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 ct scan of a brain tumor, with its diameters marked as an x. there is hypoattenuating (dark) peritumoral edema in the surrounding white matter, with a "finger-like" spread. medical 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 favor of non-invasive, high-resolution techniques, especially magnetic resonance imaging (mri) and computed tomography (ct) scans, though mri is typically the reference standard used. 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 ct scans. on mri, they appear either hypodense 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. pressure areas where the brain tissue has been compressed by a tumor also appear hyperintense on t2-weighted scans and might indicate the presence a diffuse neoplasm due to an unclear outline. swelling around the tumor known as peritumoral edema can also show a similar result. this is because these tumors disrupt the normal functioning of the bbb and lead to an increase in its permeability. more recently, advancements have been made to increase the utility of mri in providing physiological data that can help to inform diagnosis and prognosis. mri itself is sufficient in identifying the brain tumor’s location and morphology, but other types of mri may be used on top of that, such as mra, mrs, pmri, fmri, and dwi. these imaging techniques help doctors and surgeons to diagnose the type of tumor, to plan for surgery, and to assess treatment and radiation/chemotherapy. different types of mri scans magnetic resonance angiography (mra)- looks at the blood vessels in the brain. in the diagnosis of brain tumor, mras are typically carried out before surgery to help surgeons get a better understanding of the tumor vasculature. for example, a study was done where surgeons were able to separate benign brain tumors from malignant ones by analyzing the shapes of the blood vessels that were extracted from mra. although not required, some mra may inject contrast agent, gadolinium, into the patient to get an enhanced image magnetic resonance spectroscopy (mrs)- measures the metabolic changes or chemical changes inside the tumor. the most common mrs is proton spectroscopy with its frequency measured in parts per million (ppm). gliomas or malignant brain tumors have different spectra from normal brain tissue in that they have greater choline levels and lower n-acetyl aspartate (naa) signals. using mrs in brain tumor diagnosis can help doctors identify the type of tumor and its aggressiveness. for example, benign brain tumors or meningioma have increased alanine levels. it can also help to distinguish brain tumors from scar tissues or dead tissues caused by previous radiation treatment, which does not have increased choline levels that brain tumors have, and from tumor-mimicking lesions such as abscesses or infarcts. perfusion magnetic resonance imaging (pmri)- assess the blood volume and blood flow of different parts of the brain and brain tumors. pmri requires the injection of contrast agent, usually gadopentetate dimeglumine (gd-dtpa) into the veins in order to enhance the contrast. pmri provides a cerebral blood volume map that shows the tumor vascularity and angiogenesis. brain tumors would require a larger blood supply and thus, would show a high cerebral blood volume on the pmri map. the vascular morphology and degree of angiogenesis from pmri help to determine the grade and malignancy of brain tumors. for brain tumor diagnosis, pmri is useful in determining the best site to perform biopsy and to help reduce sampling error. pmri is also valuable for after treatment to determine if the abnormal area is a remaining tumor or a scar tissue. for patients that are undergoing anti-angiogenesis cancer therapy, pmri can give the doctors a better sense of efficacy of the treatment by monitoring tumor cerebral blood volume. functional mri (fmri)- measures blood flow changes in active parts of the brain while the patient is performing tasks and provides specific locations of the brain that are responsible for certain functions. before performing a brain tumor surgery on patients, neurosurgeons would use fmri to avoid damage to structures of the brain that correspond with important brain functions while resecting the tumor at the same time. preoperative fmri is important because it is often difficult to distinguish the anatomy near the tumor as it distorts its surrounding regions. neurosurgeons would use fmri to plan whether to perform a resection where tumor is surgically removed as much as possible, a biopsy where they take a surgical sampling amount to provide a diagnosis, or to not undergo surgery at all. for example, a neurosurgeon may be opposed to resecting a tumor near the motor cortex as that would affect the patient’s movements. without preoperative fmri, the neurosurgeon would have to perform an awake-craniotomy where the patient would have to interact during open surgery to see if tumor removal would affect important brain functions. diffusion weighted imaging (dwi)- a form of mri that measures random brownian motion of water molecules along a magnetic field gradient. for brain tumor diagnosis, measurement of apparent diffusion coefficient (adc) in brain tumors allow doctors to categorize tumor type. most brain tumors have higher adc than normal brain tissues and doctors can match the observed adc of the patient’s brain tumor with a list of accepted adc to identify tumor type. dwi is also useful