gliomas, such as
oligoastrocytomas
Oligoastrocytomas are a subset of brain tumors that present with an appearance of mixed glial cell origin, astrocytoma and oligodendroglioma. However, the term "Oligoastrocytoma" is now considered obsolete by the National Comprehensive Cancer Ne ...
, contain cells from different types of glia
By grade
Gliomas are further categorised according to their
grade
Grade most commonly refers to:
* Grade (education), a measurement of a student's performance
* Grade, the number of the year a student has reached in a given educational stage
* Grade (slope), the steepness of a slope
Grade or grading may also ref ...
, which is determined by
pathologic
''Pathologic'' ( rus, Мор. Утопия, Mor. Utopiya, ˈmor ʊˈtopʲɪjə, , More. Utopia – a pun on Thomas More's ''Utopia'' and the Russian word for "plague") is a 2005 role-playing and survival game developed by Russian studio Ice-Pic ...
evaluation of the tumor. The neuropathological evaluation and diagnostics of brain tumor specimens is performed according to WHO Classification of Tumours of the Central Nervous System.
* Biologically benign gliomas
HO grade I
Ho (or the transliterations He or Heo) may refer to:
People Language and ethnicity
* Ho people, an ethnic group of India
** Ho language, a tribal language in India
* Hani people, or Ho people, an ethnic group in China, Laos and Vietnam
* Hiri Mo ...
are comparatively low risk and can be removed surgically depending on their location
* Low-grade gliomas
HO grade II
Ho (or the transliterations He or Heo) may refer to:
People Language and ethnicity
* Ho people, an ethnic group of India
** Ho language, a tribal language in India
* Hani people, or Ho people, an ethnic group in China, Laos and Vietnam
* Hiri Mo ...
are well-differentiated (not
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 ...
); these tend to exhibit
benign
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, ''benign'' tumor in that a malign ...
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
HO grades III–IVgliomas are undifferentiated or
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 ...
; these are
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 ...
and carry a worse prognosis.
Of numerous grading systems in use, the most common is 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 of h ...
(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
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. In ...
(above) from the
cerebellum
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
(below).
* The
supratentorial In anatomy, the supratentorial region of the brain is the area located above the tentorium cerebelli. The area of the brain below the tentorium cerebelli is the infratentorial region. The supratentorial region contains the cerebrum, while the infra ...
is above the tentorium, in the cerebrum, and mostly found in adults (70%).
* The
infratentorial
In anatomy, the infratentorial region of the brain is the area located below the tentorium cerebelli. The area of the brain above the tentorium cerebelli is the supratentorial region. The infratentorial region contains the cerebellum
The cerebe ...
is below the tentorium, in the cerebellum, and mostly found in children (70%).
* The pontine tumors are located in the
pons
The pons (from Latin , "bridge") is part of the brainstem that in humans and other bipeds lies inferior to the midbrain, superior to the medulla oblongata and anterior to the cerebellum.
The pons is also called the pons Varolii ("bridge of Va ...
of the brainstem. The brainstem has three parts (pons, midbrain, and medulla); the pons controls critical functions such as breathing, making surgery on these extremely dangerous.
Treatment
Treatment for brain gliomas depends on the location, the cell type, and the grade of malignancy. Current treatment options include surgical removal, radiation (
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. Radia ...
), and
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. Chemotherap ...
. In some cases, tumour treating fields (
alternating electric field therapy
Alternating electric field therapy, sometimes called tumor treating fields (TTFields), is a type of electromagnetic field therapy using low-intensity, intermediate frequency electrical fields to treat cancer. A TTField-generating device manufact ...
), a recently developed technology, may be used.
Often, treatment is a combined approach, using surgery,
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. Radia ...
, and
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. Chemotherap ...
. For many, treatment consists of just surgery, or even "watchful waiting" (waiting to see when an intervention is justified due to tumour progression). Doctors carefully balance the specifics of the patient's tumour and the downsides of intervention, since there can be significant side effects from medical intervention.
Radiation and chemotherapy remain the mainstays of treatment beyond surgery. Radiation therapy is delivered in the form of external beam radiation or the
stereotactic
Stereotactic surgery is a minimally invasive form of surgical intervention that makes use of a three-dimensional coordinate system to locate small targets inside the body and to perform on them some action such as ablation, biopsy, lesion, injec ...
approach using
radiosurgery
Radiosurgery is surgery using radiation, that is, the destruction of precisely selected areas of tissue using ionizing radiation rather than excision with a blade. Like other forms of radiation therapy (also called radiotherapy), it is usually u ...
.
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 i ...
is a common chemotherapy drug which can be administered easily in an outpatient setting and is able to cross the
blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
effectively.
There are a wide variety of novel treatments currently being tested in clinical trials, ranging from IDH inhibitors like
Ivosidenib
Ivosidenib, sold under the brand name Tibsovo, is an anti-cancer medication for the treatment of acute myeloid leukemia (AML) and cholangiocarcinoma. It is a small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), which is mutated in se ...
, to the recently approved
Dendritic cell-based cancer vaccine The dendritic cell-based cancer vaccine is an innovation in therapeutic strategy for cancer patients.
Dendritic cells (DCs) are antigen presenting cells for the induction of antigen specific T cell response. DC-based immunotherapy is safe and can ...
approach.
Treatment using
immunotherapy
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
is another promising research path that may help treat glioma in the near future. Experimental therapies like oncolytic viruses have shown potential therapeutic benefits in clinical trials (but have not been approved for use in non-experimental settings).
Refractory disease
For recurrent high-grade glioblastoma, recent studies have taken advantage of
angiogenic
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...
blockers 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, l ...
in combination with conventional chemotherapy, with encouraging results.
