Keywords
brain metastases, incidence, adults, children
Outline
Introduction 11
Incidence 12
Incidence by Demographic Features 13
Incidence by Race 13
Incidence by Gender 14
Incidence by Age 14
SEER Stage of the Cancer 14
Onset of Brain Metastases from Initial Diagnosis 14
Incidence by Specific Cancer Types – Adults 15
Lung Cancer 16
Breast Cancer 17
Melanoma 17
Renal Cancer 18
Colorectal Cancer 18
Prostate Cancer 18
Esophageal Cancer 19
Ovarian Cancer 19
Choriocarcinoma 19
Testicular Cancer 19
Incidence by Specific Cancer Types – Children 20
Conclusions 21
References
Introduction
Brain metastases are the most common type of brain tumors ( ) and are associated with significant mortality and morbidity ( ). The incidence of brain metastases varies by reporting institution, and different studies have reported different results. For example, the reported incidence varies from 2.8 to 14.3 individuals per 100 000 population ( ). At the same time, study-specific data indicate a rate of 9–17% of systemic cancers being complicated by brain metastases ( ). Autopsy studies also found that 8.7–24% of patients with systemic cancers had brain metastases ( ).
With the advent of new imaging modalities, the incidence of brain metastases increased over time due to earlier detection of the lesions ( ). In addition, improved treatment for the systemic cancers increased survival and therefore the likelihood of the patient developing brain metastases over time ( ). The cohort study in Sweden found that the incidence of brain metastases doubled from 1987 to 2006 ( ).
The most common sources of brain metastases are lung cancer, breast cancer, melanoma, renal cancer, and colorectal cancer ( ). However, virtually any cancer, including prostate cancer, ovarian cancer, and liver cancer can metastasize to the brain ( ). Sometimes, patients can present with brain metastases without evidence of primary cancer ( ). The primary tumor site, if eventually detected, is often the lung ( ).
The incidence of brain metastases from various cancers changed over time. For example, during the 1980s, men had a higher incidence of brain metastases than women. This was likely due to a higher incidence of lung cancer in men at the time due to smoking ( ). A more recent cohort study in Sweden reported that women had a higher incidence of brain metastases than men ( ). This study only investigated patients who were hospitalized and included all brain metastases. The reason for this change could be due to a decreased incidence of lung cancer in men due to smoking cessation and relative increase in incidence of lung cancer in women. In addition, a relative increase in the incidence of breast cancer in women over the study period from 1987 to 2006 also contributed to increased incidence of brain metastases. The incidence of breast cancer has increased slowly over the past 20 years. At the same time, it appeared that the incidence of brain metastases from breast cancer also increased ( ).
reported that the median age at first admission due to brain metastases from systemic cancer was 67 years old among men and 64 years old among women. Half of the patients were admitted because of brain metastases as the primary diagnosis, 43% were admitted as other systemic cancers with secondary brain metastases while 7% were admitted due to other non-cancer disorders and found to have brain metastases incidentally ( ). Brain metastases are rare in children. The most common brain metastases in children are secondary to germ cell tumors, sarcoma, and neuroblastoma ( ).
Incidence
Though the overall incidence of cancer as well as death due to cancer decreased recently between 2004 and 2012, there are still a total of 1 638 910 new cancer cases, and 577 190 deaths from cancer projected to occur in the USA in 2012 ( ). Brain metastases continue to remain the major type of brain tumor, about 3–5 times higher than the number of newly diagnosed primary malignant brain tumors each year ( ). It was estimated that almost 70 000 new brain metastases would occur over the remaining lifetime of individuals who received a diagnosis of primary invasive cancer in the USA in 2007 ( ). Although the exact incidence of brain metastases is unknown, it is estimated that the incidence ranges from 2.8–11.1 per 100 000 population in studies concluded before 1990 ( ) to 7–14.3 per 100 000 population in more recent studies ( ). The incidence of lifetime brain metastases from systemic cancers was estimated to increase yearly between 2003 and 2007 ( ).
