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Author: Anil Khosla, MBBS, Assistant Professor, Department of Radiology, Section of Neuroradiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, Veterans Affairs Medical Center of St Louis

Anil Khosla is a member of the following medical societies: American College of Radiology, American Roentgen Ray Society, American Society of Neuroradiology, North American Spine Society, and Radiological Society of North America

Editors: Jeffrey L Creasy, MD, Associate Professor, Associate Section Head, Division of Neuroradiology, Director, Neuroradiology Fellowship, Department of Radiology, Vanderbilt University; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Robert L DeLaPaz, MD, Director, Professor, Department of Radiology, Division of Neuroradiology, Columbia University; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; James G Smirniotopoulos, MD, Professor of Radiology, Neurology, and Biomedical Informatics, Chairman, Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences

Author and Editor Disclosure

Synonyms and related keywords: brain metastases, brain metastasis, brain cancer, systemic cancer, brain carcinoma, metastasis, metastases, intracranial metastasis, intracranial metastases, metastatic cancer, metastatic brain cancer, metastasis detection, metastasis imaging

Background

Metastasis to the brain is the most feared complication of systemic cancer and the most common intracranial tumor in adults. The incidence of brain metastasis is rising with the increase in survival of cancer patients. Currently, cancer patients live longer as a result of important advances in cancer diagnosis and management, and in particular, the widespread use of MRI to detect small metastases. Approximately 40% of intracranial neoplasms are metastatic. Multiple, large autopsy series suggest that, in order of decreasing frequency, lung, breast, melanoma, renal, and colon cancers are the most common primary tumors to metastasize to the brain.1, 2

Brain metastases are an increasingly important cause of morbidity and mortality in cancer patients. Thus, brain metastasis presents a therapeutic challenge for the treating physician and is an emotionally and physically debilitating event for the patient. Early diagnosis and aggressive treatment of brain metastasis may result in remission of brain symptoms and may enhance the quality of the patient's life and prolong survival. The radiologist plays a primary role in the management of cancer patients by helping detect, localize, and diagnose the lesion.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Brain Cancer.

Related eMedicine topics:
Brain Metastasis 
Brainstem Gliomas
Metastatic Cancer, Unknown Primary Site

Related Medscape topics
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Specialty Site Radiology
Specialty Site Oncology
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Resource Center Pharmacologic Management of Pain 
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Pathophysiology

Metastatic spread to the brain through blood circulation occurs mostly via arterial circulation; (2) less often, it occurs via the Batson venous plexus (pelvic and GI tumors). Most metastases are round, well-demarcated lesions located at the junction of gray and white matter.3 Leakage from tumor vessels results in an extensive zone of edema surrounding the tumor.

Before entering the brain, arterial blood must pass through the lungs, where larger aggregates of tumor cells are filtered out in the capillaries; as a result, many emboli traveling to the brain via the arterial route originate either from a primary lung tumor or a metastatic site in the lung. However, single tumor cells may pass through the capillaries of the lung, and larger tumor emboli may pass from the venous circulation to the arterial circulation through a persistently patent foramen ovale between the right and left atrium of the heart.

Metastatic tumor growth in the brain depends on complex organotropic factors, as well as passive vascular delivery of tumor cells. Lesions are located in the cerebrum (80-85%), in the cerebellum (10-15%), and in the brain stem (3-5%). Slightly more than 50% of the time, metastases are multiple, not solitary; primary melanoma, as well as primary lung and breast tumors, are more likely to produce multiple metastases.

Intracranial metastases may be categorized by location as skull, dura, leptomeninges, and parenchymal brain metastases. Lesions of the brain and leptomeninges account for 80% of intracranial metastases. Meningeal carcinomatosis most commonly occurs in patients with breast carcinoma and malignant melanoma; less commonly, it occurs in patients with lymphoma, leukemia, and other tumors. Patients usually present with headache, vague neurologic complaints, and one or more cranial nerve palsies.

Frequency

United States

Approximately 170,000 cancer patients develop brain metastases annually. Intracranial metastases are seen in approximately 24% of patients who die from cancer (as reported in different series, the rate varies from 11-35%).

  • Brain metastases represent the most common neurologic manifestation of cancer, occurring in 15% of cancer patients. Intracranial metastases eventually develop in approximately one third of patients with lung carcinoma; 50% of brain metastases result from this type of cancer.
  • Brain metastases are less frequent in children; the incidence is approximately 6%.
  • Brain metastases from unknown primary neoplasms are most likely to be from a primary lung cancer (72%), followed in frequency by breast cancer, colon carcinoma, and melanoma.

