Journal of Neuro-Oncology

, Volume 105, Issue 2, pp 423–431 | Cite as

The distribution of vascular endothelial growth factor-producing cells in clinical radiation necrosis of the brain: pathological consideration of their potential roles

  • Naosuke Nonoguchi
  • Shin-Ichi MiyatakeEmail author
  • Motoi Fukumoto
  • Motomasa Furuse
  • Ryo Hiramatsu
  • Shinji Kawabata
  • Toshihiko Kuroiwa
  • Motomu Tsuji
  • Manabu Fukumoto
  • Koji Ono
Clinical Study – Patient Study


The cell type and localization of vascular endothelial growth factor (VEGF)-producing cells in human radiation necrosis (RN) are investigated from a histopathological and immunohistochemical standpoint using clinical specimens. Eighteen surgical specimens of symptomatic RN in the brain were retrospectively reviewed. These cases included different original histological tumor types and were treated with different radiation modalities. Histological analyses were performed using hematoxylin and eosin (H&E) staining, and anti-VEGF and anti-hypoxia-inducible factor (HIF)-1α immunohistochemistry. H&E staining showed marked angiogenesis and reactive astrocytosis at the perinecrotic area. The most prominent vasculature in this area was identified as telangiectasis. Immunohistochemistry indicated that HIF-1α was expressed predominantly in the perinecrotic area and that a large majority of VEGF-expressing cells were reactive astrocytes intensively distributed in this area. VEGF produced by the reactive astrocytes localized mainly in the perinecrotic area might be a major cause of both angiogenesis and the subsequent perilesional edema typically found in RN of the brain. The benefits of anti-VEGF antibody (bevacizumab) treatment in RN may be that VEGF secretion from the perinecrotic tissue is inhibited and that surgery would remove this tissue; both of these benefits result in effective reduction of edema associated with RN.


Angiogenesis Bevacizumab Boron neutron capture therapy Hypoxia-inducible factor-1α Radiation necrosis Vascular endothelial growth factor 



The first two authors contributed equally to this work. This work was partly supported by Grants-in-Aid for Scientific Research (B) (16390422 and 19390385) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology to S.-I.M. This work was also supported in part by the Takeda Science Foundation for Osaka Medical College and in part by a grant from the OMC Science Frontier Program for the Promotion of Research in Osaka Medical College to S.-I.M. We appreciate the help of Dr. Shingo Takano, Department of Neurosurgery, Tsukuba University, for providing information on immunohistochemistry of hypoxia-inducible factor-1α; and the help of Hiroko Kuwabara, Department of Pathology, Osaka Medical College, for fruitful discussion on the histological findings of the pathological specimens.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

11060_2011_610_MOESM1_ESM.doc (22 kb)
Supplementary material 1 (DOC 22 kb)
11060_2011_610_MOESM2_ESM.tif (1.7 mb)
Supplementary material 2 (TIFF 1708 kb)
11060_2011_610_MOESM3_ESM.tif (2 mb)
Supplementary material 3 (TIFF 2050 kb)
11060_2011_610_MOESM4_ESM.tif (1.7 mb)
Supplementary material 4 (TIFF 1779 kb)


