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 [1-5].
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 [4-10].
The etiology, clinical manifestations, and diagnosis of brain metastases will be reviewed here, along with an overview of the approach to treatment. Specific treatment approaches, as well as the use of systemic therapy according to the underlying cancer type, are discussed separately.
●(See "Overview of the treatment of brain metastases".)
●(See "Brain metastases in non-small cell lung cancer".)
●(See "Brain metastases in breast cancer".)
●(See "Management of brain metastases in melanoma".)
PRIMARY TUMORS — In adults, the most common primary tumors responsible for brain metastases are carcinomas, and include lung, breast, kidney, and colorectal cancers, and melanoma. By 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 [3,9,10].
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 [11,12]. In both studies, the cumulative incidence of brain metastases detected was similar:
●Lung – 16 to 20 percent
●Melanoma – 7 percent
●Renal cell cancer – 7 to 10 percent
●Breast cancer – 5 percent
●Colorectal cancer – 1 to 2 percent
In autopsy series, the reported incidence of brain metastases varies widely but is generally 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 dying from lung cancer and 21 percent of those dying from breast cancer [13].
Increasing incidence with advances in systemic therapy — Increases in the incidence of brain metastasis have been reported in several solid tumors, thought to be related, at least in part, to advances in the efficacy of systemic therapy:
●Breast cancer – Among women with breast cancer, the incidence of brain metastasis may be increasing and is particularly high in those with lung metastases and those with highly proliferative, hormone receptor-negative tumors, such as triple-negative breast cancer, and those that are also positive for human epidermal growth factor receptor 2 (HER2) overexpression [14-19]. 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 [14].
Although tumor biology might also be at least partly responsible (ie, HER2-positive breast cancers have a higher propensity for metastases to sites such as lung and brain), it is also postulated that the lack of trastuzumab penetration into the central nervous system (CNS), owing to its high molecular weight, coupled with prolonged control of what was previously rapidly lethal systemic disease, leads to "unmasking" of brain metastases that would otherwise have remained clinically silent. (See "Brain metastases in breast cancer".)
●Colorectal cancer – The increasing incidence of brain metastases in patients with metastatic colorectal cancer has been attributed to the longer survival seen with newer systemic therapies [9,20-22]. Compared with the era when fluorouracil was the sole available agent for metastatic disease, median survival has increased markedly with the introduction of oxaliplatin, irinotecan, and biologics (from 6 to 7 to beyond 24 months in selected patients). (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Overview of the therapeutic approach'.)
However, the incidence of brain metastases in metastatic colorectal cancer is still low, 2.3 percent in one series [23]. Brain metastases are usually a late-stage phenomenon, and the vast majority of patients have metastases in other sites, particularly lung. Outcomes are poor, despite aggressive treatment [24-26].
●Non-small cell lung cancer (NSCLC) – The overall incidence of brain metastases in patients with NSCLC is approximately 16 to 20 percent. However, certain molecular subtypes have an increased propensity for brain metastases, including those with an epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) rearrangement, or HER2 mutation. (See "Brain metastases in non-small cell lung cancer".)
PATHOGENESIS — The most common mechanism of metastasis to the brain is by hematogenous spread [21]. 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 [27]. 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 [27]:
●Cerebral hemispheres – approximately 80 percent
●Cerebellum – 15 percent
●Brainstem – 5 percent
Different primary tumors may have a predilection for metastasis to different areas within the brain. For example, pelvic (prostatic and uterine), gastrointestinal, and breast tumors more commonly metastasize to the posterior fossa (image 1) [27,28], 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 [29].
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 computed tomography (CT) or MRI [30]. Headache was 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 approximately 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. (See "Brain tumor headache".)
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 [29].
Seizures — New onset of seizures is the presenting symptom in 10 to 20 percent of patients [31-34]. Seizures in patients with brain metastases are almost exclusively associated with supratentorial disease [32].
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 [7,35]. Melanoma, choriocarcinoma, and thyroid and renal carcinoma have a particular propensity to bleed (image 2) [7].
DIAGNOSIS — Brain metastases must be distinguished from primary brain tumors, infectious processes, progressive multifocal leukoencephalopathy, demyelination, paraneoplastic phenomena, cerebral infarction or bleeding, and effects of treatment such as radiation necrosis. (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Differential diagnosis'.)
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 [36-39]. 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 [37,38]. CT may highlight calcifications associated with brain metastases, especially in patients with non-small cell lung cancer (NSCLC) [40].
