Brain Metastases: Epidemiology and Pathophysiology

  • Joohee Sul
  • Jerome B. Posner
Part of the Cancer Treatment and Research book series (CTAR, volume 136)


Brain metastases are a devastating complication of systemic cancer. Although they typically occur late in the course of the disease, their symptoms of seizures, paralysis and cognitive failure have a major negative impact on quality of life and, once detected, they portend a poor prognosis. Most patients die within months, either from the brain metastasis itself, or if that can be controlled, from widespread systemic disease. Recent data suggest a rise in the incidence of brain metastases [1], so that clinicians face mounting challenges in caring for these patients.


Vascular Endothelial Growth Factor Brain Metastasis Primary Central Nervous System Lymphoma Primary Brain Tumor Central Nervous System Lymphoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cappuzzo F, Mazzoni F, Maestri A, et al: Medical treatment of brain metastases from solid tumours. Forum (Genova) 2000; 10(2):137–148.Google Scholar
  2. 2.
    Posner JB: Neurologic Complications of Cancer. Philadelphia, F.A. Davis, 1995.Google Scholar
  3. 3.
    Lassman AB, DeAngelis LM: Brain metastases. Neurol Clin 2003; 21(1): 1–23.PubMedGoogle Scholar
  4. 4.
    Guomundsson KR: A survey of tumours of the central nervous system in Iceland during the 10-year period 1954–1963. Acta Neurologica Scandinavica 1970; 46:538–552.PubMedGoogle Scholar
  5. 5.
    Percy AK, Elveback LR, Okazaki H, et al: Neoplasms of the central nervous system. Epidemiologic considerations. Neurology 1972; 22:40–48.Google Scholar
  6. 6.
    Fogelholm R, Uutela T, Murros K: Epidemiology of central nervous system neoplasms. A regional survey in Central Finland. Acta Neurologica Scandinavica 1984; 69:129–136.Google Scholar
  7. 7.
    Walker AE, Robins M, Weinfeld FD: Epidemiology of brain tumors: The national survey of intracranial neoplasms. Neurology 1985; 35:219–226.PubMedGoogle Scholar
  8. 8.
    Posner JB, Chernik NL: Intracranial metastases from systemic cancer. Adv Neurol 1978; 19:575–587.Google Scholar
  9. 9.
    Cairncross JG, Kim J-H, Posner JB: Radiation therapy of brain metastases. Ann Neurol 1980; 7:529–541.PubMedGoogle Scholar
  10. 10.
    Pickren JW, Lopez G, Tsukada Y, et al: Brain metastases: An autopsy study. Cancer Treat Symp 1983; 2:295–313.Google Scholar
  11. 11.
    Shojania KG, Burton EC, McDonald KM, et al: Changes in rates of autopsy-detected diagnostic errors over time: a systematic review. JAMA 2003; 289(21):2849–2856.PubMedGoogle Scholar
  12. 12.
    Tham YL, Sexton K, Kramer R, et al: Primary breast cancer phenotypes associated with propensity for central nervous system metastases. Cancer 2006; 107(4):696–704.PubMedGoogle Scholar
  13. 13.
    Davis FG, McCarthy B, Jukich P: The descriptive epidemiology of brain tumors. Neuroimaging Clin N Am 1999; 9(4):581–594.PubMedGoogle Scholar
  14. 14.
    Johnson JD, Young B: Demographics of brain metastasis. Neurosurg Clin N Am 1996; 7(3):337–344.PubMedGoogle Scholar
  15. 15.
    Fogarty GB, Tartaguia C: The utility of magnetic resonance imaging in the detection of brain metastases in the staging of cutaneous melanoma. Clin Oncol (R Coll Radiol ) 2006; 18(4):360–362.Google Scholar
  16. 16.
    Seute T, Leffers P, Wilmink JT, et al: Response of asymptomatic brain metastases from small-cell lung cancer to systemic first-line chemotherapy. J Clin Oncol 2006; 24(13):2079–2083.PubMedGoogle Scholar
  17. 17.
