Keywords
Metastatic tumors are the most frequent type of brain tumor in adults. The reported incidence of metastatic brain tumors is increasing but the exact incidence is unknown.
1
This increase in the incidence of metastatic brain tumors is likely because of improved therapeutics resulting in increased survival after initial cancer diagnosis, an aging patient population, and improved diagnostic and screening mechanisms resulting in earlier identification and initiation of treatment in patients with primary cancer.2
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The reported incidence of metastatic brain tumors in the literature is derived from disparate data sources, such as death certificates, cancer registries (from various countries), hospital records, census data, or combinations of these sources. These data are reported in epidemiologic population-based studies or clinical or autopsy series. Each of these studies has its own inherent biases and limitations, and it is difficult to compare these studies because of variations in methodologies used to formulate the epidemiologic characteristics in each study.
As the incidence of metastatic brain tumors increases, so does the need to have a consistent and accurate understanding of the epidemiologic factors associated with these tumors. This information aids health care professionals in planning for the challenges of caring for this population of patients as well as developing preventative measures to decrease the likelihood of metastatic brain disease. The increasing number of patients with metastatic brain tumors places a burden on public health services because these patients strain diagnostic, therapeutic, and research resources.
Population-based epidemiologic studies
Population-based studies are generally considered more accurate and less biased than the more limited clinical or autopsy-based series.
2
Few population-based studies focusing on metastatic tumors of the brain have been reported in the literature, and most of these studies are decades old. Guomundsson4
published the results of a population-based study performed in Iceland reviewing the incidence of central nervous system (CNS) tumors from 1954 to 1963. The annual incidence of metastatic and primary brain tumors was reported to be 2.8 and 7.8 persons per 100,000 population, respectively. The incidence proportion (defined as the number of patients with metastatic brain tumors by the number of patients with primary brain tumors in that particular population) of metastatic brain tumors in all patients with primary systemic malignancies in that study was less than 20%.2
Percy and colleagues
5
reviewed the data from 1935 to 1968 in Rochester, Minnesota, and found a much higher incidence of 11.1 per 100,000 population; however, the study group was mixed, with some patients being diagnosed clinically and others at the time of autopsy (70% of patients) and some with tumors confirmed pathologically and others diagnosed purely based on imaging. A study from Finland evaluating patients with metastatic brain disease from 1975 to 1982 reported the annual incidence of brain metastases and primary brain tumor at 3.4 and 12.3 persons per 100,000 population, respectively; brain metastases comprised 18% of all CNS neoplasms.6
In an American survey of intracranial neoplasms, Walker and colleagues
7
used hospital discharge records from 157 hospitals across the United States from 1973 to 1974 and estimated the annual incidence of metastatic and primary brain tumors to be 8.3 and 8.2 persons per 100,000 population, respectively; the incidence proportion of brain metastases was 51%.2
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However, only 20% of all the cases reviewed in this study were pathologically verified. Counsell and colleagues8
identified 122 neuroepithelial primary brain tumors and 214 metastatic brain tumors in their population-based study of the Lothian region of Scotland from 1989 to 1990. They reported a yearly incidence of metastatic brain tumors of 14.3 persons per 100,000 population.Materljan and colleagues
9
reviewed hospital records in Labin, Croatia, from 1974 to 2001 and found a yearly incidence of metastatic and primary brain tumors to be 9.9 and 11.8 persons per 100,000 population, respectively. Barnholtz-Sloan and colleagues2
performed a population-based review of the Metropolitan Detroit Cancer Surveillance System from 1973 to 2001 (metro population approximately 4.5 million) and found the incidence proportion of brain metastasis among all patients with systemic malignancies to be 9.6%; however, this study was limited to the major types of cancer (lung, melanoma, breast, renal, colorectal). Smedby and colleagues10
used the Swedish national population-based health care registers from 1987 to 2006 and found that the annual incidence rate of hospitalization for brain metastases doubled during this period from 7 (in 1987) to 14 (in 2006) persons per 100,000 population. Schouten and colleagues11
used the Maastricht (Netherlands) Cancer Registry from 1986 to 1995, which covered 95% of the patients in this region, and identified 2724 patients with primary cancer. These patients were followed up until 1998, and 8.5% of them developed subsequent brain metastases, with 72% of the brain metastases occurring within the first year after initial primary cancer diagnosis.Although population-based epidemiologic studies are considered better than clinical and autopsy-based studies, there are still some notable limitations and biases that are inherent to these types of studies. These defined populations and hospitals being studied are subject to (and limited by) the regional referral patterns, regional access to health care and cancer treatment, and the inherent sampling biases of the pathology of that region. In addition, no 2 population regions have equivalent treatment expertise. Slight variations in clinical aggressiveness in obtaining diagnostic imaging and/or biopsies or even the frequency of autopsies potentially affect the reported incidences of metastatic tumors.
