Neuropediatrics 2001; 32(2): 75-79
DOI: 10.1055/s-2001-13872
Original Article

Georg Thieme Verlag Stuttgart · New York

High Microvessel Density in Primitive Neuroectodermal Brain Tumors of Childhood

M. A. Grotzer1,2 , R. Wiewrodt3 , Anna J. Janss2 , Huaqing Zhao4 , Avital Cnaan4 , Leslie N. Sutton5 , Lucy B. Rorke6 , P. C. Phillips2
  • 1 University Children's Hospital of Zurich, Zurich, Switzerland
  • 2 Division of Oncology, The Children's Hospital of Philadelphia, PA, USA
  • 3 Division of Pulmonary and Critical Care Medicine, University of Pennsylvania Medical Center, Philadelphia, USA
  • 4 Division of Biostatistics, The Children's Hospital of Philadelphia, PA, USA
  • 5 Division of Neurosurgery, The Children's Hospital of Philadelphia, PA, USA
  • 6 Department of Pathology, The Children's Hospital of Philadelphia, PA, USA
Further Information

Publication History

Publication Date:
31 December 2001 (online)

Microvessel density (MVD), a measure of tumor angiogenesis, has been shown to correlate significantly with overall and progression-free survival outcomes in various cancers including astrocytic brain tumors. To assess if the MVD is an independent prognostic factor in primitive neuroectodermal tumors (PNET) of the central nervous system, formalin-fixed paraffin-embedded tumor sections of 78 children with PNET were studied by CD34 immunohistochemistry to highlight endothelial cells. Microvessel density was determined in the most active area of neovascularization according to well-established methods. While it was shown that MVD showed considerable inter-tumor variability (median 75; range 20 - 345 microvessels per 0.7 mm2 field), no significant associations were found between MVD and metastasis or survival outcomes. We conclude that many PNETs are highly vascular CNS tumors, indicating potent angiogenic activity. Therefore, these tumors would be good candidates for antiangiogenic strategies. However, MVD determined in the most active area of neovascularization is not a predictor of metastatic potential or survival outcomes in childhood PNET.