In 1970, Guomundsson performed a population based epidemiologic study in Iceland that covered brain metastasis between 1954 and 1963. The annual incidence was 2.8 per 100 000 population ( ). A more extended study conducted from 1935 to 1968 by found the incidence in Minnesota in the USA was 11.1 per 100 000 population. Studies in the 1970s and 1980s showed the incidence of 3.4 per 100 000 population in Finland with 66 study subjects (1975–1983) ( ). More recent studies extended to the 1990s and 2000s showed a higher incidence than the studies conducted in the 1970s and 1980s. Materljan reported 9.9 per 100 000 population with 80 study subjects in Croatia ( ). Counsell reported 14.3 per 100 000 population with 214 study subjects in Scotland ( ). studied a large population with 15 517 subjects and clearly demonstrated that the incidence of brain metastases doubled from 7 per 100 000 in 1987 to 14 per 100 000 in 2006. Two other studies reported that the incidence proportion (also known as cumulative incidence) percentage (IP%) were 8.5% (1986–1995) in the Netherlands ( ) and 9.6% (1973–2001) in Michigan ( ).
Incidence by Demographic Features
As the incidence of the primary tumors varies with different demographic characteristics, so does the incidence of brain metastases. described that race, gender and age influence the incidence of brain metastases. The study was conducted on a population-based MDCSS (Cancer Surveillance System for the Metropolitan Detroit Area) on 16 210 patients who developed brain metastases after diagnosis with a single primary tumor between 1973 and 2001 ( ). It compared the IP% among different race, sex, age at the diagnosis and Surveillance Epidemiology and End Results Program (SEER) stage of the primary cancer.
Incidence by Race
found that the IP% of brain metastases for African Americans was significantly higher compared with that for Caucasian patients for lung, melanoma, and breast cancers. However, IP% of brain metastases for renal cancers was lower in African American patients while the IP% of brain metastases for colorectal cancers was similar between African Americans and Caucasian patients ( ).
Incidence by Gender
Investigation by found that men had higher IP% of brain metastases for each type of systemic cancer except breast cancer and lung cancer compared with women. In patients with lung cancer, the IP% for brain metastases for women was 21.8%, while IP% for men was 18.9% ( ). The exception of the higher IP% of brain metastases in women can be attributed to the fact that during that same period the incidence of lung cancer was rising in women ( ).
Incidence by Age
The IP% of brain metastases was the highest for the patients with lung cancer diagnosed at age 40–49 years; with primary melanoma, renal or colorectal cancer at age 50–59 years; and with primary breast cancer at age 20–39 years ( ). The IP% was lowest for all primary cancers at the age group above 70 years, with the exception of melanoma. Melanoma had a similar percentage in patients over 70 years old as it did in patients who were 20–39 years old ( ).
SEER Stage of the Cancer
SEER stage of the primary cancer is classified as localized, regional, distant and upstaged ( ). Barnholtz-Sloan et al. found that IP% increased as SEER stage of primary cancer increased ( ). Compared to individuals with localized and regional stages, patients with the distant-stage of primary lung, melanoma, breast, colorectal and kidney cancers had the highest IP% of brain metastases ( ). Among the five kinds of primary cancers, melanoma had the highest IP% for brain metastases, consistent with the high propensity of the melanoma to metastasize to the brain ( ).
Onset of Brain Metastases from Initial Diagnosis
A large population study based on hospital admission found that the median time between diagnosis of the primary cancer and first admission with brain metastases varied among different cancers ( ). In patients with lung cancer, the median time was 2.6 months, in breast cancer 41.7 months, in melanoma 38.6 months, in colorectal cancer 25.2 months and in kidney cancer 17.0 months ( ). The time to admission was almost twice as long among women (16.3 months) as it was among men (8.8 months) ( ). With the exception of gender-specific malignancies, the time to admission was still longer in women when compared to men with lung cancer or malignant melanoma ( ). The time to admission was found to increase with age, more so in women than in men ( ). In a separate study, found that 36% of patients with brain metastases were diagnosed within one month after their primary cancer diagnosis, 35% within 1 year of their primary cancer diagnosis, and 28%>1 year after their primary cancer diagnosis. Lung cancer was found to have the shortest interval between diagnosis and onset of brain metastases with 91% of brain metastases diagnosed within 1 year ( ).