Hospital records, registries, autopsies, and diagnostic imaging studies are subject to the inherent sampling biases, referral patterns, and treatment preferences of that particular region. Studies based on the above-mentioned data sources often underdiagnose the incidence of brain metastases. Many metastatic brain tumors are asymptomatic and are never diagnosed. In addition, patients with end-stage systemic cancer who develop neurologic symptoms near the end of life but are not clinically suitable for treatment given their systemic disease burden are never diagnosed. Up to one-third of all brain metastases are diagnosed at autopsy
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; however, autopsy rates have significantly declined over the last 3 decades.13
Furthermore, there is variability in the definition of a metastatic brain tumor in that some studies consider all brain masses in a patient with a history of cancer to be a metastatic brain tumor, whereas other studies include only pathologically verified masses (Table 1).Table 1Population-based epidemiologic studies
| Author | Study Year | Location | Brain Metastasis Incidence Rate (Persons per 100,000 Population) |
|---|---|---|---|
| Guomundsson 4 | 1954–1963 | Iceland | 2.8 |
| Percy et al 5 | 1935–1968 | Rochester, Minnesota | 11.1 |
| Fogelholm et al 6 | 1975–1982 | Finland | 3.4 |
| Walker et al 7 | 1973–1974 | United States | 8.3 |
| Counsell et al 8 | 1989–1990 | Lothian, Scotland | 14.3 |
| Materljan et al 9 | 1974–2001 | Labin, Croatia | 9.9 |
| Barnholtz-Sloan et al 2 | 1973–2001 | Detroit, Michigan | |
| Smedby et al 10 | 1987–2006 | Sweden | 7 (1987); 14 (2006) |
a Study reports incidences as incidence proportions, not incidence rate.
Cancer registries are frequently used in population-based studies to calculate incidence rates. Cancer registries have many advantages over other databases. They are usually confined to a particular state, region, or other defined location; follow all patients with a cancer diagnosis prospectively; record information with regard to status and treatment of cancer and death; and can calculate yearly incidences of cancer diagnoses for the particular population they cover. Smaller population- and hospital-based registries can interact and cooperate with each other and larger registries to cover a larger population size. Cancer registries also have limitations. They do not account for patients living within a defined region who seek medical care outside of the boundaries of the registry. In some American states, the population can be dynamic, which can affect the calculation of an accurate incidence. Further, cancer registries typically focus on and record only the primary cancer histology and primary site of the cancer and frequently do not contain information about metastatic brain tumors. These registries have also been shown to contain the International Classification of Diseases Ninth Revision coding errors and imprecise diagnostic codes.
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For example, a patient presenting with brain metastasis from a primary breast cancer is usually classified as having recurrent breast cancer rather than a separate brain metastasis.3
For these reasons, population-based and clinical studies can never be exact, and they typically underestimate the true incidence of metastatic brain tumors.Clinical studies
Clinical studies have shown a high degree of variability in their reported incidences of brain metastases and vary significantly in the size and definition of the population being studied. Kawahata and Ohtomo reported on a cohort of elderly patients (median age, 77.5 years; range, 65–88 years) hospitalized with brain tumors in Japan from 1973 to 1987. They identified 322 pathologically confirmed brain tumors with an overall frequency of brain metastases of 5.8%. A study by Grant and colleagues
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reviewed imaging files, hospital records, and cancer registries in the Lothian region of Scotland from 1989 to 1990, which includes a referral population of 1.2 million patients. They found an annual incidence of intracerebral tumors (both primary and secondary) to be 21.4 per 100,000 population. In their study, 57% and 43% of the patients had metastatic and primary brain tumors, respectively.Surgical series are an incomplete data source for brain metastasis information because they depend on patients referred for surgery and do not account for the metastases that are not treated surgically. Radiographic series are also incomplete sources to study the epidemiology of brain metastases because routine screening of the brain in patients with asymptomatic cancer is not typically performed except in certain lung cancer types (eg, small cell lung cancer) and they are also subject to the selection bias of referral patterns.
