Pathology & Oncology Research

, Volume 18, Issue 3, pp 681–690 | Cite as

Angiogenesis and Survival in Patients with Myelodysplastic Syndrome

  • Aleksandar Savic
  • Vesna Cemerikic-Martinovic
  • Sinisa Dovat
  • Nebojsa Rajic
  • Ivana Urosevic
  • Borivoj Sekulic
  • Vanja Kvrgic
  • Stevan Popovic


Angiogenesis has been implicated in the pathogenesis and prognosis of myelodysplastic syndrome (MDS). In this study, we investigated the relationship between microvessel density (MVD), vascular endothelial growth factor (VEGF) expression, common morphological and clinical factors, and survival in patients with MDS. We examined the MVD of paraffin-embedded bone marrow sections from 70 MDS patients and 31 controls. VEGF expression was determined in 50 patients and 20 controls. The median MVD in MDS patients was significantly higher than that in controls (p = 0.025), whereas there was no difference in VEGF expression between MDS patients and controls. In univariate analysis, increased MVD was associated with a shorter survival time (p = 0.023). However, in multivariate analysis, MVD was not an independent predictor of survival. The VEGF expression did not influence survival in univariate analysis. Survival was independently influenced by platelet count (p = 0.0073), cytogenetic risk category (p = 0.022), and transfusion dependence (p = 0.0073). Neither MVD nor VEGF expression were predictors for progression to acute myeloid leukemia in univariate analysis. Progression to acute myeloid leukemia was independently influenced only by the cytogenetic risk category (p = 0.022). This study confirmed increased MVD in MDS. It does not support an independent prognostic role of angiogenesis in MDS.


Myelodysplastic syndrome Angiogenesis Microvessel density VEGF Survival Prognosis 



Atypical localization of immature progenitor cells


Acute myeloid leukemia


Acute myeloid leukemia with myelodysplasia-related changes


chronic myelomonocytic leukemia




hematoxylin and eosin


International Prognostic Scoring System


Myelodysplastic syndrome


Microvessel density


Refractory anemia


Refractory anemia with excess blasts


Refractory anemia with excess blasts in transformation


Refractory anemia with ringed sideroblasts


Refractory cytopenia with multilineage dysplasia


Refractory cytopenia with unilineage dysplasia


Vascular endothelial growth factor


World Health Organization


WHO classification-based prognostic scoring system



We wish to thank Dusan Pejin and Nada Vuckovic for their support.

Contributors: All authors have actively participated to the study and approved the manuscript. Aleksandar Savic designed the research, collected patient information, analyzed and interpreted the data, and wrote the manuscript. Vesna Cemerikic-Martinovic contributed control patients, reviewed bone marrow histology. Sinisa Dovat provided critical revisions. Borivoje Sekulic and Vanja Kvrgic collected patient information. Ivana Urosevic and Nebojsa Rajic collected patient information, and contributed patients. Stevan Popovic contributed patients.

Conflicts of interest statement

There are no conflicts of interests to disclose.


