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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.
 
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.
   
== Brain tumors in infants and children ==
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====By behavior====
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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.
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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:
   
In 2000 approximately 2.76 children per 100,000 were affected by a [[brain tumor|CNS tumor]] in the United States. This rate has been increasing and by 2005 was 3.0 children per 100,000. This is approximately 2,500-3,000 pediatric brain tumors occurring each year in the US. The tumor incidence is increasing by about 2.7% per year.
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* uncontrolled mitosis (growth by division beyond the normal limits)
The [[Central Nervous System|CNS]] Cancer survival rate in children is approximately 60%.<ref>[http://seer.cancer.gov/publications/childhood/cns.pdf See Table 11.2 Survival Rate]</ref> However, this rate varies with the age of onset (younger has higher mortality) and cancer type.
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* [[anaplasia]]: the cells in the neoplasm have an obviously different form (in size and shape). Anaplastic cells display marked [[pleomorphism (cytology)|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 ([[syncytium|syncytia]]). Anaplastic nuclei are variable and bizarre in size and shape.
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* 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):
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** 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.
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** 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.
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* [[metastasis]] (spread to other locations in the body via lymph or blood).
   
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 [[ATRT|atypical teratoid rhabdoid tumor]].<ref>[http://www.childhoodbraintumor.org/InfantileBrainTumors.html ''Infantile Brain Tumors'' by Brian Rood for The Childhood Brain Tumor Foundation] (accessed July 2007)</ref>
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Of the above malignant characteristics, some elements do not apply to primary neoplasms of the brain:
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* 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]].<ref>{{cite journal |author1=Frappaz D. |author2=Mornex F. |author3=Saint-Pierre G. |author4=Ranchere-Vince D. |author5=Jouvet A. |author6=Chassagne-Clement C. |author7=Thiesse P. |author8=Mere P. |author9=Deruty R. |title=Bone metastasis of glioblastoma multiforme confirmed by fine needle biopsy |journal=Acta neurochirurgica (Wien) |volume=141 |issue=5 |pages=551–552 |year=1999 |pmid=10392217 |doi=10.1007/s007010050342}}</ref>)
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* 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.
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Of numerous [[Grading of the tumors of the central nervous system|grading systems]] in use for the classification of tumor of the central nervous system, the [[World Health Organization]] [[Grading of the tumors of the central nervous system#WHO grading|(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.
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==Signs and symptoms==
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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).
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Symptoms of solid neoplasms of the brain (primary brain tumors and secondary tumors alike) can be divided in 3 main categories:
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* 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 [[human skull|skull]] and bulging of the [[fontanelle]]s.
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* Dysfunction: depending on the tumor location and the damage it may have caused to surrounding [[Human brain|brain]] structures, either through compression or infiltration, any type of [[focal neurologic symptom]]s may occur, such as [[cognitive]] and [[behavioral]] impairment (including impaired judgment, memory loss, lack of recognition, spatial orientation disorders), [[Wiktionary:personality|personality]] or emotional changes, [[hemiparesis]], [[hypoesthesia]], [[aphasia]], [[ataxia]], [[visual field]] impairment, impaired sense of smell, impaired hearing, [[facial paralysis]], [[diplopia|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 dysfunction—either [[hypopituitarism]] or hyperproduction of pituitary [[hormones]] and [[hyperprolactinemia]] is suggestive of a pituitary tumor.
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* Irritation: abnormal fatigue, weariness, absences and [[tremor]]s, but also [[epilepsy|epileptic seizures]].
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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.
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When a person suffering from a metastasized cancer is diagnosed, a scan of the skull frequently reveals secondary tumors.
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In a recent study by the Dutch GP Association, a list of causes of headaches<ref>{{cite web|author=Gezondheid nv |url=http://www.gezondheid.be/INDEX.cfm?fuseaction=art&art_id=2663 |title=Alles over hoofdpijn |publisher=Gezondheid.be |date=2005-04-13 |accessdate=2012-02-17}}</ref> 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):
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{| class="wikitable"
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|-
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! Alarm signals
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! Possible cause
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|-
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| First headache complaint from person over 50 years old
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| brain tumor, [[Giant-cell arteritis|arteriïtis temporalis]]
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|-
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| First migraine attack in person over 40 years old
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| brain tumor
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|-
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| Headache in person under 6 years old
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| brain tumor, [[hydrocephalus]]
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|-
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| Person over 50 years old with pain at temples
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| [[Giant-cell arteritis|arteriïtis temporalis]]
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|-
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| Pregnancy with unknown [[headache]]
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| [[pre-eclampsia]]
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|-
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| Increased headaches after trauma
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| sub/epidural [[hematoma]]
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|-
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| Severe headaches and very high blood pressure
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| [[malignant hypertension]]
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|-
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| Acute severe headache
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| [[meningitis]], [[Cerebrovascular accident|CVA]] (Cerebrovascular accident or stroke), [[subarachnoidal hemorrhage]]
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|-
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| Headache and fever (with reduced consciousness)
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| meningitis
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|-