1
Clinical studies based on hospital records are limited by selection bias and often use discharge diagnoses, which can be incorrect or nonspecific. For example, Walker and colleagues7
found that approximately 10% of these discharge diagnoses lacked specificity using terminology such as probable brain tumor, brain tumor, rule out brain tumor, and suspected brain tumor.Estimates
Based on earlier and recent population-based studies that typically underestimate the number of metastatic tumors, the incidence of metastatic brain tumors should be between 7 and 14 persons per 100,000 population. The official census data estimates the US population at approximately 310 million, which would correlate with an estimate of 21,651 to 43,301 patients with newly diagnosed brain metastases in the United States in 2010.
Based on autopsy studies, up to one-fourth of patients with a diagnosis of cancer have brain metastases before death.
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Based on the annual cancer statistics report, the number of new cases of cancer reported in 2009 was 1,479,350.21
If one-fourth of these patients develop metastatic brain tumors, 369,837 of these newly diagnosed patients with cancer will develop metastatic brain tumors during their lifetime. Based on the clinical study of Schouten and colleagues11
(discussed earlier), approximately 70% of these patients develop metastatic brain tumors within the first year after diagnosis, which means at least 258,886 metastatic brain tumors were expected to develop in 2009.Primary cancer histology
One of the major factors affecting the incidence of brain metastasis is the histology of the primary cancer.
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In general, the sources of brain metastases (in descending order) are cancers of the lung, breast, skin, kidney, and gastrointestinal (GI) tract.22
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The incidences of brain metastases from other less common primary tumors are reviewed elsewhere.1
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The estimated number of new cases of lung cancer in 2009 was 219,440, with more new cases identified in men than in women; however, the incidence has been increasing in women in recent years.
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Lung cancer is generally accepted as the most frequent source of metastatic brain tumors. It accounts for 30% to 60% of all brain metastases and occurs in 17% to 65% of patients with primary lung cancer.1
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Of the various types of lung cancer, small cell lung cancer and adenocarcinoma are the most commonly identified sources of brain metastases. Lung cancer frequently presents with brain metastases causing the first symptoms prompting further workup, ultimately resulting in the diagnosis of lung cancer. The median interval between initial cancer diagnosis and identification of a metastatic brain tumor is shortest for lung cancer and ranges from 2 to 9 months,3
with 91% of patients with lung cancer being diagnosed with brain metastases within 1 year of initial diagnosis.11
The estimated number of new cases of breast cancer in 2009 was 192,370.
21
Breast cancer is typically the most common cause of brain metastasis in women. It accounts for 5% to 30% of all metastatic brain tumors in women and occurs in up to 30% of women with primary breast cancer.3
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In contrast to lung cancer, breast cancer brain metastases are commonly a late occurrence, with a median interval of 2 to 3 years between initial cancer diagnosis and identification of a metastatic brain tumor.3
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The incidence of primary malignant melanoma has been increasing over the last decade. The estimated number of new cases of primary malignant melanoma in 2009 was 68,720, with more new cases identified in men than in women.
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Of all metastatic brain tumors, melanoma accounts for 5% to 21% and has been reported as having the highest propensity to metastasize to the brain.3
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Approximately 37% of patients with stage IV melanoma develop brain metastases, and autopsy series report an incidence as high as 90% (range, 12%–90%).3
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Metastases typically occur late, with the median interval of 1 to 3 years between initial cancer diagnosis and identification of a metastatic brain tumor and multiple brain metastases being typical of this histology.3
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Metastatic melanoma to the brain is typically associated with a poorer prognosis than other brain metastases.30
The estimated number of new cases of kidney cancer (renal cell carcinoma) in 2009 was 57, 760, with more new cases identified in men than in women.
