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Hematogenous metastases of the human brain – Characteristics of peritumoral brain changes: A review

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Abstract

The brain is an important site of hematogenous metastases from malignanttumors in other organs. The effects on the brain is a combination of tissuedestruction induced by invading tumor cells and reactive alterationsoccurring around the metastases. This review focuses on neuropathologicalchanges around hematogenous metastases of the human brain. The peritumoralbrain parenchyma shows structural and functional changes of theintracerebral microvessels and edema. The endothelial cells of peritumoralmicrovessels express glucose transporter protein (GLUT 1) in the same way asthe normal brain. Reduction in immunostaining to GLUT 1 may occur in themicrovessels located within the metastases. This would indicateabnormalities of the blood-brain barrier in tumor vessels but normal barrierfunction in the peritumoral region. Reactive astrocytes and activatedmicroglial cells are both involved in the process of peritumoral gliosis.Activated glial cells produce numerous biological active compounds includingendothelin-1 which after release from such cells can influence the structureand function of the peritumoral brain tissue. Lesions of oligodendrocytesand edema may be implicated in myelin degeneration. Finally, metastases willinduce axonal and neuronal injuries as indicated by a recent study onexpression of β-amyloid precursor protein (βAPP) in reactive axonalswellings.

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References

  1. Fried BM, Buckley RC: Primary carcinoma of the lungs. Arch Pathol 9: 483–527, 1930

    Google Scholar 

  2. Delattre JY, Krol G, Thaler HT, Posner JB: Distribution of brain metastases. Arch Neurol 45: 741–744, 1988

    Google Scholar 

  3. O'Neill BP, Dinapoli RP, Okazaki H: Cerebral infarction as a result of tumor emboli. Cancer 60: 90–95, 1987

    Google Scholar 

  4. Willis RA: The Spread of Tumours of the Human Body. Butterworths, London, 1973

    Google Scholar 

  5. O'Neill BP, Buckner JC, Coffet RJ, Dinapoli RP, Shaw EG: Brain metastatic lesions. Mayo Clin Proc 69: 1062–1068, 1994

    Google Scholar 

  6. Modic M, Beale S: Magnetic resonance imaging of supratentorial neoplasms. In: Wilkins R, Rengachary S (eds) Neurosurgery Update I: Diagnosis, Operative Technique, and Neuro-Oncology. McGraw-Hill, New York 12–29, 1990

    Google Scholar 

  7. Rozental JM: Positron emission tomography (PET) and single photon emission computed tomography (SPECT) of brain tumors. Neurol Clin 9: 287–305, 1991

    Google Scholar 

  8. Hirsch FR, Paulson OB, Hansen HH, Vraa-Jensen J: Intracranial metastases in small cell carcinoma of the lung. Correlation of clinical and autopsy findings. Cancer 50: 2433–2437, 1982

    Google Scholar 

  9. Russell DS, Rubinstein LJ: Pathology of Tumours of the Nervous System. Edward Arnold, London, 1989

    Google Scholar 

  10. Zülch KJ: Brain Tumors. Springer, Berlin, 1986

    Google Scholar 

  11. Tomlinson E: Theory and practice of site-specific drug delivery. Adv Drug Del Rev 1: 187–198, 1987

    Google Scholar 

  12. Johansson BB: The physiology of the blood-brain barrier. Adv Exp Med Biol 274: 25–39, 1990

    Google Scholar 

  13. Gregoire N: The blood-brain barrier. J Neuroradiol 16(3): 238–250, 1989

    Google Scholar 

  14. Pardridge WM, Oldendorf WH, Cancilla P, Frank HJ: Blood-brain barrier: Interface between internal medicine and the brain clinical conference. Ann Intern Med 105(1): 82–95, 1986

    Google Scholar 

  15. Iannotti F, Fieschi C, Alfano B, Picozzi P, Mansi L, Pozzilli C, Punzo A, Vecchio GD, Lenzi GL, Salvatore M: Simplified, noninvasive PET measurement of blood-brain barrier permeability. J Comput Assist Tomogr 11(3): 390–397, 1987

    Google Scholar 

  16. Front D, Israel O, Kohn S, Nir I: The blood-tissue barrier of human brain tumors: correlation of scintigraphic and ultrastructural findings (concise communication). J Nucl Med 25 (4): 461–465, 1984

    Google Scholar 

  17. Kohn S, Front D, Nir I: Blood-brain barrier permeability of human gliomas as determined by quantitation of cytoplasmic vesicles of the capillary endothelium and scintigraphic findings. Cancer Invest 7(4): 313–321, 1989

    Google Scholar 

  18. Nir I, Levanon D, Iosilevsky G: Permeability of blood vessels in experimental gliomas: Uptake of 99Tc-glucoheptonate and alteration in blood-brain barrier as determined by cytochemistry and electron microscopy. Neurosurgery 25 (4): 523–532, 1989

