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Brain tumor

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Overview

Brain tumor
Classification and external resources
ICD-9 191, 225.0
MedlinePlus 007222 000768
eMedicine emerg/334
NCI Brain tumor
MeSH D001932


Brain metastasis in the right cerebral hemisphere from lung cancer shown on magnetic resonance imaging. - Brain tumor
Brain metastasis in the right cerebral hemisphere from lung cancer shown on magnetic resonance imaging.

A brain tumor or intracranial neoplasm occurs when abnormal cells form within the brain.[1] There are two main types of tumors: malignant or cancerous tumors and benign tumors.[1] Cancerous tumors can be divided into primary tumors that started within the brain and those that spread from somewhere else known as brain metastasis tumors.[2] All types of brain tumors may produce symptoms that vary depending on the part of the brain involved.[1] These may include headaches, seizures, problem with vision, vomiting, and mental changes.[2] The headache is classically worst in the morning and goes away with vomiting.[1] More specific problems may include difficulty in walking, speaking and with sensation.[2][3] As the disease progresses unconsciousness may occur.[3]

The cause of most cases is unknown.[1] Risk factors that may occasionally be involved include a number of genetic syndrome such as neurofibromatosis as well as exposure to the chemical vinyl chloride, Epstein-Barr virus, and ionizing radiation.[1][2][3] While concern has been raised about mobile phone use the evidence is not clear.[3] The most common types of primary tumors in adults are: meningiomas and astrocytomas such as glioblastomas.[2] In children the most common type is medulloblastomas.[3] Diagnosis is usually by medical examination along with computed tomography or magnetic resonance imaging.[1] This is then often confirmed by biopsy.[2] Based on the finding the tumors are divided into different grades or severity.[2]

Treatment may include some combination of surgery, radiation therapy and chemotherapy.[2] Anticonvulsant medication is needed in those who have a seizure.[2] Dexamethasone and furosemide may be used to decrease swelling around the tumor.[2] Some tumors grow sufficiently slowly that all that is required is keeping an eye on it.[2] Treatments that use a person's immune system are being studied.[1] Outcome depends on the type of tumor.[3] Gliobastomas usually have poor outcomes while meningiomas usually have good outcomes.[3] The average five year survival rate for brain cancer in the United States is 33%.[4]

Metastatic brain tumors are more common than primary brain tumors,[1] with about half of metastasis coming from lung cancer.[1] Primary brain tumors occur in around 250,000 people a year globally, making up less than 2% of cancers.[3] In children less than 15, brain tumors are second only to acute lymphoblastic leukemia as a cause of cancer.[5] In Australia the average economic costs of a case of brain cancer is $1.9 million, the greatest of any type of cancer.[6]

Signs and symptoms

Visibility of signs and symptoms of brain tumors mainly depends on two factors: the tumor size (volume) and tumor location. The moment of symptom onset, when symptoms become apparent either to the person or people around them, 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 into three main categories:

The above symptoms are true for all types of neoplasm of the brain (including secondary tumors). It is common that a person carries a primary benign neoplasm for several years and have no visible symptoms at all. Many present some uncertain 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.

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, such as TP53, are thought to be the cause of some forms of brain tumors.[7] 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.

Although studies have not shown any link between cell phone radiation and brain tumors,[8] the World Health Organization has classified mobile phone radiation on the IARC scale into Group 2B – possibly carcinogenic. That means that there "could be some risk" of carcinogenicity, so additional research into the long-term, heavy use of mobile phones needs to be conducted.[9]

Pathophysiology

The main areas of the brain and limbic system - Brain tumor
The main areas of the brain and limbic system

Anatomy

For the purpose of understanding this article some summary notes about the human brain and its different types of organic tissues will be provided. When looking at the human brain in the picture on the right, 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, 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:

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 - Brain tumor
A posterior fossa tumor leading to mass effect and midline shift

The majority of the brain is separated from the blood by the blood-brain barrier (BBB) which exerts a restrictive control as to which substances are allowed to pass. Therefore many tracers that reach tumors in the body very easily would only reach brain tumors once there is a disruption of the BBB. Therefore the disruption of the BBB (blood-brain-barrier), which can be detected by a MRI and CT, is regarded as the main diagnostic indicator for malignant gliomas, meningiomas, and brain metastases.[10]

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. Brain tumors have similar characteristics and obstacles when it comes to diagnosis and therapy with tumors located elsewhere in the body. However, they create specific issues that follow closely to the properties of the organ they are in.[10]

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

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, especially magnetic resonance imaging (MRI) and computed tomography (CT)-scans. 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 edemas, 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.

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

Tumors have characteristics that allow determination of its malignacy, 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[11]

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 more common than primary ones; in the United States there are about 170,000 new cases every year. 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 form 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; this convention is not followed 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 does not mean that an infiltrative tumor does not take up space or does not 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 do not 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.[12])
  • 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.

