Background
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.[1] 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.
Multiple brain metastasis in a patient with known non-small cell lung adenocarcinoma. There was also systemic disease in the liver. Pathophysiology
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.[2]
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.[3] 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.
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.[4]
Epidemiology
Frequency
United States
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.
Mortality/Morbidity
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 | Percentage (%) |
| Lung | 21 |
| Breast | 9 |
| Melanoma | 40 |
| Lymphoma, mainly non-Hodgkin | 1 |
| GI tract | 3 |
| Genitourinary tract | 11 |
| Osteosarcoma | 10 |
| Head and neck | 6 |
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.
Sex
Although melanoma spreads to the brain more commonly in males than in females, gender does not affect the overall incidence of brain metastases.
Age
- 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.
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| Primary Tumor Site | Percentage (%) |
| Lung | 21 |
| Breast | 9 |
| Melanoma | 40 |
| Lymphoma, mainly non-Hodgkin | 1 |
| GI tract | 3 |
| Genitourinary tract | 11 |
| Osteosarcoma | 10 |
| Head and neck | 6 |
| Group | Karnofsky Performance Status | Systemic Disease | Median Survival (mo) |
| Age ≤ 65 y | ≥ 70 | Controlled primary disease, no extracranial metastases | 7.1; 13.5 for single metastasis, 6.0 for multiple metastases |
| Age ≥ 65 y | ≥ 70 | Controlled systemic disease, with extracranial metastasis | 4.2; 8.1 for single metastasis, 4.1 for multiple metastases |
| Any age | Any | Any | 2.3 |
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