for treatment and therapy purposes where changes in diffusion can be analyzed in response to drug, radiation, or gene therapy. successful response results in apoptosis and increase in diffusion while failed treatment results in unchanged diffusion values. other types of imaging techniques computed tomography (ct) scan- uses x-rays to take pictures from different angles and computer processing to combine the pictures into a 3d image. a ct scan usually serves as an alternative to mri in cases where the patient cannot have an mri due to claustrophobia or pacemaker. compared to mri, a ct scan shows a more detailed image of the bone structures near the tumor and can be used to measure the tumor’s size. like an mri, a contrast dye may also be injected into the veins or ingested by mouth before a ct scan to better outline any tumors that may be present. ct scans use contrast materials that are iodine-based and barium sulfate compounds. the downside of using ct scans as opposed to mri is that some brain tumors do not show up well on ct scans because some intra-axial masses are faint and resemble normal brain tissue. in some scenarios, brain tumors in ct scans may be mistaken for infarction, infection, and demyelination. to suspect that an intra-axial mass is a brain tumor instead of other possibilities, there must be unexplained calcifications in the brain, preservation of the cortex, and disproportionate mass effect. ct angiography (cta)- provides information about the blood vessels in the brain using x-rays. a contrast agent is always required to be injected into the patient in the ct scanner. cta serves as an alternative to mra. positron emission tomography (pet) scan- uses radioactive substances, with the most common one being a sugar known as fdg. this injected substance is taken up by cells that are actively dividing. tumor cells are more active in dividing so they would absorb more of the radioactive substance. after injection, a scanner would be used to create an image of the radioactive areas in the brain. pet scans are used more often for high-grade tumors than for low-grade tumors. it is useful after treatment to help doctors determine if the abnormal area on an mri image is a remaining tumor or a scar tissue. scar tissues will not show up on pet scans while tumors would. however, these techniques cannot alone diagnose high- versus low-grade gliomas, and thus the definitive diagnosis of brain tumor should only be confirmed by histological examination of tumor tissue samples obtained either by means of brain biopsy or open surgery. the histological examination is essential for determining the appropriate treatment and the correct prognosis. this examination, performed by a pathologist, typically has three stages: interoperative examination of fresh tissue, preliminary microscopic examination of prepared tissues, and follow-up examination of prepared tissues after immunohistochemical staining or genetic analysis. pathology micrograph of an oligodendroglioma, a type of brain cancer. brain biopsy. h&e stain tumors have characteristics that allow the determination of malignancy and how they will evolve, and determining these characteristics 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 nucleus of anaplastic cells is usually unnaturally shaped or oversized. 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 their capacity to multiply (i.e., uncontrollable growth due to failure of differentiation). atypia: an indication of abnormality of a cell (which may be indicative of malignancy). significance of the abnormality is highly dependent on context. neoplasia: 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, which may, in turn, have secondary symptoms. necrosis: the (premature) death of cells, caused by external factors such as infection, toxin or trauma. necrotic cells send the wrong chemical signals which prevent phagocytes from disposing of the dead cells, leading to a buildup of dead tissue, cell debris and toxins at or near the site of the necrotic cells arterial and venous hypoxia, or the deprivation of adequate oxygen supply to certain areas of the brain, occurs when a tumor makes use of nearby blood vessels for its supply of blood and the neoplasm enters into competition for nutrients with the surrounding brain tissue. more generally a neoplasm may cause release of metabolic end products (e.g., free radicals, altered electrolytes, neurotransmitters), and release and recruitment of cellular mediators (e.g., cytokines) that disrupt normal parenchymal function. classification tumors can be benign or malignant, can occur in different parts of the brain, and may be classified as primary or secondary. a primary tumor is one that has started in the brain, as opposed to a metastatic tumor, which is one that has spread to the brain from another area of the body. the incidence of metastatic tumors is approximately four times greater than primary tumors. 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. grading of the tumors of the central nervous system commonly occurs on a 4-point scale (i-iv) created by the world health organization in 1993. grade i tumors are the least severe and commonly associated with long-term survival, with severity and prognosis worsening as the grade increases. low-grade tumors are often benign, while higher grades are aggressively malignant and/or metastatic. other grading scales do exist, many based upon the same criteria as the who scale and graded from