Types

Tumors can be benign or malignant, can occur in different parts of the brain, and may or may not be primary tumors. A primary tumor is one that has started in the brain, as opposed to a metastatic tumor, which is something that has spread to the brain from another part of the body.[13] The incidence of metastatic tumors are more prevalent than primary tumors by 4:1.[14] Tumors may or may not be symptomatic: some tumors are discovered because the patient has symptoms, others show up incidentally on an imaging scan, or at an autopsy.

The most common primary brain tumors are:[15]

These common tumors can also be organized according to tissue of origin as shown below:[16][verification needed]

Tissue of origin

Children Adults
Astrocytes Pilocytic Astrocytoma (PCA) Glioblastoma Multiforme (GBM)
Oligodendrocytes Oligodendroglioma
Ependyma Ependymoma
Neurons Medulloblastoma
Meninges Meningioma

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 resection of the tumor with the objective of removing as many tumor cells as possible.
  • Radiotherapy: the most commonly used treatment for brain tumors; the tumor is irradiated with beta, x rays or gamma rays.
  • Chemotherapy: is a treatment option for cancer, however it is seldom used to treat brain tumors as the blood and brain barrier prevents the drugs from reaching the cancerous cells. Chemotherapy can be thought of as a poison that prevents the growth and division of all cells in the body including cancerous cells. This causes the significant side effects experienced by patients undergoing chemotherapy.
  • A variety of experimental therapies are available through clinical trials.[17]

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.[18]

Surgery

The primary and most desired course of action described in medical literature is surgical removal (resection) via craniotomy. Minimally invasive techniques are becoming the dominant trend in neurosurgical oncology.[19] 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 5-aminolevulinic acid that causes them to fluoresce.[20] 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 and the prognosis in such cases is determined by the primary tumor, but is generally poor.

Radiation therapy

The goal of radiation therapy is to 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. Forms used include stereotactic radiosurgery, such as Gamma knife, Cyberknife or Novalis Tx radiosurgery.[21][unreliable medical source?]

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, the most common, and brachytherapy and proton therapy, the last especially used for children.

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.[22] 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 MD 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.[23][24]

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.[25]

Other

A shunt may be used to relieve symptoms by reducing hydrocephalus caused by blockage of cerebrospinal fluid.[26]

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, focal brainstem gliomas in children, seems open to exceptional prognosis and long-term survival has frequently been reported.[27]

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, then by chemotherapy. Most patients with glioblastoma take a corticosteroid, typically dexamethasone, during their illness to palliate symptoms. Experimental treatments include gamma-knife radiosurgery,[28] boron neutron capture therapy and gene transfer.[29]

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".[30] A median survival of up to 16.7 years has been reported for low grade oligodendrogliomas.[31]

Epidemiology

The incidence of low-grade astrocytoma has not been shown to vary significantly with nationality. However, studies examining the incidence of malignant central nervous system (CNS) tumors have shown some variation with national origin. Since some 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.[32]

Worldwide data on incidence of cancer can be found at the WHO (World Health Organisation) and is handled by the IARC (International Agency for Research on Cancer) located in France.[33]

Figures for incidences of cancers of the brain show a significant difference between more- and less-developed countries (the less-developed countries have lower incidences of tumors of the brain) — this could be explained by undiagnosed tumor-related deaths (patients in extreme poor situations do not get diagnosed, simply because they do not 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 patient's life before tumors develop or tumors become life-threatening. Nevertheless studies[which?] suggest that certain forms of primary brain tumors are more prevalent among certain groups of the population.

United States

For the United States in the year 2005, it was projected that there would be 43,800 new cases of brain tumors [34][35] which accounted for less than 1 percent of all cancers, 2.4 percent of all cancer deaths,[36] and 20–25 percent of pediatric cancers.[36][37] Ultimately, it is estimated there are 13,000 deaths per year in the United States alone as a result of brain tumors.[35]

Research

Vesicular stomatitis virus

In 2000, researchers at the University of Ottawa, led by John Bell, discovered that the vesicular stomatitis virus, or VSV, can infect and kill cancer cells, without affecting healthy cells if coadministered with interferon.[38][39]

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.[40][unreliable medical source?]

Retroviral replicating vectors

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

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.[41] 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.[42][unreliable medical source?] Subsequently, in preparation for human clinical trials, this technology was further developed by Tocagen, Inc. (Toca 511 & Toca FC) It has been under investigation since 2010 in a Phase I/II clinical trial for the potential treatment of recurrent high grade glioma including glioblastoma multiforme (GBM) and anaplastic astrocytoma. No results have yet been published.[43]

Children

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 1985–94 than in 1975–83. 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.[44]

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.[45] Germ cell tumors, including teratoma, make up just 3% of pediatric primary brain tumors, but the worldwide incidence varies significantly.[46]

See also

References

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