    Larcos G, Maisey MN: FDG-PET screening for cerebral metastases in patients with suspected malignancy. Nucl Med Commun 1996; 17(3):197–198.PubMedGoogle Scholar
  18. 18.
    Gavrilovic IT, Posner JB: Brain metastases: epidemiology and pathophysiology. J Neurooncol 2005; 75(1):5–14.PubMedGoogle Scholar
  19. 19.
    Barnholtz-Sloan JS, Sloan AE, Lai P, et al: Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan Detroit cancer surveillance system. J Clin Oncol 2004; 22(14):2865–2872.PubMedGoogle Scholar
  20. 20.
    Walker AE, Adamkiewitcz JJ: Pseudotumor cerebri associated with prolonged corticosteroid therapy: reports of four cases. JAMA 1964; 188:779–784.PubMedGoogle Scholar
  21. 21.
    Schouten LJ, Rutten J, Huveneers HAM, et al: Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 2002; 94(10):2698–2705.PubMedGoogle Scholar
  22. 22.
    Madajewicz S, Karakousis C, West CR, et al: Malignant melanoma brain metastases. Review of Roswell Park Memorial Institute experience. Cancer 1984; 53(11):2550–2552.PubMedGoogle Scholar
  23. 23.
    Hutter A, Schwetye KE, Bierhals AJ, et al: Brain neoplasms: epidemiology, diagnosis, and prospects for cost-effective imaging. Neuroimaging Clin N Am 2003; 13(2):237–242.PubMedGoogle Scholar
  24. 24.
    Nussbaum ES, Djalilian HR, Cho KH, et al: Brain metastases - Histology, multiplicity, surgery, and survival. Cancer 1996; 78(8):1781–1788.PubMedGoogle Scholar
  25. 25.
    Bartelt S, Lutterbach J: Brain metastases in patients with cancer of unknown primary. J Neurooncol 2003; 64(3):249–253.PubMedGoogle Scholar
  26. 26.
    Polyzoidis KS, Miliaras G, Pavlidis N: Brain metastasis of unknown primary: a diagnostic and therapeutic dilemma. Cancer Treat Rev 2005; 31(4):247–255.PubMedGoogle Scholar
  27. 27.
    Gabos Z, Sinha R, Hanson J, et al: Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer. J Clin Oncol 2006; 20;24(36):5658–63.PubMedGoogle Scholar
  28. 28.
    Daryanani D, Plukker JT, de Jong MA, et al: Increased incidence of brain metastases in cutaneous head and neck melanoma. Melanoma Res 2005; 15(2):119–124.PubMedGoogle Scholar
  29. 29.
    Nishizaki T, Saito K, Jimi Y, et al: The role of cyberknife radiosurgery/radiotherapy for brain metastases of multiple or large-size tumors. Minim Invasive Neurosurg 2006; 49(4):203–209.PubMedGoogle Scholar
  30. 30.
    Delattre J-Y, Krol G, Thaler HT, et al: Distribution of brain metastases. Arch Neurol 1988; 45:741–744.PubMedGoogle Scholar
  31. 31.
    Patchell RA, Tibbs PA, Walsh JW: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494–500.PubMedCrossRefGoogle Scholar
  32. 32.
    Vannucci RC, Baten M: Cerebral metastatic disease in childhood. Neurology 1974; 24(10):981–985.PubMedGoogle Scholar
  33. 33.
    Graus F, Walker RW, Allen JC: Brain metastases in children. J Pediatr 1983; 103(4):558–561.PubMedGoogle Scholar
  34. 34.
    Bouffet E, Doumi N, Thiesse P, et al: Brain metastases in children with solid tumors. Cancer 1997; 79(2):403–410.PubMedGoogle Scholar
  35. 35.
    Schulenburg A, Ulrich-Pur H, Thurnher D, et al: Neoplastic stem cells: A novel therapeutic target in clinical oncology. Cancer 2006; 107(10):2512–2520.PubMedGoogle Scholar
  36. 36.
    Fidler IJ, Kripke ML: Metastasis results from preexisting variant cells within a malignant tumor. Science 1977; 197(4306):893–895.PubMedGoogle Scholar
  37. 37.
