Demographics of Brain Metastasis

1042-3680/96 $0.00 + .20

MANAGEMENT OF CEREBRAL METASTASES

DEMOGRAPHICS OF BRAIN METASTASIS John D. Johnson, MD, and Byron Young, MD

The American Cancer Society has estimated that in 1995approximately1,252,000 new cases of cancer will be diagnosed and 547,000 people will die from cancer. Some of the more commonly diagnosed new cancers are located in the prostate gland (244,000 new cases), the breast (183,400 new cases), the lung (169,000 new cases), the colon and rectum (138,000 new cases), the skin (melanoma: 34,100 new cases), and the ovary (26,600 new cases). 86 Brain metastases are neoplasms that originate in tissues outside the central nervous system and spread secondarily to involve the brain. The term single brain metastasis refers to an apparently single cerebral lesion, with no implication about the extent of cancer elsewhere in the body. The term solitary brain metastasis, on the other hand, describes the rare occurrence of an isolated brain lesion with no other evidence of metastatic cancer elsewhere in the body.

vous system (CNS) in Iceland and reported an annual incidence of 2.8 metastatic brain tumors per 100,000 patients. The average annual incidence for primary brain tumors during this same period was 7.8 per 100,000 patients. Guomundsson stated that the incidence of metastatic tumors was underreported. In 1972, Percy and colleagues62 published a review of CNS neoplasms in Olmstead County, Minnesota and found an incidence of 11.1 metastatic brain tumors per 100,000 patients. Similarly, the incidence of primary brain tumors was 12.5 per 100,000 patients. The authors suggested that metastasis was inadequately reported and the actual number was higher. The incidence of brain metastasis in Central Finland between 1975 and 1985 was 3.4 per 100,000 patients, whereas the incidence of primary tumors during this period was 12.3 per 100,000 patients. Again, the authors stated that the incidence of metastatic lesions was underreported. 33

INCIDENCE OF BRAIN METASTASES

Ratio of Brain Metastasis to Primary Tumors

Three general approaches have been used to obtain demographic data about brain metastases: epidemiologic studies, clinical studies, and autopsy series. Few detailed epidemiologic series address the issue of the incidence of brain metastasis. From 1954 through 1963, Guomundsson39 performed a survey of tumors of the central ner-

Because of the past reluctance of neurosurgeons to operate on patients with systemic cancer, the ratio of brain metastasis to other types of brain tumors has been quite difficult to determine. Metastatic tumors were largely underrepresented in earlier neurosurgical series because of the general attitude of the day that

From the Division of Neurosurgery, University of Kentucky Medical Center, Lexington, Kentucky

NEUROSURGERY CLINICS OF NORTH AMERICA VOLUME 7 •NUMBER 3 • JULY 1996

337

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JOHNSON & YOUNG

"surgery, whether radical or palliative, is of no ultimate benefit to these patients insofar as prolongation of life is concerned." 37 A 10-year review of the Mayo Clinic (Rochester, MN) experience through January 1929 concluded that "the incidence of metastatic tumors of the brain is at least 5% of all tumors of the brain." 27 In a 1926 review of Dr. Harvey Cushing's clinic, the overall frequency of metastatic tumors was believed to be approximately 4%.37 Cushing23 stated with regard to metastatic tumors, "Their relative scarcity in the series of brain tumors as a whole, viz., 3.2 per cent, by no means represents their true clinical incidence, for we refrain when possible from accepting patients with obvious intracranial metastasis since so little can be done for them by surgical procedures." Brain metastases are now recognized as the most common intracranial tumor, significantly outnumbering primary brain tumors. 67· 85· 86 Over the past 60 to 70 years, the ratio of metastatic brain tumors to primary tumors reported in neurosurgical series has been increasing. In 1932, Cushing23 reported that metastatic tumors accounted for approximately 4% of all brain tumors. Stortebecker, in 1954, found that 3.5% of all brain tumors were metastatic.76 This percentage has substantially increased since that time (Tables 1 and 3). The ratio of metastatic brain neoplasms to primary brain tumors in neurosurgical series is lower than that in autopsy series, probably because only patients who are candidates for surgery are referred to neurosurgeons. 84 The third method commonly used to determine the ratio of brain metastases to primary brain tumors is autopsy studies. Table 1 reviews several studies from 1906 onward. The