  1. 1.
    Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid, and other disease. Nat Med 1:27–31PubMedCrossRefGoogle Scholar
  2. 2.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186PubMedCrossRefGoogle Scholar
  3. 3.
    Padro T, Ruiz S, Bieker R et al (2000) Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood 95:2637–2644PubMedGoogle Scholar
  4. 4.
    Hussong JW, Rodgers JM, Shami PJ (2000) Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 95:309–313PubMedGoogle Scholar
  5. 5.
    Lundberg LG, Lerner R, Sundelin P et al (2000) Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity. Am J Pathol 157:15–19PubMedCrossRefGoogle Scholar
  6. 6.
    Mesa RA, Hanson CA, Rajkumar SV et al (2000) Evaluation and clinical correlations of bone marrow angiogenesis in myelofibrosis with myeloid metaplasia. Blood 96:3374–3380PubMedGoogle Scholar
  7. 7.
    Peterson L, Kini AR (2001) Angiogenesis is increased in B-cell chronic lymphocytic leukemia. Blood 97:2529PubMedCrossRefGoogle Scholar
  8. 8.
    Rajkumar SV, Leong T, Roche PC et al (2000) Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 6:3111–3116PubMedGoogle Scholar
  9. 9.
    Aguayo A, Kantarjian H, Manshouri T et al (2000) Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 96:2240–2245PubMedGoogle Scholar
  10. 10.
    Pruneri G, Bertolini F, Soligo D et al (1999) Angiogenesis in myelodysplastic syndromes. Br J Cancer 81:1398–1401PubMedCrossRefGoogle Scholar
  11. 11.
    Korkolopoulou P, Apostolidou E, Pavlopoulos PM et al (2001) Prognostic evaluation of the microvascular network in myelodysplastic syndromes. Leukemia 15:1369–1376PubMedCrossRefGoogle Scholar
  12. 12.
    Lundberg LG, Hellstrom-Lindberg E, Kanter-Lewensohn L et al (2006) Angiogenesis in relation to clinical stage, apoptosis and prognostic score in myelodysplastic syndromes. Leuk Res 30:247–253PubMedCrossRefGoogle Scholar
  13. 13.
    Alexandrakis MG, Passam FH, Pappa CA et al (2005) Relation between bone marrow angiogenesis and serum levels of angiogenin in patients with myelodysplastic syndromes. Leuk Res 29:41–46PubMedCrossRefGoogle Scholar
  14. 14.
    Gale NW, Yancopoulos GD (1999) Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 13:1055–1066PubMedCrossRefGoogle Scholar
  15. 15.
    Bellamy WT, Richter L, Sirjani D et al (2001) Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood 97:1427–1434PubMedCrossRefGoogle Scholar
  16. 16.
    Wimazal F, Krauth MT, Vales A et al (2006) Immunohistochemical detection of vascular endothelial growth factor (VEGF) in the bone marrow in patients with myelodysplastic syndromes: correlation between VEGF expression and the FAB category. Leuk Lymphoma 47:451–460PubMedCrossRefGoogle Scholar
  17. 17.
    Bennett JM, Catovsky D, Daniel MT et al (1982) Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189–199PubMedGoogle Scholar
  18. 18.
    Brunning RD, Orazi A, Germing U et al (2008) Myelodysplastic syndromes/Neoplasms, overview. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. IARC, Lyon, pp 88–93Google Scholar
  19. 19.
    Greenberg P, Cox C, LeBeau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088PubMedGoogle Scholar
  20. 20.
    Thiele J, Kvasnicka HM, Facchetti F et al (2005) European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90:1128–1132PubMedGoogle Scholar
  21. 21.
    Tricot G, De Wolf-Peeters C, Vlietinck R et al (1984) Bone marrow histology in myelodysplastic syndromes. II. Prognostic value of abnormal localization of immature precursors in MDS. Br J Haematol 58:217–225PubMedCrossRefGoogle Scholar
  22. 22.
    Perez-Atayde AR, Sallan SE, Tedrow U et al (1997) Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol 150:815–821PubMedGoogle Scholar
  23. 23.
    Keith T, Araki Y, Ohyagi M et al (2007) Regulation of angiogenesis in the bone marrow of myelodysplastic syndromes transforming to overt leukaemia. Br J Haematol 137:206–215PubMedCrossRefGoogle Scholar
  24. 24.
    Malcovati L, Germing U, Kuendgen A et al (2007) Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 25:3503–3510PubMedCrossRefGoogle Scholar
  25. 25.
    Verstovsek S, Estey E, Manshouri T et al (2002) Clinical relevance of vascular endothelial growth factor receptors 1 and 2 in acute myeloid leukaemia and myelodysplastic syndrome. Br J Haematol 118:151–156PubMedCrossRefGoogle Scholar
  26. 26.
    Gabrilove J (2001) Angiogenic growth factors: autocrine and paracrine regulation of survival in hematologic malignancies. Oncologist 6(Suppl 5):4–7PubMedCrossRefGoogle Scholar
  27. 27.
    Dias S, Hattori K, Zhu Z et al (2000) Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest 106:511–521PubMedCrossRefGoogle Scholar
  28. 28.
    Padro T, Bieker R, Ruiz S et al (2002) Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR(VEGFR-2) in the bone marrow of patients with acute myeloid leukemia. Leukemia 16:1302–1310PubMedCrossRefGoogle Scholar
  29. 29.
    Germing U, Hildebrandt B, Pfeilstöcker M et al (2005) Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS). Leukemia 19:2223–2231PubMedCrossRefGoogle Scholar
  30. 30.
    Sperr WR, Wimazal F, Kundi M et al (2001) Survival analysis and AML development in patients with de novo myelodysplastic syndromes: comparison of six different prognostic scoring systems. Ann Hematol 80:272–277PubMedCrossRefGoogle Scholar
  31. 31.
    Horny HP, Sotlar K, Valent P (2007) Diagnostic value of histology and immunohistochemistry in myelodysplastic syndromes. Leuk Res 31:1609–1616PubMedCrossRefGoogle Scholar
  32. 32.
    Valent P, Horny HP, Bennett JM et al (2007) Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: consensus statements and report from a working conference. Leuk Res 31:727–736PubMedCrossRefGoogle Scholar
  33. 33.
    Patsouris E, Katsarou O, Korkolopoulou P et al (2004) Increased microvascular network in bone marrow of HIV-positive haemophilic patients. HIV Med 5:18–25PubMedCrossRefGoogle Scholar
  34. 34.
    List A, Dewald G, Bennett J et al (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355:1456–1465PubMedCrossRefGoogle Scholar
  35. 35.
    Raza A, Reeves JA, Feldman EJ et al (2008) Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 111:86–93PubMedCrossRefGoogle Scholar
  36. 36.
    Musto P (2004) Thalidomide therapy for myelodysplastic syndromes: current status and future perspectives. Leuk Res 28:325–332PubMedCrossRefGoogle Scholar
  37. 37.
    Giles FJ, Stopeck AT, Silverman LR et al (2003) SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood 102:795–801PubMedCrossRefGoogle Scholar
  38. 38.
    Giles FJ, Bellamy WT, Estrov Z et al (2006) The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Leuk Res 30:801–811PubMedCrossRefGoogle Scholar
  39. 39.
    Oh ST, Gotlib J (2008) Antiangiogenic therapy in myelodysplastic syndromes: is there a role? Curr Hematol Malig Rep 3:10–18PubMedCrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2012

Authors and Affiliations

  • Aleksandar Savic
    • 1
  • Vesna Cemerikic-Martinovic
    • 2
  • Sinisa Dovat
    • 3
  • Nebojsa Rajic
    • 1
  • Ivana Urosevic
    • 1
  • Borivoj Sekulic
    • 1
  • Vanja Kvrgic
    • 1
  • Stevan Popovic
    • 1
  1. 1.Clinic of HematologyClinical Center of Vojvodina, Faculty of MedicineNovi SadSerbia
  2. 2.Pathohistology Laboratory BeolabBelgradeSerbia
  3. 3.College of Medicine, Milton S. Hershey Medical Center, Children’s Hospital, Department of Pediatrics, H085, Division of Pediatric Hematology/OncologyPennsylvania State UniversityHersheyUSA

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