Mortality/Morbidity

The prognosis for patients with brain metastases typically is poor. Therapeutic considerations must be individualized; there are many relevant factors, including the patient's neurologic status, the extent of systemic tumor, the number and location of brain metastases, and the sensitivity of the tumor to radiation and chemotherapy. Patients with the best prognostic indicators often die within 18-24 months. Of particular relevance to imaging is the fact that for patients with a solitary brain metastasis who undergo treatment by surgical resection, the survival rate after 1 year is approximately doubled. Most available treatment is palliative; however, consideration should be given to prolonging the patient's quality of life through specific therapy to the brain.

Sex

Brain metastases demonstrate the same predilection for gender that the primary tumors do. Lung cancer is the most common source of metastases in male patients, whereas breast cancer is the most common source in female patients. As the frequency of lung cancer in women increases, it may become the most common primary tumor to metastasize to the brain in women as well.

Age

The incidence of brain metastases as determined on the basis of age parallels that of primary systemic tumors. Most brain metastases occur in patients 35-70 years of age.

Clinical Details

Approximately two thirds of brain metastases are symptomatic at some point. Symptoms primarily are caused by (1) increased intracranial pressure resulting in headache, nausea, vomiting, confusion, and lethargy and (2) focal irritation or destruction of neurons resulting in hemiparesis, visual field defects, aphasia, focal seizures, ataxia, and other focal neurologic signs or deficits.

The most common symptoms, in order of decreasing frequency, are headache, focal weakness, and mental status changes. Symptoms typically are of gradual onset. However, if seizures are excluded, 5-10% of patients develop other acute symptoms. An acute strokelike presentation may occur and often is precipitated by hemorrhage into the tumor.

Hemorrhage is present in 3-14% of metastases; it is most often seen in metastases from melanoma, choriocarcinoma, and renal, thyroid, lung, breast, and germ-cell tumors. Bronchogenic metastases are the most common hemorrhagic lesions because they occur in much greater numbers. Generalized or focal seizures may occur in 20% of patients with brain metastases.

Different primary tumors spread to the brain at different points in the disease course. The median latent interval between the initial diagnosis of a primary tumor and the diagnosis of brain metastases varies from 6-9 months for lung cancer and from 2-3 years for melanoma, breast, and colon cancer. In 20% of patients, metastases are detected during diagnosis of the primary tumor; in 50% of patients, they are detected within 1 year of the diagnosis.

In 5-10% of cancer patients, brain metastasis is the first clinical manifestation of systemic cancer. Lung carcinoma is the primary tumor in 45% of those in whom the primary site is discovered.

Surgical resection is the preferred treatment for patients with one apparent metastasis detected on enhanced CT or MRI. Radiosurgery is a simple, effective, noninvasive, cost-effective method of treating surgically inaccessible lesions; it is a therapeutic option in 2-6 of cases of brain metastases.

With regard to screening for intracranial metastases, no consensus has been reached concerning when to use CT or MRI for initial staging evaluation of a patient with cancer. However, brain MRI for patients with primary cancers that frequently metastasize to the brain (eg, bronchogenic carcinoma) is probably cost effective. Numerous studies have shown that contrast-enhanced MRI detects 2-3 times as many lesions as contrast-enhanced CT, especially lesions less than 5 mm in diameter. In addition, approximately 20% of patients with solitary metastatic lesions on CT show multiple lesions on MRI. The decision to perform imaging for patients with other cancers is made on the basis of the clinical evaluation.

In the presence of multiple cerebral metastases from an unknown primary source, a limited search for the primary tumor is of value; such a search includes a chest radiograph, breast examination and mammography, and abdominal ultrasound (US). An extensive search for an occult malignancy is unrewarding. Surgery may be required for patients presenting with a solitary intracranial tumor or to search for a possible primary tumor.

It has been shown that treatment with dexamethasone leads to a reduction in evidence on MRI of peritumoral edema and, occasionally, a lessening in the extent of contrast enhancement. If a lesion is found and a definitive diagnosis cannot be established, biopsy should be performed.
 
Surgical removal of the lesion is indicated for single or solitary brain metastasis in patients with good systemic performance status, because surgery is both diagnostic and therapeutic.
 