more recent studies report that approximately 25% of patients with systemic cancer have intracranial metastasis (Table 5). Although all

three methods of estimating the actual ratio of brain metastasis to primary tumors provide approximations, autopsy studies probably provide the most accurate estimates. Autopsy studies, however, usually come from referral centers and are drawn only from select patients for whom next of kin agree to the autopsy, often because of specific questions about the cause of death. Additionally, many lesions detected by autopsy may have been clinically silent. Posner and colleagues13 estimate that approximately one third of lesions identified at autopsy are asymptomatic. Despite numerous studies, the exact incidence of brain metastasis remains uncertain. A study by Posner and colleagues68 found that 24% of patients who died of cancer and underwent autopsy at the Memorial Sloan-Kettering Cancer Center (New York, NY) had intracranial metastases. By multiplying the number of cancer deaths in 1994 (as estimated by the American Cancer Society) by this figure (24%), Posner67 estimated that more than 125,000 patients developed brain metastases during that year. Multiplying the 1995 American Cancer Society statistics by 24% provides a current estimate that 131,280 patients dying from cancer would have intracranial metastases (Table 5).86 The apparent increase in the ratio of brain metastases to primary tumors may be the result of a number of factors. For example, improved treatment of primary cancer and systemic metastases with the resultant increase in survival times may allow cells sequestered in a protective "sanctuary" behind the blood-brain

Table 1. CENTRAL NERVOUS SYSTEM METASTASES AT AUTOPSY

Authors

Frequency (%)

Cases with Central Nervous System Lesions/Number of Patients

Krasting, 1906 Neustaedter, 1944 Earle, 1954 Chason et al. , 1963 Aronson et al, 1964 Koyama and Takakura, 1969 Posner and Chernik, 1978 Takakura et al, 1982 Pickren et al, 1983

5.7 2.3 11 .1 18.2 16.5 12.0 24.1 25.6 8.7

59/935 153/6761 167/1498* 200/1096 397/2406 127/1060 572/2375 860/3359 954/10,916

Sites Analyzed IC, IC, IC IC, IC, IC IC IC B

VC VC VC VC

Includes Lymphoma or Leukemia Yes No Yes No Yes No No No

IC = intracranial, VC = vertebral canal, B = brain only. * Adult men only. Adapted from Takakura K, Sano K, Hojo S, et al: Metastatic Tumors of the Central Nervous System. Tokyo, lgaku-Shoin, 1982, p 9; with permission.

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DEMOGRAPHICS OF BRAIN METASTASIS

Table 2. SITES OF PRIMARY TUMORS IN MEN AND WOMEN Men

Women

Primary Sites

Number of Tumors

Frequency(%)

Number of Tumors

Frequency (%)

Lung Breast Gastrointestinal tract Urinary tract Melanoma Prostate Head and neck Female reproductive system Sarcomas Liver, biliary tract, and pancreas Thyroid Others

251 6 46 33 24 37 17

55.5 1.3 10.2 7.3 5.3 8.2 3.8

98 272 30 19 23

19.2 53.2 5.9 3.8 4.5

6 14 7 11

1.3 3.1 1.5 2.4

12 21 14 8 8 6

2.3 4.1 2.7 1.6 1.6 1.2

Total

452

100

511

100

Adapted from Takakura K, Sano K, Hojo S, et al: Metastatic Tumors of the Central Nervous System. Tokyo, lgaku-Shoin, 1982, p 13; with permission.

