Brain tumor

Brain tumor
Classification and external resources
Brain metastasis in the right cerebral hemisphere from lung cancer shown on T1-weighted magnetic resonance imaging with intravenous contrast.
ICD-10	C71, D33.0-D33.2
ICD-9	191, 225.0
DiseasesDB	30781
MedlinePlus	007222 000768
eMedicine	emerg/334
MeSH	D001932

A brain tumor is an intracranial solid neoplasm, a tumor (defined as an abnormal growth of cells) within the brain or the central spinal canal.

Brain tumors include all tumors inside the cranium or in the central spinal canal. They are created by an abnormal and uncontrolled cell division, usually in the brain itself, but also in lymphatic tissue, in blood vessels, in the cranial nerves, in the brain envelopes (meninges), skull, pituitary gland, or pineal gland. Within the brain itself, the involved cells may be neurons or glial cells (which include astrocytes, oligodendrocytes, ependymal cells, and myelin-producing Schwann cells). Brain tumors may also spread from cancers primarily located in other organs (metastatic tumors).

Any brain tumor is inherently serious and life-threatening because of its invasive and infiltrative character in the limited space of the intracranial cavity. However, brain tumors (even malignant ones) are not invariably fatal, especially lipomas which are inherently benign. Brain tumors or intracranial neoplasms can be cancerous (malignant) or non-cancerous (benign); however, the definitions of malignant or benign neoplasms differs from those commonly used in other types of cancerous or non-cancerous neoplasms in the body. Its threat level depends on the combination of factors like the type of tumor, its location, its size and its state of development. Because the brain is well protected by the skull, the early detection of a brain tumor only occurs when diagnostic tools are directed at the intracranial cavity. Usually detection occurs in advanced stages when the presence of the tumor has caused unexplained symptoms.

Primary (true) brain tumors are commonly located in the posterior cranial fossa in children and in the anterior two-thirds of the cerebral hemispheres in adults, although they can affect any part of the brain.

Signs and symptoms

The visibility of signs and symptoms of brain tumors mainly depends on two factors: tumor size (volume) and tumor location. The moment that symptoms will become apparent, either to the person or people around him (symptom onset) is an important milestone in the course of the diagnosis and treatment of the tumor. The symptom onset - in the timeline of the development of the neoplasm - depends in many cases on the nature of the tumor but in many cases is also related to the change of the neoplasm from "benign" (i.e. slow-growing/late symptom onset) to more malignant (fast growing/early symptom onset).

Symptoms of solid neoplasms of the brain (primary brain tumors and secondary tumors alike) can be divided in 3 main categories :

• Consequences of intracranial hypertension : The symptoms that often occur first are those that are the consequences of increased intracranial pressure: Large tumors or tumors with extensive perifocal swelling (edema) inevitably lead to elevated intracranial pressure (intracranial hypertension), which translates clinically into headaches, vomiting (sometimes without nausea), altered state of consciousness (somnolence, coma), dilation of the pupil on the side of the lesion (anisocoria), papilledema (prominent optic disc at the funduscopic eye examination). However, even small tumors obstructing the passage of cerebrospinal fluid (CSF) may cause early signs of increased intracranial pressure. Increased intracranial pressure may result in herniation (i.e. displacement) of certain parts of the brain, such as the cerebellar tonsils or the temporal uncus, resulting in lethal brainstem compression. In very young children, elevated intracranial pressure may cause an increase in the diameter of the skull and bulging of the fontanelles.
• Dysfunction : depending on the tumor location and the damage it may have caused to surrounding brain structures, either through compression or infiltration, any type of focal neurologic symptoms may occur, such as cognitive and behavioral impairment (including impaired judgment, memory loss, lack of recognition, spatial orientation disorders), personality or emotional changes, hemiparesis, hypoesthesia, aphasia, ataxia, visual field impairment, impaired sense of smell, impaired hearing, facial paralysis, double vision, dizziness, but more severe symptoms might occur too such as: paralysis on one side of the body hemiplegia or impairment to swallow . These symptoms are not specific for brain tumors — they may be caused by a large variety of neurologic conditions (e.g. stroke, traumatic brain injury). What counts, however, is the location of the lesion and the functional systems (e.g. motor, sensory, visual, etc.) it affects. A bilateral temporal visual field defect (bitemporal hemianopia—due to compression of the optic chiasm), often associated with endocrine disfunction—either hypopituitarism or hyperproduction of pituitary hormones and hyperprolactinemia is suggestive of a pituitary tumor.
• Irritation : abnormal fatigue, weariness, absences and tremors, but also epileptic seizures.