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| Stiffness of the neck/neurological dysfunction
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| meningitis, brain tumor
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|-
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| Headache with signs of elevated [[intracranial pressure]]
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| brain tumor
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|-
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| Focal neurological dysfunction
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| brain tumor
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|-
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| Early morning vomiting or vomiting unrelated to headache or other illness
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| brain tumor
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|-
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| Behavioral changes or rapid decline in school results
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| brain tumor
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|}
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==Cause==
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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 gene]]s 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.
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Although studies have not shown any link between [[Mobile phone radiation and health|cell phone radiation]] and brain tumors,<ref>{{cite journal|last=Frei|first=P|coauthors=Poulsen, AH, Johansen, C, Olsen, JH, Steding-Jessen, M, Schüz, J|title=Use of mobile phones and risk of brain tumours: update of Danish cohort study.|journal=BMJ (Clinical research ed.)|date=2011 Oct 19|volume=343|pages=d6387|pmid=22016439|doi=10.1136/bmj.d6387|pmc=3197791}}</ref> the [[World Health Organization]] has classified mobile phone radiation on the [[International Agency for Research on Cancer|IARC]] scale into [[List of IARC Group 2B carcinogens|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.<ref name="WHO_IARC_110531">{{cite press release|url= http://www.iarc.fr/en/media-centre/pr/2011/pdfs/pr208_E.pdf |format= PDF|title= IARC classifies radiofrequency electromagnetic fields as possibly carcinogenic to humans|work= [[World Health Organization]] press release N° 208|publisher= [[International Agency for Research on Cancer]]|date= 2011-05-31|accessdate= 2011-06-02}}</ref>
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==Types==
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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 [[metastasis|metastatic]] tumor, which is something that has spread to the brain from another part of the body.<ref>{{cite web|url=http://www.cancer.gov/cancertopics/wyntk/brain/page1|title=What you need to know about brain tumors|accessdate=February 25, 2012|publisher=National Cancer Institute}}</ref> 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.
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The most common primary brain tumors are:<ref>{{Cite book
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| publisher = Springer
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| isbn = 978-1-84882-910-7
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| editor = Lee, Joung H.
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| author=Park, Bong Jin; Kim, Han Kyu; Sade, Burak; Lee, Joung H.
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| chapter=Epidemiology
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| title = Meningiomas: Diagnosis, Treatment, and Outcome
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| year = 2009
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|page=11
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}}
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</ref>
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* [[Gliomas]] (50.3%)
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* [[Meningiomas]] (20.9%)
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* [[Pituitary adenomas]] (15%)
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* [[Nerve sheath tumors]] (8%)
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==Pathophysiology==
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[[Image:Vertebrate-brain-regions.png|thumb|alt=Corresponding regions of human and shark brain are shown. The shark brain is splayed out, while the human brain is more compact. The shark brain starts with the medulla, which is surrounded by various structures, and ends with the telencephalon. The cross-section of the human brain shows the medulla at the bottom surrounded by the same structures, with the telencephalon thickly coating the top of the brain. |Main anatomical regions of the vertebrate brain]]
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===Anatomy===
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From the [[Human brain|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.
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When reading 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.
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===Meninges===
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Human brains are surrounded by a system of [[connective tissue]] membranes called [[meninges]] that separate the [[Human skull|skull]] from the [[Human brain|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 [[Ventricular system|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.
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Tumors of the meninges are [[meningioma]] and are often [[benign neoplasms]].
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===Brain matter===
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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:
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*[[telencephalon]] (cerebral hemispheres or [[cerebrum]])
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*[[mesencephalon]] (midbrain)
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*[[cerebellum]]
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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.
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Primary tumors of the glial cells are called [[Glioma]] and often are malignant by the time they are diagnosed.
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===Spinal cord and other tissues===
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*The pink area in picture is called the [[pons]] and is a specific region that consists of myelinated axons much like the spinal cord
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*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
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*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==
 
==Diagnosis==
Although there is no specific clinical symptom or sign for brain tumors, slowly progressive [[focal neurologic signs]] and signs of elevated intracranial pressure, as well as epilepsy in a patient with a negative history for epilepsy should raise red flags. However, a sudden onset of symptoms, such as an [[epilepsy|epileptic seizure]] in a patient with no prior history of epilepsy, sudden [[intracranial hypertension]] (this may be due to bleeding within the tumor, brain swelling or obstruction of [[cerebrospinal fluid]]'s passage) is also possible.
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[[File:Postermass.png|thumb|A posterior fossa tumor leading to mass effect and midline shift]]
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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.
   
Symptoms include phantom [[odor]]s and [[taste]]s. Often, in the case of metastatic tumors, the smell of [[vulcanized rubber]] is prevalent.{{Fact|date=March 2007}}
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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, [[otolaryngology|otolaryngological]] (or ENT) and/or electrophysiological exams. The use of [[electroencephalography]] (EEG) often plays a role in the diagnosis of brain tumors.
   