    Google Scholar 

  19. Coomber BL, Stewart PA, Hayakawa K, Farrell CL, Maestro RFD: Quantitative morphology of human glioblastoma multiform microvessels: structural basis of blood-brain barrier defect. J Neurooncol 5(4): 299–307, 1987

    Google Scholar 

  20. Vriesendorp FJ, Peagram C, Bigner DD, Groothuis DR: Concurrent measurements of blood flow and transcapillary transport in xenotransplanted human gliomas in immunosuppressed rats. J Natl Cancer Inst 79(1): 123–130, 1987

    Google Scholar 

  21. Debbage PL, Gabius HJ, Bise K, Marguth F: Cellular glycoconjugates and their potential endogenous receptors in the cerebral microvasculature of man: A glycohistochemical study. Eur J Cell Biol 46(3): 425–434, 1988

    Google Scholar 

  22. Stewart PA, Hayakawa K, Farrell CL, Maestro RFD: Quantitative study of microvessel ultrastructure in human peritumoral brain tissue. Evidence for a blood-brain barrier defect. J Neurosurg 67(5): 697–705, 1987

    Google Scholar 

  23. Zagzag D, Goldenberg M, Brem S: Angiogenesis and blood-brain barrier breakdown modulate CT contrast enhancement: An experimental study in a rabbit brain-tumor model. AJR 153(1): 141–146, 1989

    Google Scholar 

  24. Yoshimine T, Ushio Y, Hayakawa T, Moto OT, Maruno M, Mogami H: Growth activity of tumors at different intracranial structures: Immunohistochemical study with bromodeoxyuridine. Acta Neuropathol (Berl) 71: 15–18, 1986

    Google Scholar 

  25. Ballinger WEJ, Schimpff RD: An experimental model for cerebral metastasis: Preliminary light and ultrastructural studies. J Neuropathol Exp Neurol 38: 19–34, 1979

    Google Scholar 

  26. Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GM: Brain metabolism during fasting. J Clin Invest 46: 1589–1595, 1967

    Google Scholar 

  27. Buschiazzo PM, Terrell EB, Regen DM: Sugar transport across the blood-brain barrier. Am J Physiol 219: 1505–1513, 1970

    Google Scholar 

  28. Pardridge WM: Brain metabolism: A perspective from the blood-brain barrier. Physiol Rev 63: 1481–1535, 1983

    Google Scholar 

  29. Kalaria RN, Gravina SA, Schmidley JW, Perry G, Harik SI: The glucose transporter of the human brain and blood-brain barrier. Ann Neurol 24: 757–764, 1988

    Google Scholar 

  30. Gerhart D, LeVasseur R, Broderius M, Drewes L: Glucose transporter localization in brain using light and electron immunocytochemistry. J Neurosci Res 22: 464–472, 1989

    Google Scholar 

  31. Pardridge W, Boado R, Farrell C: Brain-type glucose transporter (glut 1) is selectively localized to the blood-brain barrier: Studies with quantitative western blotting and in situ hybridization. J Biol Chem 265: 18035–18040, 1990

    Google Scholar 

  32. Harik S, Kalaria R, Andersson L, Lundahl P, Perry G: Immunocytochemical localization of the erythroid glucose transporter: Abundance in tissues with barrier functions. J Neurosci 10: 3862–3872, 1990

    Google Scholar 

  33. Takata K, Kasahara T, Kasahara M, Ezaki O, Hirano H: Erythrocyte/HepG2-type glucose transporter is concentrated in cell of blood-tissue barriers. Biochem Biophys Res Commun 173: 67–73, 1990

    Google Scholar 

  34. Guerin C, Laterra J, Hruban R, Brem H, Drewes L, Goldstein G: The glucose transporter and blood-brain barrier of human brain tumors. Ann Neurol 28: 758–765, 1990

    Google Scholar 

  35. Guerin C, Laterra J, Drewes L, Brem H, Goldstein G: Vascular expression of glucose transporter in experimental brain neoplasms. Am J Pathol 140: 417–425, 1992

    Google Scholar 

  36. Harik S, Roessman U: The erythrocyte-type glucose transporter in blood vessels of primary and metastatic brain tumors. Ann Neurol 29: 487–491, 1991

    Google Scholar 

  37. Zhang M, Olsson Y: Vascular expression of glucose transporter in and around hematogenous metastases of the human brain. Immunohistochemical observations. APMIS 104: 293–301, 1996

    Google Scholar 

  38. Neubürger K, Singer L: Über reaktive Veränderungen in der Umgebung carcinomatöser und sarkomatöser Hirntumoren. Virsch Arch 255: 555–579, 1925