Patients with multiple brain metastases or poor systemic performance status are possible candidates for whole-brain radiation therapy or radiosurgery.4, 5

Preferred Examination

Most patients with a known primary tumor undergo imaging studies when neurologic signs and symptoms develop. MRI with contrast enhancement currently is the procedure of choice, because MRI is more sensitive and specific than other imaging modalities in determining the presence, location, and number of metastases. Contrast-enhanced CT is used widely because of its accessibility and low cost.6

Limitations of Techniques

Approximately one third of patients operated on for a single cerebral metastasis diagnosed with contrast-enhanced CT probably have more than one lesion. Contrast-enhanced MRI is more sensitive than CT in detecting the number of cerebral metastases.

Medical care is influenced significantly by the additional information gained from gadolinium-enhanced MR studies. If a solitary metastasis is found, definitively ruling out the presence or absence of additional lesions is important for diagnosis and for deciding upon possible surgical management. Standard-dose or high-dose gadolinium-enhanced MRI may demonstrate additional lesions that suggest metastatic disease. Use of magnetization transfer with single-dose gadolinium administration is roughly equivalent to triple-dose, postcontrast, spin-echo imaging in detecting lesions and lesion conspicuity.



Brain, Abscess
Brain, Hypertensive Hemorrhage
Brain, Lymphoma
Brain, Stroke
Meningioma, Brain

Other Problems To Be Considered

Other problems or factors to consider include the following:

  • History of systemic cancer and a single supratentorial lesion (nearly 90% of such patients are diagnosed with brain metastases)
  • Single brain lesions and no history of cancer (15% of such patients receive a histologic diagnosis of brain metastases)
  • Multiple intracranial lesions without history of cancer (in older patients, metastases should be considered)
  • Solitary or multiple brain masses (40% of all intracranial tumors are metastatic)
  • The differential diagnosis for a solitary mass includes inflammatory disease, cerebrovascular disease, degenerative disease, and primary neoplasm
  • The differential diagnosis for multiple lesions (more likely to be metastases) includes multicentric glioma, multifocal abscesses, toxoplasmosis, lymphoma, and multiple enhancing infarcts
  • Brain vasculitis



Findings

Skull radiograms may detect multiple lytic or sclerotic deposits when the metastatic process involves the cranium. Lung and breast tumors are the most common primary malignancies to affect the skull. Multiple lytic lesions secondary to multiple myeloma tend to be uniformly small. Blastic metastases are seen in patients with primary prostate cancer or in patients who have undergone treatment for breast cancer. Calcifications are uncommon in metastases but do occur in primary adenocarcinoma, osteogenic sarcoma, and lung and breast carcinoma. Plain radiographs are not helpful in detecting metastatic disease of the brain.

Degree of Confidence

Multiple lytic or blastic lesions are highly suggestive of a metastatic process. Solitary lesions must be differentiated from other pathologic processes affecting the skull vault.

False Positives/Negatives

Normal anatomic variants, such as emissary vein, arachnoid granulation, and bone island, may mimic a metastatic lesion in a known cancer patient. Use of CT with bone windows may eliminate false diagnoses.



Findings

Metastases frequently are multiple; they are seen at the junction of gray and white matter, usually with significant surrounding edema (see Images 2-3). CT findings are as follows7, 8:

  • On noncontrast CT, the density of metastatic lesions may be less than (see Image 3), equal to, or greater than (see Image 9) that of adjacent brain parenchyma. Most of the patterns are variable and are nondiagnostic.
  • Noncontrast CT is performed to detect hemorrhage into metastases. Hyperdensity in a metastasis is more likely to be hemorrhage (see Image 9) than calcification (see Image 11).
  • IV administration of contrast material (30-40 g iodine) increases the diagnostic accuracy of CT. Most metastases enhance after a standard dose of IV contrast. Use of a higher dose of contrast (80-85 g of iodine) and delaying scanning by 1-3 hours after injection of the contrast agent lead to a further increase in the detection of multiple metastases; such an approach is appropriate if MRI is not available.
  • The detection of additional metastases has important diagnostic and therapeutic implications. In cases in which there is no known primary cancer, if a solitary lesion is found on routine enhanced CT, the presence of an additional lesion may suggest a metastatic process, provided the solitary lesion is believed to be a primary lesion. In cases involving a solitary metastatic lesion of the brain, detection of an additional lesion may have a bearing on treatment; with multiple lesions, surgical treatment may be forgone in favor of chemotherapy, radiation therapy, or both.

Contrast-enhanced CT is effective in detecting major leptomeningeal spread (see Image 8). Contrast-enhancing subdural or epidural metastases may be seen, usually secondary to calvarial lesions (see Image 10). Of breast, lung, prostate, and renal-cell neoplasms, 5% metastasize to the calvarium; of these, 15% extend into the subdural space.