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 modalities, such as [[computed tomography]] (CT) and especially [[magnetic resonance imaging]] (MRI). 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. Perifocal edema also appears hyperintense on T2-weighted MRI. [[Contrast agent]] uptake, sometimes in characteristic patterns, can be demonstrated on either CT or MRI-scans in most malignant primary and metastatic brain tumors. This is due to the fact that these tumors disrupt the normal functioning of the [[blood-brain barrier]] and lead to an increase in its permeability.
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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 [[human skull|skull]] and bulging of the [[fontanelle]]s. More complex symptoms such as endocrine dysfunctions should alarm doctors not to exclude brain tumors.
   
Electrophysiological exams, such as [[electroencephalography]] (EEG) play a marginal role in the diagnosis of brain tumors.
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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 symptom]]s, such as [[cognitive]] and [[behavioral]] impairment (including impaired judgment, memory loss, lack of recognition, spatial orientation disorders), [[Wiktionary:personality|personality]] or emotional changes, [[hemiparesis]], [[hypoesthesia]], [[aphasia]], [[ataxia]], [[visual field]] impairment, impaired sense of smell, impaired hearing, [[facial paralysis]], [[diplopia|double vision]], or more severe symptoms such as [[tremor]]s, 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.
   
The definitive [[diagnosis]] of brain tumor can only be confirmed by [[histology|histological examination]] of [[tumor]] [[Biological tissue|tissue]] samples obtained either by means of brain [[biopsy]] or open [[surgery]]. The histologic examination is essential for determining the appropriate treatment and the correct [[prognosis]].
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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.
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* 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.
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*[[Contrast agent]] uptake, sometimes in characteristic patterns, can be demonstrated on either CT or MRI-scans in most malignant primary and metastatic brain tumors.
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*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)
   
To identify whether a person has a brain tumor [http://www.rapidtest.com/listB.html ELISA test kit] could be a help. It can identify different substances in our body.
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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.
   
==Treatment and prognosis==
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{{Reference necessary|text=[[Glioblastoma multiforme]] and [[astrocytoma|anaplastic astrocytoma]] have been associated{{By whom|date=July 2009}} with the genetic acute hepatic [[porphyria]]s ([[porphyria cutanea tarda|PCT]], [[acute intermittent porphyria|AIP]], [[hereditary coproporphyria|HCP]] and [[variegate porphyria|VP]]), including positive testing associated with drug refractory seizures.|date=December 2011}} Unexplained complications associated with drug treatments with these tumors should alert physicians to an undiagnosed neurological porphyria.
[[Meningiomas]], with the exception of some tumors located at the [[skull base]], can be successfully removed surgically, but the chances are less than 50%. In more difficult cases, [[stereotactic]] [[radiosurgery]], such as [[Gamma Knife]] [[radiosurgery]], remains a viable option.
 
   
Most [[pituitary adenoma]]s can be removed surgically, often using a minimally invasive approach through the [[nasal cavity]] and [[skull base]] ([[trans-nasal, trans-sphenoidal approach]]). Large [[pituitary adenoma]]s require a [[craniotomy]] (opening of the skull) for their removal. Radiotherapy, including [[stereotactic]] approaches, is reserved for the inoperable cases.
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The definitive [[medical diagnosis|diagnosis]] of brain tumor can only be confirmed by [[histology|histological examination]] of [[tumor]] [[Biological tissue|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.
   
Although there is no generally accepted therapeutic management for primary brain tumors, a surgical attempt at tumor removal or at least [[cytoreduction]] (that is, removal of as much tumor as possible, in order to reduce the number of tumor cells available for proliferation) is considered in most cases.<ref>Nakamura M, Konishi N, Tsunoda S, Nakase H, Tsuzuki T, Aoki H, Sakitani H, Inui T, Sakaki T. ''Analysis of prognostic and survival factors related to treatment of low-grade astrocytomas in adults.'' Oncology 2000;58:108-16. PMID 10705237.</ref> However, due to the infiltrative nature of these lesions, tumor recurrence, even following an apparently complete surgical removal, is not uncommon. 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.
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===Pathology===
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[[Image:Oligodendroglioma1 high mag.jpg|thumb|[[Micrograph]] of an [[oligodendroglioma]], a type of brain cancer. Brain [[biopsy]]. [[H&E stain]].]]
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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.
   
Survival rates in primary brain tumors depend on the type of tumor, age, functional status of the patient, the extent of surgical tumor removal, to mention just a few factors.<ref>Nicolato A, Gerosa MA, Fina P, Iuzzolino P, Giorgiutti F, Bricolo A. ''Prognostic factors in low-grade supratentorial astrocytomas: a uni-multivariate statistical analysis in 76 surgically treated adult patients.'' Surg Neurol 1995;44:208-21; discussion 221-3. PMID 8545771.</ref>
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[[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).
   