  1. 1.
    Hopewell JW (1998) Radiation injury to the central nervous system. Med Pediatr Oncol Suppl 1:1–9CrossRefGoogle Scholar
  2. 2.
    Fitzek MM, Thornton AF, Rabinov JD, Lev MH, Pardo FS, Munzenrider JE, Okunieff P, Bussiere M, Braun I, Hochberg FH, Hedley-Whyte ET, Liebsch NJ, Harsh GRt (1999) Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial. J Neurosurg 91:251–260PubMedCrossRefGoogle Scholar
  3. 3.
    Iuchi T, Hatano K, Narita Y, Kodama T, Yamaki T, Osato K (2006) Hypofractionated high-dose irradiation for the treatment of malignant astrocytomas using simultaneous integrated boost technique by IMRT. Int J Radiat Oncol Biol Phys 64:1317–1324PubMedCrossRefGoogle Scholar
  4. 4.
    Kawabata S, Miyatake S, Kuroiwa T, Yokoyama K, Doi A, Iida K, Miyata S, Nonoguchi N, Michiue H, Takahashi M, Inomata T, Imahori Y, Kirihata M, Sakurai Y, Maruhashi A, Kumada H, Ono K (2009) Boron neutron capture therapy for newly diagnosed glioblastoma. J Radiat Res 50:51–60PubMedCrossRefGoogle Scholar
  5. 5.
    Miyatake S, Kawabata S, Kajimoto Y, Aoki A, Yokoyama K, Yamada M, Kuroiwa T, Tsuji M, Imahori Y, Kirihata M, Sakurai Y, Masunaga S, Nagata K, Maruhashi A, Ono K (2005) Modified boron neutron capture therapy for malignant gliomas performed using epithermal neutron and two boron compounds with different accumulation mechanisms: an efficacy study based on findings on neuroimages. J Neurosurg 103:1000–1009PubMedCrossRefGoogle Scholar
  6. 6.
    Tanaka M, Ino Y, Nakagawa K, Tago M, Todo T (2005) High-dose conformal radiotherapy for supratentorial malignant glioma: a historical comparison. Lancet Oncol 6:953–960PubMedCrossRefGoogle Scholar
  7. 7.
    Ohguri T, Imada H, Kohshi K, Kakeda S, Ohnari N, Morioka T, Nakano K, Konda N, Korogi Y (2007) Effect of prophylactic hyperbaric oxygen treatment for radiation-induced brain injury after stereotactic radiosurgery of brain metastases. Int J Radiat Oncol Biol Phys 67:248–255PubMedCrossRefGoogle Scholar
  8. 8.
    Guttin PH (1991) Treatment of radiation necrosis of the brain. Raven, New YorkGoogle Scholar
  9. 9.
    Leibel SA, Gutin PH, Wara WM, Silver PS, Larson DA, Edwards MS, Lamb SA, Ham B, Weaver KA, Barnett C et al (1989) Survival and quality of life after interstitial implantation of removable high-activity iodine-125 sources for the treatment of patients with recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 17:1129–1139PubMedCrossRefGoogle Scholar
  10. 10.
    Levin VA, Bidaut L, Hou P, Kumar AJ, Wefel JS, Bekele BN, Prabhu S, Loghin M, Gilbert MR, Jackson EF (2011) Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys 79(5):1487–1495PubMedCrossRefGoogle Scholar
  11. 11.
    Gonzalez J, Kumar AJ, Conrad CA, Levin VA (2007) Effect of bevacizumab on radiation necrosis of the brain. Int J Radiat Oncol Biol Phys 67:323–326PubMedCrossRefGoogle Scholar
  12. 12.
    Torcuator R, Zuniga R, Mohan YS, Rock J, Doyle T, Anderson J, Gutierrez J, Ryu S, Jain R, Rosenblum M, Mikkelsen T (2009) Initial experience with bevacizumab treatment for biopsy confirmed cerebral radiation necrosis. J Neurooncol 94:63–68PubMedCrossRefGoogle Scholar
  13. 13.
    Furuse M, Kawabata S, Kuroiwa T, Miyatake SI (2010) Repeated treatments with bevacizumab for recurrent radiation necrosis in patients with malignant brain tumors: a report of 2 cases. J Neurooncol 102(3):471–475PubMedCrossRefGoogle Scholar
  14. 14.
    Miyatake S, Kawabata S, Nonoguchi N, Yokoyama K, Kuroiwa T, Matsui H, Ono K (2009) Pseudoprogression in boron neutron capture therapy for malignant gliomas and meningiomas. Neuro Oncol 11:430–436PubMedCrossRefGoogle Scholar
  15. 15.
    Miyashita M, Miyatake S, Imahori Y, Yokoyama K, Kawabata S, Kajimoto Y, Shibata MA, Otsuki Y, Kirihata M, Ono K, Kuroiwa T (2008) Evaluation of fluoride-labeled boronophenylalanine-PET imaging for the study of radiation effects in patients with glioblastomas. J Neurooncol 89:239–246PubMedCrossRefGoogle Scholar
  16. 16.
    Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ (2000) Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 93:1003–1013PubMedCrossRefGoogle Scholar
  17. 17.
    Stummer W, Stocker S, Wagner S, Stepp H, Fritsch C, Goetz C, Goetz AE, Kiefmann R, Reulen HJ (1998) Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence. Neurosurgery 42:518–525 discussion 525–516PubMedCrossRefGoogle Scholar
  18. 18.
    Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312PubMedCrossRefGoogle Scholar
  19. 19.
    Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309PubMedCrossRefGoogle Scholar
  20. 20.
    Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J (1989) Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84:1470–1478PubMedCrossRefGoogle Scholar
  21. 21.
