Metastatic+Brain+Tumors

=**Metastatic Brain Tumors**=

**Introduction**
Metastatic brain tumors are the most prevalent type of brain cancer in adults. Metastatic brain tumors represent a type of cancer that starts in the body and spreads to the brain. This happens as cancer cells leave the primary site organ and enter the circulatory system. These cells then travel to the brain, forming a tumor. These tumors can be singular or represent multiple brain tumors. The most common primary sites, where the tumor originates, are the lungs, breasts, skin, colon and kidney. Typically the metastatic brain tumor contains the same type of cancer cells as the tumor in the primary site. However, some brain tumors can develop alternate forms of cancer cells as the tumor reaches the brain. There has been an increase in the number of metastatic brain tumors recently as the survival length of primary cancers has increased, allowing for more time for the cancer cells to spread to the brain. Metastatic brain tumors create problems for the CNS by taking up space within the the brain, placing pressure on the tissue of the functional structures surrounding the tumor. This may cause headaches, nausea/vomiting, limb weakness, speech problems, visual deficits or visual problems. Furthermore, neurological deficits are often seen in patients with metastatic brain tumors, with the effects depending on the location of the tumor in the brain.

Anatomical Structures Affected in the Central Nervous System
When tumors metastasize to the brain, they cause neurological deficits, each depending on the area of the brain being affected by the tumor. The three areas most often affected by metastatic brain tumors are:

Cerebral Cortex: The gross anatomy of the cerebrum consists of two hemispheres, left and right. Between the hemispheres lies the corpus callosum, a collection of white matter serving to connect them. Each hemisphere is divided into 4 lobes: frontal, parietal, temporal and occipital. The cerebrum can be further divided into the dienchephalon and telencephalon. The diencephalon consists of the thalamus and hypothalamus while the telencephalon consists of the cortex, subcortical fibers and basal nuclei. The cortex within the telencephalon is made up of folds called gyri and has grooves between these folds called sulci. The cerebral cortex is the most common site of formation of brain metastases, about 80%. It constitutes the gray matter covering the hemispheres within the brain. The primary cortices are involved in receiving sensory input or in directing limb and eye movements. The association cortices are involved in more complex functions and work to synthesize movement. Metastatic brain tumors in the cerebral cortex cause problems to different motor functions depending on the location of the tumor within the cortex. As they relate to movement, tumors in the frontal lobe cause problems with motor planning, speech formation and general execution of movement. Tumors in the parietal lobe affect the patient's ability to orient themselves, move and recognize and perceive stimuli. Metastatic brain tumors in the occipital lobe cause visual problems. Lastly, tumors in the temporal lobe affect the recognition and perception of auditory stimuli and speech. The major pathways affected by tumors in the cerebral cortex are the direct motor cortical pathway and indirect cortical pathways.

Cerebellum: About 15% of metastases form in the cerebellum, a structure in the posterior portion of the brain. This structure lies within the occipital and temporal lobes. The role of the cerebellum is to modulate motor commands being sent through descending pathways to improve the adaptability and accuracy of movements. The main functions that the cerebellum modulates are posture and balance maintenance, coordination of movements and motor learning. It receives input from proprioceptors and vestibular receptors to make adjustments necessary to account for changes in body position and load on muscles. Furthermore, the cerebellum coordinates the force and timing of movements to ensure fluid movements. Lastly, the cerebellum is important in storing motor information when developing motor plans for certain movements, usually based on a trial and error process. This too is important in ensuring the fluidity of movements. Tumors present in the cerebellum affect the three subdivisions, causing problems with motor and sensory functions that the cerebellum controls. The first of these is the vestibulocerebellum that controls vestibular reflexes and posture. A tumor in the vestibulocerebellum will cause problems with the vetibulospinal tracts that control extensor muscles supporting posture and balance. The second subdivision affected is the spinocerebellum. A tumor in this section causes problems with motor coordination as the spinocerebellum receives input from the spinocerebellar tract and projects to the vestibulospinal, rubrospinal and reticulospinal tracts. The connection of all these tracts at the cerebellum produces a center for integration of sensory input to modulate controlled, coordinated movements that is compromised by the presence of a tumor. The last subdivision is the cerebrocerebellum which is connected to the cerebral cortex through the VL thalamus and pontine nuclei. Tumors in this subdivision cause problems with the timing and planning of movements. Although loss of coordinated movement is the most prominent functional disorder involved with tumors in the cerebellum, other problems include intentional tremor, dysdiadochokinesia and loss of motor learning, especially seen in the vestibulo-ocular reflex.