Patients with benign gliomas may survive for many years<ref>Janny P, Cure H, Mohr M, Heldt N, Kwiatkowski F, Lemaire JJ, Plagne R, Rozan R. ''Low grade supratentorial astrocytomas. Management and prognostic factors.'' Cancer 1994;73:1937-45. PMID 8137221.</ref><ref>Piepmeier J, Christopher S, Spencer D, Byrne T, Kim J, Knisel JP, Lacy J, Tsukerman L, Makuch R. ''Variations in the natural history and survival of patients with supratentorial low-grade astrocytomas.'' Neurosurgery 1996;38:872-8; discussion 878-9. PMID 8727811.</ref>
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[[Atypia]]: is an indication of abnormality of a cell (which may be indicative for malignancy). Significance of the abnormality is highly dependent on context.
while survival in most cases of [[glioblastoma multiforme]] is limited to a few months after diagnosis.
 
   
The main treatment option for single metastatic tumors is surgical removal, followed by radiotherapy and/or chemotherapy. Multiple metastatic tumors are generally treated with radiotherapy ''and'' chemotherapy. [[Stereotactic]] [[radiosurgery]], such as [[Gamma Knife]] [[radiosurgery]], remains a viable option.
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[[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 [[Parenchyma|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
However, the prognosis in such cases is determined by the primary tumor, and it is generally poor.
+
  +
[[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<ref name=necrs>{{cite web|url=http://www.nlm.nih.gov/medlineplus/ency/article/002266.htm |title=Necrosis: MedlinePlus Medical Encyclopedia |publisher=Nlm.nih.gov |date=2012-02-07 |accessdate=2012-02-17}}</ref>
  +
  +
Arterial and venous [[hypoxia (medical)|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.
  +
  +
==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. Thus the significant side effects associated and experienced by patients undergoing chemotherapy.
  +
* A variety of experimental therapies are available through clinical trials<ref>The Musella Foundation For Brain Tumor Research & Information, Inc ''[http://www.virtualtrials.com/serchfrm.cfm Clinical Trials and Noteworthy Treatrmets for Brain Tumors]'' Retrieved 2012-06-03.</ref>
  +
  +
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.<ref>{{cite journal |author=Nicolato A, Gerosa MA, Fina P, Iuzzolino P, Giorgiutti F, Bricolo A |title=Prognostic factors in low-grade supratentorial astrocytomas: a uni-multivariate statistical analysis in 76 surgically treated adult patients |journal=Surg Neurol |volume=44 |issue=3 |pages=208–21; discussion 221–3 |year=1995 |month=Sep |pmid=8545771 |url=http://linkinghub.elsevier.com/retrieve/pii/0090-3019(95)00184-0 |doi=10.1016/0090-3019(95)00184-0}}</ref>
  +
  +
===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 adenoma]]s can be removed surgically, often using a minimally invasive approach through the [[nasal cavity]] and skull base (trans-nasal, trans-sphenoidal approach). Large [[pituitary adenoma]]s 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 [[Aminolevulinic acid|5-aminolevulinic acid]] that causes them to [[Fluorescence|fluoresce]].<ref name="Brain tumor clinical trials database">{{cite web |url= http://www.cliniclog.com/brain_tumour_trials.php |title=Introduction to brain cancer |work=cliniclog.com |author=Paul Brennan |accessdate=December 19, 2011|date=August 4, 2008.}}</ref> 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 [[epilepsy|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 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 radiosurgery|Novalis Tx]] [[radiosurgery]].<ref>[http://www.sdcyberknife.com/comparison.htm Radiosurgery treatment comparisons - Cyberknife, Gamma knife, Novalis Tx]</ref>
  +
  +
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.<ref>Cancer Research UK ''[http://www.cancerhelp.org.uk/help/default.asp?page=5301 Treating secondary brain tumours with WBRT]'' Retrieved 2012-06-05</ref> 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.<ref>MD Anderson Cancer Center ''[http://www.mdanderson.org/diseases/braincancer/display.cfm?id=8f11775f-75bb-4d7b-b3ac46878a1d56d0&method=displayfull&pn=00c8a30f-c468-11d4-80fb00508b603a14 Whole Brain Radiation increases risk of learning and memory problems in cancer patients with brain metastases]'' Retrieved 2012-06-05</ref><ref>International RadioSurgery Association ''[http://www.irsa.org/metastatic_tumors.html Metastatic brain tumors]'' Retrieved 2012-06-05</ref>
  +
  +
===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.<ref>UCLA Neuro-Oncology Program ''[http://www.neurooncology.ucla.edu/Performance/GlioblastomaMultiforme.aspx How Our Patients Perform : Glioblastoma Multiforme]'' Retrieved 2012-06-05</ref>