21
The incidence proportion of metastatic brain tumors from renal cancer in patients with primary renal tumors ranges from 5.5% to 11%.2
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, 31
, 32
The median interval between initial cancer diagnosis and identification of a metastatic renal brain tumor is approximately 1 to 2 years.3
The estimated number of new cases of GI cancer in 2009 was 146,970, with a few more new cases identified in men than in women.
21
Colorectal cancers account for 1.4% to 4.8% of all metastatic brain tumors, and approximately 10% of patients with stage IV colorectal cancer have brain metastases.3
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, , 35
, 36
The median interval between initial GI cancer diagnosis and identification of a metastatic brain tumor is approximately 2 to 3 years.3
Other factors
Other factors that have been reported to affect the incidence of brain metastases are the stage of the primary cancer, age, sex, and race.
2
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Barnholtz-Sloan and colleagues2
reported that there was a statistically significant trend of increased incidence proportion of metastatic brain tumors with increasing SEER (Surveillance, Epidemiology, and End Results) stage of all primary cancers (lung, breast, melanoma, renal, GI) included in their study. The primary cancer with the highest incidence proportion of brain metastasis was distant-stage melanoma, which correlates with previous studies reporting a high propensity for melanoma to metastasize to the brain. In patients with breast cancer, stage-related factors that have been shown to be associated with an increased risk of brain metastases are lymph node status, tumor grade, and primary tumor size.37
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, 39
, 40
Age at diagnosis of primary cancer has a significant effect on the incidence of brain metastases. Metastatic brain tumors are more common in adults than in children, with the highest incidence in general occurring in patients aged 50 to 80 years.
20
, 33
, 41
However, the peak ages for brain metastases from breast cancer seem to be lower than the peak ages for other primary pathologies. In a population-based assessment of brain metastases in the Metropolitan Detroit Cancer Surveillance System, the peak incidence proportion for breast cancer brain metastases was during the third decade (for lung cancer, it was during the fourth decade). The median age of patients with breast cancer brain metastases is 5 years less than that of patients without brain metastases.25
Although the absolute number of patients with brain metastases is higher in the older population with cancer, younger adult patients with cancer may have a higher proportion of brain metastasis, which may be because of biologic differences and a more aggressive cancer phenotype in these younger adult patients.
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The most common brain metastases in children are leukemia and lymphoma.20
When considering only solid tumor primary cancers, osteogenic sarcoma, rhabdomyosarcoma, and Ewing sarcoma are the most common primary cancers causing brain metastases.41
In children with solid primary tumors, brain metastases occur in 4% to 13% of the patients.22
, 41
, 44
, 45
A few studies have reported differences in incidences of brain metastases based on gender
2
, 7
; however, most have not.3
Lung cancer and breast cancer are the most common sources of brain metastases in men and women, respectively. However, the incidence of primary lung cancer as well as metastases is increasing in women.2
The incidence of primary malignant melanoma and, subsequently, melanoma brain metastases is increasing in men.2
Barnholtz-Sloan and colleagues
2
found an increased incidence proportion of breast cancer and melanoma metastases in African American patients compared with all other patients. The finding that race affects the incidence of brain metastases may be related to the specific population that was studied in the metropolitan Detroit area. Most studies have not reported race as a factor affecting the incidence of brain metastases.Summary
The exact incidence of metastatic brain tumors is unknown, and the reported incidences in the literature are estimates at best. Epidemiologic population-based studies, clinical studies, and autopsy series have limitations; however, it is clear that metastatic brain tumors are the most frequent type of brain tumor in adults and their incidence is significantly higher than that of primary brain tumors. Primary cancer histology, age at diagnosis, and primary tumor stage are significant factors that affect the epidemiology of metastatic brain disease.
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Footnotes
Disclosures: The authors have nothing to disclose.
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© 2011 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
