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Expression of VEGF and microvessel density in patients with multiple myeloma: clinical and prognostic significance

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Abstract

The conflicting data are reported on the clinical significance of VEGF deregulation and intensity of angiogenesis in multiple myeloma. The aim of this study was to evaluate the incidence and prognostic significance of VEGF expression and microvessel density (MVD) in multiple myeloma, as well as the relationship of their expression with selected clinical data, histological features, and proliferative activity of myeloma cells. We analyzed bone marrow biopsy specimens obtained from 59 patients with newly diagnosed multiple myeloma. Expression of VEGF and MVD was analyzed using standard immunohistochemical method (antibodies against VEGF and CD34, respectively) on B5-fixed and routinely processed paraffin-embedded bone marrow specimens. MVD was estimated by counting the number of microvessels in three “hot spots” at 400× magnification. VEGF immunoreactivity was estimated on the basis of intensity and percentage of positive plasma cells. VEGF was expressed in 47/59 (79.7%) specimens. There was no significant correlation between VEGF overexpression and age, clinical stage, the extent of osteolytic lesions, type of monoclonal protein, hemoglobin concentration, platelet count, serum concentration of creatinine, calcium, and albumins, the extent of bone marrow infiltration, histological grade, and proliferative activity index (measured with Ki-67 immunoreactivity). No significant difference was observed regarding the overall survival between VEGF-positive and VEGF-negative patients (29 vs. 34 months, P = 0.8). Median MVD was 15, ranging from 1 to 89 microvessels per three “hot spots”. There was significant correlation between MVD and histological grade, the extent of bone marrow infiltration, and proliferative activity. Significant difference was observed regarding the overall survival between patients with low MVD (<15) and patients with high MVD (≥15) (46 vs. 22 months, P = 0.009; univariate analysis). The results of this study did not reveal clinical significance of VEGF overexpression in multiple myeloma. On the contrary, the extent of bone marrow angiogenesis is an indicator of biological potency of malignant clone and a predictor of poor survival in newly diagnosed myeloma.

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References

  1. Pratt G. Molecular aspects of multiple meloma. Mol Pathol. 2002;55:273–83.

    Article  PubMed  CAS  Google Scholar 

  2. Hallek M, Bergsagel Pl, Anderson KC. Multiple myeloma: increasing evidence for a multistep transformation process. Blood. 1998;91(1):3–21.

    PubMed  CAS  Google Scholar 

  3. Folkman J. Tumor angiogenesis. In: Mendelshon J, Howley PM, Israel MA, Liotta LA, editors. The molecular basis of cancer. Philadelphia: W.B. Saunders; 1995. p. 206–32.

    Google Scholar 

  4. Rajkumar VS, Mesa R, Fonseca R, Shroeder G, Plevak M, Dispenzieri A, et al. Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis. Clin Cancer Res. 2002;8(7):2210–16.

    PubMed  Google Scholar 

  5. Vacca A, Ribatti D. Bone marrow angiogenesis in multiple myeloma. Leukemia. 2006;20(2):193–9.

    Article  PubMed  CAS  Google Scholar 

  6. Rajkumar VS, Leong T, Roche P, Fonseca R, Dispenzieri A, Lacy QM, et al. Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res. 2000;6(3):3111–6.

    PubMed  CAS  Google Scholar 

  7. Sezer O, Niemoller K, Eucker J, Jakob C, Kaufmann O, Zavrski I, et al. Bone marrow microvessel density is a prognostic factor for survival in patients with multiple myeloma. Ann Hematol. 2001;79(10):574–7.

    Article  Google Scholar 

  8. Pruneri G, Ponzoni M, Ferreri A, Decarli N, Tresoldi M, Raggi F, et al. Microvessel density, a surrogate marcer of angiogenesis, is significantly related to survival in multiple myeloma patients. Br J Hematol. 2002;118(3):817–20.

    Article  Google Scholar 

  9. Podar K, Anderson K. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implication. Blood. 2005;105(4):1383–95.

    Article  PubMed  CAS  Google Scholar 

  10. Chronic Leukemia-Myeloma Task Force. Guidelines for protocol studies. Cancer Chemother Rep. 1973;4:145–53.

    Google Scholar 

  11. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Cancer. 1875;36:842–54.

    Article  Google Scholar 

  12. Sailer M, Vykoupil KF, Peest D, Coldewey R, Deicher H, Georgii A. Prognostic relevance of a histologic classification system applied in bone marrow biopsies from patients with multiple myeloma: a histopathological evaluation of biopsies from 153 untreated patients. Eur J Haematol. 1995;54:137–46.

    Article  PubMed  CAS  Google Scholar 

  13. Bartl R, Frisch B, Burkhardt R, Fateh-Moghadam AF, Mahl G, Gierster P, et al. Bone marow histology in myeloma: its importance in diagnosis, prognosis, classification and staging. Br J Haematol. 1982;51:361–75.

    Article  PubMed  CAS  Google Scholar 

  14. Remmele W, Stenger HE. Vorschlag zur einheitlichen definition eines immunoreactiven score (IRS) fuer den immunohistochemischen oestrogenrezeptor-nachweis (ER-ICA) im mammakarzinomgewebe. Pathologe. 1987;8(3):138–40.

    PubMed  CAS  Google Scholar 

  15. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis correlation in invasive breast carcinoma. N Engl J Med. 1991;324(1):1–8.

    PubMed  CAS  Google Scholar 

  16. Lai MD, Medeiros LJ, Wilson CS, Sun NC, Koo C, McCourty A, et al. Expression of the cell-cycle-related proteins E2F-1, p53, mdm-2, p21waf−1, and Ki-67 in multiple myeloma: correlation with cyclin-D1 immunoreactivity. Mod Pathol. 1998;11(7):642–7.