Degree of Confidence

On findings of multiple, enhancing solid lesions at the gray matter–white matter junction and prominent surrounding edema in a patient with known primary cancer, a diagnosis of metastases may be confidently made. Approximately 90% of patients with a history of cancer who present with a single supratentorial lesion have brain metastases.

Patients with multiple lesions are even more likely to have metastatic disease. Before undergoing definitive therapy, patients who are found to have a single metastasis on contrast-enhanced CT should undergo a contrast-enhanced MRI examination, if facilities for such an examination are available.

False Positives/Negatives

Routine cranial CT is useful in the staging of cancer in the patient with nonsmall-cell lung cancer; cranial CT has a sensitivity of 92%, a specificity of 99%, and an accuracy of 98% in detecting brain metastases. Contrast-enhanced CT is perhaps the best method to identify calvarial metastases. In studies comparing contrast-enhanced CT with contrast-enhanced MRI, approximately 20% of patients who demonstrated a single lesion on CT demonstrated multiple lesions on MRI. Mostly, the lesions missed on contrast-enhanced CT were smaller (<2 cm in diameter) and were located next to the bone in a frontotemporal location. Dural-based metastases may mimic meningioma.



Findings

Multiple lesions (see Images 4-5) with marked vasogenic edema (see Image 1) and mass effect are typically seen in patients with brain metastases.9, 10, 11, 12, 13, 14 MRI findings are as follows:

  • Lesions are isointense to mildly hypointense on T1-weighted images; they are hyperintense on T2-weighted images or with fluid attenuation inversion recovery.
  • Surrounding edema is relatively hypointense on fluid attenuation inversion recovery and on T1-weighted images (see Image 1); they are hyperintense on T2-weighted images.
  • Hemorrhagic metastases or melanoma lesions are hyperintense on T1-weighted images.
  • On T2-weighted images, mucinous adenocarcinoma may be hypointense, owing to calcification; hemorrhagic metastases may be hypointense, owing to the chronic breakdown of blood products.
  • Following administration of a contrast agent, solid, nodular (see Image 1), or irregular ring patterns (see Image 5) of enhancement are seen. Nonenhancing lesions (see Image 12) are less likely to be metastases.
  • Contrast-enhanced MRI is the best method for detection of meningeal tumor seeding, which appears as abnormal dural enhancement (see Image 7). This is a nonspecific finding; however, in the correct clinical setting, it correlates with the presence of sheets of tumor cells affecting the meninges.

The usefulness of diffusion-weighted and perfusion-weighted imaging and proton-MR spectroscopy in the initial diagnosis of brain metastases has not been established.

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy.

NSF/NFD has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape.

Degree of Confidence

Gadolinium-enhanced MRI is superior to contrast-enhanced CT in the diagnosis of brain metastases. Gadolinium-enhanced MRI has the following advantages:

  • It is useful for detecting smaller lesions.
  • It provides better soft tissue contrast.
  • It provides relatively stronger enhancement with paramagnetic contrast agents.
  • Bone artifacts are not present in the images.
  • It provides less partial-volume effects, particularly for lesions adjacent to bones.
  • It provides direct multiplanar imaging.

High-dose gadoteridol (ProHance) is better able to detect additional smaller lesions than routine-dose gadopentetate dimeglumine (Magnevist). Detection of additional lesions is important when considering surgical treatment of a solitary lesion. Magnetization transfer used with routine-dose gadolinium contrast is closely comparable to the high-dose technique.

False Positives/Negatives

On imaging, dural-based metastases (see Image 6) may resemble meningioma. Leptomeningeal carcinomatosis (see Image 7) may resemble chronic meningitis; however, an appropriate history or detection of primary cancer may be sufficient for establishing the diagnosis. Leptomeningeal enhancement may occur after the administration of radiation or following extra-axial hemorrhage; it may also occur below a craniotomy site. Single or multiple ring-enhancing lesions with edema may resemble infectious processes. Solitary lesions resemble primary brain tumors.



Findings

US has no role in the diagnosis of brain metastases. Intraoperative US may help in the surgical removal of brain metastases.



Findings

Currently, nuclear medicine studies are not employed routinely as primary imaging techniques for detecting intracranial metastatic disease.

Typical findings are multiple intracerebral areas of increased activity. The standard isotope used is technetium Tc 99m. On isotope whole-body bone scans, calvarial metastases may appear as multiple focal areas of increased activity. With whole-body 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) used in cancer staging, intracerebral metastases may appear as areas of increased metabolism.15, 16, 17, 18

Degree of Confidence

Radionuclide studies are sensitive but are highly nonspecific. In studies involving a small number of patients, FDG-PET demonstrated low sensitivity and low specificity. Currently, FDG-PET is not considered superior to CT or MRI in the initial evaluation of suspected brain metastases.

