INTRODUCTION — Brain metastases are the most common intracranial tumors in adults, accounting for significantly more than one-half of brain tumors. In patients with systemic malignancies, brain metastases occur in 10 to 30 percent of adults and 6 to 10 percent of children .
The incidence of brain metastases may be increasing, due to both improved detection of small metastases by magnetic resonance imaging (MRI) and better control of extracerebral disease resulting from improved systemic therapy.
EPIDEMIOLOGY — In adults, the most common primary tumors responsible for brain metastases are carcinomas, and include lung, breast, kidney, and colorectal cancers, and melanoma. In contrast, carcinomas of the prostate, esophagus, and oropharynx and non-melanoma skin cancers rarely metastasize to the brain. In children, the most common sources of brain metastases are sarcomas, neuroblastoma, and germ cell tumors .
For all types of cancer, brain metastases diagnosed during life are relatively uncommon. This was illustrated in two large series, one from the Metropolitan Detroit Cancer Surveillance System and the other from a Dutch series. In both studies, the cumulative incidence of detected brain metastases was similar among all patients diagnosed with cancer:
In autopsy series, the reported incidence of brain metastases varies widely, but generally is substantially higher than that diagnosed antemortem. This is illustrated by a review that found that brain metastases occur in as many as 64 percent of patients with lung cancer and 21 percent of those with breast cancer.
The incidence of brain metastases among women with breast cancer may be increasing, and is particularly high in those with lung metastases and highly-proliferative, hormone receptor-negative tumors that are positive for HER2 overexpression. In one series, 15 of 50 patients (30 percent) presenting with lung metastases as the first site of relapse subsequently developed brain metastases during follow-up . One possible explanation is that the blood brain barrier prevents access of chemotherapeutic agents to undetected metastases. Treatment of non-brain metastases by newer therapeutic regimens may control systemic tumor growth, allowing time for the development of brain metastases.
The incidence of brain metastases in patients with metastatic colorectal cancer and non-small cell lung cancer also appears to be increasing . This may be due to improved diagnosis with newer imaging modalities and/or more effective treatment of systemic disease, allowing patients a longer time during which brain metastases can become manifest.
PATHOGENESIS — The most common mechanism of metastasis to the brain is by hematogenous spread . Metastases are usually located directly at the junction of the gray matter and white matter where blood vessels decrease in diameter and act as a trap for clumps of tumor cells . Brain metastases also tend to be more common at the terminal "watershed areas" of arterial circulation . The distribution of metastases roughly follows the relative weight and blood flow in each area :
Different primary tumors may have a predilection for metastasis to different areas within the brain. For example, pelvic (prostatic and uterine) and gastrointestinal tumors more commonly metastasize to the posterior fossa , while metastases of small cell carcinoma of the lung are equally distributed in all regions of the brain. The reasons for these differences are unclear but may be due to cell surface properties of the metastatic cells and the endothelium within the central nervous system (CNS) vasculature.
CLINICAL MANIFESTATIONS — Brain metastases have highly variable clinical features and should be suspected in any cancer patient who develops neurologic symptoms or behavioral abnormalities. However, multiple other causes can also be responsible. In an analysis of over 800 cancer patients evaluated for neurologic symptoms, only 16 percent had brain metastases .
In the majority of patients, a gradually expanding tumor mass and its associated edema cause symptoms. Less commonly, intratumoral hemorrhage, obstructive hydrocephalus, or embolization by tumor cells result in symptoms.
Headache — Headaches occur in approximately 40 to 50 percent of patients with brain metastases. The frequency is higher when multiple lesions are present or a metastasis is located in the posterior fossa . Although the classic early morning headache is uncommon, it is highly suggestive when present.
These general features were illustrated in a review of 111 consecutive patients with primary or metastatic brain tumors identified by CT or MRI . Headaches were present in 48 percent and equally affected those with primary and metastatic tumors. The headaches were similar to tension type in 77 percent, migraine in 9 percent, and other types in 14 percent. The typical headache was bifrontal but worse ipsilaterally; it was the worst symptom in about one-half of patients. In contrast to tension type headaches, brain tumor headaches were worse with bending over in 32 percent, and nausea or vomiting was present in 40 percent. Worsening headache may also follow maneuvers that raise intrathoracic pressure, such as coughing, sneezing, or the Valsalva maneuver. The "classic" early morning brain tumor headache was uncommon.
Features suggestive of a possible brain tumor in the patient complaining of headaches include nausea and vomiting, a change in prior headache pattern, an abnormal neurologic examination, and positional worsening.
Focal neurologic dysfunction — Focal neurologic dysfunction is the presenting symptom of 20 to 40 percent of patients. Hemiparesis is the most common complaint but the manifestations depend upon the location of the metastases .
Cognitive dysfunction — Cognitive dysfunction, including memory problems and mood or personality changes, is the presenting problem in 30 to 35 percent of patients. However, metabolic encephalopathy is a much more common cause of cognitive dysfunction than metastatic disease in cancer patients who develop an altered mental status .