The above symptoms are true for ALL types of neoplasm of the brain (including secondary tumors). It is common that a person carry a primary benign neoplasm for several years and have no visible symptoms at all. Many present some vague and intermittent symptoms like headaches and occasional vomiting or weariness, which can be easily mistaken for gastritis or gastroenteritis. It might seem strange that despite having a mass in his skull exercising pressure on the brain the patient feels no pain, but as anyone who has suffered a concussion can attest, pain is felt on the outside of the skull and not in the brain itself. The brain has no nerve sensors in the meninges (outer surface) with which to feel or transmit pain to the brain's pain center; it cannot signal pain without a sensory input. That is why secondary symptoms like those described above should alert doctors to the possible diagnosis of a neoplasm of the brain.

When a person suffering from a metastasized cancer is diagnosed, a scan of the skull frequently reveals secondary tumors.

In a recent study by the Dutch GP Association,^[1] a list of causes of headaches^[2] was published, that should alert GP's to take their diagnosis further then to choose for symptomatic treatment of headaches with simple pain medication (note the occurrence of brain tumors as possible cause):

Alarm signals	Possible cause
First headache complaint from person over 50 years old	brain tumor, arteriïtis temporalis
First migraine attack in person over 40 years old	brain tumor
Headache in person under 6 years old	brain tumor, hydrocephalus
Person over 50 years old with pain at temples	arteriïtis temporalis
Pregnancy with unknown headache	pre-eclampsia
Increased headaches after trauma	sub/epidural hematoma
Severe headaches and very high blood pressure	malignant hypertension
Acute severe headache	meningitis, CVA (Cerebrovascular accident or stroke), subarachnoidal hemorrhage
Headache and fever (with reduced consciousness)	meningitis
Stiffness of the neck/neurological dysfunction	meningitis, brain tumor
Headache with signs of elevated intracranial pressure	brain tumor
Focal neurological dysfunction	brain tumor
Early morning vomiting or vomiting unrelated to headache or other illness	brain tumor
Behavioral changes or rapid decline in school results	brain tumor

Cause

Aside from exposure to vinyl chloride or ionizing radiation, there are no known environmental factors associated with brain tumors. Mutations and deletions of so-called tumor suppressor genes are thought to be the cause of some forms of brain tumors. People with various inherited diseases, such as Von Hippel-Lindau syndrome, multiple endocrine neoplasia, neurofibromatosis type 2 are at high risk of developing brain tumors. Cell phone use does not appear to be related.^[3]

Pathophysiology

Main anatomical regions of the vertebrate brain

Anatomy

From the brain-wikipedia article and for the purpose of understanding this article some summary notes about the brain and its different types of organic tissues will be provided.

When reading the human brain in the picture on the left, only a few of the areas are really of interest to us. The first type of tissue encountered beneath the skullbone in the intracranial cavity is actually not shown on this picture: the meninges. This is what is inflamed in meningitis.

Meninges

Human brains are surrounded by a system of connective tissue membranes called meninges that separate the skull from the brain. This three-layered covering is composed of (from the outside in) the dura mater ("hard mother"), arachnoid mater ("spidery mother"), and pia mater ("soft mother"). The arachnoid and pia are physically connected and thus often considered as a single layer, the pia-arachnoid. Below the arachnoid is the subarachnoid space which contains cerebrospinal fluid (CSF also called "liquor" in Latin), which circulates in the narrow spaces between cells and through cavities called ventricles, and serves to nourish, support, and protect the brain tissue. Blood vessels enter the central nervous system through the perivascular space above the pia mater. The cells in the blood vessel walls are joined tightly, forming the blood-brain barrier which protects the brain from toxins that might enter through the blood. Tumors of the meninges are meningioma and are often benign neoplasms.

Brain matter

The brains of vertebrates (including humans) are made of very soft tissue, with a texture that has been compared to gelatin. Living brain tissue is pinkish on the outside and mostly white on the inside, with subtle variations in color. Three separate brain areas make up the majority of brain volume:

• • telencephalon (cerebral hemispheres or cerebrum)
  • mesencephalon (midbrain)
  • cerebellum

These areas are composed of two broad classes of cells: neurons and glia. These two types are equally numerous in the brain as a whole, although glial cells outnumber neurons roughly 4 to 1 in the cerebral cortex. Glia come in several types, which perform a number of critical functions, including structural support, metabolic support, insulation, and guidance of development.

Primary tumors of the glial cells are called Glioma and often are malignant by the time they are diagnosed.

Spinal cord and other tissues

• The pink area in picture is called the pons and is a specific region that consists of myelinated axons much like the spinal cord
• The yellow region is the diencephalon (thalamus and hypothalamus) which consist also of neuron and glial cell tissue with the hypophysis (or pituitary gland) and pineal gland (which is glandular tissue) attached at the bottom; tumors of the pituitary and pineal gland are often benign neoplasms
• The turquoise region or medulla oblongata is the end of the spinal cord and is composed mainly of neuron tissue enveloped in Schwann cells and meninges tissue. Our spinal cord is made up of bundles of these axons. Glial cells such as Schwann cells in the periphery or, within the cord itself, oligodendrocytes, wrap themselves around the axon, thus promoting faster transmission of electrical signals and also providing for general maintenance of the environment surrounding the cord, in part by shuttling different compounds around, responding to injury, etc.