    Google Scholar 

  39. Henschen F: Tumoren des Zentralnervensystems und seiner Hüllen. In: Lubarsch O, Henke F, Rössle R (eds) Handbuch der Speziellen Patologischen Anatomie und Histologie. Springer Verlag, Berlin 413–665, 1955

    Google Scholar 

  40. Willis RA: Secondary tumors. In: Minckler J (ed) Pathology of the Nervous System. McGraw-Hill, New York pp 2178, 1971

    Google Scholar 

  41. Zhang M, Olsson Y: ?-Amyloid precursor protein accumulates in axon around hematogenous metastases of the human brain. Immunohistochemical observations. Clinical Neuropathology 15: 74–78, 1996

    Google Scholar 

  42. Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyruther K, Fischer P, Masters CL, Price DL: Precursor of amyloid protein in Alzheimer's disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci USA 87: 1561–1565, 1990

    Google Scholar 

  43. Sherriff FE, Bridges LR, Gentleman SM, Sivaloganathan S, Wilson S: Markers of axonal injury in post mortem human brain. Acta Neuropathol 88: 433–440, 1994

    Google Scholar 

  44. Sherriff FE, Bridges LR, Sivaloganathan S: Early detection of axonal injury after human head trauma using immunocytochemistry for ?-amyloid precursor protein. Acta Neuropathol 87: 55–62, 1994

    Google Scholar 

  45. Cochran E, Bacci B, Chen Y, Patton A, Gambetti P, Autilio-Gambetti L: Amyloid precursor protein and ubiquitin immunoreactivity in dystrophic axons is not unique to Alzheimer's disease. Am J Pathol 139: 485–489, 1991

    Google Scholar 

  46. Ohgami T, Kitamoto T, Tateishi J: Alzheimer's amyloid precursor protein accumulates within axonal swellings in human brain lesions. Neurosci Lett 136: 75–78, 1992

    Google Scholar 

  47. Gentleman SM, Nash MJ, Sweeting CJ, Graham DI, Roberts GW: ?-Amyloid precursor protein (?APP) as a marker for axonal injury after head injury. Neurosci Lett 160: 139–144, 1993

    Google Scholar 

  48. Lewén A, Li GL, Nilsson P, Olsson Y, Hillered L: Mild focal cerebral trauma produces local and remote changes of APP-immunoreactivity. NeuroReport 6: 357–360, 1995

    Google Scholar 

  49. Povlishock JT: Traumatically induced axonal injury: Pathogenesis and pathobiological implications. Brain Pathol 2: 1–12, 1992

    Google Scholar 

  50. Yaghmai A, Povlishock J: Traumatically induced reactive change as visualized through the use of monoclonal antibodies targeted to neurofilament subunits. J Neuropathol Exp Neurol 51: 158–176, 1992

    Google Scholar 

  51. Pfeiffer SE, Betschart B, Cook J, Mancini P, Morris R: Glial cell. In: Fedoroff S, Hertz L (eds) Cell, Tissue and Organ Cultures in Neurobiology. Academic Press, New York 287–346, 1977

    Google Scholar 

  52. Duffy PE: Astrocytes: Normal, Reactive and Neoplastic. Raven Press, New York, 1983

    Google Scholar 

  53. Korbsch H: Über die paralyseähnliche Verlaufsart des Tumor cerebri. Ein Fall von multiplem metastatischen Carcinom. Arch f Psychiatr 72: 165–195, 1924

    Google Scholar 

  54. Hilpert P: Über das metastatische Carcinom des Zentralnervensystems. Arch f Psychiatrie 77: 93–114, 1926

    Google Scholar 

  55. Eng LF, Ghirnikar RS: GFAP and astrogliosis. Brain Pathol 4: 229–237, 1994

    Google Scholar 

  56. Nathaniel EJH, Nathaniel DR: Astroglial response to degeneration of dorsal root fibers in adult rat spinal cord. Exp Neurol 54: 60–76, 1977

    Google Scholar 

  57. Gray EG, Guillery RW: Synaptic morphology in the normal and degenerating nervous system. Int Rev Cytol 19: 111–182, 1966

    Google Scholar 

  58. Cook RD, Wisniewski HM: The role of oligodendroglia and astroglia in Wallerian degeneration of the optic nerve. Brain Res 61: 191–206, 1973

    Google Scholar 

  59. Anderson CA, Westrum LE: An electron microscopic study of the normal synaptic relationships and early degenerative chandes in the rat olfactory tubercule. Z Zellforsch 127: 462–482, 1972

    Google Scholar 

  60. Zhang M, Olsson Y: Reactions of astrocytes and microglial cells around hematogenous metastases of the human brain. Expression of endothelin like immunoreactivity in reactive astrocytes and activation of microglial cells. J Neurol Sci 134: 26–32, 1995