Brain metastases are most commonly discrete, circumscribed masses that enhance after contrast administration (image 1 and image 3 and image 4 and image 5). Some metastases are cystic or have both cystic and solid components (image 3). Other imaging features that can help differentiate brain metastases from other CNS lesions include the following [6]:
●The presence of multiple lesions (image 3)
●Localization at the junction of the gray and white matter (image 3 and image 4)
●Circumscribed margins, in contrast to high-grade glioma, which has infiltrative margins (image 1 and image 2 and image 3 and image 4)
●Large volume of associated vasogenic edema compared with the size of the lesion (image 4)
●Absence of marked reduced diffusivity, particularly in the center or core of the lesion; reduced water diffusion in the center of a mass is more typical of pyogenic brain abscess
●Almost all brain metastases enhance, but the pattern of enhancement is variable (image 1 and image 3 and image 4 and image 5)
Perfusion-weighted imaging is an MRI method that measures cerebral blood flow and volume after the administration of intravenous contrast. As such, it enables study of tissue perfusion at the capillary level and has been used to characterize brain tumors [41]. Studies have shown that the percentage of signal recovery, obtained from the time-signal curve, can be used to differentiate metastasis from high-grade glioma and primary CNS lymphoma [42-44].
Biopsy — Biopsy should be performed when the diagnosis of brain metastases is in doubt. Biopsy material is most commonly obtained at the time of a resection. 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 6 of 54 patients with a single lesion [45]. These six patients had primary brain tumors, infections, 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 [46,47]. Imaging studies are often inconclusive, but the presence of edema in the underlying brain and an irregular margin of the lesion may suggest a dural metastasis instead of a meningioma (image 5). However, biopsy or surgical resection of the lesion may be required to establish the diagnosis. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Diagnostic evaluation'.)
Unknown primary tumor — In approximately 80 percent of patients, brain metastases develop after the diagnosis of systemic cancer (metachronous presentation) [1]. In the remaining patients, brain metastases become evident either at the same time (synchronous presentation) or before the primary tumor is found (precocious presentation). In these situations, histopathology of the biopsy specimen, including immunohistochemistry, can often help identify the primary [48]. Lung cancer is the most common cancer type associated with a synchronous presentation of brain and systemic disease [49,50].
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 [51-54]. Other relatively frequent sites include melanoma and colon cancer, while the primary remains unknown in approximately 25 to 30 percent of cases. (See "Overview of the classification and management of cancers of unknown primary site".)
The history and physical examination demonstrate the site of origin in one-quarter to one-third of patients. Chest CT scan should be performed since this significantly increases the likelihood of detecting a lung cancer. 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) [51]. 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 — Patients with a single or limited number of small metastases should be differentiated from those with more extensive involvement since 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 [6,36,37]. 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 [27].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Brain cancer (The Basics)" and "Patient education: Brain metastases (The Basics)")
●Beyond the Basics topics (see "Patient education: Low-grade glioma in adults (Beyond the Basics)" and "Patient education: High-grade glioma in adults (Beyond the Basics)" and "Patient education: Meningioma (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Brain metastases are the most common intracranial tumors in adults, occurring in approximately 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. (See 'Primary tumors' above.)
●Clinical manifestations – 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 cases. (See 'Clinical manifestations' above.)
●Diagnosis – Contrast-enhanced MRI is the most reliable imaging procedure to make the diagnosis. Brain metastases are most commonly circumscribed, solid, spherical masses that enhance after contrast administration and often have surrounding edema (image 1 and image 2 and image 4). Some metastases are cystic or have a mix of cystic and solid features (image 3). (See 'Imaging studies' above.)
●Differential diagnosis – Brain metastases must be distinguished from primary brain tumors, infectious processes, demyelination, cerebral infarction or bleeding, and effects of treatment such as radiation necrosis. Radiographic features that can help differentiate brain metastases from other central nervous system (CNS) lesions include the following:
•The presence of multiple lesions (image 2)
•Localization at the junction of the gray and white matter (image 3)
•Circumscribed margins (image 1)
•Large amounts of vasogenic edema compared with the size of the lesion (image 5)
●Role of biopsy – In patients with a single intracranial lesion, biopsy may be required to make a definitive diagnosis, especially when there is minimal or no systemic disease or only a remote history of cancer. In such cases, biopsy material is most commonly obtained at the time of a resection. (See 'Biopsy' above and 'Unknown primary tumor' above.)
●Management – Patient treatment depends upon the overall prognosis and includes specific measures directed against metastases as well as the prevention and management of complications. (See "Overview of the treatment of brain metastases".)
