Abstract

CancerVolume 77, Issue 2 p. 362-372 Original ArticleFree Access Microvessel density is a prognostic indicator for patients with astroglial brain tumors Steven P. Leon M.D., Steven P. Leon M.D. Neurosurgical Laboratories and Brain Tumor Center, Brigham and Women's Hospital, Children's Hospital, Dana Farber Cancer Institute, Department of Surgery, Harvard Medical School, Boston, MassachusettsSearch for more papers by this authorRebecca D. Folkerth M.D., Rebecca D. Folkerth M.D. Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital, Department of Pathology, Harvard Medical School, Boston, MassachusettsSearch for more papers by this authorPeter McL. Black M.D. Ph.D., Corresponding Author Peter McL. Black M.D. Ph.D. Neurosurgical Laboratories and Brain Tumor Center, Brigham and Women's Hospital, Children's Hospital, Dana Farber Cancer Institute, Department of Surgery, Harvard Medical School, Boston, MassachusettsBrigham and Women's Hospital, 75 Francis Street, Boston, MA 02115===Search for more papers by this author Steven P. Leon M.D., Steven P. Leon M.D. Neurosurgical Laboratories and Brain Tumor Center, Brigham and Women's Hospital, Children's Hospital, Dana Farber Cancer Institute, Department of Surgery, Harvard Medical School, Boston, MassachusettsSearch for more papers by this authorRebecca D. Folkerth M.D., Rebecca D. Folkerth M.D. Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital, Department of Pathology, Harvard Medical School, Boston, MassachusettsSearch for more papers by this authorPeter McL. Black M.D. Ph.D., Corresponding Author Peter McL. Black M.D. Ph.D. Neurosurgical Laboratories and Brain Tumor Center, Brigham and Women's Hospital, Children's Hospital, Dana Farber Cancer Institute, Department of Surgery, Harvard Medical School, Boston, MassachusettsBrigham and Women's Hospital, 75 Francis Street, Boston, MA 02115===Search for more papers by this author First published: 15 January 1996 https://doi.org/10.1002/(SICI)1097-0142(19960115)77:23.0.CO;2-ZCitations: 327AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract BACKGROUND Microvessel density in tumors, a measure of angiogenesis, has been shown to be a prognostic indicator that correlates with an increased risk of metastasis in various epithelial cancers and with overall and relapse free survival in patients with breast cancer. Astrocytic brain tumors, particularly malignant astrocytomas, are recognized to be highly vascular tumors with potent angiogenic activity. However, the prognostic significance of microvessel density in these tumors is not known. METHODS Sections from formalin fixed paraffin embedded tumor tissue from 93 unselected adult patients with supratentorial astrocytic brain tumors were immunostained for factor VIII-related antigen in order to highlight microvessel endothelial cells. Microvessels were counted at 200× and 400× magnification. Microvessel density was graded as 1+ to 4+ on 1 low power field, without knowledge of clinical outcome. Microvessel count and microvessel grade were correlated with postoperative survival using the Cox proportional hazards regression model. The prognostic significance of microvessel count and grade were also compared with established prognostic indicators, including patient age, Karnofsky performance status, and tumor histology using multivariate analyses. RESULTS Both microvessel grade and microvessel count correlated significantly with postoperative survival by univariate analysis in both previously untreated and treated patients. Patients with tumors containing a microvessel Grade of 3+ or 4+ had significantly shorter survival time than patients with a microvessel Grade of 1+ or 2+ (P = 0.0022). Likewise, patients with microvessel counts of 70 or greater had significantly shorter survival than those with microvessel counts of fewer than 70 (P = 0.041). Patient age, Karnofsky performance status, tumor histology, and extent of resection were also correlated with survival by univariate analysis. Microvessel count was further shown to be an independent prognostic indicator by multivariate analyses. There were correlations between microvessel density and patient age and between microvessel density and astrocytic tumor grade. CONCLUSIONS These findings support the importance of microvessel density as a prognostic indicator of postoperative survival of patients with astroglial brain tumors. Regional tumor heterogeneity may limit the use of these techniques for routine pathologic examination. Cancer 1996;77:362-72. References 1 Burger PC, Vogel S, Green SB, Strike TA. Glioblastoma multiforme and anaplastic astrocytoma: pathologic criteria and prognostic implications. Cancer 1985; 56: 1106–11. 10.1002/1097-0142(19850901)56:53.0.CO;2-2 PubMedWeb of Science®Google Scholar 2 Russell DS, Rubinstein LJ. Pathology of tumors of the nervous system. Baltimore: Williams and Wilkins, 1989. Google Scholar 3 Kleihues P, Burger PC, Scheithauer BW. Histological typing of tumors of the central nervous system. 2nd Edition. Berlin: Springer-Verlag, 1993: 11–30. 10.1007/978-3-642-84988-6_3 Google Scholar 4 Sheline GE. Radiation therapy of brain tumors. Cancer 1977; 39: 873–81. 10.1002/1097-0142(197702)39:2+3.0.CO;2-Y PubMedWeb of Science®Google Scholar 5 Bloom HJG. Intracranial tumors: response and resistance to therapeutic endeavors, 1970–1980. Int J Radiat Oncol Biol Phys 1982; 8: 1083–1113. 10.1016/0360-3016(82)90056-6 CASPubMedWeb of Science®Google Scholar 6 Nelson DF, Diener-West M, Weinstein AS, Schoenfield D, Nelson JS, Sause WT, et al. A randomized comparison of misonidazole sensitized radiotherapy plus BCNU and radiotherapy plus BCNU for treatment of malignant glioma after surgery: final report of an RTOG study. Int J Radiat Oncol Biol Phys 1986; 12: 1793–1800. 10.1016/0360-3016(86)90321-4 CASPubMedWeb of Science®Google Scholar 7 Nelson DF, Curran WJ, Scott C, Nelson JS, Weinstein AS, Ahmad K, et al. Hyperfractionated radiation therapy and bischlorethyl nitrosurea in the treatment of malignant glioma: possible advantage observed at 72.0 Gy in 1.2 B.I.D. fractions: report of the radiation therapy oncology group protocol 8302. Int J Radiat Oncol Biol Phys 1993; 25: 193–207. 10.1016/0360-3016(93)90340-2 CASPubMedWeb of Science®Google Scholar 8 Deutch M, Green SB, Strike TA, Burger PC, Robertson JT, Selker RG, et al. Results of a randomized trial comparing BCNU plus radiotherapy, streptozocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following misonidazole plus radiotherapy in the postoperative treatment of malignant glioma. Int J Radiat Oncol Biol Phys 1989; 16: 1389–96. 10.1016/0360-3016(89)90939-5 PubMedWeb of Science®Google Scholar 9 Winger MJ, Macdonald DR, Cairncross JG. Supratentorial anaplastic gliomas in adults: the prognostic importance of extent of resection and prior low-grade glioma. J Neurosurg 1989; 71: 487–93. 10.3171/jns.1989.71.4.0487 CASPubMedWeb of Science®Google Scholar 10 Curran WJ, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ, et al. Recursive partitioning analysis of prognostic factors in three radiation therapy oncology group trials. J Natl Cancer Inst 1993; 85: 704–10. Google Scholar 11 Devaux BC, O'Fallon JR, Kelly PJ. Resection, biopsy, and survival in malignant glial neoplasms: a retrospective study of clinical parameters, therapy and outcome. J Neurosurg 1993; 78: 767–75. 