False Positives/Negatives

In older reports, radionuclide imaging was reported to detect intracerebral metastases in approximately 90% of patients, but the findings were nonspecific. Neoplasm, inflammation, vascularity, or trauma may cause the abnormal uptake. FDG-PET has been reported to detect approximately two thirds of brain metastases resulting from systemic cancer.



Findings

Angiography currently is not used as a primary diagnostic procedure for metastatic disease. Rarely, preoperative angiography and embolization of large hypervascular metastases from renal and thyroid cancer may be useful.

Degree of Confidence

Angiography is useful in evaluating tumor vascularity in selected metastatic lesions before biopsy is performed.

False Positives/Negatives

The results of angiography are nonspecific in the diagnosis of metastases.



Endovascular procedures employing particles or surgical gelatin (Gelfoam) may be used for presurgical or palliative embolization of hypervascular tumors.19



Management of brain metastases: role of radiotherapy alone or in combination with other treatment modalities.
Program in Evidence-based Care - State/Local Government Agency [Non-U.S.].  2004 Mar 30.  35 pages.  NGC:003529
 
Pre-irradiation evaluation and management of brain metastases.
American College of Radiology - Medical Specialty Society.  1999 (revised 2005).  7 pages.  NGC:004635
 
Single brain metastasis.
American College of Radiology - Medical Specialty Society.  1999 (revised 2006).  7 pages.  NGC:005132
 
Multiple brain metastases.
American College of Radiology - Medical Specialty Society.  1999 (revised 2006).  8 pages.  NGC:005553



Media file 1:  Sagittal T1-weighted precontrast and postcontrast MRI. A surgically proven, solitary right parietal metastasis is seen with a single, 1-cm, enhancing right parietal nodule and extensive surrounding edema typical of a metastasis.
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Media type:  MRI

Media file 2:  Contrast-enhanced CT demonstrates multiple enhancing metastatic nodules at the gray-white junction in a patient with known colon cancer.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  CT

Media file 3:  Precontrast- and postcontrast-enhanced CT demonstrates multiple ring-enhancing lesions (thick, peripheral, ringlike) in the left hemisphere with prominent surrounding edema and mass effect in a patient with known lung cancer.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  CT

Media file 4:  Coronal contrast-enhanced T1-weighted MRI. Multiple solid and cystic supratentorial and infratentorial mass lesions are seen in a patient with known breast cancer. Note the cystic, ring-enhancing, and solid patterns.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  MRI

Media file 5:  Axial contrast-enhanced T1-weighted MRI of a patient with known lung cancer. Multiple, small ring-enhancing lesions are seen in both hemispheres.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  MRI

Media file 6:  Sagittal contrast-enhanced MRI of a patient with known prostate cancer. The solitary enhancing right parietal extra-axial lesion is a surgically proven dural metastasis.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  MRI

Media file 7:  Coronal contrast-enhanced MRI of a patient with known melanoma. Note the linear enhancement in the sulci and brain surface of the right frontal and temporal lobes suggestive of leptomeningeal carcinomatosis. The cancer was proven by cerebrospinal fluid cytology.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  MRI

Media file 8:  Precontrast- and postcontrast-enhanced CT of a patient with breast cancer. Linear enhancement in the anterior falx and medial sulci of both frontal lobes suggests leptomeningeal and dural carcinomatosis.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  CT

Media file 9:  Noncontrast CT of a patient with lung cancer. Multiple high-density lesions are seen in both cerebral hemispheres, suggestive of hemorrhagic metastases.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  CT

Media file 10:  Contrast-enhanced CT and bone CT of a patient with breast cancer. Multiple irregular and aggressive lytic lesions are seen in the calvarium with dural-based metastases.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  CT

Media file 11:  Precontrast- and postcontrast-enhanced CT scan of a patient with mucin-secreting adenocarcinoma of the stomach. Multiple calcified nodules are seen in the surgically proven metastasis.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  CT

Media file 12:  T2-weighted and postcontrast T1-weighted MRI of a patient with uterine cancer. Well-defined, nonenhancing, round lesion with fluid signal intensity is seen in the right temporal lobe, with prominent surrounding edema. This is a surgically proven cystic metastasis.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  MRI



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Brain, Metastases excerpt

Article Last Updated: Sep 8, 2008