barrier to multiply and become symptomatic.35·40·55·61 In addition, with an aging population, more people will be at risk for the development of primary systemic cancer, and as a result, the number of brain metastases will also increase. Finally, a greater awareness of brain metastasis among physicians since the early 1900s, coupled with dramatically improved imaging studies, may aid in the increased diagnosis of CNS metastases. 9• 19• 24· 72· 78· 87

time of death. 79 The incidence of intracranial metastasis peaks in the fifth to seventh decades.79 Patients with cerebral sarcoma and melanoma die at a younger age. Leukemia accounts for most metastatic CNS lesions in young patients. In general, regardless of the type of primary systemic tumor, the frequency of metastatic lesions found at the time of autopsy tends to decline after age 70.4· 35· 48· 64· 79

Gender

Age

More than 60% of patients with CNS metastases are between 50 and 70 years of age at the Table 3. NEUROSURGICAL SERIES OF BRAIN METASTASIS

Source Meagher and Eisenhardt, 1931 Cushing, 1932 Elkington , 1935 Livingston et al, 1948 Christensen , 1949 Sti:irtebecker, 1954 Petit-Dutaillis et al, 1956 Zu lch, 1957 Simionescu , 1960 Richards and McKissock, 1963 Eck et al, 1965 Arseni and Constantinescu, 1975 Paillas and Pellet, 1976

Brain metastases occur almost equally often among men and women.64 Cancer of the testes metastasizes to the brain more frequently than ovarian cancers (20.7% versus 1.9%), and cancer of the penis metastasizes to the brain more frequently than cancer of the external female genitalia (12.5% versus 3.5%). 64

Number of Brain Tumors

Metastatic Tumors(%)

1850

3.0

2023 805 1256 2023 4444 594 6000 195 3890

4.2 9.0 4.1 3.9 3.5 25.0 4.0 6.7 10.0

Race has no definite effect on the frequency of brain metastasis. Nevertheless, melanoma is 10 times more common among whites and tends to metastasize to the brain. 64 -68· 86

904 1217

13.0 13.0

1472

12.0

The most common solid organ childhood tumors other than primary brain tumors are neuroblastomas, Wilms' tumor, and the sarcomas, including rhabdomyosarcoma, Ewing's

Race

Children

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Table 4. PERCENTAGE OF CENTRAL NERVOUS SYSTEM METASTASES FROM PRIMARY SITES Primary Sites

Baker, 1942

Lesse and Netsky, 1954

Chason et al, 1963

Vieth and Odom, 1965*

Posner, 1980

Takakura et al, 1982

Posner, 1995

Number of Tumors

114(%)

193 (%)

200 (%)

313 (%)

235 (%)

860 (%)

210 (%)

Lung Breast Gastrointestinal tract Urinary tract Melanoma Prostate Female reproductive system Source

21 .0 21 .0 11.4 10.5 7.8 0.9

25.9 36.8 5.7 5.2 1.6 2.6 1.6

61.0 5.0 7.5 5.0 5.0 4.5 1.5

27.5 16.3 5.1 7.0 15.7 0 0

26.0 14.0

36.7 31.0 7.4 4.9 5.2 2.8 1.9

40.5 18.6 6.7 6.2 9.5 0.9 4.8

CNS

CNS

IC

B

IC

B

B

=

Brain only, IC

=

5.3 IC intracranial, CNS

=

21.3

central nervous system.

* Surgical series.

sarcoma, and osteogenic sarcoma. The frequency of intracranial metastasis in children ranges from 6% to 13% and is lower than the 20% to 40% rate for adults. 38• 65 - 68• 83 The most common cause of childhood CNS metastasis is leukemia; next is lymphoma. 79 Osteogenic sarcoma and rhabdomyosarcoma are the most frequent causes of solid brain metastasis among children younger than 15 years of age, whereas germ cell tumors are the most frequent solid brain metastasis for patients 15 to 21 years of age. 38 A review of 14 children with sarcomas that stabilized or responded clinically to treatment

revealed that 36% (5 of 14) suffered relapses with development of cerebral metastasis. 35 From 1973 to 1982, the rate of intracranial spread of Wilms' tumor decreased significantly; this decline has been attributed to improved treatment regimens. 38 Graus and colleagues38 found evidence of hemorrhagic metastases at the time of autopsy in 50% of their patients. SPECIFIC TUMOR TYPES