10.3171/jns.1993.78.5.0767 PubMedWeb of Science®Google Scholar 12 Burger PC, Shibata T, Kleihues P. The use of the monoclonal antibody Ki-67 in the identification of proliferating cells: application to surgical neuropathology. Am J Surg Pathol 1986; 10: 611–17. 10.1097/00000478-198609000-00003 PubMedWeb of Science®Google Scholar 13 Hoshino T, Nagashima T, Murovic JA, Wilson CB, Edwards MSB, Gutin PH, et al. In situ cell kinetics studies on human neuroectodermal tumors with bromodeoxyuridine labeling. J Neurosurg 1986; 64: 453–9. 10.3171/jns.1986.64.3.0453 CASPubMedWeb of Science®Google Scholar 14 Labrousse F, Daumas-Duport C, Batorski L, Hoshino T. Histologic grading and bromodeoxyuridine labeling index of astrocytomas: comparative study in a series of 60 cases. J Neurosurg 1991; 75: 202–5. 10.3171/jns.1991.75.2.0202 CASPubMedWeb of Science®Google Scholar 15 Hoshino T, Ahn D, Prados MD, Lamborn K, Wilson CB. Prognostic significance of the proliferative potential of intracranial gliomas measured by bromodeoxyuridine labeling. Int J Cancer 1993; 53: 550–5. 10.1002/ijc.2910530404 CASPubMedWeb of Science®Google Scholar 16 Montine TJ, Vandersteenhoven JJ, Aguzzi A, Boyko OB, Dodge RK, Kerns BJ, et al. Prognostic significance of Ki-67 proliferation index in supratentorial fibrillary astrocytic neoplasms. Neurosurgery 1994; 34: 674–9. 10.1227/00006123-199404000-00016 CASPubMedWeb of Science®Google Scholar 17 Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 1972; 175: 409–416. 10.1097/00000658-197203000-00014 CASPubMedWeb of Science®Google Scholar 18 Hobson B, Denekamp J. Endothelial proliferation in tumors and normal tissues: continuous labelling studies. Br J Cancer 1984; 49: 405–13. 10.1038/bjc.1984.66 CASPubMedWeb of Science®Google Scholar 19 Findlay JK. Angiogenesis in reproductive tissues. J Endocrinol 1986; 111: 357–366. 10.1677/joe.0.1110357 CASPubMedWeb of Science®Google Scholar 20 Folkman J, Klagsbrun M. Angiogenic factors. Science 1987; 235: 442. 10.1126/science.2432664 CASPubMedWeb of Science®Google Scholar 21 Gimbrone MA, Leapman S, Cotran RS, Folkman J. Tumor dormancy in vivo by prevention of neovascularization. J Exp Med 1972; 136: 261–76. 10.1084/jem.136.2.261 CASPubMedWeb of Science®Google Scholar 22 Gimbrone MA, Cotran RS, Leapman S, Folkman J. Tumor growth neovascularization: an experimental model using rabbit cornea. J Natl Cancer Inst 1974; 52: 413–27. 10.1093/jnci/52.2.413 Google Scholar 23 Folkman J, Watson K, Ingber D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 1989; 339: 58–61. 10.1038/339058a0 CASPubMedWeb of Science®Google Scholar 24 Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990; 82: 4–6. 10.1093/jnci/82.1.4 CASPubMedWeb of Science®Google Scholar 25 Weidner N, Semple JP, Welch WR, Folkman J. Tumor Angiogenesis and Metastasis–correlation in invasive breast carcinoma. N Engl J Med 1991; 324: 1–8. 10.1056/NEJM199101033240101 CASPubMedWeb of Science®Google Scholar 26 Larsen NS. Angiogenesis research yields new approaches to cancer treatment and prognosis. J Natl Cancer Inst 1993; 85: 1629–30. 10.1093/jnci/85.20.1629 CASPubMedWeb of Science®Google Scholar 27 Chodak GW, Hospelhorn V, Judge SM, Mayforth R, Koeppen H, Sasse J. Increased levels of fibroblast growth factor-like activity in urine from patients with bladder or kidney cancer. Cancer Res 1988; 48: 2083–8. CASPubMedWeb of Science®Google Scholar 28 Fujimoto K, Ichimori Y, Kakizoe T, Okajima E, Sakamoto H, Sugimura T, et al. Increased serum levels of basic fibroblast growth factor in patients with renal cell carcinoma. Biochem Biophys Res Commun 1991; 180: 386–92. 