Relative effectiveness
A 2017 meta-analysis compared surgical resection versus biopsy as the initial surgical management option for a person with a low-grade glioma.
Results show the evidence is insufficient to make a reliable decision.
The relative effectiveness of surgical resection compared to biopsy for people with malignant glioma (high-grade) is unknown.
For high-grade gliomas, a 2003 meta-analysis compared radiotherapy with radiotherapy and chemotherapy. It showed a small but clear improvement from using chemotherapy with radiotherapy. A 2019 meta-analysis suggested that for people with less aggressive gliomas, radiotherapy may increase the risk of long term neurocognitive side effects.
Whilst, evidence is uncertain on whether there are long term neurocognitive side effects associated with chemoradiotherapy.
Temozolomide is effective for treating Glioblastoma Multiforme (GBM) compared to radiotherapy alone.
A 2013 meta-analysis showed that Temozolomide prolongs survival and delays progression, but is associated with an increase in side effects such as blood complications, fatigue, and infection.
For people with recurrent GBM, when comparing temozolomide with chemotherapy, there may be an improvement in the
time-to-progression and the person's quality of life, but no improvement in overall survival, with temozolomide treatment.
Evidence suggests that for people with recurrent high-grade gliomas who have not had chemotherapy before, there are similar survival and time-to-progression outcomes between treatment with temozolomide or the chemotherapy multidrug known as PCV (procarvazine, lomustine and vincristine).
A mutational analysis of 23 initial low-grade gliomas and recurrent tumors from the same patients has challenged the benefits and usage of Temozolomide. The study showed that when lower-grade brain tumors of patients are removed and patients are further treated with Temozolomide, 6 out of 10 times the recurrent tumors were more aggressive and acquired alternative and more mutations. As one of the last authors, Costello, stated "They had a 20- to 50-fold increase in the number of mutations. A patient who received surgery alone who might have had 50 mutations in the initial tumor and 60 in the recurrence. But patients who received TMZ might have 2,000 mutations in the recurrence." Further, new mutations were verified to carry known signatures of Temozolomide induced mutations. The research suggests that Temozolomide for the treatment of certain brain tumors should be thoroughly thought. Unjudicious usage of Temozolomide might lower the prognosis of the patients further, or increase their burden. Further understanding of the mechanisms of Temozolomide induced mutations and novel combination approaches could be promising.
Prognosis
Prognosis of gliomas is given in relation to what grade (as scored by the World Health Organization system) of tumour the patient presents with. Typically, any tumour presenting as above WHO grade I (i.e. a malignant tumour as opposed to a benign tumour) will have a prognosis resulting in eventual death, varying from years (WHO grade II/III) to months (WHO grade IV).
Prognosis can also be given based on cellular subtype, which may also impact prognosis.
Low grade
For low-grade tumors, the prognosis is somewhat more optimistic. Patients diagnosed with a low-grade glioma are 17 times as likely to die as matched patients in the general population.
The age-standardized 10-year relative survival rate was 47%.
One study reported that low-grade
oligodendroglioma
Oligodendrogliomas are a type of glioma that are believed to originate from the oligodendrocytes of the brain or from a glial precursor cell. They occur primarily in adults (9.4% of all primary brain and central nervous system tumors) but are also ...
patients have a median survival of 11.6 years; another reported a median survival of 16.7 years. Unfortunately, approximately 70% of low-grade (WHO grade-II) will progress to high-grade tumours within 5–10 years
High grade
This group comprises
anaplastic astrocytoma
Anaplastic astrocytoma is a rare WHO grade III type of astrocytoma, which is a type of cancer of the brain. In the United States, the annual incidence rate for anaplastic astrocytoma is 0.44 per 100,000 people.
Signs and symptoms
Initial present ...
s and
glioblastoma multiforme
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...
. Whereas the median overall survival of anaplastic (WHO grade III) gliomas is approximately 3 years,
glioblastoma multiforme
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...
has a poor median overall survival of c. 15 months.
Postoperative conventional daily radiotherapy improves survival for adults with good functional well‐being and high grade glioma compared to no postoperative radiotherapy. Hypofractionated radiation therapy has similar efficacy for survival as compared to conventional radiotherapy, particularly for individuals aged 60 and older with glioblastoma.
Diffuse intrinsic pontine glioma
Diffuse intrinsic pontine glioma primarily affects children, usually between the ages of 5 and 7. The median survival time with DIPG is under 12 months. Surgery to attempt tumour removal is usually not possible or advisable for DIPG. By their very nature, these tumours invade diffusely throughout the brain stem, growing between normal nerve cells. Aggressive surgery would cause severe damage to neural structures vital for arm and leg movement, eye movement, swallowing, breathing, and even consciousness. Trials of drug candidates have been unsuccessful. The disease is primarily treated with radiation therapy alone.
''IDH1'' and ''IDH2-''mutated glioma
Patients with glioma carrying mutations in either ''IDH1'' or ''IDH2'' have a relatively favorable survival, compared with patients with glioma with wild-type ''IDH1/2'' genes. In WHO grade III glioma, ''IDH1/2''-mutated glioma have a median prognosis of ~3.5 years, whereas ''IDH1/2'' wild-type glioma perform poor with a median overall survival of c. 1.5 years.
In glioblastoma, the difference is larger. There, ''IDH1/2'' wild-type glioblastoma have a median overall survival of 1 year, whereas ''IDH1/2''-mutated glioblastoma have a median overall survival of more than 3 years.
References
External links
Gliomaa
the Human Protein AtlasAmerican Brain Tumor Association: Malignant Gliomas*
ttps://web.archive.org/web/20070703183739/http://rad.usuhs.mil/rad/who/who-index.html WHO Classification of GliomaGlioma ImagesMedPix Database
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