    Pantel K, Brakenhoff RH: Dissecting the metastatic cascade. Nat Rev Cancer 2004; 4(6):448–456.PubMedGoogle Scholar
  38. 38.
    Lee JM, Dedhar S, Kalluri R, et al: The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 2006; 172(7): 973–981.PubMedGoogle Scholar
  39. 39.
    Hay ED: The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn 2005; 233(3):706–720.PubMedGoogle Scholar
  40. 40.
    Larue L, Bellacosa A: Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3’ kinase/AKT pathways. Oncogene 2005; 24(50):7443–7454.PubMedGoogle Scholar
  41. 41.
    Ewing J: Metastasis. In: Ewing J, (ed): Neoplastic Diseases: A Treatise on Tumours. Philadelphia, W.B. Saunders, 1940:62–74.Google Scholar
  42. 42.
    Fidler IJ, Yano S, Zhang RD, et al: The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 2002; 3(1):53–57.PubMedGoogle Scholar
  43. 43.
    Paget S: The distribution of secondary growths in cancer of the breast. Cancer Metastasis Rev. 1989; 8(2):98–101.PubMedGoogle Scholar
  44. 44.
    Fidler IJ: The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 2003; 3(6):453–458.PubMedGoogle Scholar
  45. 45.
    Tarin D, Price JE, Kettlewell MG, et al: Mechanisms of human tumor metastasis studied in patients with peritoneovenous shunts. Cancer Res 1984; 44(8):3584–3592.PubMedGoogle Scholar
  46. 46.
    Chambers AF, MacDonald IC, Schmidt EE, et al: Steps in tumor metastasis: New concepts from intravital videomicroscopy. Cancer Metastasis Rev 1995; 14(4):279–301.PubMedGoogle Scholar
  47. 47.
    Weiss L: Comments on hematogenous metastatic patterns in humans as revealed by autopsy. Clin Exp Metastasis 1992; 10:191–199.PubMedGoogle Scholar
  48. 48.
    Sugarbaker EV: Cancer metastasis: a product of tumor-host interactions. Curr Probl Cancer 1979; 3(7):1–59.PubMedGoogle Scholar
  49. 49.
    Nathoo N, Chahlavi A, Barnett GH, et al: Pathobiology of brain metastases. J Clin Pathol 2005; 58(3):237–242.PubMedGoogle Scholar
  50. 50.
    Puduvalli VK: Brain metastases: biology and the role of the brain microenvironment Curr Oncol Rep 2001; 3(6):467–475.PubMedGoogle Scholar
  51. 51.
    Cavallaro U, Christofori G: Cell adhesion in tumor invasion and metastasis: loss of the glue is not enough. Biochim Biophys Acta Rev Cancer 2001; 1552(1):39–45.Google Scholar
  52. 52.
    Steeg PS: Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 2006; 12(8):895–904.PubMedGoogle Scholar
  53. 53.
    Hirohashi S: Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol 1998;153(2):333–339.PubMedGoogle Scholar
  54. 54.
    Nieman MT, Prudoff RS, Johnson KR, et al: N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol 1999; 147(3):631–644.PubMedGoogle Scholar
  55. 55.
    Li G, Satyamoorthy K, Herlyn M: N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res 2001; 61(9):3819–3825.PubMedGoogle Scholar
  56. 56.
    Wyckoff JB, Jones JG, Condeelis JS, et al: A critical step in metastasis: In vivo analysis of intravasation at the primary tumor. Cancer Research 2000; 60(9):2504–2511.PubMedGoogle Scholar
  57. 57.
    Arnold SM, Young AB, Munn RK, et al: Expression of p53, bcl-2, E-cadherin, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 in paired primary tumors and brain metastasis. Clin Cancer Res 1999; 5(12):4028–4033.PubMedGoogle Scholar
  58. 58.
    Jäälinojä J, Herva R, Korpela M, et al: Matrix metalloproteinase 2 (MMP-2) immunoreactive protein is associated with poor grade and survival in brain neoplasms. J Neurooncol 2000; 46(1):81–90.PubMedGoogle Scholar
  59. 59.