The most common origins of brain metastasis include primary cancer of the lung, breast,

Table 5. INCIDENCE OF INTRACRANIAL METASTASIS FROM SYSTEMIC CANCER

Primary Tumors Lung Breast Colon and rectum Urinary organs Melanoma Prostate Pancreas Leukemia Lymphoma (nonHodgkin's) Female genital tract All sites Primary brain and CNS tumors

Estimated New Cases (US: 1995)*

Estimated Deaths (US: 1995)*

Percent with lntracranial Tumor at Autopsy at MSKCCt (%)

Estimated Total Deaths with lntracranial Tumor

169,900 183,400 138,200 79,300 34,100 244,000 24,000 25,700 50,900

157,400 46,240 55,300 22,900 7200 40,400 27,000 20,400 22,700

34 30 7 23 72 31:j: 7 23 16

53,516 13,872 3871 5267 5184 12,524 1890 4692 3632

80,900

26,400

7

1848

1,252,000 17,200

547,000 13,300

24

131,280 13,300

CNS = Central nervous system, MSKCC = Memorial Sloan-Kettering Cancer Center. * Data from Wingo PA, Tong T, Bolden S: Cancer statistics, 1995. CA Cancer J Clin 45:8-30, 1995. t Data from Posner JB, Chernik NL: lntracranial metastases from systemic cancer. Adv Neurol 19:579-592, 1978. :j: Largely skull and dura. § Largely leptomeningeal. Adapted from Posner JB: Neurologic Complications of Cancer. Contemporary Neurology Series, Vol 45. Philadelphia, Davis, 1995, p 4; with permission.

DEMOGRAPHICS OF BRAIN METASTASIS

skin (melanoma), and gastrointestinal tract. Brain metastases most often come from lung cancer. Single metastatic lesions are most common among patients with primary tumors of the breast or kidney, whereas multiple metastatic lesions are most common with primary tumors of the lung and skin (melanoma). 67 Hemorrhage is more common with metastases from melanoma, choriocarcinoma, renal cell carcinoma, and bronchogenic carcinoma, and may be the symptom for which patients first seek treatment. 52· 65 Skull metastases are common among patients with cancer of the breast and prostate. 67 Pituitary metastases may occur with both breast and prostate cancer. 3· 22· 67 Breast metastases occasionally involve the posterior lobe and may be associated with diabetes insipidus.41 · 54· 71 Lung

Primary tumors in the lung are the most common cause of brain metastasis for men and the second most common source for women. Since 1987, more women have died of lung cancer than of breast cancer, which had been the primary cause of cancer deaths for women for 40 years. Primary lung tumors account for approximately 30% to 60% of all brain metastases.?, s, 1?, 46, 47, 5o, 53, 77, 79, ss Eighteen percent to 65% of patients with lung cancer will develop brain metastasis. 1· 11 • 59· 79 CT scans demonstrated cerebral metastases in 6% to 10.8% of neurologically asymptomatic patients undergoing staging for resection of primary lung tumors. 43· 73 After small-cell lung carcinoma, adenocarcinoma is the next most likely type of primary lung tumor to metastasize to the brain. 11 • 34· 59· 69 Approximately two thirds of brain metastases from the lung are multiple.8·17·50 Some evidence suggests that carcinomas originating in the periphery of the lungs spread more frequently to the CNS than do centrally occurring carcinomas. 80 Approximately 10% of patients with small-cell lung cancer will have CNS metastasis at initial presentation.59· 82 A study of patients with smallcell bronchogenic carcinoma found that "the probability of developing a CNS metastasis increased with lengthening patient survival to a level of 80 percent after 2 years." 59 Breast

Ten percent to 30% of all brain metastases among women originate from primary breast

