Brain metastases are cancer cells that have spread to the brain from primary tumors in other organs in the body (see the image below). Metastatic tumors are among the most common mass lesions in the brain. An estimated 24-45% of all cancer patients in the United States have brain metastases. 
Approximately 60% of patients with brain metastases have subacute symptoms. Symptoms are usually related to the location of the tumor and may include the following:
See Clinical Presentation for more detail.
Laboratory investigations include blood work, such as CBC, electrolyte panel, coagulation screen, and liver function panel.
Images provide information on tumor burden in the brain and associated structures, in addition to the rest of the body, and are integral part in formulating the optimal treatment plan.
Imaging studies include the following:
Computerized tomography (CT)
Positron emission tomography (PET)
Magnetic Resonance Imaging (MRI)
See Workup for more detail.
Medical treatments consist of symptomatic and systematic treatments. Medical management of metastatic diseases has mainly focused on the treatment of cerebral edema, headache, and seizure.
Other options are radiation therapy (whole brain radiation, focal beam, and stereotactic radiation therapy), chemotherapy, combined therapies, experimental therapies, and integration therapy.
Most tumors that metastasize to the brain are not chemosensitive, though small-cell lung cancer, breast cancer, and lymphoma respond to chemotherapy. In most cases, 2-3 chemotherapeutic agents are used in combination and in conjunction with whole-brain radiation therapy (WBRT).
Radiation therapy has become a mainstream therapy for brain metastasis. Radiation therapy includes WBRT and stereotactic radiosurgery.
Stereotactic radiosurgery is a more preferred treatment modality for radio-resistant lesions such as nonsmall cell lung cancer, renal cell carcinoma, and melanoma. It is also more frequently used to treat the resection cavity of brain metastasis, particularly in patients with breast metastatic disease.
Surgical resection is considered standard care for solitary metastases larger than 3 cm and in noneloquent areas of the brain.
Other indications for surgical resection include the following:
Limited and/or controlled systemic disease
Karnofsky score greater than 70
One symptomatic lesion with multiple asymptomatic lesions
Contraindications to surgery include a radiosensitive tumor (e.g., small-cell lung tumor), patient life expectancy < 3 months (WBRT indicated), and multiple lesions.
Metastatic tumors are among the most common mass lesions in the brain. In the United States, an estimated 98,000-170,000 cases occur each year. This is about 24-45% of all cancer patients.  The prevalence of brain metastasis is thought to be 120,000-140,000 per year. This disease accounts for 20% of cancer deaths annually, a rate that can be traced to an increase in the median survival of patients with cancer because of modern therapies, increased availability of advanced imaging techniques for early detection, and vigilant surveillance protocols for monitoring recurrence. In addition, most systemic treatments (eg, the use of chemotherapeutic agents, which may penetrate the brain poorly) can transiently weaken the blood-brain barrier (BBB) and allow systemic disease to be seeded in the CNS, leaving the brain a safe haven for tumor growth.
Metastases from systemic cancer can affect the brain parenchyma, its covering, and the skull. This discussion is restricted to the incidence, pathophysiology, and management of metastases to the brain parenchyma.
To metastasize, tumor cells have to gain access to the circulation, survive while circulating, pass through the microvasculature of the adopted organs, extravasate into the organ parenchyma, and reestablish themselves at the secondary site. This process requires the tumor cells to penetrate the basement membrane and cross the subendothelial membrane. Tumor cells achieve this by producing proteolytic enzymes, particularly metalloproteinases and cathepsins to help them to break down the basal matrix and enhance their invasiveness. Tumor cells modulate the expression of fibronectin, collagen, or laminin, and change the type of integrin receptor on their surface and on the surface of the surrounding stromal cells, resulting in desegregation of the stromal cells and creating a permissive environment for them to expand and invade.
Invading cells detach from the tumor mass, disperse, and traverse the epithelial/endothelial boundary; they will use the vascular conduit to colonize distant organs. Furthermore, they have to survive intravascular circulation and avoid immune surveillance during this journey. They accomplish that by coating themselves with a shield made out of the coagulating elements such as fibrin and platelets in the blood. These metastatic emboli also produce adherens to slow themselves down to a halt in the blood stream. These adheren molecules allow the circulating cancer cells to reattach onto the vascular wall and gain entry to the host tissue by disruption of the endothelial barrier. This leads to re-establishment of distant micrometastasis.
