Brain tumor

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

The cause of most brain tumors is unknown. Risk factors that may occasionally be involved include a number of inherited conditions known asneurofibromatosis as well as exposure to the industrial chemical vinyl chloride, the Epstein-Barr virus, and ionizing radiation. While concern has been raised about mobile phone use, the evidence is not clear. The most common types of primary tumors in adults are: meningiomas (usually benign), andastrocytomas such as glioblastomas. In children, the most common type is a malignant medulloblastoma. Diagnosis is usually by medical examinationalong with computed tomography or magnetic resonance imaging. This is then often confirmed by a biopsy. Based on the findings, the tumors are divided into different grades of severity.

Treatment may include some combination of surgery, radiation therapy and chemotherapy. Anticonvulsant medication may be needed if seizures occur. Dexamethasone and furosemide may be used to decrease swelling around the tumor.Some tumors grow gradually, requiring only monitoring and possibly needing no further intervention. Treatments that use a person's immune system are being studied. Outcome varies considerably depending on the type of tumor and how far it has spread at diagnosis. Glioblastomas usually have poor outcomes while meningiomas usually have good outcomes.The average five-year survival rate for brain cancer in the United States is 33%.

Secondary or metastatic brain tumors are more common than primary brain tumors, with about half of metastases coming from lung cancer. Primary brain tumors occur in around 250,000 people a year globally, making up less than 2% of cancers. In children younger than 15, brain tumors are second only to acute lymphoblastic leukemia as a cause of cancer. In Australia the average economic cost of a case of brain cancer is $1.9 million, the greatest of any type of cancer.

Signs and symptoms

Signs and symptoms of a brain tumor mainly depend on the size of the tumor and its location. The symptom onset – in the timeline of the development of the tumor – depends in many cases on the nature of the tumor (as to it being benign or malignant), and in many cases is also related to the change in the nature of the neoplasm, from slow-growing, late-symptom-onset benign to faster-growing, early-symptom-onset malignant.

Symptoms of both primary and secondary brain tumors can be divided into three main categories:

• Symptoms as consequences of increased intracranial pressure (often first noticed): Large tumors or tumors with extensive peritumoral swelling (edema) inevitably lead to elevated intracranial pressure which translates clinically intoheadaches, vomiting (with or 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) can also present such symptoms. Increased intracranial pressure may result in brain herniation (i.e. displacement) of certain parts of the brain, such as thecerebellar tonsils or the temporal uncus, resulting in lethal brainstem compression. In very young children, elevated intracranial pressure may cause an increase in the diameter of the skull and bulging of the fontanelles.
• Dysfunction: depending on the tumor location and the damage it may have caused to surrounding brain structures, either through compression or infiltration, any type of focal neurologic symptoms may occur, such as cognitive andbehavioral impairment (including impaired judgment, memory loss, lack of recognition, spatial orientation disorders),personality or emotional changes, hemiparesis, hypoesthesia, aphasia, ataxia, visual field impairment, impaired sense of smell, impaired hearing, facial paralysis, double vision, dizziness, but more severe symptoms might occur too, such as paralysis on one side of the body hemiplegia or impairment in swallowing. 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.

• Irritation: abnormal fatigue, weariness, absences and tremors, but also epileptic seizures.

A benign brain tumor may be present for some years and be asymptomatic. Others might present ambiguous and intermittent symptoms like headaches and vomiting or weariness and so be mistaken for gastrointestinal disorders. In these cases secondary symptoms need to be looked into.

Cause

Epidemiological studies are required to determine risk factors. Aside from exposure to vinyl chloride or ionizing radiation, there are no known environmental factors associated with brain tumors. Mutations and deletions of so-called tumor suppressor genes, such as P53, are thought to be the cause of some forms of brain tumor. Inherited conditions, such asVon Hippel–Lindau disease, multiple endocrine neoplasia, and neurofibromatosis type 2 carry a high risk for the development of brain tumors.

Although studies have not shown any link between cell phone or mobile phone radiation and the occurrence of brain tumors, the World Health Organization has classified mobile phone radiation on the IARC scale into Group 2B – possibly carcinogenic.

Pathophysiology

The main areas of the brain and limbic system

Meninges

Human brains are surrounded by a system of connective tissue membranes calledmeninges that separate the brain from the skull. This three-layered covering is composed of (from the outside in) the dura mater ("hard mother"), arachnoid mater("spidery mother"), and pia mater ("tender mother"). The arachnoid and pia are physically connected and thus often considered as a single layer, the pia-arachnoid. Between the arachnoid mater and the pia mater is the subarachnoid space which contains cerebrospinal fluid (CSF). This fluid circulates in the narrow spaces between cells and through the cavities in the brain called ventricles, 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 meningiomas and are often benign.

Brain matter

The brains of humans and other vertebrates are composed of very soft tissue and a gelatin-like texture. Living brain tissue has a pink tint in color on the outside (grey matter), and nearly complete white on the inside (white matter), with subtle variations in color. Three separate brain areas make up most of the brain's volume:

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

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

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

Spinal cord and other tissues

The pons in the brainstem is a specific region that consists of myelinated axons much like the spinal cord. The thalamusand hypothalamus of the diencephalon also consist of neuron and glial cell tissue with the hypophysis (pituitary gland) andpineal gland (which is glandular tissue) attached at the bottom; tumors of the pituitary and pineal gland are often benign. The medulla oblongata is at the start of the spinal cord and is composed mainly of neuron tissue enveloped in Schwann cells and meninges tissue. The 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 in response to injury or other stimulus.

Diagnosis

A posterior fossa tumor leading to mass effect and midline shift

Most of the brain is separated from the blood by the blood-brain barrier (BBB), which exerts a restrictive control as to which substances are allowed to pass. Therefore many tracers that reach tumors in the body very easily would only reach brain tumors once there is a disruption of the BBB. Thus the disruption of the BBB, which can be detected by a MRI and CT, is regarded as the main diagnostic indicator for malignant gliomas, meningiomas, and brain metastases.^[12]

Although there is no specific or singular clinical symptom or sign for any brain tumors, the presence of a combination of symptoms and the lack of corresponding clinical indications of infections or other causes can be an indicator to redirect diagnostic investigation towards the possibility of an intracranial neoplasm. Brain tumors have similar characteristics and obstacles when it comes to diagnosis and therapy with tumors located elsewhere in the body. However, they create specific issues that follow closely to the properties of the organ they are in.

The diagnosis will often start by taking a medical history noting medical antecedents, and 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 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 increasedintracranial 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

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. 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. However, it is not possible to diagnose high- versus low-grade gliomas based on enhancement pattern alone.

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

Pathology

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

Tumors have characteristics that allow determination of malignacy 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 nuclei of anaplastic cells are 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 in 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 for 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 prevents 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

Secondary brain tumors

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

Secondary brain tumors are more common than primary ones; in the United States there are about 170,000 new cases every year. Secondary brain tumors are the most common cause of tumors in the intracranial cavity. The skull bone structure can also be subject to a neoplasm that by its very nature reduces the volume of the intracranial cavity, and can damage the brain.

By behavior

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

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

Of the above malignant characteristics, some elements do not apply to primary neoplasms of the brain:

• Primary brain tumors rarely metastasize to other organs; some forms of primary brain tumors can metastasize but will not spread outside the intracranial cavity or the central spinal canal. Due to the BBB, 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.)
• 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.