Brain Stem: About 5% of metastases form in the brain stem which is made up of the pons, medulla and midbrain. From the brain stem come direct projections to the spinal cord.These projections terminate directly on interneurons and motor neurons, influencing the control of motor activity. Out of the pons, the vestibulospinal and reticulospinal tracts arise. From the midbrain comes the rubrospinal, tectospinal and interstitiospinal tracts. Tumors in the brain stem have negative effects on the control of balance and posture, synergistic whole-limb movements and coordination of movements of the head and body, all of which are monitored by the medial (ventromedial) descending pathways (vestibulospinal, reticulospinal and tectospinal tracts from the brain stem). Furthermore, metastatic brain tumors will cause issues with the control of fine movements of distal limbs typically monitored by the lateral (dorsolateral) pathway associated with the rubrospinal tract from the midbrain.

Causes
The general cause of a metastatic brain tumor is the spreading of cancer cells from a primary site outside of the brain to the brain through the circulatory system. These cancer cells leave the affected organ or area and enter the blood. The immune system attempts to destroy these cancerous cells, but if there are too many cells entering the blood, they will override the effects of the immune system or cause the immune system to become tolerant of these cells. The surviving cancerous cells then use the circulatory or lymphatic system to spread to other organs. The most common pathway is first to the lungs then to the brain. Often times the cancer cells move away from the primary site while the tumor is still in the early stages of development in that area. They may then remain dormant in the new area or develop rapidly, causing new symptoms typical of cancer in that area. Typically, the development of the cancer cells in the migratory area is independent of the progression of the tumor in the primary site. Lung cancer metastases found in the brain often develop rapidly as the lungs flow directly to the brain. This is a common incidence of the metastatic tumor being identified before the tumor in the primary site, the lungs. Spreading cancer cells tend to metastasize in particular organs in which there are attractant molecules selective to the cells of the primary site. These molecules, chemokines, guide cancerous cells to the metastatic site. Similarly, adherent molecules in particular organs only allow select cells from other organs to stick at the metastatic site.

Typical Diagnosis
==== A metastatic brain tumor is found when a patient develops neurological problems and a CT scan or MRI reveals a tumor in a region of the brain. Other methods used to determine the presence or extent of a brain tumor include magnetic resonance spectrometry (MRS), in order to determine the chemical contents within the brain, and position emission tomography (PET), to find how the tumor uses glucose to supply itself. If the metastatic brain tumor is found first, full body PET scans can be utilized to find the location of the primary site. These scans provide information on the exact position of the tumor within the brain or spinal cord, the size and number of the tumors and impact the tumor(s) have on nearby structures. Furthermore, examination of tumor tissue under a microscope following surgery or a biopsy can give more exact information about the pathological diagnosis of the tumor. Spinal taps can also be used to examine the cerebrospinal fluid that has been invaded by tumor cells. Typically the brain tumor is revealed secondary to the finding of a tumor in the primary site. However, there are times in which the brain tumor is found and the primary site cannot be found. This is termed an unknown primary site. Often times the metastatic brain tumor is found incidentally after an MRI for a different medical reason reveals a tumor in the brain. Recognition of the brain tumor(s) in this manner accounts for only about 10% of metastatic brain tumors and occurs before the finding of the primary tumor site. Sometimes the primary tumor is too small to recognize or cause symptoms. In this case, blood markers, scans or tissue samples can help guide the search for the primary tumor.

Lungs
The most common primary site for metastatic brain tumors is in the lungs. In this situation, the brain tumor is often found before or at the same time as the primary site tumor. Lung metastases usually come with multiple brain tumors.

Breasts
Breast cancer provides the second most common primary site for metastatic brain tumors. Brain metastases are usually found around 2 years after the primary site tumor is found, but 5-10 year delays in the recognition of metastatic brain tumors is common. Brain metastases are more common in younger and premenopausal women. Two or more brain tumors usually accompany breast metastases.