  +
  +
===Other===
  +
A [[Shunt (medical)|shunt]] is used not as a cure but to relieve symptoms by reducing hydrocephalus caused by blockage of [[cerebrospinal fluid]].<ref>{{cite web|author=February 17, 2012 |url=http://www.emedicinehealth.com/normal_pressure_hydrocephalus/page9_em.htm |title=Normal Pressure Hydrocephalus Causes, Symptoms, Treatment - Next Steps on eMedicineHealth |publisher=Emedicinehealth.com |date= |accessdate=2012-02-17}}</ref>
  +
  +
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 [[Medulloblastoma#Treatment and prognosis|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<ref>{{cite web|url=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 |title=Brain Stem Gliomas in Childhood |publisher=Childhoodbraintumor.org |date= |accessdate=2012-02-17}}</ref> seems open to exceptional prognosis and long-term survival has frequently been reported.
  +
  +
===Glioblastoma multiforme===
  +
{{Main|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 [[Segmental resection|resection]] of the tumor, followed by radiotherapy between two and four weeks after the [[craniotomy|surgical procedure]] to remove the cancer. This is followed by [[temozolomide|chemotherapy]]. Most patients with glioblastoma take a [[corticosteroid]], typically [[dexamethasone]], during their illness to palliate symptoms. Experimental treatments include [[gamma-knife radiosurgery]],<ref>{{cite web|url=http://brain.mgh.harvard.edu/patientguide.htm |title=GBM Guide - MGH Brain Tumor Center |publisher=Brain.mgh.harvard.edu |date= |accessdate=2012-02-17}}</ref> [[boron neutron capture therapy]] and [[gene transfer]].<ref>Chien-Kuo Tai, Noriyuki Kasahara ''[http://www.nhhs.net/ourpages/auto/2009/3/25/49144229/Ram_s%20second%20paper.pdf Replication-competent retrovirus vectors for cancer gene therapy]'' Frontiers in Bioscience 13, 3083-3095, January 1, 2008</ref>
  +
  +
===Oligodendrogliomas===
  +
{{Main|Oligodendroglioma}}
  +
Oligodendroglioma is an incurable but slowly progressive malignant brain tumor. They can be treated with [[Segmental resection|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".<ref>{{cite web|url=http://www.neurology.org/cgi/content/abstract/66/2/247 |title=Oligodendroglial tumor chemotherapy using "decreased-dose-intensity" PCV: A Singapore experience |publisher=Neurology.org |date=2006-01-24 |accessdate=2012-02-17}}</ref> A median survival of up to 16.7 years has been reported for low grade [[oligodendrogliomas]].<ref>{{cite web|url=http://www.neurology.org |title=Neurology |publisher=Neurology |date= |accessdate=2012-02-17}}</ref>
  +
  +
==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.<ref name=gallo>{{cite journal|author=George I Jallo, MD, & Ethan A Benardete, MD, PhD|title=Low-Grade Astrocytoma|year=2010|month=January|url=http://emedicine.medscape.com/article/1156429-overview}}</ref>
  +
  +
<!--{{cite journal |author=Ana M Crespo-Rodríguez; James G Smirniotopoulos; Elisabeth J Rushing |title=MR and CT imaging of 24 pleomorphic xanthoastrocytomas (PXA) and a review of the literature. |journal= Neuroradiology |volume=49 |issue= 4|pages=307–15 |year=2007 |month=April |pmid=17205313 |doi= 10.1007/s00234-006-0191-z|url=http://www.biomedsearch.com/nih/MR-CT-imaging-24-pleomorphic/17205313.html}} -->
  +
  +
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.<ref>{{cite web|url=http://www-dep.iarc.fr |title=CANCERMondial |publisher=Dep.iarc.fr |date= |accessdate=2012-02-17}}</ref>
  +
  +
<!-- following tables were extracted from the online database GloboCancer :
  +
*[[Regional Summary of Occurence of cancers of the Brain & nervous system in Women]],
  +
*[[Regional Summary of Occurence of cancers of the Brain & nervous system in Men]],
  +
*[[Country based Incidence Rate of cancers of the Brain & nervous system in Women]],
  +
*[[Country based Incidence Rate of cancers of the Brain & nervous system in Men]]
  +
Some conclusions can be drawn from these figures. -->
  +
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 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 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 diagnoses of malignant neoplasms of the brain for the year 2007 (in absolute figures and in rates per 100,000)<ref>Cancer Research UK ''[http://info.cancerresearchuk.org/cancerstats/types/brain/incidence/ Brain and other CNS tumours - UK incidence statistics]'' Updated: 19 July 2011</ref>:
  +
  +
{| class="wikitable"
  +
|-
  +
!Measures || Sex || 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+
  +
|-
  +
| rowspan="2"| Absolute figures || M || || 2,131 || 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
  +
|-
  +
| rowspan="2"|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
  +
|}
  +
  +