    Connolly DT, Olander JV, Heuvelman D, Nelson R, Monsell R, Siegel N, Haymore BL, Leimgruber R, Feder J (1989) Human vascular permeability factor. Isolation from U937 cells. J Biol Chem 264:20017–20024PubMedGoogle Scholar
  22. 22.
    Zacchigna S, Tasciotti E, Kusmic C, Arsic N, Sorace O, Marini C, Marzullo P, Pardini S, Petroni D, Pattarini L, Moimas S, Giacca M, Sambuceti G (2007) In vivo imaging shows abnormal function of vascular endothelial growth factor-induced vasculature. Hum Gene Ther 18:515–524PubMedCrossRefGoogle Scholar
  23. 23.
    Kimura R, Nakase H, Tamaki R, Sakaki T (2005) Vascular endothelial growth factor antagonist reduces brain edema formation and venous infarction. Stroke 36:1259–1263PubMedCrossRefGoogle Scholar
  24. 24.
    van Bruggen N, Thibodeaux H, Palmer JT, Lee WP, Fu L, Cairns B, Tumas D, Gerlai R, Williams SP, van Lookeren Campagne M, Ferrara N (1999) VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 104:1613–1620PubMedCrossRefGoogle Scholar
  25. 25.
    Li YQ, Ballinger JR, Nordal RA, Su ZF, Wong CS (2001) Hypoxia in radiation-induced blood-spinal cord barrier breakdown. Cancer Res 61:3348–3354PubMedGoogle Scholar
  26. 26.
    Nordal RA, Nagy A, Pintilie M, Wong CS (2004) Hypoxia and hypoxia-inducible factor-1α target genes in central nervous system radiation injury: a role for vascular endothelial growth factor. Clin Cancer Res 10:3342–3353PubMedCrossRefGoogle Scholar
  27. 27.
    Minchenko A, Bauer T, Salceda S, Caro J (1994) Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab Invest 71:374–379PubMedGoogle Scholar
  28. 28.
    Fang J, Yan L, Shing Y, Moses MA (2001) HIF-1alpha-mediated up-regulation of vascular endothelial growth factor, independent of basic fibroblast growth factor, is important in the switch to the angiogenic phenotype during early tumorigenesis. Cancer Res 61:5731–5735PubMedGoogle Scholar
  29. 29.
    Ikeda E, Achen MG, Breier G, Risau W (1995) Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem 270:19761–19766PubMedCrossRefGoogle Scholar
  30. 30.
    Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845PubMedCrossRefGoogle Scholar
  31. 31.
    Kalaria RN, Cohen DL, Premkumar DR, Nag S, LaManna JC, Lust WD (1998) Vascular endothelial growth factor in Alzheimer’s disease and experimental cerebral ischemia. Brain Res Mol Brain Res 62:101–105PubMedCrossRefGoogle Scholar
  32. 32.
    Miyatake S, Kuroiwa T, Kajimoto Y, Miyashita M, Tanaka H, Tsuji M (2007) Fluorescence of non-neoplastic, magnetic resonance imaging-enhancing tissue by 5-aminolevulinic acid: case report. Neurosurgery 61:E1101–E1103 discussion E1103–1104PubMedCrossRefGoogle Scholar
  33. 33.
    Calvo W, Hopewell JW, Reinhold HS, Yeung TK (1988) Time- and dose-related changes in the white matter of the rat brain after single doses of X rays. Br J Radiol 61:1043–1052PubMedCrossRefGoogle Scholar
  34. 34.
    Burger PC, Mahley MS Jr, Dudka L, Vogel FS (1979) The morphologic effects of radiation administered therapeutically for intracranial gliomas: a postmortem study of 25 cases. Cancer 44:1256–1272PubMedCrossRefGoogle Scholar
  35. 35.
    Gaensler EH, Dillon WP, Edwards MS, Larson DA, Rosenau W, Wilson CB (1994) Radiation-induced telangiectasia in the brain simulates cryptic vascular malformations at MR imaging. Radiology 193:629–636PubMedGoogle Scholar
  36. 36.
    Poussaint TY, Siffert J, Barnes PD, Pomeroy SL, Goumnerova LC, Anthony DC, Sallan SE, Tarbell NJ (1995) Hemorrhagic vasculopathy after treatment of central nervous system neoplasia in childhood: diagnosis and follow-up. AJNR Am J Neuroradiol 16:693–699PubMedGoogle Scholar
  37. 37.
    Rabin BM, Meyer JR, Berlin JW, Marymount MH, Palka PS, Russell EJ (1996) Radiation-induced changes in the central nervous system and head and neck. Radiographics 16:1055–1072PubMedGoogle Scholar
  38. 38.
    Burger P, Boyko O (1991) The pathology of central nervous system radiation injury. In: Gutin PH, Leibel SA, Sheline GE (eds) Radiation injury to the nervous system. Raven Press, New York, pp 191–208Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Naosuke Nonoguchi
    • 1
  • Shin-Ichi Miyatake
    • 1
    Email author
  • Motoi Fukumoto
    • 2
  • Motomasa Furuse
    • 1
  • Ryo Hiramatsu
    • 1
  • Shinji Kawabata
    • 1
  • Toshihiko Kuroiwa
    • 1
  • Motomu Tsuji
    • 3
  • Manabu Fukumoto
    • 2
  • Koji Ono
    • 4
  1. 1.Department of NeurosurgeryOsaka Medical CollegeTakatsukiJapan
  2. 2.Department of Pathology, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
  3. 3.Department of Clinical PathologyOsaka Medical CollegeTakatsukiJapan
  4. 4.Particle Radiation Oncology Research Center, Research Reactor InstituteKyoto UniversityKumatoriJapan

Personalised recommendations