Skin
Melanoma metastases are the second most common metastatic brain tumor in males. These cancerous cells can spread to the brain or the meninges, the covering of the brain and spinal cord. They are typically found multiple years after the primary site tumor is found and come with multiple metastases. These tumors are typically blood rich and sensitive to bleeding.

Colon
Colon metastases in the brain are usually found several years after the finding of the primary site tumor. There is usually only a singular brain tumor accompanying colon metastases.

Kidney
Kidney metastases are often found a few years beyond the finding of the primary tumor. Single tumors in the brain are typical. These metastases are also sensitive to bleeding.

These are the most common primary sites, but brain metastases can originate anywhere in the body.

Considerations
Before a treatment plan is generated, physicians must look at a number of medical factors. These include medical history, cancer history, status of that history, number and size of metastatic tumors and the location of the tumors in the brain or spinal cord. Early treatment typically focuses on controlling symptoms such as swelling and seizures. These include steroids (dexamethasone and decadron to reduce swelling) and antiepileptic drugs (lacosamide or levetiracetam orphenytoin to control seizures). The number of metastatic tumors is not the sole predictor of well-being post treatment. Neurological function and the status of the primary site tumor play a large role in post treatment functioning. The type of cancer and genetic alterations also have a role in the success of treatment. Sometimes the treatment used for the primary site cancer and the metastases matches, but sometimes treatments differ.

Surgery
Typically surgery is one of the first methods of treatment considered for a metastatic brain tumor. Surgery is determined to be the best mode of tumor removal if the tumor is greater than 3 cm, lies outside of a functional area of the brain such as the language or motor areas and is limited in other areas of the body. Likewise, if the patient is experiencing symptoms, surgery is the most commonly selected treatment form. If the tumors are spread out within the brain, or if they are found to be in a functional area, surgery is not suggested. If surgery is not the best option, a biopsy may still be performed to confirm the characteristics of the tumor.

Radiation
Radiation can be selected as a treatment method for both singular and multiple brain metastases. It can be used to treat the cancer, prevent the spreading of a newly developed primary site cancer or relieve symptoms of brain metastases that cannot be totally cured. This last option is termed palliative treatment and is the most common form of radiation. There are multiple types of radiation used to treat metastatic brain tumors including:
 * 1) Whole Brain Radiation: This type of radiation is often used when multiple brain metastases are present. It is given out in 5-15 doses called fractions in order to protect the brain from the toxic effects of the radiation. Small-cell lung cells and germ-cell tumors are more sensitive to whole brain radiation than other types of lung, breast, skin and kidney cancers.
 * 2) Radiosurgery: This treatment highly focuses higher doses of radiation in a particular spot in order to avoid damage to normal brain tissue. It is more commonly used when the tumor is small (less than 3 cm) and in functional areas of the brain like the speech and motor areas. Radiosurgery can be used to reach deeper parts of the brain where surgery is not a viable treatment option. It sometimes also follows whole brain radiation to better serve a localized area.
 * 3) Brachytherapy: Also known as interstitial therapy, brachytherapy is rarely used today. It is the use of radioactive materials implanted in a localized area through surgery to provide radiation to the tumor there.
 * 4) Radioenhancers: These compounds make the tumor more sensitive to radiation.

Medical therapy

 * 1) Chemotherapy: Because of the blood-brain barrier, chemotherapy wasn't formerly typically used as a cure for metastatic brain tumors. However, new studies have shown that some target agents used for non-small cell lung cancer, breast cancer and melanoma are effective in treating brain metastases from these primary sites. Typically, 2-3 agents are used with whole brain radiation to attempt to treat the patient. Intra-CSF chemotherapy can be effective in treating metastases in the meninges. This treatment consists of drugs placed in the brain/spine water compartment.
 * 2) Targeted therapy: Targeted therapies are similar to radiosurgery in that they project a concentrated dose of radiation directly to a metastatic brain tumor. This type of treatment is less invasive than surgery and provides less radiation to the normal cells within the brain than whole brain radiation. One of the main methods for providing targeted therapy is the Gamma Knife approach.