10.1016/S0006-291X(05)81305-1 CASPubMedWeb of Science®Google Scholar 29 Li V, Watanabe H, Yu C. Cerebrospinal fluid from pediatric brain tumor patients contains a mitogen for capillary endothelial cells. Mol Biol Cell 1992; 3(Suppl): 235a, 1360A. Google Scholar 30 Nguyen M, Watanabe H, Budson A, Richie JP, Hayes DF, Folkman J. Basic fibroblast growth factor is elevated in the urine of patients with a wide variety of neoplasms. Mol Biol Cell 1992; 3(Suppl): 234a, 1358A. Google Scholar 31 Watanabe H, Nguyen M, Schizer M, Li V, Hayes DF, Sallan S, et al. Basic fibroblast growth factor in human serum: a prognostic test for breast cancer. Mol Biol Cell 1992; 3(Suppl): 234a, 1359A. Google Scholar 32 Nguyen M, Watanabe H, Budson A, Richie JP, Folkman J. Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of bladder cancer patients. J Natl Cancer Inst 1993; 85: 241–2. 10.1093/jnci/85.3.241 PubMedWeb of Science®Google Scholar 33 Soutter AD, Nguyen M, Watanabe H, Folkman J. Basic fibroblast growth factor secreted by an animal tumor is detectable in urine. Cancer Res 1993; 53: 5297–9. CASPubMedWeb of Science®Google Scholar 34 Li VW, Folkerth RD, Watanabe H, Channing Y, Rupnick M, Barnes P, et al. Basic fibroblast growth factor in the cerebrospinal fluid of children with brain tumors–correlation with microvessel count in the tumor. Lancet 1994; 344: 82–6. 10.1016/S0140-6736(94)91280-7 PubMedWeb of Science®Google Scholar 35 Srivastava A, Laidler P, Davies RP, Horgan K, Hughes LE. The prognostic significance of tumor vascularity in intermediate-thickness (0.76–4.0 mm thick) skin melanoma: a quantitative histologic study. Am J Pathol 1988; 133: 419–23. CASPubMedWeb of Science®Google Scholar 36 Bosari S, Lee AKC, DeLellis RA, Wiley BD, Heatley GJ, Silverman ML. Microvessel quantitation and prognosis in invasive breast carcinoma. Hum Pathol 1992; 23: 755–61. 10.1016/0046-8177(92)90344-3 CASPubMedWeb of Science®Google Scholar 37 Horak E, Leek R, Klenk N, LeJeune S, Smith K, Stuart N, et al. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 1992; 340: 1120–4. 10.1016/0140-6736(92)93150-L CASPubMedWeb of Science®Google Scholar 38 Macchiarini P, Fontanini G, Hardin MJ, Squartini F, Angeletti CA. Relation of neovascularization to metastasis of non-small-cell lung cancer. Lancet 1992; 340: 145–6. 10.1016/0140-6736(92)93217-B CASPubMedWeb of Science®Google Scholar 39 Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, et al. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 1992; 84: 1875–87. 10.1093/jnci/84.24.1875 PubMedWeb of Science®Google Scholar 40 Toi M, Kashitani J, Tominaga T. Tumor angiogenesis is an independent prognostic indicator in primary breast carcinoma. Int J Cancer 1993; 55: 371–374. 10.1002/ijc.2910550305 CASPubMedWeb of Science®Google Scholar 41 Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 1993; 143: 401–9. CASPubMedWeb of Science®Google Scholar 42 Brem S, Cotran R, Folkman J. Tumor angiogenesis: a quantitative method for histologic grading. J Natl Cancer Inst 1972; 48: 347–56. CASPubMedWeb of Science®Google Scholar 43 Brem S. The role of vascular proliferation in the growth of brain tumors. Clin Neurosurg 1976; 23: 440–53. 10.1093/neurosurgery/23.CN_suppl_1.440 CASPubMedGoogle Scholar 44 Brem H, Tamargo RJ, Guerin C, Brem SS, Brem H. Brain tumor angiogenesis. Mount Kisco: Futura Publishing Company, Inc., 1988: 89–102. Web of Science®Google Scholar 45 Burger PC, Scheithauer BW, Vogel FS. Brain tumors. In surgical pathology of the nervous system and its coverings. 