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tumors.?, s, 46, 53, 79, 81, 84, ss Approximately 20% to 30% of patients with breast cancer will develop a brain metastasis.1· 4· 18· 21· 67· 81 These metastases may be single in up to 42% of patients but are rarely solitary (only 3% in one study). 81 CNS metastases occur late, and the CNS may be the first site of recurrence. Isolated CNS metastases may reflect the previously mentioned "pharmacologic sanctuary" created by chemotherapy's improved suppression of systemic disease, with less effectiveness in controlling metastasis to the brain.61 · 81

Melanoma

In 1995, melanoma will be diagnosed in approximately 34,100 patients; the rate of melanoma has increased by approximately 4% each year since 1973.86 The incidence of CNS metastasis among patients with malignant melanoma varies from 17.5% to 90% in autopsy series. 2· 18·51 ·64 In several studies, melanoma has been shown to have the highest rate of metastasis to the brain when compared with other tumors. 18· 64 Of patients with brain metastasis, approximately 5% to 21 % will have melanoma as the primary tumor.18, 46, 47, 53, 65, 77, 88 Brain metastases from melanoma are frequently multiple and have an increased incidence of leptomeningeal spread. 10• 25· 51 In a review by Byrne, 12 29% of patients with melanoma brain metastases had evidence of hemorrhagic metastases. Patients with metastases from melanoma have a high incidence of seizures; approximately one half of the patients in one study suffered seizures. 12· 36 The cause of this increased incidence of seizures may be the multiplicity of the metastatic lesions, the tendency for melanoma lesions to be located in the gray matter rather than the gray-white junctions, or the tendency for lesions to bleed and promote an epileptogenic focus. 12

Choriocarcinoma

Choriocarcinoma is a rare cancer occurring after approximately 1 of every 500,000 pregnancies and in 1of30 hydatidiform moles. Of patients with choriocarcinoma, 8.8% to 21.4% will have CNS metastases.6· 42 The incidence of hemorrhage into these metastatic lesions is increased, and these metastases often present as large intracranial hemorrhages. 52 Nearly

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JOHNSON & YOUNG

20% of patients with pulmonary metastases will also have CNS metastases. 6 Gastrointestinal Tract

Of patients with gastrointestinal cancer, only 1.3% to 9.7% will develop CNS metastases.14' 18, 65, 67, 88 Colon carcinoma is the most frequent gastrointestinal source of brain metastases; esophageal, pancreatic, and small bowel carcinomas metastasize less frequently to the brain. In one study, 85% of patients with brain metastases from primary colon tumors had radiographic evidence of pulmonary metastasis.14 Brain metastases from primary neoplasms of the liver, Vater's ampulla, and the bile duct are rare, with only occasional case reports found in the literature. Genitourinary

Genitourinary tumors metastasize comparatively infrequently to the brain. In two separate autopsy series, Castaldo15 and Catane16 found intracranial prostate metastases in 8 of 189 patients (4.2%) and 4 of 91 patients (4.4%) with stage C or D cancer, respectively. None of 1042 women with stage 0 cervical cancer and 6 of 1219 women (0.5%) with stage 1 or greater cervical cancer had evidence of brain metastasis. 74 A collected series of autopsies by Mayer and colleagues55 in 1978 revealed only 5 cases of cerebral metastases in 567 examinations of patients with ovarian cancer. In 1989, Hardy and Harvey40 reported cerebral metastases in 6 of 52 (11.6%) of their patients undergoing chemotherapy for ovarian cancer.

CONCLUSION

Brain metastases are the most common intracranial tumor, significantly outnumbering primary brain tumors. The apparent increase in the ratio of brain metastases to primary tumors may be the result of a number of factors, including the possibility of a CNS "pharmacologic sanctuary," an aging population, and improved imaging studies. Among adults, the most common origins of brain metastasis include primary tumors of the lung, breast, skin (melanoma), and gastrointestinal tract. Among patients younger than 21 years of age, brain metastases most often arise from the sarcomas and germ cell tumors. ACKNOWLEDGMENT The authors thank Flo Witte, Director of the Publications Office of the Department of Surgery, for her editorial assistance and Roy A. Patch ell, MD, for his critical reading of the chapter.

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