    Boyd TS, Mehta MP: Radiosurgery for brain metastases. Neurosurg Clin N Am 1999; 10(2):337–350.PubMedGoogle Scholar
  60. 60.
    Folgueras AR, Pendas AM, Sanchez LM, et al: Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol 2004; 48(5–6):411–424.PubMedGoogle Scholar
  61. 61.
    Attwell S, Roskelley C, Dedhar S: The integrin-linked kinase (ILK) suppresses anoikis. Oncogene 2000; 19(33):3811–3815.PubMedGoogle Scholar
  62. 62.
    Douma S, Van LT, Zevenhoven J, et al: Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 2004; 430(7003):1034–1039.PubMedGoogle Scholar
  63. 63.
    Hanna N: Inhibition of experimental tumor metastasis by selective activation of natural killer cells. Cancer Res 1982; 42(4):1337–1342.PubMedGoogle Scholar
  64. 64.
    Borsig L, Wong R, Hynes RO, et al: Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc Natl Acad Sci U S A 2002; 99(4):2193–2198.PubMedGoogle Scholar
  65. 65.
    Felding-Habermann B, O’Toole TE, et al: Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci USA 2001; 98(4):1853–1858.PubMedGoogle Scholar
  66. 66.
    Camerer E, Qazi AA, Duong DN, et al: Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood 2004; 104(2):397–401.PubMedGoogle Scholar
  67. 67.
    Hwang TL, Close TP, Grego JM, et al: Predilection of brain metastasis in gray and white matter junction and vascular border zones. Cancer 1996; 77(8):1551–1555.PubMedGoogle Scholar
  68. 68.
    Cascino TL, Leavengood JM, Kemeny N, et al: Brain metastases from colon cancer. J Neurooncol 1983; 1:203–209.PubMedGoogle Scholar
  69. 69.
    Hirshberg A, Leibovich P, Horowitz I, et al: Metastatic tumors to postextraction sites. J Oral Maxillofac Surg 1993; 51(12):1334–1337.PubMedCrossRefGoogle Scholar
  70. 70.
    Nielson SL, Posner JB: Brain metastasis localized to an area of infarction. J Neurooncol 1983; 1:191–195.Google Scholar
  71. 71.
    Smith DB, Howell A, Harris M, et al: Carcinomatous meningitis associated with infiltrating lobular carcinoma of the breast. Eur J Surg Oncol 1985; 11:33–36.PubMedGoogle Scholar
  72. 72.
    Pasqualini R, Arap W: Profiling the molecular diversity of blood vessels. Cold Spring Harb Symp Quant Biol 2002; 67:223–225.PubMedGoogle Scholar
  73. 73.
    Trepel M, Arap W, Pasqualini R: In vivo phage display and vascular heterogeneity: implications for targeted medicine. Curr Opin Chem Biol 2002; 6(3):399–404.PubMedGoogle Scholar
  74. 74.
    Brayton J, Qing Z, Hart MN, et al: Influence of adhesion molecule expression by human brain microvessel endothelium on cancer cell adhesion. J Neuroimmunol 1998; 89(1–2):104–112.PubMedGoogle Scholar
  75. 75.
    Friedl P, Wolf K: Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 2003; 3(5):362–374.PubMedGoogle Scholar
  76. 76.
    Harabin-Slowinska M, Slowinski J, Konecki J, et al: Expression of adhesion molecule CD44 in metastatic brain tumors. Folia Neuropathol 1998; 36(3):179–184.PubMedGoogle Scholar
  77. 77.
    Marchetti D, Li J, Shen R: Astrocytes contribute to the brain-metastatic specificity of melanoma cells by producing heparanase. Cancer Res 2000; 60(17):4767–4770.PubMedGoogle Scholar
  78. 78.
    Kosir MA, Wang W, Zukowski KL, et al: Degradation of basement membrane by prostate tumor heparanase. J Surg Res 1999; 81(1):42–47.PubMedGoogle Scholar
  79. 79.
    Hedley BD, Allan AL, Chambers AF: Tumor dormancy and the role of metastasis suppressor genes in regulating ectopic growth. Future Oncol 2006; 2(5):627–641.PubMedGoogle Scholar
  80. 80.