Incidence by Specific Cancer Types – Adults
Primary lung cancer, breast cancer, melanoma, renal cancer, and colorectal cancer are the most common primary cancers responsible for brain metastasis ( Table 2.1 ) ( ). Of all the primary tumors, lung cancer has the highest incidence of brain metastases. Melanoma, testicular and renal carcinomas have the greatest propensity to metastasize to the brain, but their relative rarity explains the low incidence of these neoplasms in large series of patients with brain metastases ( ). In 1994 and 1995, Posner reviewed 284 brain metastases from systemic carcinomas as defined by computed tomography (CT) or magnetic resonance imaging (MRI) scans. The investigators found that 38% of the metastases were from lung cancer, 19% from breast cancer, 13% from melanoma, 4% from renal cancer, and 1% were unknown ( ). Between 1986 and 1995 in the Netherlands, the IP% or percentage cumulative incidence of brain metastasis after 5 years from the first diagnosis was estimated to be 16.3% in patients with lung carcinoma, 9.8% in patients with renal carcinoma, 7.4% in patients with melanoma, 5.0% in patients with breast carcinoma, and 1.2% in patients with colorectal carcinoma ( ). The incidence was lower in patients with lung and breast carcinoma diagnosed before 1991 when compared with patients diagnosed after 1991 ( ). Another study, which analyzed patients over a period of 28 years from 1973 to 2001, found that the total IP% of brain metastases was the highest for lung cancer (19.9%) ( ). This was followed by melanoma (6.9%), renal cancer (6.5%), breast cancer (5.1%), and colorectal cancer (1.8%) ( ). Smedby et al. then reported the different incidence of brain metastases among men and women in Sweden ( ). Among patients with one primary solid tumor, the most common cancers causing brain metastases in men were lung cancer (44%), malignant melanoma (12%), colorectal cancer (9%) and prostate cancer (9%). Among women, the most common cancers causing brain metastases were lung (33%), breast (33%) and colorectal cancer (7%), and malignant melanoma (6%) ( ).
| Authors | Posner et al. | Schouten et al. | Barnholtz-Sloan et al. | Smedby et al. | |
|---|---|---|---|---|---|
| Publication year | 1996 | 2002 | 2004 | 2009 | |
| Study years | 1994–1995 | 1986–1995 | 1973–2001 | 1987–2006 | |
| Sex | M and F | M and F | M and F | F | M |
| Lung cancer | 38% | 16.3 | 19.9 | 33 | 44 |
| Breast cancer | 19 | 5 | 5.1 | 33 | |
| Melanoma | 13 | 7.4 | 6.9 | 5.8 | 12.3 |
| Renal cancer | 4 | 9.8 | 6.5 | 4.7 | 7.8 |
| Colorectal cancer | n/a | 1.2 | 1.8 | 7.4 | 9 |
| Other cancer | – | – | – | 5.6* | 8.6** |
| Unknown | 1 | – | – | 10.5 | 18.2 |
Lung Cancer
Lung cancer is the leading cause of cancer death in both men and women in the USA, accounting for 28% of all cancer deaths ( ). Non-small cell lung cancer (NSCLC) comprises approximately 85% of lung cancer cases ( ). In 2012, 226 160 new cases of lung cancer and 160 340 deaths from lung cancer were expected ( ). The brain is one of the most common sites for cancer recurrence after definitive treatment for lung cancer. The risk of developing brain metastases for locally advanced (stage III) NSCLC is 24–55% ( ). An earlier study found that the incidence of brain metastases was 24% in a consecutive group of 259 patients with inoperable adenocarcinoma of the lung ( ). More cases of brain metastases were identified at autopsy with 38 (44%) patients out of 87 autopsies presenting with brain metastases. Eleven of these patients (29%) were not diagnosed clinically before death. Patients younger than 60 years old and with initial performance status above 60% and patients responding to chemotherapy had higher risk for developing brain metastasis during treatment than other patients. This higher risk was very likely due to the fact that increased survival increases the risk of developing brain metastases, as seen in brain metastases from adenocarcinoma of the lung ( ).
analyzed outcomes in 211 patients who were treated with neoadjuvant therapy for stage III NSCLC before surgical resection between 1990 and 2004 and found that the most common site of initial recurrence was the brain, with 22 (43%) patients developing brain metastasis as the site of first failure, which represented 71% of all isolated recurrences. Ultimately, 28 patients (55%) developed brain metastases at some point during their clinical course.
In early stages (Stage I and Stage II) of NSCLC, Hubbs et al. found that the 5-year actuarial risk of developing brain metastases was 10%, much lower compared with higher stages. Of patients developing brain metastases, the brain was the sole site of failure in 43%. On multivariate analysis, younger age, larger tumor size, lymphovascular space invasion, and hilar lymph node involvement were associated with an increased risk of developing brain metastases ( ).
