Glioma
Encyclopedia
A glioma is a type of tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

 that starts in the brain or spine. It is called a glioma because it arises from glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...

s. The most common site of gliomas is the brain
Brain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...

.

By type of cell

Gliomas are named according to the specific type of cell they share histological features with, but not necessarily originate from. The main types of gliomas are:
  • Ependymoma
    Ependymoma
    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 ependymoma is the fourth ventricle...

    s — ependymal cells.
  • Astrocytoma
    Astrocytoma
    Astrocytomas are a type of neoplasm of the brain. 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 usually affect other organs...

    s — astrocyte
    Astrocyte
    Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...

    s (glioblastoma multiforme
    Glioblastoma multiforme
    Glioblastoma multiforme is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells and accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBMs...

     is the most common astrocytoma).
  • Oligodendroglioma
    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 but are also found in children...

    s — oligodendrocyte
    Oligodendrocyte
    Oligodendrocytes , or oligodendroglia , are a type of brain cell. They are a variety of neuroglia. Their main function is the insulation of axons in the central nervous system of some vertebrates...

    s.
  • Mixed gliomas, such as oligoastrocytomas, contain cells from different types of glia.

By grade

Gliomas are further categorized according to their grade
Grading (tumors)
In pathology, grading is a measure of the cell appearance in tumors and other neoplasms. Some pathology grading systems apply only to malignant neoplasms ; others apply also to benign neoplasms. The neoplastic grading is a measure of cell anaplasia in the sampled tumors arising from the...

, which is determined by pathologic
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....

 evaluation of the tumor.

  • Low-grade gliomas [WHO grade II] are well-differentiated (not anaplastic
    Anaplasia
    Anaplasia refers to a reversion of differentiation in cells and is characteristic of malignant neoplasms . Sometimes, the term also includes an increased capacity for multiplication. Lack of differentiation is considered a hallmark of aggressive malignancies. The term anaplasia literally means "to...

    ); these are not benign
    Cancer
    Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

     but still portend a better prognosis for the patient.
  • High-grade [WHO grade III-IV] gliomas are undifferentiated or anaplastic; these are malignant
    Cancer
    Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

     and carry a worse prognosis.


Of numerous grading systems in use, the most common is the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 (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
Tentorium cerebelli
The tentorium cerebelli or cerebellar tentorium is an extension of the dura mater that separates the cerebellum from the inferior portion of the occipital lobes.-Anatomy:...

. The tentorium separates the cerebrum (above) from the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...

 (below).
  • supratentorial
    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 infratentorial region contains the cerebellum....

    : above the tentorium, in the cerebrum, mostly found in adults (70%).
  • infratentorial: below the tentorium, in the cerebellum, mostly found in children (70%).
  • pontine: located in the pons
    Pons
    The pons is a structure located on the brain stem, named after the Latin word for "bridge" or the 16th-century Italian anatomist and surgeon Costanzo Varolio . It is superior to the medulla oblongata, inferior to the midbrain, and ventral to the cerebellum. In humans and other bipeds this means it...

     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.

Signs and symptoms

Symptoms of gliomas depend on which part of the central nervous system is affected. A brain glioma
Brain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...

 can cause headaches, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

 and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

, seizures, and cranial nerve disorders as a result of increased intracranial pressure. A glioma of the optic nerve
Optic nerve
The optic nerve, also called cranial nerve 2, transmits visual information from the retina to the brain. Derived from the embryonic retinal ganglion cell, a diverticulum located in the diencephalon, the optic nerve doesn't regenerate after transection.-Anatomy:The optic nerve is the second of...

 can cause visual loss. Spinal cord gliomas can cause pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

, weakness
Weakness
Weakness is a symptom represented, medically, by a number of different conditions, including: lack of muscle strength, malaise, dizziness, or fatigue. 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...

, or numbness in the extremities. Gliomas do not metastasize
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...

 by the bloodstream, but they can spread via the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...

 and cause "drop metastases" to the spinal cord.

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

The exact causes of gliomas are not known. Hereditary genetic disorders such as neurofibromatoses (type 1 and type 2) and tuberous sclerosis complex are known to predispose to their development.

Gliomas have been correlated to the electromagnetic radiation
Electromagnetic radiation
Electromagnetic radiation is a form of energy that exhibits wave-like behavior as it travels through space...

 from cell phones, and a link between the cancer and cell phone usage is considered plausible, though there is no conclusive evidence. Most glioblastomas are infected with cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...

, however the significance of this is not known.

Pathophysiology

High-grade gliomas are highly-vascular tumors and have a tendency to infiltrate. They have extensive areas of necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

 and hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

. Often tumor growth causes a breakdown of the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

 in the vicinity of the tumor. As a rule, high-grade gliomas almost always grow back even after complete surgical excision, and so are commonly called recurrent cancer of the brain.

On the other hand, 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
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...

 (TP53) is an early mutation. TP53 is the "guardian of the genome," which, during DNA and cell duplication, makes sure that the DNA is copied correctly and destroys the cell (apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

) if the DNA is mutated and can't be fixed. When TP53 itself is mutated, other mutations can survive. Phosphatase and tensin homolog (PTEN), another protein that also helps destroy cells with dangerous mutations, is itself lost or mutated. Epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...

 (EGFR), 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. Recently, mutations in IDH1 and IDH2
IDH2
Isocitrate dehydrogenase [NADP], 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 two distinct subclasses, one of which utilizes NAD as the...

 were found to be part of the mechanism and associated with a more favorable prognosis. The IDH1 and IDH2 genes are significant because they are involved in the citrate cycle in mitochondria. Mitochondria are involved in apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

. Furthermore, the altered glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...

 metabolism in some cancer cells leads to low oxygen (hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

). The normal response to hypoxia is to stimulate the growth of new blood vessels (angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...