    Luzzi KJ, MacDonald IC, Schmidt EE, et al: Multistep nature of metastatic inefficiency - Dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 1998; 153(3): 865–873.PubMedGoogle Scholar
  81. 81.
    Braun S, Pantel K, Muller P, et al: Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000; 342(8):525–533.PubMedGoogle Scholar
  82. 82.
    Kirsch M, Schackert G, Blkack PM: Angiogenesis, metastasis, and endogenous inhibition. J Neuro-Oncol 2000; 50(1–2):173–180.Google Scholar
  83. 83.
    Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285(21):1182–1186.PubMedCrossRefGoogle Scholar
  84. 84.
    Folkman J: How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clower Memorial Award Lecture. Cancer Res 1986; 46: 467–473.PubMedGoogle Scholar
  85. 85.
    Folkman J, Klagsbrun M: Angiogenic factors. Science 1987; 235(4787): 442–447.PubMedGoogle Scholar
  86. 86.
    Machein MR, Plate KH: VEGF in brain tumors. J Neurooncol 2000; 50(1–2): 109–120.PubMedGoogle Scholar
  87. 87.
    Poon RT, Fan ST, Wong J: Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001; 19(4):1207–1225.PubMedGoogle Scholar
  88. 88.
    McDonald DM, Baluk P: Significance of blood vessel leakiness in cancer. Cancer Res 2002; 62(18):5381–5385.PubMedGoogle Scholar
  89. 89.
    Bergers G, Benjamin LE: Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3(6):401–410.PubMedGoogle Scholar
  90. 90.
    Joyce JA: Therapeutic targeting of the tumor microenvironment. Cancer Cell 2005; 7(6):513–520.PubMedGoogle Scholar
  91. 91.
    He BP, Wang JJ, Zhang X, et al: Differential reactions of microglia to brain metastasis of lung cancer. Mol Med 2006; 12(7–8):161–170.PubMedGoogle Scholar
  92. 92.
    Klein CA, Blankenstein TJ, Schmidt-Kittler O, et al: Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 2002; 360(9334):683–689.PubMedGoogle Scholar
  93. 93.
    Auperin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999; 341(7):476–484.PubMedGoogle Scholar
  94. 94.
    Foldi M: The brain and the lymphatic system (I). Lymphology 1996; 29(1): 1–9.PubMedGoogle Scholar
  95. 95.
    Foldi M: The brain and the lymphatic system (II). Lymphology 1996; 29(1):10–14.PubMedGoogle Scholar
  96. 96.
    Knopf PM, Cserr HF, Nolan SC, et al: Physiology and immunology of lymphatic drainage of interstitial and cerebrospinal fluid from the brain. Neuropathol Appl Neurobiol 1995; 21:175–180.PubMedGoogle Scholar
  97. 97.
    Johnston M, Zakharov A, Papaiconomou C, et al: Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species. Cerebrospinal Fluid Res 2004: 1(1):2.PubMedGoogle Scholar
  98. 98.
    Koh L, Zakharov A, Johnston M: Integration of the subarachnoid space and lymphatics: is it time to embrace a new concept of cerebrospinal fluid absorption? Cerebrospinal Fluid Res 2005; 20, 2:6.Google Scholar
  99. 99.
    Moon KS, Jung S, Lee MC, et al: Metastatic glioblastoma in cervical lymph node after repeated craniotomies: report of a case with diagnosis by fine needle aspiration. J Korean Med Sci 2004; 19(6):911–914.PubMedGoogle Scholar
  100. 100.
    Brown MT, McClendon RE, Gockerman JP: Primary central nervous system lymphoma with systemic metastasis: case report and review. J Neurooncol 1995; 23(3):207–221.PubMedGoogle Scholar
  101. 101.
    Barone TA, Plunkett RJ, Hohmann P, et al: An experimental model of human leukemic meningitis in the nude rat. Blood 1997;90(1):298–305.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Joohee Sul
    • 1
  • Jerome B. Posner
    • 1
  1. 1.Department of NeurologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA

Personalised recommendations