Diagnosis

A posterior fossa tumor leading to mass effect and midline shift

Although there is no specific or singular clinical symptom or sign for any brain tumors, the presence of a combination of symptoms and the lack of corresponding clinical indications of infections or other causes can be an indicator to redirect diagnostic investigation towards the possibility of an intracranial neoplasm.

The diagnosis will often start with an interrogation of the patient to get a clear view of his medical antecedents, and his current symptoms. Clinical and laboratory investigations will serve to exclude infections as the cause of the symptoms. Examinations in this stage may include the eyes, otolaryngological (or ENT) and/or electrophysiological exams. The use of electroencephalography (EEG) often plays a role in the diagnosis of brain tumors.

Swelling, or obstruction of the passage of cerebrospinal fluid (CSF) from the brain may cause (early) signs of increased intracranial pressure which translates clinically into headaches, vomiting, or an altered state of consciousness, and in children changes to the diameter of the skull and bulging of the fontanelles. More complex symptoms such as endocrine dysfunctions should alarm doctors not to exclude brain tumors.

A bilateral temporal visual field defect (due to compression of the optic chiasm) or dilatation of the pupil, and the occurrence of either slowly evolving or the sudden onset of focal neurologic symptoms, such as cognitive and behavioral impairment (including impaired judgment, memory loss, lack of recognition, spatial orientation disorders), personality or emotional changes, hemiparesis, hypoesthesia, aphasia, ataxia, visual field impairment, impaired sense of smell, impaired hearing, facial paralysis, double vision, or more severe symptoms such as tremors, paralysis on one side of the body hemiplegia, or (epileptic) seizures in a patient with a negative history for epilepsy, should raise the possibility of a brain tumor.

Imaging plays a central role in the diagnosis of brain tumors. Early imaging methods —invasive and sometimes dangerous— such as pneumoencephalography and cerebral angiography, have been abandoned in recent times in favor of non-invasive, high-resolution techniques, such as computed tomography (CT)-scans and especially magnetic resonance imaging (MRI). Neoplasms will often show as differently colored masses (also referred to as processes) in CT or MRI results.

• Benign brain tumors often show up as hypodense (darker than brain tissue) mass lesions on cranial CT-scans. On MRI, they appear either hypo- (darker than brain tissue) or isointense (same intensity as brain tissue) on T1-weighted scans, or hyperintense (brighter than brain tissue) on T2-weighted MRI, although the appearance is variable.
• Contrast agent uptake, sometimes in characteristic patterns, can be demonstrated on either CT or MRI-scans in most malignant primary and metastatic brain tumors.
• Perifocal edema, or pressure-areas, or where the brain tissue has been compressed by an invasive process also appears hyperintense on T2-weighted MRI, they might indicate the presence a diffuse neoplasm (unclear outline)

This is because these tumors disrupt the normal functioning of the blood-brain barrier and lead to an increase in its permeability. However it is not possible to diagnose high versus low grade gliomas based on enhancement pattern alone.

Glioblastoma multiforme and anaplastic astrocytoma have been associated^[who?] with the genetic acute hepatic porphyrias (PCT, AIP, HCP and VP), including positive testing associated with drug refractory seizures. Unexplained complications associated with drug treatments with these tumors should alert physicians to an undiagnosed neurological porphyria.

The definitive diagnosis of brain tumor can only be confirmed by histological examination of tumor tissue samples obtained either by means of brain biopsy or open surgery. The histological examination is essential for determining the appropriate treatment and the correct prognosis. This examination, performed by a pathologist, typically has three stages: interoperative examination of fresh tissue, preliminary microscopic examination of prepared tissues, and followup examination of prepared tissues after immunohistochemical staining or genetic analysis.

Pathology

Micrograph of an oligodendroglioma, a type of brain cancer. Brain biopsy. H&E stain.

Tumors have characteristics that allow determination of its malignacy dangerous a tumor, how it will evolve and it will allow the medical team to determine the management plan.

Anaplasia: or dedifferentiation; loss of differentiation of cells and of their orientation to one another and blood vessels, a characteristic of anaplastic tumor tissue. Anaplastic cells have lost total control of their normal functions and many have deteriorated cell structures. Anaplastic cells often have abnormally high nuclear-to-cytoplasmic ratios, and many are multinucleated. Additionally, the nuclei of anaplastic cells are usually unnaturally shaped or oversized nuclei. Cells can become anaplastic in two ways: neoplastic tumor cells can dedifferentiate to become anaplasias (the dedifferentiation causes the cells to lose all of their normal structure/function), or cancer stem cells can increase in their capacity to multiply (i.e., uncontrollable growth due to failure of differentiation).

Atypia: is an indication of abnormality of a cell (which may be indicative for malignancy). Significance of the abnormality is highly dependent on context.

