Glioma

A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.

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 they share histological features with, but not necessarily originate from. The main types of gliomas are:


 * Ependymomas — ependymal cells.
 * Astrocytomas — astrocytes (glioblastoma multiforme is the most common astrocytoma).
 * Oligodendrogliomas — oligodendrocytes.
 * Mixed gliomas, such as oligoastrocytomas, contain cells from different types of glia.

By grade
Gliomas are further categorized according to their grade, which is determined by pathologic evaluation of the tumor.


 * Low-grade gliomas [WHO grade II] are well-differentiated (not anaplastic); these are not benign but still portend a better prognosis for the patient.
 * High-grade [WHO grade III-IV] gliomas are undifferentiated or anaplastic; these are malignant and carry a worse prognosis.

Of numerous grading systems in use, the most common is the World Health Organization (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 (above) from the cerebellum (below).


 * supratentorial: 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 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 can cause headaches, nausea and vomiting, seizures, and cranial nerve disorders as a result of increased intracranial pressure. A glioma of the optic nerve can cause visual loss. Spinal cord gliomas can cause pain, weakness, or numbness in the extremities. Gliomas do not metastasize by the bloodstream, but they can spread via the cerebrospinal fluid 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 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, 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 and hypoxia. Often tumor growth causes a breakdown of the blood-brain barrier 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 (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) 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 (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 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. Furthermore, the altered glycolysis metabolism in some cancer cells leads to low oxygen (hypoxia). The normal response to hypoxia is to stimulate the growth of new blood vessels (angiogenesis). 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 patients have a median survival of 11.6 years; another reported a median survival of 16.7 years.

Treatment
Treatment for brain gliomas depends on the location, the cell type and the grade of malignancy. Often, treatment is a combined approach, using surgery, radiation therapy, and chemotherapy. The radiation therapy is in the form of external beam radiation or the stereotactic approach using radiosurgery. Spinal cord tumors can be treated by surgery and radiation. Temozolomide is a chemotherapeutic drug that is able to cross the blood-brain barrier 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 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 and with a low incidence of early adverse events."

Research
The use of oncolytic viruses or gene therapy using prodrug converting retroviruses and adenoviruses is being studied for the treatment of gliomas.

THC
Cannabinoids "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/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 — 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, M.D., Ph.D., of the University of California, San Francisco. "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–peptide 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.