). So these two genes may contribute to both the lack of apoptosis and vascularization of gliomas.

Prognosis

Gliomas are rarely curable. The prognosis for patients with high-grade gliomas is generally poor, and is especially so for older patients. Of 10,000 Americans diagnosed each year with malignant gliomas, about half are alive 1 year after diagnosis, and 25% after two years. Those with anaplastic astrocytoma survive about three years. Glioblastoma multiforme has a worse prognosis with less than a 12-month average survival after diagnosis, though this has extended to 14 months with more recent treatments .

For low-grade tumors, the prognosis is somewhat more optimistic. One study reported that low-grade oligodendroglioma
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 but are also found in children...

 patients have a median survival of 11.6 years; another reported a median survival of 16.7 years.

Treatment

Treatment for brain gliomas
Brain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...

 depends on the location, the cell type and the grade of malignancy. Often, treatment is a combined approach, using surgery, radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...

, and chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

. The radiation therapy is in the form of external beam radiation or the stereotactic
Stereotactic surgery
Stereotactic surgery or stereotaxy is a minimally invasive form of surgical intervention which makes use of a three-dimensional coordinates system to locate small targets inside the body and to perform on them some action such as ablation, biopsy, lesion, injection, stimulation, implantation,...

 approach using radiosurgery
Radiosurgery
Radiosurgery is a medical procedure that allows non-invasive treatment of benign and malignant tumors. It is also known as stereotactic radiotherapy, when used to target lesions in the brain, and stereotactic body radiotherapy when used to target lesions in the body...

. Spinal cord tumors can be treated by surgery and radiation. Temozolomide
Temozolomide
Temozolomide Temozolomide Temozolomide (brand names Temodar and Temodal is an oral alkylating agent which can be used for the treatment of Grade IV astrocytoma — an aggressive brain tumor, also known as glioblastoma multiforme as well as melanoma, a form of skin cancer...

 is a chemotherapeutic drug that is able to cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

 effectively and is currently being used in therapy for high-grade tumors.

Refractory disease

For recurrent high-grade glioblastoma, recent studies have taken advantage of angiogenic blockers such as bevacizumab
Bevacizumab
Bevacizumab is a drug that blocks angiogenesis, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas....

 in combination with conventional chemotherapy, with encouraging results.

Relative effectiveness

A 2007 meta-analysis compared surgical resection and biopsy as the initial surgical management option. Results show that there is insufficient evidence to make a reliable decision.
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. For Glioblastoma Multiforme, a 2008 meta-analysis showed that Temozolomide is an effective treatment for "prolonging survival and delaying progression as part of primary therapy without impacting on QoL
Quality of life (healthcare)
Quality of Life is a phrase used to refer to an individual’s total wellbeing. This includes all emotional, social, and physical aspects of the individual’s life. However, when the phrase is used in reference to medicine and healthcare as Health Related Quality of Life, it refers to how the...

 and with a low incidence of early adverse events."

Research

The use of oncolytic virus
Oncolytic virus
An oncolytic virus is a virus that preferentially infects and lyses cancer cells; these have obvious functions for cancer therapy, both by direct destruction of the tumour cells, and, if modified, as vectors enabling genes expressing anticancer proteins to be delivered specifically to the tumor...

es or gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...

 using prodrug converting retroviruses and adenoviruses is being studied for the treatment of gliomas.

THC

Cannabinoids
Cannabinoids
Cannabinoids are a class of chemical compounds that include the phytocannabinoids , and chemical compounds that mimic the actions of phytocannabinoids or have a similar structure...

 "may represent a new class of anticancer drugs that retard cancer growth, inhibit angiogenesis and the metastic spreading of cancer cells." Pilot studies have been completed.

Oncophage, or vitespen

The European orphan status vaccine and Russian approved vaccine/drug Oncophage, now renamed "vitespen", are currently used at the Brain Tumor Research Center at the University of California, San Francisco, which has begun enrolling patients into a Phase 2 clinical trials in combination with the standard of care — radiation therapy plus temozolomide
Temozolomide
Temozolomide Temozolomide Temozolomide (brand names Temodar and Temodal is an oral alkylating agent which can be used for the treatment of Grade IV astrocytoma — an aggressive brain tumor, also known as glioblastoma multiforme as well as melanoma, a form of skin cancer...

 — for newly diagnosed glioma patients. The overall goals of the investigator-sponsored study are to evaluate median overall survival, progression-free survival and immunologic response to vaccine treatment. The FDA has now set a provision allowing patients to receive such care using experimental drugs such as Oncophage to those in need with no other resource for care in the United States.

"To date, improvements in overall survival for newly diagnosed glioma patients have been negligible", said the principal investigator, Andrew T. Parsa. "The rationale for moving Oncophage into this patient population and combining it with radiation and Temodar was underscored by the encouraging results from the ongoing Phase 2 study in recurrent glioma, a more challenging patient population where the results showed overall survival increasing to approximately 10.5 months" from a median of 6.5 months after surgery.

The autologous tumour derived heat shock protein
Heat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...

peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 complex 96 (HSPPC-96) vaccine called "vitespen" has shown a promising safety profile in trials to date. In phase III clinical trials against melanoma and kidney cancer, it was shown to have very low toxicity.

Others

A 2005, review found Ukrain may have the potential to be a cancer treatment, however the research is preliminary.

5-aminolevulinic acid, a drug that makes certain cells, including gliomas, fluorescent, has been used to make surgical removal of gliomas more effective by making it easier to identify and remove them during surgery.

External links

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