Neoplasia: is the (uncontrolled) division of cells; as such neoplasia is not problematic but its consequences are: the uncontrolled division of cells means that the mass of a neoplasm increases in size, and in a confined space such as the intracranial cavity this quickly becomes problematic because the mass invades the space of the brain pushing it aside, leading to compression of the brain tissue and increased intracranial pressure and destruction of brain parenchyma. Increased Intracranial pressure (ICP) may be attributable to the direct mass effect of the tumor, increased blood volume, or increased cerebrospinal fluid (CSF) volume may in turn have secondary symptoms

Necrosis: is the (premature) death of cells, caused by external factors such as infection, toxin or trauma. Necrotic cells send the wrong chemical signals which prevents phagocytes from disposing of the dead cells, leading to a build up of dead tissue, cell debris and toxins at or near the site of the necrotic cells^[4]

Arterial and venous hypoxia, or the deprivation of adequate oxygen supply to certain areas of the brain, occurs when a tumor makes use of nearby blood vessels for its supply of blood and the neoplasm enters into competition for nutrients with the surrounding brain tissue.

More generally a neoplasm may cause release of metabolic end products (e.g., free radicals, altered electrolytes, neurotransmitters), and release and recruitment of cellular mediators (e.g., cytokines) that disrupt normal parenchymal function.

Classification

Secondary brain tumors

Secondary tumors of the brain are metastatic tumors that invaded the intracranial sphere from cancers originating in other organs. This means that a cancerous neoplasm has developed in another organ elsewhere in the body and that cancer cells have leaked from that primary tumor and then entered the lymphatic system and blood vessels. They then circulate through the bloodstream, and are deposited in the brain. There, these cells continue growing and dividing, becoming another invasive neoplasm of the primary cancer's tissue. Secondary tumors of the brain are very common in the terminal phases of patients with an incurable metastasized cancer; the most common types of cancers that bring about secondary tumors of the brain are lung cancer, breast cancer, malignant melanoma, kidney cancer and colon cancer (in decreasing order of frequency).

Secondary brain tumors are the most common cause of tumors in the intracranial cavity.

The skull bone structure can also be subject to a neoplasm that by its very nature reduces the volume of the intracranial cavity, and can damage the brain.

By behavior

Brain tumors or intracranial neoplasms can be cancerous (malignant) or non-cancerous (benign). However, the definitions of malignant or benign neoplasms differs from those commonly used in other types of cancerous or non-cancerous neoplasms in the body. In cancers elsewhere in the body, three malignant properties differentiate benign tumors from malignant forms of cancer: benign tumors are self-limited and do not invade or metastasize. Characteristics of malignant tumors include:

• uncontrolled mitosis (growth by division beyond the normal limits)
• anaplasia: the cells in the neoplasm have an obviously different form (in size and shape). Anaplastic cells display marked pleomorphism. The cell nuclei are characteristically extremely hyperchromatic (darkly stained) and enlarged; the nucleus might have the same size as the cytoplasm of the cell (nuclear-cytoplasmic ratio may approach 1:1, instead of the normal 1:4 or 1:6 ratio). Giant cells - considerably larger than their neighbors - may formed and possess either one enormous nucleus or several nuclei (syncytia). Anaplastic nuclei are variable and bizarre in size and shape.
• invasion or infiltration (medical literature uses these terms as synonymous equivalents. However, for clarity, the articles that follow adhere to a convention that they mean slightly different things (so readers should note that this convention is not kept outside these articles):
  • Invasion or invasiveness is the spatial expansion of the tumor through uncontrolled mitosis, in the sense that the neoplasm invades the space occupied by adjacent tissue, thereby pushing the other tissue aside and eventually compressing the tissue. Often these tumors are associated with clearly outlined tumors in imaging.
  • Infiltration is the behavior of the tumor either to grow (microscopic) tentacles that push into the surrounding tissue (often making the outline of the tumor undefined or diffuse) or to have tumor cells "seeded" into the tissue beyond the circumference of the tumorous mass; this doesn't mean that an infiltrative tumor doesn't take up space or doesn't compress the surrounding tissue as it grows, but an infiltrating neoplasm makes it difficult to say where the tumor ends and the healthy tissue starts.
• metastasis (spread to other locations in the body via lymph or blood).

Of the above malignant characteristics, some elements don't apply to primary neoplasms of the brain:

• Primary brain tumors rarely metastasize to other organs; some forms of primary brain tumors can metastasize but will not spread outside the intracranial cavity or the central spinal canal. Due to the blood-brain barrier cancerous cells of a primary neoplasm cannot enter the bloodstream and get carried to another location in the body. (Occasional isolated case reports suggest spread of certain brain tumors outside the central nervous system, e.g. bone metastasis of glioblastoma multiforme.^[5])
• Primary brain tumors generally are invasive (i.e. they will expand spatially and intrude into the space occupied by other brain tissue and compress those brain tissues), however some of the more malignant primary brain tumors will infiltrate the surrounding tissue.