Conclusion
Metastatic brain tumors come from cancerous cells that originated in another part of the body, the primary site, and traveled to the brain, typically through the circulatory system. The most common primary sites are the lungs, breasts, skin, colon and kidney. Metastatic brain tumors most often form in the cerebral cortex, but can also be found in the cerebellum and brain stem. In addition to causing headaches, nausea and seizures due to the increased pressure in the brain, metastatic brain tumors can cause neurological deficits, the outcomes of which depend on where in the brain the tumor is found. These symptoms include loss of postural control, motor coordination, motor planning and balance. Metastatic brain tumors are usually diagnosed through the use of MRIs and CT scans when the patient experiences neurological deficits. Sometimes these findings can come before the finding of the primary site, but this is rare. Often times a biopsy is utilized to better understand the characteristics of the tumor. Common treatments for metastatic brain tumors include surgery, whole brain radiation, radiosurgery and, although rarely used, chemotherapy. Unfortunately, the median survival length for untreated patients is only 1 month. Those treated with whole brain radiation can expect to live 3 to 4 months, while those who have surgery followed by whole brain radiation typically survive for 10 months. Median survival lengths for those receiving radiotherapy is around 9 months.

Key Terms

 * Biopsy:** The examination of tissue removed from the body to determine the extent of disease in that area
 * Brain Stem:** The central trunk of the brain including the pons, midbrain and medulla. Site of 5% of brain metastases
 * Cerebellum:** Section in posterior portion of the brain important in coordinating movement. Site of 15% of brain metastases
 * Cerebral Cortex:** The outer layer of the cerebrum that constitutes the gray matter. Site of 80% of brain metastases
 * Chemotherapy:** The treatment of cancer through the use of cytotoxic drugs
 * Computed Tomography:** The use of computer processed combinations of X-rays to give a picture of structures within the body
 * Melanoma:** A tumor consisting of melanin forming cells, typically associated with skin cancer
 * Metastatic:** Relating to a change in form or location, the spread of a disease-producing agent
 * Primary Site:** Origin of cancerous cells in the body before they metastasize to the brain
 * Whole Brain Radiation:** A type of external radiation therapy used to treat a brain metastasis that cannot be removed by surgery

Suggested Readings
Highlights the treatment of brain metastases with, specifically, radiotherapy. Shows how the introduction of CT into the medical field has affected how brain tumor patients are cared for. Reviews the diagnostic techniques and typical sites and histology of brain metastases. Reviews the typical methods for producing images of the brain for patients with suspected brain metastases and typical findings of these imaging techniques. Reviews how medical approaches to treating metastatic brain tumor patients has changed and the effects these new treatments have had.
 * Horizons in Cancer Research **in //Nova Biomedical Series.// [|Horizons in Cancer Research]
 * The Impact of Computed Tomography on the Care of Patients with Suspected Brain Tumor **in //Wolters Kluwer Health.// [|Impact of CT on Patient Care]
 * Neuropathology of Brain Metastases **in //Surgical Neurology International.// [|Neuropathology of Brain Metastases]
 * Imaging of Brain Metastases **in //Surgical Neurology International.// [|Imaging of Brain Metastases]
 * Current Approaches to the Treatment of Metastatic Brain Tumors **in //US National Library of Medicine.// [|Current Brain Tumor Treatment]

Quiz
1. What is the most common primary site for brain metastases? a. Kidney b. Lung c. Skin d. Limbs 2. What is the primary hindrance of chemotherapy in its effect on brain metastases? a. The cytotoxins are not strong enough to treat the tumor b. Agents have a difficult time penetrating the blood-brain barrier c. The equipment needed to release chemicals into the brain are not developed yet d. Brain tumors do not respond to chemotherapy 3. A metastatic brain tumor found in the cerebellum will cause problems with which of the following functions? a. Motor coordination b. Postural control c. Balance maintenance d. All of the above 4. Which of the following methods is not typically used in diagnosing a metastatic brain tumor? a. MRI b. CT scan c. X-ray d. Biopsy 5. When is radiosurgery typically used instead of surgery to treat a metastatic brain tumor? a. The tumor is less than 3 cm b. The tumor lies in a deep part of the brain c. a and b d. None of the above 6. Metastatic brain tumors are typically recognized before the finding of the primary tumor site. T/F 7. Metastatic brain tumors occur in the brain stem more often than the cerebellum. T/F 8. The number of metastatic tumors within the brain is the sole determinant of well-being after treatment. T/F 9. Brachytherapy is commonly used today as a treatment for metastatic brain tumors. T/F 10. Tumors from the primary site most often travel to the brain through the circulatory system. T/F 11. Compare the neurological deficits that would be seen in a metastatic brain tumor found in the cerebral cortex and the cerebellum. 12. Describe the typical method of diagnosing a metastatic brain tumor. 13. Compare the characteristics of different metastatic brain tumors projecting from three different common primary sites.