    PubMed  CAS  Google Scholar 

  17. Vacca A, Ria R, Ribatti D, Semeraro F, Djonov V, Raimondo F, et al. A paracrine loop in the vascular ebnothelial growth factor pathway triggers tumor angiogenesis and growth in multiple myeloma. Haematologica. 2003;88(2):176–85.

    PubMed  CAS  Google Scholar 

  18. Choi JH, Ahn MJ, Jang SJ, Park CK, Park YW, Oh HS, et al. Absence of clinical prognostic value of vascular endothelial growth factor and microvessel density in multiple myeloma. Int J Hematol. 2002;76(5):460–4.

    Article  PubMed  CAS  Google Scholar 

  19. Bellamy WT. Expression of vascular endothelial growth factor and its receptors in multiple myeloma and other hematopoietic malignancies. Semin Oncol. 2001;28(6):551–9.

    Article  PubMed  CAS  Google Scholar 

  20. Xu JL, Lai R, Kinoshita T, Nakashima N, Nagasaka T. Proliferation, apoptosis, and intramural vascularitis in multiple myeloma: correlation with the clinical stage and cytological stage and cytological grade. J Clin Pathol. 2002;55(7):530–4.

    PubMed  CAS  Google Scholar 

  21. Ribas C, Colleoni GVB, Silva MR, Carregoza MJ, Bordin JO. Prognostic significance of vascular endothelial growth factor immunoexpression in the context of adverse standard prognostic factors in multiple myeloma. Eur J Haematol. 2004;73(5):311–7.

    Article  PubMed  CAS  Google Scholar 

  22. Kumar S, Witzig TE, Timm M, Haug J, Wellik L, Fonseca R, et al. Expression of VEGF and its receptors by myeloma cells. Leukemia. 2003;17(10):2025–31.

    Article  PubMed  CAS  Google Scholar 

  23. Kumar S, Witzig TE, Thompson MA, Haug J, Timm T, Wellik L, et al. Expression of angiogenic cytokines by plasma cells: a comparison of MGUS, smoldering myeloma and newly diagnosed symptomatic myeloma. Blood. 2002;100:807a (abstract).

    Google Scholar 

  24. Uneda S, Matsuno F, Sonoki T, Tniguchi I, Kawano F, Hata H. Expression of vascular endothelial growth factor and angiopoietin-2 in myeloma cells. Hematologica. 2003;88(1):113–5.

    CAS  Google Scholar 

  25. Usnarska-Zubkiewicz L, Mazur G, Wrobel T, Poreba M, Kuliczowski K. Expression of serum vascular endothelial growth factor correlates with clinical outcome in multiple myeloma. Pol Arch Med Wewn. 2003;110(1):719–22.

    PubMed  CAS  Google Scholar 

  26. Jelkmann W. Pitfalls in the measurement of circulating vascular endothelial growth factor. Clin Chem. 2001;47:617–23.

    PubMed  CAS  Google Scholar 

  27. Pruneri G, Bertolini F, Soligo D, Carboni N, Cortelezzi A, Ferrucci PF, et al. Angiogenesis in myelodysplastic syndromes. Br J Cancer. 1999;81:1398–401.

    Article  PubMed  CAS  Google Scholar 

  28. Bhatti SS, Kumar L, Dinda AK, Dawar R. Prognostic value of bone marrow angiogenesis in multiple myeloma: use of light microscopy as well as computerized image analyzer in the assessment of microvessel density and total vascular area in multiple myeloma and its correlation with various clinical, histological and laboratory parameters. Am J Hematol. 2006;81(9):649–56.

    Article  PubMed  Google Scholar 

  29. Kumar S, Gertz MA, Dispenzieri A, Lacy MQ, Wellik LA, Fonseca R, et al. Prognostic value of bone marrow angiogenesis in patients with multiple myeloma undergoing high-dose therapy. Bone Marrow Transplant. 2004;34:235–9.

    Article  PubMed  CAS  Google Scholar 

  30. Vacca A, Ribatti D, Roncali L, Ranieri G, Serio G, Silvestrias F, et al. Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol. 1994;87(3):503–8.

    Article  PubMed  CAS  Google Scholar 

  31. Alexandrakis MG, Passam FH, Dambaki C, Pappa CA, Stathopoulus E. The relationship between bone marrow angiogenesis and the proliferation index Ki-67 in multiple myeloma. J Clin Pathol. 2004;57:856–860.

    Article  PubMed  CAS  Google Scholar 

  32. Dankbar B, Padro T, Leo R, Feldman B, Kropff M, Mesters RM, et al. Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood. 2000;95(8):428–35.

    Google Scholar 

  33. Podar K, Tzu Tai Y, Davies FE, Lenzsch S, Sattler M, Hideshima T, et al. Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood. 2001;98(2):428–35.

    Article  PubMed  CAS  Google Scholar 

  34. Ahn MJ, Park CK, Choi J, Lee WM, Choi Y, Kim IS, et al. Clinical significance of microvessel density in multiple myeloma patients. J Korean Med Sci. 2001;16(1):45–50.

    PubMed  CAS  Google Scholar 

  35. Du W, Hattori Y, Hashiguchi A, Kondoh K, Hozumi N, Sakamoto M, et al. Tumor angiogenesis in the bone marrow of multiple myeloma patients and its alteration by thalidomide treatment. Pathol Int. 2004;54(5):285–94.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Olivera Marković.

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Marković, O., Marisavljević, D., Čemerikić, V. et al. Expression of VEGF and microvessel density in patients with multiple myeloma: clinical and prognostic significance. Med Oncol 25, 451–457 (2008). https://doi.org/10.1007/s12032-008-9066-y

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  • DOI: https://doi.org/10.1007/s12032-008-9066-y

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