Of numerous grading systems in use for the classification of tumor of the central nervous system, the World Health Organization (WHO) grading system is commonly used for astrocytoma. Established in 1993 in an effort to eliminate confusion regarding diagnoses, the WHO system established a four-tiered histologic grading guideline for astrocytomas that assigns a grade from 1 to 4, with 1 being the least aggressive and 4 being the most aggressive.

Treatment

When a brain tumor is diagnosed, a medical team will be formed to assess the treatment options presented by the leading surgeon to the patient and his/her family. Given the location of primary solid neoplasms of the brain in most cases a "do-nothing" option is usually not presented. Neurosurgeons take the time to observe the evolution of the neoplasm before proposing a management plan to the patient and his/her relatives. These various types of treatment are available depending on neoplasm type and location and may be combined to give the best chances of survival:

• surgery: complete or partial ressection of the tumor with the objective of removing as many tumor cells as possible
• radiotherapy
• chemotherapy, with the aim of killing as many as possible of cancerous cells left behind after surgery and of putting remaining tumor cells into a nondividing, sleeping state for as long as possible
• A variety of experimental therapies are available through clinical trials^[6]

Survival rates in primary brain tumors depend on the type of tumor, age, functional status of the patient, the extent of surgical tumor removal and other factors specific to each case.^[7]

Surgery

The primary and most desired course of action described in medical literature is surgical removal (resection) via craniotomy. Minimally invasive techniques are being studied but are far from being common practice. The prime remediating objective of surgery is to remove as many tumor cells as possible, with complete removal being the best outcome and cytoreduction ("debulking") of the tumor otherwise. In some cases access to the tumor is impossible and impedes or prohibits surgery.

Many meningiomas, with the exception of some tumors located at the skull base, can be successfully removed surgically. Most pituitary adenomas can be removed surgically, often using a minimally invasive approach through the nasal cavity and skull base (trans-nasal, trans-sphenoidal approach). Large pituitary adenomas require a craniotomy (opening of the skull) for their removal. Radiotherapy, including stereotactic approaches, is reserved for inoperable cases.

Several current research studies aim to improve the surgical removal of brain tumors by labeling tumor cells with a chemical (5-aminolevulinic acid) that causes them to fluoresce.^[8] Postoperative radiotherapy and chemotherapy are integral parts of the therapeutic standard for malignant tumors. Radiotherapy may also be administered in cases of "low-grade" gliomas, when a significant tumor burden reduction could not be achieved surgically.

Any person undergoing brain surgery may suffer from epileptic seizures. Seizures can vary from absences to severe tonic-clonic attacks. Medication is prescribed and administered to minimize or eliminate the occurrence of seizures.

Multiple metastatic tumors are generally treated with radiotherapy and chemotherapy rather than surgery. the prognosis in such cases is determined by the primary tumor, but is generally poor.

Radiation therapy

The goal of radiation therapy is to selectively kill tumor cells while leaving normal brain tissue unharmed. In standard external beam radiation therapy, multiple treatments of standard-dose "fractions" of radiation are applied to the brain. This process is repeated for a total of 10 to 30 treatments, depending on the type of tumor. This additional treatment provides some patients with improved outcomes and longer survival rates.

Radiosurgery is a treatment method that uses computerized calculations to focus radiation at the site of the tumor while minimizing the radiation dose to the surrounding brain. Radiosurgery may be an adjunct to other treatments, or it may represent the primary treatment technique for some tumors.

Radiotherapy may be used following, or in some cases in place of, resection of the tumor. Forms of radiotherapy used for brain cancer include external beam radiation therapy, brachytherapy, and in more difficult cases, stereotactic radiosurgery, such as Gamma knife, Cyberknife or Novalis Tx radiosurgery.^[9]

Radiotherapy is the most common treatment for secondary brain tumors. The amount of radiotherapy depends on the size of the area of the brain affected by cancer. Conventional external beam 'whole brain radiotherapy treatment' (WBRT) or 'whole brain irradiation' may be suggested if there is a risk that other secondary tumors will develop in the future.^[10] Stereotactic radiotherapy is usually recommended in cases involving fewer than three small secondary brain tumors.

In 2008 a study published by the University of Texas M. D. Anderson Cancer Center indicated that cancer patients who receive stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) for the treatment of metastatic brain tumors have more than twice the risk of developing learning and memory problems than those treated with SRS alone.^[11][12]

Chemotherapy

Patients undergoing chemotherapy are administered drugs designed to kill tumor cells. Although chemotherapy may improve overall survival in patients with the most malignant primary brain tumors, it does so in only about 20 percent of patients. Chemotherapy is often used in young children instead of radiation, as radiation may have negative effects on the developing brain. The decision to prescribe this treatment is based on a patient’s overall health, type of tumor, and extent of the cancer. The toxicity and many side effects of the drugs, and the uncertain outcome of chemotherapy in brain tumors puts this treatment further down the line of treatment options with surgery and radiation therapy preferred.