Answers:
b,b,d,c,,c,T,F,F,F,T 11. As they relate to movement, tumors in the frontal lobe cause problems with motor planning, speech formation and general execution of movement. Tumors in the parietal lobe affect the patient's ability to orient themselves, move and recognize and perceive stimuli. Metastatic brain tumors in the occipital lobe cause visual problems. In contrast, a tumor in the cerebellum will cause problems with the vetibulospinal tracts that control extensor muscles supporting posture and balance. The second subdivision affected is the spinocerebellum. A tumor in this section causes problems with motor coordination as the spinocerebellum receives input from the spinocerebellar tract and projects to the vestibulospinal, rubrospinal and reticulospinal tracts. The connection of all these tracts at the cerebellum produces a center for integration of sensory input to modulate controlled, coordinated movements that is compromised by the presence of a tumor. The last subdivision is the cerebrocerebellum which is connected to the cerebral cortex through the VL thalamus and pontine nuclei. Tumors in this subdivision cause problems with the timing and planning of movements. 12. A metastatic brain tumor is found when a patient develops neurological problems and a CT scan or MRI reveals a tumor in a region of the brain. Other methods used to determine the presence or extent of a brain tumor include magnetic resonance spectrometry (MRS), in order to determine the chemical contents within the brain, and position emission tomography (PET), to find how the tumor uses glucose to supply itself. If the metastatic brain tumor is found first, full body PET scans can be utilized to find the location of the primary site. These scans provide information on the exact position of the tumor within the brain or spinal cord, the size and number of the tumors and impact the tumor(s) have on nearby structures. Furthermore, examination of tumor tissue under a microscope following surgery or a biopsy can give more exact information about the pathological diagnosis of the tumor. Spinal taps can also be used to examine the cerebrospinal fluid that has been invaded by tumor cells.[4] Typically the brain tumor is revealed secondary to the finding of a tumor in the primary site. However, there are times in which the brain tumor is found and the primary site cannot be found. This is termed an unknown primary site. Often times the metastatic brain tumor is found incidentally after an MRI for a different medical reason reveals a tumor in the brain. Recognition of the brain tumor(s) in this manner account for only about 10% of metastatic brain tumors and occur before the finding of the primary tumor site.[1] Sometimes the primary tumor is too small to recognize or cause symptoms. In this case, blood markers, scans or tissue samples can help guide the search for the primary tumor. 13. 1)Lungs The most common primary site for metastatic brain tumors is in the lungs.[1] In this situation, the brain tumor is often found before or at the same time as the primary site tumor. Lung metastases usually come with multiple brain tumors. 2)Breasts Breast cancer provides the second most common primary site for brain metastatic tumors. Brain metastases are usually found around 2 years after the primary site tumor is found, but 5-10 year delays in the recognition of metastatic brain tumors is common. Brain metastases are more common in younger and premenopausal women. Two or more brain tumors usually accompany breast metastases. 3)Skin Melanoma metastases are the second most common metastatic brain tumor in males. These cancerous cells can spread to the brain or the meninges, the covering of the brain and spinal cord. They are typically found multiple years after the primary site tumor is found and come with multiple metastases. These tumors are typically blood rich and sensitive to bleeding. 4)Colon Colon metastases in the brain are usually found several years after the finding of the primary site tumor. There is usually only a singular brain tumor accompanying colon metastases. 5)Kidney Kidney metastases are often found a few years beyond the finding of the primary tumor. Single tumors in the brain are typical. These metastases are also sensitive to bleeding. (Any 3 will suffice)