Seizures — New onset of seizures is the presenting symptom in 10 to 20 percent of patients . Seizures in patients with brain metastases are almost exclusively associated with supratentorial disease .
Stroke — Another 5 to 10 percent present acutely due to stroke caused by hemorrhage into a metastasis, hypercoagulability, invasion or compression of an artery by tumor, or embolization of tumor cells . Melanoma, choriocarcinoma, and thyroid and renal carcinoma have a particular propensity to bleed .
DIAGNOSIS — Brain metastases must be distinguished from primary brain tumors, infectious processes, progressive multifocal leukoencephalopathy, demyelination, cerebral infarction or bleeding, and effects of treatment such as radiation necrosis. Imaging studies provide useful information but brain biopsy is necessary in some cases for a definitive diagnosis. Other important diagnostic issues include determining the number and location of metastases and the evaluation of the patient without a known primary tumor.
Imaging studies — Contrast-enhanced MRI is the preferred imaging study for the diagnosis of brain metastases. Contrast-enhanced MRI is more sensitive than either nonenhanced MRI or CT scanning in detecting lesions in patients suspected of having cerebral metastases, and in differentiating metastases from other central nervous system (CNS) lesions . In one report of 23 patients, for example, contrast-enhanced MRI demonstrated more than 67 definite or typical parenchymal metastases compared to more than 40 with T2-weighted MRI, and only 37 with double-dose contrast-enhanced CT .
Radiographic features that can help differentiate brain metastases from other CNS lesions include the following :
Experimental techniques such as magnetization transfer (MT) and triple dosegadolinium imaging have further improved lesion detection with MRI. In one study of 52 patients, for example, MT imaging showed more metastases than gradient-echo T1-weighted images in 23 percent of patients . Newer modalities such as echo planar imaging, spectroscopy, PET, and SPECT, also may prove to be useful . They are mainly used to differentiate tumor from radiation necrosis rather than for the initial diagnosis of brain metastases.
Brain biopsy — Biopsy should be performed whenever the diagnosis of brain metastases is in doubt. This is particularly important in patients with a single lesion. The importance of biopsy was demonstrated in a study in which the diagnosis of metastasis was changed by biopsy in six of 54 patients with a single lesion  . These six patients had primary brain tumors or infectious or inflammatory processes.
Breast cancer patients with a single dural-based lesion pose a particular diagnostic dilemma, since the incidence of meningiomas is increased in these patients . Imaging studies are often inconclusive, and biopsy or surgical resection of the lesion may be required to establish the diagnosis.
Brain metastases without a known primary tumor — In about 80 percent of patients, brain metastases develop after the diagnosis of systemic cancer (metachronous presentation) . In the remaining patients, brain metastases become evident at the same time (synchronous presentation) or before the primary tumor is found (precocious presentation). Histopathology of the biopsy specimen, including immunohistochemistry, can often help identify the primary .
For patients who present with biopsy-proven brain metastases without a known primary tumor, the lung should be the primary focus of the evaluation. Over 60 percent of such patients have a primary lung cancer or pulmonary metastases from a primary tumor located elsewhere . Other frequent sites include melanoma, colon cancer, and breast cancer, while the primary remains unknown in approximately 25 to 30 percent of cases.
The history and physical examination demonstrate the site of origin in one-quarter to one-third of patients. In the others, a chest radiograph should be the first imaging test obtained. If this is nondiagnostic, a chest CT scan should be performed since this significantly increases the likelihood of detecting a lung tumor. This was illustrated in a report of 31 patients who presented with brain metastases without a known primary and subsequently were determined to have primary lung cancer by CT scan; chest radiographs were positive in only 19 (59 percent) . These patients should also have a CT scan of the abdomen and pelvis and a bone scan to determine the extent of metastatic disease.
Positron emission tomography (PET) may also be useful in these patients, either by identifying the primary tumor, or by finding other sites of metastatic disease that can be biopsied more readily.
Number of metastases — It is important to differentiate patients with a single or limited number of small metastases from those with more extensive involvement since the subsequent treatment may be different. Although earlier studies based upon CT scans suggested that as many as 50 percent of patients had a single metastasis, MRI suggests that the true frequency of single metastases is lower, accounting for only one-fourth to one-third of patients with cerebral metastases. Metastases from breast, colon, and renal cell carcinoma are more often single, while lung cancer and malignant melanoma have a greater tendency to produce multiple metastases .
SUMMARY — Brain metastases are the most common intracranial tumors in adults, occurring in about 10 percent of cancer patients at some point during their illness and accounting for significantly more than one-half of all brain tumors. Lung cancer, melanoma, renal cell carcinoma, and breast cancer are the most common primary tumors that metastasize to the brain.
Metastases can cause a variety of symptoms, including headache, focal neurologic deficits, cognitive dysfunction, seizures, and stroke. The development of any neurologic symptom in a patient with cancer requires consideration of the diagnosis of metastasis, although other causes are responsible in the majority of instances .
Contrast-enhanced MRI is the most reliable imaging procedure to make the diagnosis. In patients with a single intracranial lesion, biopsy may be required to make a definitive diagnosis