The propensity of brain metastasis varies among the pathological subtypes of lung cancer. Most studies concluded that NSCLC is the most common primary lung cancer to develop brain metastases ( ). However, one autopsy study revealed that 40% of the patients with SCLC developed brain metastases while less than 20% of the patients in NSCLC have CNS involvement ( ). Of NSCLC, non-squamous cell lung cancers were observed to have higher risk of developing brain metastasis. reviewed 181 lung cancer individuals with brain metastasis at initial staging. They found that patients with adenocarcinoma and large-cell carcinoma had greater risk of brain metastases than patients with squamous cell carcinoma. There was no correlation between the number/distribution of brain metastases and tumor histology ( ). They reviewed 211 patients with stage III NSCLC and found that 63% (19/30) of patients with non-squamous lung cancer and 43% (9/21) with squamous lung cancer developed brain metastasis over a 5-year period.
As new treatments for NSCLC led to increased survival, it was noticed that the incidence of brain metastases was decreasing. found that the patients with somatic epidermal growth factor receptor (EGFR) mutations who received treatment with targeted tyrosine kinase inhibitors (gefitinib or erlotinib) had a lower incidence of brain metastases than the previously published rates. The EGFR somatic mutation was found to be associated both with increased response rates in patients treated with gefitinib or erlotinib and with longer median survival ( ). Lung cancer is also the tumor most likely to spread to the brain with unknown primary tumor on presentation. More than two-thirds of the brain metastases with unknown primary tumor at initial work up were eventually found to originate from lung ( ).
Breast Cancer
Breast cancer currently has the second highest incidence of brain metastases after lung cancer. New cases of breast cancer are estimated at 340 650 in 2012 with 226 870 in women and 2190 in men ( ). Total incidence of brain metastases from breast cancer varies from 1.4% to 30% – depending on the data source ( ). Researchers noted that the incidence of breast cancer metastases was on the rise. This was very likely due to improved control of the systemic disease and to the consequent prolonged life span ( ). The interval between the diagnosis of primary breast cancer and the identification of brain metastases was an average of 2–3 years ( ).
A large patient population study, with 50 528 breast cancer patients followed over a median of 3.5 years, completed in Sweden, found that 1.4% of patients were admitted to hospital with brain metastases ( ). Compared with the period 1998–2000, patients diagnosed with breast cancer in 2004–2006 had a 44% increased risk of being admitted to hospital with brain metastases ( ). Pestalozzi et al. studied 9524 women with early breast cancer over a 13-year follow-up period between 1978 and 1999 without trastuzumab treatment. This study showed an incidence of 5.2% of brain metastases ( ). The established risk factors for development of brain metastases from primary breast cancer were HER2-positive status, estrogen receptor negativity, high Ki-67 index/high grade, tumor size larger than 2 cm, node positive disease,<35–50 years old, expression of EGFR and cytokeratin 5/6 ( ). It was unclear whether trastuzumab treatment altered the risk for developing brain metastasis from primary breast cancer.
Melanoma
The total estimated new cases of melanoma in 2012 were 76 250 with 44 250 cases in men and 34 350 in women ( ). Melanoma is the second to third most common primary tumor that develops brain metastases, accounting for 5–21% of all metastatic brain tumors ( ). The incidence of CNS metastases in advanced malignant melanoma was 46% when diagnosed clinically, and 75% when diagnosed through autopsy, as evaluated by a retrospective study of 122 patients seen at Wayne State University over a 12-year period ( ). Meningeal involvement was suspected clinically in 10.6% of the patients and it was found during autopsy in 52% of patients. The incidence was 6.7–8% when all stages of melanoma were included ( ). The study of 2516 patients with malignant melanoma showed that 201 (8%) developed CNS metastasis during a follow-up period of an average of 11 years (total follow up was between 7 and 18 years) ( ). The overall cumulative incidence at 5, 10 and 15 years was 7, 9, 9.5 % respectively. The median interval between initial diagnoses of malignant melanoma to the CNS metastasis was 2.6 years (0 day–20 years) ( ). At autopsy, 6.3% of the cases with metastatic melanoma were diagnosed.