UCLA Neuro-Oncology publishes real-time survival data for patients with a diagnosis of glioblastoma multiforme. They are the only institution in the United States that displays how brain tumor patients are performing on current therapies. They also show a listing of chemotherapy agents used to treat high grade glioma tumors.^[13]

Other

A shunt is used not as a cure but to relieve symptoms by reducing hydrocephalus caused by blockage of cerebrospinal fluid.^[14]

Researchers are presently investigating a number of promising new treatments including gene therapy, highly focused radiation therapy, immunotherapy and novel chemotherapies. A variety of new treatments are being made available on an investigational basis at centers specializing in brain tumor therapies.

Prognosis

The prognosis of brain cancer varies based on the type of cancer. Medulloblastoma has a good prognosis with chemotherapy, radiotherapy, and surgical resection while glioblastoma multiforme has a median survival of only 12 months even with aggressive chemoradiotherapy and surgery. Brainstem gliomas have the poorest prognosis of any form of brain cancer, with most patients dying within one year, even with therapy that typically consists of radiation to the tumor along with corticosteroids. However, one type of brainstem glioma, a focal^[15] seems open to exceptional prognosis and long-term survival has frequently been reported.

Glioblastoma multiforme

Main article: Glioblastoma multiforme

Glioblastoma multiforme is the deadliest and most common form of malignant brain tumor. Even when aggressive multimodality therapy consisting of radiotherapy, chemotherapy, and surgical excision is used, median survival is only 12–17 months. Standard therapy for glioblastoma multiforme consists of maximal surgical resection of the tumor, followed by radiotherapy between two and four weeks after the surgical procedure to remove the cancer. This is followed by chemotherapy. Most patients with glioblastoma take a corticosteroid, typically dexamethasone, during their illness to palliate symptoms. Experimental treatments include gamma-knife radiosurgery,^[16] boron neutron capture therapy and gene transfer.^[17]

Oligodendrogliomas

Main article: Oligodendroglioma

Oligodendroglioma is an incurable but slowly progressive malignant brain tumor. They can be treated with surgical resection, chemotherapy, and/or radiotherapy. For suspected low-grade oligodendrogliomas in select patients, some neuro-oncologists opt for a course of watchful waiting, with only symptomatic therapy. Tumors with the 1p/19q co-deletion have been found to be especially chemosensitive, and one source reports oligodendrogliomas to be "among the most chemosensitive of human solid malignancies".^[18] A median survival of up to 16.7 years has been reported for low grade oligodendrogliomas.^[19]

Epidemiology

The incidence of low-grade astrocytoma has not been shown to vary significantly with nationality. However, studies examining the incidence of malignant CNS tumors have shown some variation with national origin. Since some of these high-grade lesions arise from low-grade tumors, these trends are worth mentioning. Specifically, the incidence of CNS tumors in the United States, Israel, and the Nordic countries is relatively high, while Japan and Asian countries have a lower incidence. These differences probably reflect some biological differences as well as differences in pathologic diagnosis and reporting.^[20]

Worldwide data on incidence of cancer can be found at the WHO (world health organisation) and is handled by the AIRC (Agency for Interanctional Research on Cancer) located in France.^[21]

Figures for incidences of cancers of the brain show a significant difference between more and less developed countries (i.e. the less-developed countries have lower incidences of tumors of the brain) this could be explained by undiagnosed tumor-related deaths (patient in extreme poor situations don't get diagnosed simply because they don't have access to the modern diagnostic facilities required to diagnose a brain tumor) and by deaths caused by other poverty related causes that preempt a patients life before tumors develop or tumors become life threatening. Nevertheless studies have been made that certain forms of primary brain tumors are more prevalent among certain groups of the population.

United Kingdom

From the British national statistics data about new diagnosis of malignant neoplasms of the brain for the year 2007 (in absolute figures and in rates per 100.000)

Measures	Gender	DASR	All ages	Under 1	1-4	5-9	10-14	15-19	20-24	25-29	30-34	35-39	40-44	45-49	50-54	55-59	60-64	65-69	70-74	75-79	80-84	85+
Absolute figures	M		2.13	7	34	40	31	37	33	48	61	87	100	116.1	142	242	264	258	237	193	128	73
	F		1.598	7	42	39	37	28	25	37	50	42	73	87	99	140	191	166	169	158	111	97
Rates per 100.000 inhabitants	M	7,7	8,5	2,1	2,8	2,7	2,0	2,1	1,9	2,8	3,7	4,6	5,1	6,6	9,3	15,7	18,6	24,0	25,8	26,7	26,6	21,2
	F	5,3	6,2	2,2	3,6	2,8	2,5	1,7	1,5	2,2	3,0	2,2	3,7	4,9	6,3	8,8	12,9	14,3	16,2	17,1	15,1	12,8

