Brain tumor
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A brain tumor is any intracranial mass created by an abnormal and uncontrolled growth of cells either normally found in the brain itself (neurons, glial cells - astrocytes, oligodendrocytes, ependymal cells, lymphatic tissue, blood vessels), in the cranial nerves (myelin producing cells 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 2000, it was estimated that there were 16,500 new cases of brain tumors1, which accounted for 1.4% of all cancers, 2.4% of all cancer deaths2, and 20%-25% of pediatric cancers2,3. Ultimately, it is estimated that there are 13,000 deaths/year as a result of brain tumors1.
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Causes
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 supressor genes are incriminated in some forms of brain tumors. Patients with various inherited diseases, such as Von Hippel-Lindau syndrome, multiple endocrine neoplasia, neurofibromatosis type 2 are at high risk of developing brain tumors.
Classification
In contrast to tumors originating elsewhere in the body, differentiating primary "brain tumors" - these are the true brain tumors, arising exclusively from cells normally present in the brain itself - into benign and malignant is of relative and limited clinical value, since even histologically-benign tumors grow by infiltration of healthy brain tissue and, in time, tend to transform into malignant forms (anaplastic degeneration). True benign intracranial tumors arise mainly from the meninges (meningiomas - about 95% are benign), pituitary gland (pituitary adenomas) and the myelin sheath of cranial nerves - (neuromas or Schwanomas, e.g. acoustic neuroma).
Most primary brain tumors (gliomas) originate from glia: astrocytes - astrocytomas, oligodendrocytes - oligondedrogliomas. There are also mixed forms, with both an astrocytic and an oligodendroglial cell component. These are called mixed gliomas or oligoastrocytomas. Additionally, 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, and oligoastrocytomas may be "benign" or malignant. Glioblastoma multiforme represents the most aggresive 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.
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 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 lesions can mimic tumors of the central nervous system. These include tuberculosis of the brain and cerebral abscess.
Symptoms
The kind of symptoms brain tumors may cause 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, i.e. 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 epilepsy4 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 intracranial hypertension. Intracranial hypertension 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 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 congitive and behavioral impairment, personality changes, hemiparesis, (hemi)hypesthesia, aphasia, ataxia, visual field impairment, facial paralysis, double vision, tremmor etc. It cannot be stressed enough that 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.
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 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.
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 (see magnetic resonance imaging) scans, or hyperintense (brighter than brain tissue) on T2-weighted MRI (see magnetic resonance imaging). Perifocal edema also appears hyperintense on T2-weighted MRI. Contrast agent uptake, sometimes in caracteristic 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.
Electrophysiological exams, such as electroencephalography (EEG) play a marginal role in the diagnosis of brain tumors.
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 histologic examination is essential for determining the appropriate treatment and the correct prognosis for each individual patient.
Treatment and Prognosis
Meningiomas, with the exception of some tumors located at the skull base, can be successfully removed surgically. In more difficult cases, stereotactic radiotherapy remains a viable option.
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 the inoperable cases.
Although there is no generally accepted therapeutic management for primary brain tumors, a surgical attempt at tumor removal or at least cytoreduction - i.e., removal of as much tumor as possible, in order to reduce the number of tumor cells available for proliferation - has to be considered in most cases5. 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.
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 factors6.
Patients with "benign" ("low-grade") gliomas may survive for many years7,8 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. However, the prognosis in such cases is determined by the primary tumor, and it is generally poor.
References
- Note 1: Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000;50:7-33. PDF (http://caonline.amcancersoc.org/cgi/reprint/50/1/7.pdf). PMID 10735013.
- Note 2: American Cancer Society (http://www.cancer.org/). Accessed June 2000.
- Note 3: Chamberlain MC, Kormanik PA. Practical guidelines for the treatment of malignant gliomas. West J Med 1998;168:114-120. PMID 9499745.
- Note 4: Lopez MBS, Laws ER Jr. Neurosurgical Focus 12(2), Article 1, 2002.
- Note 5: 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.
- Note 6: 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.
- Note 7: 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.
- Note 8: 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.de: Hirntumor