3rd edition. New York: Churchill Livingstone, 1991: 193–437. Web of Science®Google Scholar 46 Daumas-Duport C, Scheithauer B, O'Fallon J, Kelly P. Grading of astrocytomas: a simple and reproducible method. Cancer 1988; 62: 2152–65. 10.1002/1097-0142(19881115)62:103.0.CO;2-T CASPubMedWeb of Science®Google Scholar 47 Pinkus GS, Etheridge CL, O'Connor EM. Are keratin proteins a better tumor marker than epithelial membrane antigen?: a comparative immunohistochemical study of various paraffin-embedded neoplasms using monoclonal and polyclonal antibodies. Am J Clin Pathol 1986; 85: 269–77. 10.1093/ajcp/85.3.269 CASPubMedWeb of Science®Google Scholar 48 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–81. 10.1002/cncr.21979 CASWeb of Science®Google Scholar 49 Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163–70. CASPubMedGoogle Scholar 50 Cox DR. Regression models and life-tables (with discussion). J Roy Soc Stat (B) 1972; 34: 187–220. 10.1111/j.2517-6161.1972.tb00899.x Google Scholar 51 Peduzzi PN, Hardy RJ, Holford TR. A stepwise variable selection for nonlinear regression models. Biometrics 1980; 36: 511–6. 10.2307/2530219 CASPubMedWeb of Science®Google Scholar 52 Glantz MJ, Burger PC, Herndon II JE, Friedman AH, Cairncross JG, Vick NA, et al. Influence of the type of surgery on the histologic diagnosis in patients with anaplastic gliomas. Neurology 1991; 41: 1741–4. 10.1212/WNL.41.11.1741 CASPubMedWeb of Science®Google Scholar 53 Fox SB, Gatter KC, Bicknell R, Going JJ, Stanton P, Cooke TG, et al. Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. Cancer Res 1993; 53: 4161–3. CASPubMedWeb of Science®Google Scholar 54 Feigen I, Allen LB, Lipkin L, Gross SW. The endothelial hyperplasia of the cerebral blood vessels with brain tumors, and its sarcomatous transformation. Cancer 1958; 11: 264–77. 10.1002/1097-0142(195803/04)11:23.0.CO;2-D PubMedWeb of Science®Google Scholar 55 Haddad SF, Moore SA, Schelper RL, Goeken JA. Vascular smooth muscle hyperplasia underlies the formation of glomeruloid vascular structures of glioblastoma multiforme. J Neuropathol Exp Neurol 1992; 51: 488–92. 10.1097/00005072-199209000-00002 CASPubMedWeb of Science®Google Scholar 56 von Deimling A, von Ammon K, Schoenfeld D, Wiestler OD, Seizinger BR, Louis DN. Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol 1993; 3: 19–26. 10.1111/j.1750-3639.1993.tb00721.x CASPubMedWeb of Science®Google Scholar 57 Burger PC, Kleihues P. Cytologic composition of the untreated glioblastoma with implications for evaluation of needle biopsies. Cancer 1989; 63: 2014–23. 10.1002/1097-0142(19890515)63:103.0.CO;2-L CASPubMedWeb of Science®Google Scholar 58 Paulus W, Peiffer J. Intratumoral histologic heterogeneity of gliomas. Cancer 1989; 64: 442–7. 10.1002/1097-0142(19890715)64:23.0.CO;2-S CASPubMedWeb of Science®Google Scholar 59 Coons SW, Johnson PC. Regional heterogeneity in the proliferative activity of human gliomas as measured by the Ki-67 labeling index. J Neuropathol Exp Neurol 1993; 52: 609–18. 10.1097/00005072-199311000-00008 CASPubMedWeb of Science®Google Scholar 60 Wesseling P, van der Laak AWM, De Leeww H, Ruiter DJ, Burger PC. Quantitative immunohistological analysis of the microvascular in untreated human glioblastoma multiforme. J Neurosurg 1994; 81: 902–9. 10.3171/jns.1994.81.6.0902 CASPubMedWeb of Science®Google Scholar Citing Literature Volume77, Issue215 January 1996Pages 362-372 ReferencesRelatedInformation