^[22]

United States

In the United States in the year 2005, it was estimated there were 43,800 new cases of brain tumors (Central Brain Tumor Registry of the United States, Primary Brain Tumors in the United States, Statistical Report, 2005–2006),^[23] which accounted for 1.4 percent of all cancers, 2.4 percent of all cancer deaths,^[24] and 20–25 percent of pediatric cancers.^[24][25] Ultimately, it is estimated there are 13,000 deaths per year in the United States alone as a result of brain tumors.^[23]

Research

Vesicular stomatitis virus

In 2000, researchers at the University of Ottawa, led by John Bell PhD., discovered that the vesicular stomatitis virus, or VSV, can infect and kill cancer cells, without affecting healthy cells if coadministered with interferon.^[26]

The initial discovery of the virus' oncolytic properties were limited to only a few types of cancer. Several independent studies have identified many more types susceptible to the virus, including glioblastoma multiforme cancer cells, which account for the majority of brain tumors.

In 2008, researchers artificially engineered strains of VSV that were less cytotoxic to normal cells. This advance allows administration of the virus without coadministration with interferon. Consequently administration of the virus can be given intravenously or through the olfactory nerve. In the research, a human brain tumor was implanted into mice brains.

Research on virus treatment like this has been conducted for some years, but no other viruses have been shown to be as efficient or specific as the VSV mutant strains. Future research will focus on the risks of this treatment, before it can be applied to humans.^[27]

Retroviral replicating vectors

Led by Prof. Nori Kasahara, researchers from USC, who are now at UCLA, reported in 2001 the first successful example of applying the use of retroviral replicating vectors towards transducing cell lines derived from solid tumors.^[28] Building on this initial work, the researchers applied the technology to in vivo models of cancer and in 2005 reported a long-term survival benefit in an experimental brain tumor animal model.^[29] Subsequently, in preparation for human clinical trials, this technology was further developed by Tocagen, Inc.^[30] and is currently under clinical investigation in a Phase I/II trial for the potential treatment of recurrent high grade glioma including glioblastoma multiforme (GBM) and anaplastic astrocytoma.^[31]

In children

A brainstem glioma in four year old. MRI sagittal, without contrast

In the US, about 2000 children and adolescents younger than 20 years of age are diagnosed with malignant brain tumors each year. Higher incidence rates were reported in 1975–83 than in 1985–94. There is some debate as to the reasons; one theory is that the trend is the result of improved diagnosis and reporting, since the jump occurred at the same time that MRIs became available widely, and there was no coincident jump in mortality. The central nervous system (CNS) cancer survival rate in children is approximately 60%. The rate varies with the type of cancer and the age of onset: younger patients have higher mortality.^[32]

In children under 2, about 70% of brain tumors are medulloblastoma, ependymoma, and low-grade glioma. Less commonly, and seen usually in infants, are teratoma and atypical teratoid rhabdoid tumor.^[33] Germ cell tumors, including teratoma, make up just 3% of pediatric primary brain tumors, but the worldwide incidence varies significantly.^[34]

See also

• Craterization
• List of notable brain tumor patients
• Radiosurgery
• Stereotactic surgery
• Radiation therapy
• Grading of the tumors of the central nervous system
• Visualase Laser Technology for Tumor Ablation (LITT)