Tumor cells can survive in environments of low oxygen tension. When a tumor increases in volume by more than 2-3 times, the tumor expresses angiogenic factors such as angiopoietin-2 and vascular endothelial growth factors. These angiogenic modulators promote sprouting of surrounding blood vessels, which results in tumor angiogenesis. Additionally, these paracrine factors influence the readiness of target organs to accept tumor growth to prepare a favorable microenvironment for the tumor to undergo exponential growth and become a macrometastasis. 
Different tumors metastasize preferentially to different organs. Cells with similar embryologic origins are generally believed to have similar growth constraints and express similar sets of adhesion molecules, such as addressins. An example is melanoma; the cells are closely related to CNS cells (they are derived from the neural crest cells), and melanoma commonly metastasizes to the brain. Certain cell-surface markers in cancer are indicators and/or predictors of distant metastasis, eg, nm23 and CD44 in breast cancer.  Similarly, breast cancer cells that are HER positive are more likely to metastasis to the brain.  Renal, gastrointestinal, and pelvic cancer tend to metastasize to the cerebellum, whereas breast cancer is more commonly found in the posterior pituitary. Thus, the trafficking of cancer cells to their final destination is not entirely random and may be guided by factors produced by stromal cells of their host organ.
Recently, it has been shown that metastases may have originated from cancer initiating cells, which are more resistant to therapy by virtue of their stemlike properties.  Additionally, cancer cells recruit bone marrow–derived cells to modify the microenvironment of distant recipient sites, forming a premetastatic niche by alternating the level of fibronectin and making the site more favorable for the colonization of metastatic tumor. 
Cancer cells have been shown to recruit bone marrow—derived cells to modify the microenvironment of distant recipient site; the formation of a premetastatic niche by alternating the level of fibronectin and making the site more favorable for the colonization of metastatic tumor. 
The incidence of metastatic brain tumors exceeds that of primary brain tumors, accounting for 50% of total brain tumors and for as many as 30% of tumors seen on imaging studies alone. An estimated 100,000 new cases are diagnosed per year in the United States; about 60% of patients are aged 50-70 years.
More than 20% of patients with systemic disease have brain metastasis on autopsy. About 15% of patients with cancer present with neurologic symptoms before their systemic cancer is diagnosed. Among them, 43-60% have an abnormal chest radiograph suggestive of bronchogenic primary or other metastases to the lung. In 9%, the CNS is the only site of spread. About 10% of patients with proven metastatic disease have no identifiable primary source.
The most common origins of brain metastasis are systemic cancer of the lung, breast, skin, or GI tract. In 2700 cases from the Memorial Sloan-Kettering Cancer Center in New York, the distribution of primary cancers was as follows: 48% lung, 15% breast, 9% melanoma, 1% lymphoma (mainly non-Hodgkin), 3% GI (3% colon and 2% pancreatic), 11% genitourinary (21% kidney, 46% testes, 5% cervix, 5% ovary), 10% osteosarcoma, 5% neuroblastoma, and 6% head and neck tumor. Of note, renal, GI, and pelvic cancers tend to metastasize to the cerebellum, whereas breast cancer most commonly affects the posterior pituitary. Cancer-cell trafficking may not be entirely random, and factors produced by stromal cells may guide their final destination in the brain.
Table 1 shows other data for sources of brain metastases.
Table 1. Sources of Primary Tumor in Brain Metastases (Open Table in a new window)
Primary Tumor Site
Lymphoma, mainly non-Hodgkin
Head and neck
Primary lung tumors account for 50% of all metastatic brain tumors. Lung cancer is the most common origin of metastatic disease. Of lung cancer patients who survive for more than 2 years, 80% will have brain metastases.
The average time interval between the diagnosis of primary lung cancer and brain metastases is 4 months. Interestingly, small cell carcinomas, which are only 20% of all lung cancers, account for 50% of brain metastases from lung cancer. In a retrospective study, 6.8% of the first cancer recurrence was in the brain.
Breast tumor is the main source of metastatic disease in women, followed by melanoma, renal, and colorectal tumors. Breast cancer is a heterogeneous disease demonstrating genotypic and phenotypic diversity. The interval between the diagnosis of primary breast cancer and brain metastasis can be up to 3 years. The first site of distant failure is the brain, alone or as a component of metastatic disease, and a proportionately high number are ER- or HER2 negative. Yet HER positive cancer is twice as common to metastasize to the brain. Additionally, it has been shown that nm23 and CD44 in breast cancer are indicators for distant metastasis.