    Google Scholar 

  61. Eng LF: Regulation of glial intermediate filaments in astrogliosis. In: Norenberg MD, Hertz L, Schousboe A (eds) The Biochemical Pathology of Astrocytes. Alan Liss, Inc., New York 79–90, 1988

    Google Scholar 

  62. Eddleston M, Mucke L: Molecular profile of reactive astrocytes implications for their role in neurologic disease. Neuroscience 54: 15–36, 1993

    Google Scholar 

  63. Eng LF: Astrocytic response to injury. Curr Iss Neur Regen Res 1: 247–255, 1988

    Google Scholar 

  64. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411–415, 1988

    Google Scholar 

  65. Miller RC, Pelton JT, Huggins JP: Endothelins–from receptors to medicine. TIPS 14: 54–60, 1993

    Google Scholar 

  66. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T: The human endothelin family: Three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA 86: 2863–2867, 1989

    Google Scholar 

  67. Supattapone S, Simpson AWM, Ashley CC: Free calcium rise and mitogenesis in glial cells caused by endothelin. Biochemic Biophys Res Comm 165: 1115–1122, 1989

    Google Scholar 

  68. MacCumber M, Ross CA, Snyder H: Endothelin in brain: Receptors, mitogenesis, and biosynthesis in glial cells. Proc Natl Acad Sci USA 87: 2359–2363, 1990

    Google Scholar 

  69. Giaid A, Gibson SJ, Ibrahim N, Legon S, Bloom S, Yanagisawa M, Masaki T, Varndell I, Polak J: Endothelin 1 an endothelium-derived peptide is expressed in neurons of the human spinal cord and dorsal root ganglia. Proc Natl Acad Sci USA 86: 7634–7638, 1989

    Google Scholar 

  70. Giaid A, Gibson SJ, Herrero MT, Gentleman S, Legon S, Yanagisawa M, Masaki T, Ibrahim NBN, Roberts GW, Rossi ML: Topographical localization of endothelin mRNA and peptide immunoreactivity in neurons of the human brain. Histochemistry 95: 303–314, 1991

    Google Scholar 

  71. Jiang MH, Hoog A, Ma KC, Nie XJ, Olsson Y, Zhang WW: Endothelin-1-like immunoreactivity is expressed in human reactive astrocytes. Neuroreport 4: 935–937, 1993

    Google Scholar 

  72. Nie XJ, Höög A, Jiang MH, Ma KC, Olsson Y, Zhang WW: Endothelin-like immunoreactivity is expressed in reactive astrocytes in cases of cerebral infarcts and lacunes. Eur J Neurol 1: 135–140, 1994

    Google Scholar 

  73. Zhang WW, Badonic T, Höög A, Jiang MH, Ma KC, Nie XJ, Olsson Y: Astrocytes in Alzheimer's disease express immunoreactivity to the vaso-constrictor endothelin-1. J Neurol Sci 122: 90–96, 1994

    Google Scholar 

  74. Yamashita K, Kataoka Y, Niwa M, Shigematsu K, Himeno A, Koizumi S, Taniyama K: Increased production of endothelins in the hippocampus of stroke-prone spontaneously hypertensive rats following transient forebrain ischemia: Histochemical evidence. Cel Mol Neurobiol 13: 15–23, 1993

    Google Scholar 

  75. Ehrenreich H, Anderson RW, Fox CH, Rieckmann P, Hoffman GS, Travis WD, Coligan JE, Kehrl JH, Fauci AS: Endothelins, peptides with potent vasoactive properties are produced by human macrophages. J Exp Med 172: 1741–1748, 1990

    Google Scholar 

  76. Ehrenreich H, Kehrl JH, Anderson RW, Rieckmann P, Vitkovic L, Coligan JE, Fauci AS: A vasoactive peptide, endothelin-3, is produced by and specifically binds to primary astrocytes. Brain Res 538: 54–58, 1991

    Google Scholar 

  77. Gehrmann J, Kreutzberg GW: Monoclonal antibodies against macrophages/microglia: Immunocytochemical studies of early microglia activation in experimental neuropathology. Clin Neuropath 12: 301–306, 1993

    Google Scholar 

  78. Altman J: Microglia emerge from the fog. TINS 17: 47–49, 1994

    Google Scholar 

  79. Banati RB, Gehrmann J, Schubert P, Kreutzberg GW: Cytotoxicity of microglia. Glia 7: 111–118, 1993

    Google Scholar 

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Zhang, M., Olsson, Y. Hematogenous metastases of the human brain – Characteristics of peritumoral brain changes: A review. J Neurooncol 35, 81–89 (1997). https://doi.org/10.1023/A:1005799805335

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