Renal Cancer
Renal cancer accounts for approximately 3% of all cases of adult malignancies worldwide ( ). In 2012, the estimated number of new renal cancer cases was 64 700 in both men and women. More cases were seen in men than women (40 250 vs. 24 520) ( ). Renal cell carcinoma (RCC) is the most common type of renal cancer (92%) and very frequently metastasizes to the brain with an incidence varying from 5.5% to 13.2%, ( ,). RCC is one of the cancers with high incidence of hemorrhagic brain metastases and large peritumoral vasogenic edema ( ). Median interval between the initial treatment of the primary lesion and the diagnosis of brain metastasis was 1.6 years. The mean interval between the RCC diagnosis and identification of brain metastasis is approximately 1–2 years. However, RCC can have brain metastases occurring as late as 10–20 years after initial nephrectomy.
Colorectal Cancer
Colorectal cancer (CRC) is the third to fifth most common cancer in both men and women ( ). An estimated 103 170 cases of colon cancer and 40 290 cases of rectal cancer were expected to occur in 2012 ( ). However, the incidence of brain metastases is low, being reported recently from 0.62% to 4% ( ). reviewed colorectal carcinoma cases with brain metastases at Dartmouth-Hitchcock Medical Center between 1984 and 2006. They found that the incidence of brain metastases from CRC was 2.3%. The cerebellum was the most common area of brain involvement. Primary tumor in the left colon, long-standing pulmonary metastases, especially those with recent progression and CXCR4 expression by tumor cells were all associated with increased risk of brain metastases.
Prostate Cancer
Prostate cancer is the most common cancer in men in the USA. An estimated 241 740 new cases of prostate cancer occurred in the USA during 2012 ( ). The reported incidence of brain metastases from prostate cancer was 0.47% to 8.6%. According to this reported incidence, an estimate of 1136 to 20 790 new cases of brain metastases from prostate cancer could be expected to occur in 2013.
Esophageal Cancer
The incidence rate for esophageal adenocarcinoma increased significantly among white men (1.8% per year), white women (2.1% per year) and Hispanic men (2.8% per year) during 1999–2008 ( ). Although esophageal cancer is not one of the leading cancer etiologies and the estimated new cases in 2012 were only 17 460 ( ), the incidence of brain metastases from esophageal carcinoma (especially the adenocarcinoma subtype) is relatively high. Up to 16% of the patients with esophageal adenocarcinoma develop brain metastasis.
Ovarian Cancer
Ovarian cancer represents 3% of all cancers in women ( ). The incidence of reported CNS metastases from ovarian cancers was low in the past. Among a large population study with 1316 ovarian cancer patients, only 14 patients had CNS metastasis ( ). The incidence was 1.1%. Median interval from the diagnosis of ovarian carcinoma to the diagnosis of CNS metastases was 1.2–2.8 years.
Choriocarcinoma
Choriocarcinoma is an uncommon tumor but has a very high propensity to metastasize to the brain. This malignancy is seen in both men and women. In women, choriocarcinoma manifests as the gestational type or malignant gestational trophoblastic tumor related to a mole pregnancy. The overall reported incidence of choriocarcinoma was one per 24 096 pregnancies between 1973 and 1982 ( ). However, the numbers declined by 2.8% per year demonstrated by population-based data between 1973 and 1999. The incidence of CNS metastases from gestational choriocarcinoma varies from 8.8% to 9.3% ( ). They found that approximately half of the patients with choriocarcinoma had CNS metastases on presentation and the other half developed the metastases during therapy ( ). Patients with CNS metastases on presentation had a better prognosis than patients with late development of CNS metastases during therapy ( ). In men, choriocarcinoma manifests as a particular type of testicular germ cell carcinoma. The incidence of CNS metastases was reported as 30.8% (4/13) in a small patient population study ( ).
Testicular Cancer
Testicular cancer is not very common, but can metastasize to the brain. The incidence of CNS metastases was mainly obtained from studies in the 1970s and no recent large patient population study was conducted except for case reports. The incidence of brain metastases was 29.5% (23/78) from a study of 78 autopsied cases ( ). This study found that the patients had seminoma (6/19, 31.6%), embryonal carcinoma (6/21, 28.6%), teratocarcinoma (5/18, 27.8%), choriocarcinoma (1/4) and other mixed germinal carcinoma (5/16, 31.3%) ( ). The metastases included yolk sac carcinoma in addition to the testicular cancer subtypes reported in the above ( ).
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