===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),<ref name=r1>{{cite journal |author=Greenlee RT, Murray T, Bolden S, Wingo PA |title=Cancer statistics, 2000 |journal=CA Cancer J Clin |volume=50 |issue=1 |pages=7–33 |year=2000 |pmid=10735013|url=http://onlinelibrary.wiley.com/doi/10.3322/canjclin.50.1.7/full |doi=10.3322/canjclin.50.1.7}}</ref> which accounted for less than 1 percent of all cancers, 2.4 percent of all cancer deaths,<ref name=r2>American Cancer Society, Inc.[http://www.cancer.org/Cancer/BrainCNSTumorsinAdults/DetailedGuide/brain-and-spinal-cord-tumors-in-adults-key-statistics What are the key statistics about brain and spinal cord tumors?] Last Revised: 01/05/2012</ref> and 20–25 percent of pediatric cancers.<ref name=r2/><ref>{{cite journal |author=Chamberlain MC, Kormanik PA |title=Practical guidelines for the treatment of malignant gliomas |journal=West J Med. |volume=168 |issue=2 |pages=114–20 |year=1998 |month=Feb |pmid=9499745 |pmc=1304839 }}</ref> Ultimately, it is estimated there are 13,000 deaths per year in the United States alone as a result of brain tumors.<ref name=r1/>
  +
  +
==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]].<ref>Rebecca Auer, John C Bell ''[http://www.futuremedicine.com/doi/full/10.2217/fon.11.134 Oncolytic viruses: smart therapeutics for smart cancers]'' Future Oncology January 2012, Vol. 8, No. 1, Pages 1-4 doi:10.2217/fon.11.134</ref><ref>Ken Garber ''[http://jnci.oxfordjournals.org/content/98/5/298.full China Approves World's First Oncolytic Virus Therapy For Cancer Treatment]'' JNCI (1 March 2006) 98 (5): 298-300; doi:10.1093/jnci/djj111
  +
  +
</ref>
  +
  +
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 [[mouse|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.<ref>Yale University ''[http://opa.yale.edu/news/article.aspx?id=1488 Yale Lab Engineers Virus That Can Kill Deadly Brain Tumors]''; February 21, 2008.</ref>
  +
  +
===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.<ref>; Christopher R. Logg, Chien-Kuo Tai, Aki Logg, W. French Anderson, Noriyuki Kasahara. Human Gene Therapy. May 2001, ''[http://www.liebertonline.com/doi/abs/10.1089/104303401750195881 A Uniquely Stable Replication-Competent Retrovirus Vector Achieves Efficient Gene Delivery in Vitro and in Solid Tumors]'' 12(8): 921-932"</ref> 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.<ref>Chien-Kuo Tai1, Wei Jun Wang, Thomas C. Chen and Noriyuki Kasahara, Molecular Therapy (2005) ''[http://www.nature.com/mt/journal/v12/n5/full/mt20051365a.html Single-Shot, Multicycle Suicide Gene Therapy by Replication-Competent Retrovirus Vectors Achieves Long-Term Survival Benefit in Experimental Glioma]'' 12, 842–851</ref> Subsequently, in preparation for human clinical trials, this technology was further developed by Tocagen, Inc. ([[Toca 511 & Toca FC]]) 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.<ref>Clinical Trials.gov (January 2011) ''[http://clinicaltrials.gov/ct2/show/NCT01156584?term=toca+511&rank=1 A Study of a Replication Competent Retrovirus Administered to Subjects With Recurrent Glioblastoma (GBM)]</ref>
  +
  +
  +
== Brain tumors in infants and children ==
  +
[[Image:Tumor BrainstemGlioma2.JPG|thumb|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 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 [[Magnetic resonance imaging|MRIs]] became available widely, and there was no coincident jump in [[Mortality rate|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.<ref>{{cite web |url= http://seer.cancer.gov/publications/childhood/cns.pdf|format= PDF|title= CNS and Miscellaneous Intracranial and Instraspinal Neoplasms|accessdate= 4 December 2008|last= Gurney|first= James G|coauthors= Smith, Malcolm A; Bunin, Greta R|date= |work= SEER Pediatric Monograph|publisher= [[National Cancer Institute]]|pages= 51–52 (incidence); pp. 56–57 (trends); p. 57 (survival)|quote= <nowiki>[</nowiki>re incidence<nowiki>]</nowiki> 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.}}</ref>
  +
  +
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 [[ATRT|atypical teratoid rhabdoid tumor]].<ref>[http://www.childhoodbraintumor.org/InfantileBrainTumors.html ''Infantile Brain Tumors'' by Brian Rood for The Childhood Brain Tumor Foundation] (accessed July 2007)</ref> [[Germ cell tumor]]s, including [[teratoma]], make up just 3% of pediatric primary brain tumors, but the worldwide incidence varies significantly.<ref name=pmid18586924>{{cite journal
  +
| author = Echevarría ME, Fangusaro J, Goldman S
  +
| title = Pediatric central nervous system germ cell tumors: a review
  +
| journal = Oncologist
  +
| volume = 13
  +
| issue = 6
  +
| pages = 690–9
  +
| year = 2008
  +
| month = June
  +
| pmid = 18586924
  +
| doi = 10.1634/theoncologist.2008-0037
  +
}}</ref>
   