References

1. ^ http://nhg.artsennet.nl
2. ^ http://www.gezondheid.be/INDEX.cfm?fuseaction=art&art_id=2663
3. ^ Frei, P; Poulsen, AH, Johansen, C, Olsen, JH, Steding-Jessen, M, Schüz, J (2011 Oct 19). "Use of mobile phones and risk of brain tumours: update of Danish cohort study.". BMJ (Clinical research ed.) 343: d6387. PMID 22016439. 
4. ^ http://www.nlm.nih.gov/medlineplus/ency/article/002266.htm
5. ^ Frappaz D, Mornex F, Saint-Pierre G, Ranchere-Vince D, Jouvet A, Chassagne-Clement C, Thiesse P, Mere P, Deruty R. (1999). "Bone metastasis of glioblastoma multiforme confirmed by fine needle biopsy". Acta neurochirurgica (Wien) 141 (5): 551–552. doi:10.1007/s007010050342. PMID 10392217. 
6. ^ http://www.virtualtrials.com/serchfrm.cfm
7. ^ Nicolato A, Gerosa MA, Fina P, Iuzzolino P, Giorgiutti F, Bricolo A (Sep 1995). "Prognostic factors in low-grade supratentorial astrocytomas: a uni-multivariate statistical analysis in 76 surgically treated adult patients". Surg Neurol 44 (3): 208–21; discussion 221–3. doi:10.1016/0090-3019(95)00184-0. PMID 8545771. http://linkinghub.elsevier.com/retrieve/pii/0090-3019(95)00184-0. 
8. ^ Clinical trials in brain tumors.. Accessed June 2000.
9. ^ Radiosurgery treatment comparisons - Cyberknife, Gamma knife, Novalis Tx
10. ^ Treating secondary brain tumours with WBRT
11. ^ Whole Brain Radiation increases risk of learning and memory problems in cancer patients with brain metastases
12. ^ IRSA - International RadioSurgery Association - Metastatic brain tumors
13. ^ neurooncology ucla real-time survival data
14. ^ http://www.emedicinehealth.com/normal_pressure_hydrocephalus/page9_em.htm
15. ^ http://www.childhoodbraintumor.org/index.php?option=com_content&view=article&id=57:brain-stem-gliomas-in-childhood&catid=34:brain-tumor-types-and-imaging&Itemid=53
16. ^ http://brain.mgh.harvard.edu/patientguide.htm
17. ^ http://www.nhhs.net/ourpages/auto/2009/3/25/49144229/Ram_s%20second%20paper.pdf
18. ^ http://www.neurology.org/cgi/content/abstract/66/2/247
19. ^ http://www.neurology.org
20. ^ George I Jallo, MD, & Ethan A Benardete, MD, PhD (January 2010). Low-Grade Astrocytoma. http://emedicine.medscape.com/article/1156429-overview. 
21. ^ http://www-dep.iarc.fr
22. ^ http://www.statistics.gov.uk/downloads/theme_health/2007cancerfirstrelease.xls
23. ^ ^{a b} Greenlee RT, Murray T, Bolden S, Wingo PA (2000). "Cancer statistics, 2000". CA Cancer J Clin 50 (1): 7–33. doi:10.3322/canjclin.50.1.7. PMID 10735013. http://caonline.amcancersoc.org/cgi/reprint/50/1/7. 
24. ^ ^{a b} American Cancer Society. Accessed June 2000.
25. ^ Chamberlain MC, Kormanik PA (Feb 1998). "Practical guidelines for the treatment of malignant gliomas". West J Med. 168 (2): 114–20. PMC 1304839. PMID 9499745. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1304839. 
26. ^ Researchers Find Cancer-Killing Virus; July 24, 2000.
27. ^ Yale Lab Engineers Virus That Can Kill Deadly Brain Tumors; February 21, 2008.
28. ^ [1]; Christopher R. Logg, Chien-Kuo Tai, Aki Logg, W. French Anderson, Noriyuki Kasahara. Human Gene Therapy. May 2001, A Uniquely Stable Replication-Competent Retrovirus Vector Achieves Efficient Gene Delivery in Vitro and in Solid Tumors" 12(8): 921-932"
29. ^ [2]; Chien-Kuo Tai1, Wei Jun Wang, Thomas C. Chen and Noriyuki Kasahara, Molecular Therapy (2005) "Single-Shot, Multicycle Suicide Gene Therapy by Replication-Competent Retrovirus Vectors Achieves Long-Term Survival Benefit in Experimental Glioma" 12, 842–851
30. ^ http://www.tocagen.com
31. ^ [3]; Clinical Trials.gov (January 2011) "A Study of a Replication Competent Retrovirus Administered to Subjects With Recurrent Glioblastoma (GBM)"
32. ^ Gurney, James G; Smith, Malcolm A; Bunin, Greta R. "CNS and Miscellaneous Intracranial and Instraspinal Neoplasms" (PDF). SEER Pediatric Monograph. National Cancer Institute. pp. 51–52 (incidence); pp. 56–57 (trends); p. 57 (survival). http://seer.cancer.gov/publications/childhood/cns.pdf. Retrieved 4 December 2008. "[re incidence] In the US, approximately 2,200 children and adolescents younger than 20 years of age are diagnosed with malignant central nervous system tumors each year. More than 90 percent of primary CNS malignancies in children are located within the brain." 
33. ^ Infantile Brain Tumors by Brian Rood for The Childhood Brain Tumor Foundation (accessed July 2007)
34. ^ Echevarría ME, Fangusaro J, Goldman S (June 2008). "Pediatric central nervous system germ cell tumors: a review". Oncologist 13 (6): 690–9. doi:10.1634/theoncologist.2008-0037. PMID 18586924. 

External links

• UWO Brain tumors, Approach to..
• Management Neuro-oncology disorders
• Brain tumour information from Cancer Research UK
• UK brain and CNS tumour statistics from Cancer Research UK
• Brain and CNS cancers at the Open Directory Project
• WebMD: Brain Cancer Health Center
• Medical Image Database MR and CT Scans of Brain Tumors
• Medical Encyclopedia MayoClinic: Brain tumor
• Brain Tumor: Definitions Neurosurgery UCLA
• Medline Plus: Brain Cancer – Interactive Health Tutorials
• Cancer.Net: Brain Tumor - Information from the American Society of Clinical Oncology
• Brain Tumor Locations Differential Diagnosis
• MedPix Teaching File MR Scans of Primary Brain Lymphoma