Melanoma commonly metastasizes to the brain. Melanoma has an increased incidence among other systemic cancers in terms of metastasizing to the brain. About 40-60% of patients with melanoma will have brain metastasis. Melanoma cells are closely related to CNS cells due to their embryonic origin and neural crest cells, and they share common antigens such as MAG-1 and MAG-2. After melanoma is detected in the brain, median survival is 3 months. These metastases are poorly responsive to all treatments. Approximately 14% of cases have no identifiable primary tumor. Melanomagenic tumors also involve the pial/arachnoid. In CT imaging, they are marginally enhanced with contrast compared with bronchogenic cancer. They are distinctive in MRI because of the melanin or due to hemorrhage. Others metastatic tumors that commonly bleed are thyroid and renal cell carcinoma. Unfortunately, patients with brain metastasis from melanoma are known to do poorly despite therapy.
Metastatic disease from the breast, thyroid, renal cells, and colon are more commonly found as a single metastatic lesion, whereas metastatic disease from lung cancer and melanoma are more commonly found to be multiple lesions. Testicular tumor is a uncommon cancer and yet it more frequently metastasizes to the brain as compared with lung cancer.
Patients with brain metastasis at the same time of having systemic cancer (synchronous metastasis) tend to do worse as compared with patients with metachronous metastatic disease.
Although melanoma spreads to the brain more commonly in males than in females, gender does not affect the overall incidence of brain metastases.
About 60% of patients are aged 50-70 years.
CNS metastasis is not common in children; it accounts for only 6% of CNS tumors in children.
Leukemia accounts for most metastatic CNS lesions in young patients, followed by lymphoma, osteogenic sarcoma, and rhabdomyosarcoma.
Germ-cell tumors are common in adolescents and young adults aged 15-21 years.
Nussbaum ES, Djalilian HR, Cho KH, Hall WA. Brain metastases. Histology, multiplicity, surgery, and survival. Cancer. 1996 Oct 15. 78(8):1781-8. [Medline].
Santarelli JG, Sarkissian V, Hou LC, Veeravagu A, Tse V. Molecular events of brain metastasis. Neurosurg Focus. 2007 Mar 15. 22(3):E1. [Medline].
Andrade AC, Ferruzzi DS, Panis C. Brain-metastatic breast cancer: clinical considerations and pharmacological approaches. Anticancer Agents Med Chem. 2016 Apr 4. [Medline].
Rusciano D, Burger MM. Mechanisms of Metastases. levine AJ, Schmidek HH (eds). In Molecular Genetics of Nervous System Tumors. New York: John Wiley & Son; 1993.
Nolte SM, Venugopal C, McFarlane N, Morozova O, Hallett RM, O’Farrell E. A Cancer Stem Cell Model for Studying Brain Metastases From Primary Lung Cancer. J Natl Cancer Inst. 2013 Feb 15. [Medline].
Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005 Dec 8. 438(7069):820-7. [Medline].
Sheehan J. Radiosurgery for breast cancer. J Neurosurg. 2011 Mar. 114(3):790-1; discussion 791. [Medline].
Hanssens P, Karlsson B, Yeo TT, Chou N, Beute G. Detection of brain micrometastases by high-resolution stereotactic magnetic resonance imaging and its impact on the timing of and risk for distant recurrences. J Neurosurg. 2011 Sep. 115(3):499-504. [Medline].
Tien RD, Felsberg GJ, Friedman H, Brown M, MacFall J. MR imaging of high-grade cerebral gliomas: value of diffusion-weighted echoplanar pulse sequences. AJR Am J Roentgenol. 1994 Mar. 162(3):671-7. [Medline].
Shonka N, Venur VA, Ahluwalia MS. Targeted Treatment of Brain Metastases. Curr Neurol Neurosci Rep. 2017 Apr. 17 (4):37. [Medline].
Galicich JH, French LA. Use of dexamethasone in the treatment of cerebral edema resulting from brain tumors and brain surgery. Am Pract Dig Treat. 1961 Mar. 12:169-74. [Medline].
Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer. 2012 Sep. 77(3):556-60. [Medline].
Soffietti R, Trevisan E, Rudà R. Targeted therapy in brain metastasis. Curr Opin Oncol. 2012 Nov. 24(6):679-86. [Medline].
Verma J, Jonasch E, Allen P, Tannir N, Mahajan A. Impact of tyrosine kinase inhibitors on the incidence of brain metastasis in metastatic renal cell carcinoma. Cancer. 2011 Nov 1. 117(21):4958-65. [Medline].
Azim HA, Azim HA Jr. Systemic treatment of brain metastases in HER2-positive breast cancer: current status and future directions. Future Oncol. 2012 Feb. 8(2):135-44. [Medline].
Mulcahy N. Spare the Hippocampus in Brain Radiotherapy, Preserve Memory. Available at http://www.medscape.com/viewarticle/811926. Accessed: October 7, 2013.
Minniti G, Clarke E, Lanzetta G, Osti MF, Trasimeni G, Bozzao A. Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis. Radiat Oncol. 2011. 6:48. [Medline].
Bindal RK, Sawaya R, Leavens ME, Lee JJ. Surgical treatment of multiple brain metastases. J Neurosurg. 1993 Aug. 79(2):210-6. [Medline].
Cho KH, Hall WA, Lee AK. Stereotactic radiosurgery for patients with single brain metastasis. J Radiol. 1998. 1:79-85.
Auchter RM, Lamond JP, Alexander E, et al. A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys. 1996 Apr 1. 35(1):27-35. [Medline].
Nieder C, Mehta MP, Geinitz H, Grosu AL. Prognostic and predictive factors in patients with brain metastases from solid tumors: A review of published nomograms. Crit Rev Oncol Hematol. 2018 Jun. 126:13-18. [Medline].
Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997 Mar 1. 37(4):745-51. [Medline].
Bindal AK, Bindal RK, Hess KR, et al. Surgery versus radiosurgery in the treatment of brain metastasis. J Neurosurg. 1996 May. 84(5):748-54. [Medline].
DeAngelis LM, Mandell LR, Thaler HT, et al. The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery. 1989 Jun. 24(6):798-805. [Medline].
Debinski W, Tatter SB. Convection-enhanced delivery for the treatment of brain tumors. Expert Rev Neurother. 2009 Oct. 9(10):1519-27. [Medline].
Harding A. Skipping Whole-Brain Radiation May Be OK With Multiple Metastases. Medscape Medical News. Available at http://www.medscape.com/viewarticle/822786. Accessed: April 7, 2014.
Jensen CA, Chan MD, McCoy TP, et al. Cavity-directed radiosurgery as adjuvant therapy after resection of a brain metastasis. J Neurosurg. 2011 Jun. 114(6):1585-91. [Medline].
Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011 Jan 10. 29(2):134-41. [Medline]. [Full Text].
Lo SS, Sloan AE, Machtay M. Stereotactic radiosurgery for more than four brain metastases. Lancet Oncol. 2014 Apr. 15(4):362-3. [Medline].
Pullen LC. Biomarker identifies brain metastases in lung cancer patients. Medscape Medical News. November 20, 2013. [Full Text].
Rusciano D, Burger MM. Mechanisms of metastases. Levine AJ, Schmidek HH, eds. Molecular Genetics of Nervous System Tumors. New York, NY: Wiley-Liss; 1993.
Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014 Apr. 15(4):387-95. [Medline].
Primary Tumor Site
Lymphoma, mainly non-Hodgkin
Head and neck
Karnofsky Performance Status
Median Survival, mo
Age 65 y or younger
70 or higher
Controlled primary disease; no extracranial metastases
7.1 overall; 13.5 for single metastasis, 6 for multiple metastases
Age 65 y or older
70 or higher
Uncontrolled systemic disease; extracranial metastasis
4.2 overall; 8.1 for single metastasis, 4.1 for multiple metastases
Victor Tse, MD, PhD Clinical Professor, (Affiliated Clinical Educator Line), Department of Neurosurgery, Stanford University School of Medicine; Neurosurgeon, Kaiser Neuroscience of Northern California
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Jorge C Kattah, MD Head, Associate Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria
Disclosure: Nothing to disclose.
Nicholas Lorenzo, MD, MHA, CPE Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc
Disclosure: Nothing to disclose.
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