A shunt operation is used not as a cure but to relieve the symptoms.[http://www.emedicinehealth.com/normal_pressure_hydrocephalus/page9_em.htm] The [[hydrocephalus]] caused by the blocking [[drainage]] of the [[cerebrospinal fluid]] can be removed with this operation.
 
   
 
==See also==
 
==See also==
 
*[[ICD-10 Chapter II: Neoplasms; Chapter III: Diseases of the blood and blood-forming organs, and certain disorders involving the immune mechanism]]
 
*[[ICD-10 Chapter II: Neoplasms; Chapter III: Diseases of the blood and blood-forming organs, and certain disorders involving the immune mechanism]]
  +
*[[Craterization]]
  +
*[[List of notable brain tumor patients]]
  +
*[[Radiosurgery]]
  +
*[[Stereotactic surgery]]
  +
*[[Radiation therapy]]
  +
*[[Grading of the tumors of the central nervous system]]
   
 
==References==
 
==References==
Line 100: Line 105:
   
 
==External links==
 
==External links==
[http://rad.usuhs.edu/rad/location/location_frame.html Brain Lesion Locator] Differential Diagnosis of Brain Lesions
+
* [http://www.cancerhelp.org.uk/type/brain-tumour/ Brain tumour information] from [[Cancer Research UK]]
+
* [http://www.cancer.net/cancer-types/brain-tumor Cancer.Net: Brain Tumor] - Information from the [[American Society of Clinical Oncology]]
+
* [http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/NeuroOncology/default.htm Neuro-Oncology:] Cancer Management Guidelines
  +
* [http://www.mayoclinic.com/health/brain-tumor/DS00281 MayoClinic: Brain tumor] Medical Encyclopedia
  +
* [http://neurosurgery.ucla.edu/body.cfm?id=294 Brain Tumor:] Definitions Neurosurgery UCLA
  +
* [http://rad.usuhs.edu/medpix/kiosk_image.html?pt_id=13381&imageid=52032 MedPix Teaching File] MR Scans of Primary Brain Lymphoma, etc.
  +
* {{DMOZ|/Health/Conditions_and_Diseases/Cancer/Brain_and_CNS/|Brain and CNS cancers}}
   
   
 
{{Nervous tissue tumors}}
 
{{Nervous tissue tumors}}
   
  +
{{DEFAULTSORT:Brain Tumor}}
  +
[[Category:Brain disorders]]
  +
[[Category:Brain neoplasms]]
  +
[[Category:Disorders causing seizures]]
  +
[[Category:Nervous system neoplasms]]
   
 
<!--
 
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Brain met.jpg|
Brain tumor
ICD-10 C71, D33.0-D33.2
ICD-9 191, 225.0
OMIM [1]
DiseasesDB 30781
MedlinePlus 007222 000768
eMedicine emerg/334
MeSH {{{MeshNumber}}}

A brain tumor is any intracranial tumor created by abnormal and uncontrolled cell division, normally either in the brain itself (neurons, glial cells (astrocytes, oligodendrocytes, ependymal cells), lymphatic tissue, blood vessels), in the cranial nerves (myelin-producing Schwann cells), in the brain envelopes (meninges), skull, pituitary and pineal gland, or spread from cancers primarily located in other organs (metastatic tumors). 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. In the United States in the year 2005, it was estimated that 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),[1] which accounted for 1.4 percent of all cancers, 2.4 percent of all cancer deaths,[2] and 20–25 percent of pediatric cancers.[2][3] Ultimately, it is estimated that there are 13,000 deaths/year as a result of brain tumors.[1]



ClassificationEdit

Primary tumorsEdit

Tumors occurring in the brain include: astrocytoma, pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor, oligodendrogliomas, ependymoma, glioblastoma multiforme, mixed gliomas, oligoastrocytomas, medulloblastoma, retinoblastoma, neuroblastoma, germinoma and teratoma.

Most primary brain tumors originate from glia (gliomas) such as astrocytes (astrocytomas), oligodendrocytes (oligodendrogliomas), or ependymal cells (ependymoma). There are also mixed forms, with both an astrocytic and an oligodendroglial cell component. These are called mixed gliomas or oligoastrocytomas. Plus, mixed glio-neuronal tumors (tumors displaying a neuronal, as well as a glial component, e.g. gangliogliomas, disembryoplastic neuroepithelial tumors) and tumors originating from neuronal cells (e.g. gangliocytoma, central gangliocytoma) can also be encountered.

Other varieties of primary brain tumors include: primitive neuroectodermal tumors (PNET, e.g. medulloblastoma, medulloepithelioma, neuroblastoma, retinoblastoma, ependymoblastoma), tumors of the pineal parenchyma (e.g. pineocytoma, pineoblastoma), ependymal cell tumors, choroid plexus tumors, neuroepithelial tumors of uncertain origin (e.g. gliomatosis cerebri, astroblastoma), etc.

From a histological perspective, astrocytomas, oligondedrogliomas, oligoastrocytomas, and teratomas may be benign or malignant. Glioblastoma multiforme represents the most aggressive variety of malignant glioma. At the opposite end of the spectrum, there are so-called pilocytic astrocytomas, a distinct variety of astrocytic tumors. The majority of them are located in the posterior cranial fossa, affect mainly children and young adults, and have a clinically favorable course and prognosis. Teratomas and other germ cell tumors also may have a favorable prognosis, although they have the capacity to grow very large.