References

  • 1 Albright A L, Wisoff J H, Zeltzer P M, Boyett J M, Rorke L B, Stanley P. Effects of medulloblastoma resections on outcome in children: a report from the Children's Cancer Group.  Neurosurgery. 1996;  38 265-271
  • 2 Assimakopoulou M, Stiropoulou-Bonikou G, Maraziotis T, Papdakis N, Varakis I. Microvessel density in brain tumors.  Anticancer Res. 1997;  17 4747-4754
  • 3 Brem S. Angiogenesis and cancer control: from concept to therapeutic trial.  Cancer Control. 1999;  6 436-458
  • 4 Bëlien J AM, Van Diest P J, Baak J PA. Relationship between vascularization and proliferation in invasive breast cancer.  J Pathol. 1999;  189 309-318
  • 5 Cavenee W K, Furnari F B, Nagane M. et al .Diffusely infiltrating astrocytomas. Kleihues P, Cavenee WK Pathology and Genetics of Tumours of the Nervous System. Lyon; IARC Press 2000: 10-21
  • 6 Cohen B H, Zeltzer P M, Boyett J M. Prognostic factors and treatment results for supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: a Children's Cancer Group randomized trial.  J Clin Oncol. 1995;  13 1687-1696
  • 7 Cox D R. Regression models and life-tables.  J R Stat Soc. 1972;  34 187-220
  • 8 De Placido S, Carlomagno C, Ciardiello F, De Laurentiis M, Pepe S, Panico L. et al . Measurement of neovascularization is an independent prognosticator of survival in node-negative breast cancer patients with long-term follow-up.  Clin Cancer Res. 1999;  5 2854-2859
  • 9 Eggert A, Grotzer M A, Ikegaki N, Liu X-G, Evans A E, Brodeur G M. Expression of neurotrophin receptor TrkA inhibits angiogenesis in neuroblastoma.  Med Pediatr Oncol. 2000;  35 569-572
  • 10 Folkman J. Tumor angiogenesis: therapeutic implications.  N Engl J Med. 1971;  285 1182-1186
  • 11 Folkman J. Clinical applications of research on angiogenesis.  N Engl J Med. 1995;  333 1757-1763
  • 12 Folkman J, Watson K, Ingber D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia.  Nature. 1989;  339 58-61
  • 13 Fox S B, Gatter K C, Bicknell R, Going J J, Stanton P, Cooke T G. et al . Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer.  Cancer Res. 1993;  53 4161-4163
  • 14 Garton G R, Schomberg P J, Scheithauer B W, Shaw E G, Ilstrup D M, Blackwell C R. et al . Medulloblastoma-prognostic factors and outcome of treatment: review of the Mayo clinic experience.  Mayo Clin Proc. 1990;  65 1077-1086
  • 15 Gettman M T, Pacelli A, Slezak J, Bergstralh E J, Blute M, Zincke H. et al . Role of microvessel density in predicting recurrence in pathologic stage T3 prostatic adenocarcinoma.  Urology. 1999;  54 479-485
  • 16 Gilbertson R J, Jaros E, Perry R H, Kelly P J, Lunec J, Pearson A DJ. Mitotic percentage index: a new prognostic factor for childhood medulloblastoma.  Eur J Cancer. 1997;  33 609-615
  • 17 Grotzer M A, Janss A J, Fung K-M, Biegel J A, Sutton L N, Rorke L B. et al . TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors.  J Clin Oncol. 2000;  18 1027-1035
  • 18 Grotzer M A, Geoerger B, Janss A J, Zhao H, Rorke L B, Sutton L N. et al . Prognostic significance of Ki-67 (MIB-1) proliferation index in childhood primitive neuroectodermal tumors of the central nervous system.  Med Pediatr Oncol. (in press); 
  • 19 Grotzer M A, Janss A J, Fung K-M, Sutton L N, Zhao H, Trojanowski J Q. et al . Abundance of apoptotic neoplastic cells in diagnostic biopsy samples is not a prognostic factor in childhood primitive neuroectodermal tumors of the central nervous system.  J Pediatr Hematol Oncol. (in press); 
  • 20 Isobe N, Uozumi T, Kurisu K, Kawamoto K. Experimental studies of the antitumor effect of TNP-470 on malignant brain tumors.  Neuropediatrics. 1996;  27 136-142
  • 21 Janss A J, Yachnis A T, Silber J H, Trojanowski J Q, Lee V M, Sutton L N. et al . Glial differentiation predicts poor clinical outcome in primitive neuroectodermal brain tumors.  Ann Neurol. 1996;  39 481-489
  • 22 Kim J YH, Sutton M E, Lu D J, Cho T A, Goumnerova L C, Goritchenko L. et al . Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastoma.  Cancer Res. 1999;  59 711-719
  • 23 Leon S P, Folkerth R D, Black P McL. Microvessel density is a prognostic indicator for patients with astroglial brain tumors.  Cancer. 1996;  77 362-372
  • 24 Li V W, Folkerth R D, Watanabe H, Yu C, Rupnick M, Barnes P. et al . Microvessel count and cerebrospinal fluid basic fibroblast growth factor in children with brain tumours.  Lancet. 1994;  344 82-86
  • 25 Mirabell R, Tolnay M, Bieri S, Probst A, Sappino A, Berchtold W. et al . Pediatric medulloblastoma: prognostic value of p53, bcl-2, Mib-1, and microvessel density.  J Neuro-Oncol. 1999;  45 103-110
  • 26 Nakagawara A, Arima-Nakagawara M, Scavarda N J, Azar C G, Cantor A B, Brodeur G M. Association between high levels of expression of the trk gene and favorable outcome in human neuroblastoma.  N Engl J Med. 1993;  328 847-854
  • 27 Packer R J, Siegel K R, Sutton L N, Evans A E, D'Angio G J, Rorke L B. et al . Efficacy of adjuvant chemotherapy for patients with poor-risk medulloblastoma: a preliminary report.  Ann Neurol. 1988;  24 503-508
  • 28 Packer R J, Sutton L N, Elterman R, Lange B, Goldwein J W, Nicholson H S. et al . Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy.  J Neurosurg. 1994;  81 690-698
  • 29 Scheurlen W G, Schwabe G C, Joos S, Mollenhauer J, Sörensen N, Kühl J. Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome.  J Clin Oncol. 1998;  16 2478-2485
  • 30 Tait D M, Thornton-Jones H, Bloom H JG, Lemerle J, Morris-Jones P. Adjuvant chemotherapy for medulloblastoma: the first multi-center control trial of the International Society of Paediatric Oncology (SIOP I).  Eur J Cancer. 1990;  26 464-469
  • 31 Weidner N. Intratumor microvessel density as a prognostic factor in cancer.  Am J Pathol. 1995;  147 9-19
  • 32 Weidner N. Tumor vascularity and proliferation: clear evidence of a close relationship.  J Pathol. 1999;  189 297-299
  • 33 Weidner N, Semple J P, Welch W R, Folkman J. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma.  N Engl J Med. 1991;  324 1-8
  • 34 Yamazaki K, Abe S, Takekawa H, Sukoh N, Ogura S, Nakajima I. et al . Tumor angiogenesis in human lung adenocarcinoma.  Cancer. 1994;  74 2245-2250
  • 35 Zeltzer P M, Boyett J M, Finlay J L, Albright A L, Rorke L B, Milstein J M. et al . Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study.  J Clin Oncol. 1999;  17 832-845

M. D. Michael A. Grotzer

University Children's Hospital

Steinwiesstrasse 75

8032 Zurich

Switzerland

Email: Michael.Grotzer@kispi.unizh.ch

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