Another type of primary intracranial tumor is primary cerebral lymphoma, also known as primary CNS lymphoma, which is a type of non-Hodgkin's lymphoma that is much more prevalent in those with severe immunosuppression, e.g. AIDS.

In contrast to other types of cancer, primary brain tumors rarely metastasize, and in this rare event, the tumor cells spread within the skull and spinal canal through the cerebrospinal fluid, rather than via bloodstream to other organs.

There are various classification systems currently in use for primary brain tumors, the most common being the World Health Organization (WHO) brain tumor classification, introduced in 1993.

Secondary tumors and non-tumor lesionsEdit

Secondary or metastatic brain tumors originate from malignant tumors (cancers) located primarily in other organs. Their incidence is higher than that of primary brain tumors. The most frequent types of metastatic brain tumors originate in the lung, skin (malignant melanoma), kidney (hypernephroma), breast (breast carcinoma), and colon (colon carcinoma). These tumor cells reach the brain via the blood-stream.

Some non-tumoral masses and lesions can mimic tumors of the central nervous system. These include tuberculosis of the brain, cerebral abscess (commonly in toxoplasmosis), and hamartomas (for example, in tuberous sclerosis and von Recklinghausen neurofibromatosis).

Symptoms of brain tumors may depend on two factors: tumor size (volume) and tumor location. The time point of symptom onset in the course of disease correlates in many cases with the nature of the tumor ("benign", i.e. slow-growing/late symptom onset, or malignant (fast growing/early symptom onset).

Many low-grade (benign) tumors can remain asymptomatic (symptom-free) for years and they may accidentally be discovered by imaging exams for unrelated reasons (such as a minor trauma).

New onset of epilepsy[4] is a frequent reason for seeking medical attention in brain tumor cases.

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), dilatation of the pupil on the side of the lesion (anisocoria), papilledema (prominent optic disc at the funduscopic 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 young children, elevated intracranial pressure may cause an increase in the diameter of the skull and bulging of the fontanelles.

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, personality changes, hemiparesis, (hemi) hypesthesia, aphasia, ataxia, visual field impairment, facial paralysis, double vision, tremor etc. 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.

By behaviorEdit

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.[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.


Signs and symptomsEdit

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:

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, a list of causes of headaches[6] 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

CauseEdit

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.

Although studies have not shown any link between cell phone radiation and brain tumors,[7] 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.[8]

TypesEdit

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.[9] 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:[10]

PathophysiologyEdit

File:Vertebrate-brain-regions.png

AnatomyEdit

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 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.

MeningesEdit

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 matterEdit

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 tissuesEdit

  • 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.

DiagnosisEdit

File:Postermass.png

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.

Template:Reference necessary 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.

PathologyEdit

File:Oligodendroglioma1 high mag.jpg

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.

TreatmentEdit

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. Thus the significant side effects associated and experienced by patients undergoing chemotherapy.
  • A variety of experimental therapies are available through clinical trials[12]

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.[13]

SurgeryEdit

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 5-aminolevulinic acid that causes them to fluoresce.[14] 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 therapyEdit

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.[15]

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.[16] 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.[17][18]

ChemotherapyEdit

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.[19]

OtherEdit

A shunt is used not as a cure but to relieve symptoms by reducing hydrocephalus caused by blockage of cerebrospinal fluid.[20]

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.

PrognosisEdit

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[21] seems open to exceptional prognosis and long-term survival has frequently been reported.

Glioblastoma multiformeEdit

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,[22] boron neutron capture therapy and gene transfer.[23]

OligodendrogliomasEdit

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".[24] A median survival of up to 16.7 years has been reported for low grade oligodendrogliomas.[25]

EpidemiologyEdit

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.[26]


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.[27]

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 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 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 KingdomEdit

From the British national statistics data about new diagnoses of malignant neoplasms of the brain for the year 2007 (in absolute figures and in rates per 100,000)[28]:

Measures Sex 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 2,131 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

United StatesEdit

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),[1] which accounted for less than 1 percent of all cancers, 2.4 percent of all cancer deaths,[2] and 20–25 percent of pediatric cancers.[2][29] Ultimately, it is estimated there are 13,000 deaths per year in the United States alone as a result of brain tumors.[1]

ResearchEdit

Vesicular stomatitis virusEdit

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.[30][31]

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.[32]

Retroviral replicating vectorsEdit

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.[33] 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.[34] Subsequently, in preparation for human clinical trials, this technology was further developed by Tocagen, Inc. (Toca 511 & Toca FC) 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.[35]


Brain tumors in infants and children Edit

File:Tumor BrainstemGlioma2.JPG

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.[36]

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.[37] Germ cell tumors, including teratoma, make up just 3% of pediatric primary brain tumors, but the worldwide incidence varies significantly.[38]


See alsoEdit

ReferencesEdit

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