Abstract
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.
Similar content being viewed by others
Abbreviations
- ALIP:
-
Atypical localization of immature progenitor cells
- AML:
-
Acute myeloid leukemia
- AML-MRC:
-
Acute myeloid leukemia with myelodysplasia-related changes
- CMML:
-
chronic myelomonocytic leukemia
- FAB:
-
French-American-British
- H&E:
-
hematoxylin and eosin
- IPSS:
-
International Prognostic Scoring System
- MDS:
-
Myelodysplastic syndrome
- MVD:
-
Microvessel density
- RA:
-
Refractory anemia
- RAEB:
-
Refractory anemia with excess blasts
- RAEB-T:
-
Refractory anemia with excess blasts in transformation
- RARS:
-
Refractory anemia with ringed sideroblasts
- RCMD:
-
Refractory cytopenia with multilineage dysplasia
- RCUD:
-
Refractory cytopenia with unilineage dysplasia
- VEGF:
-
Vascular endothelial growth factor
- WHO:
-
World Health Organization
- WPSS:
-
WHO classification-based prognostic scoring system
References
Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid, and other disease. Nat Med 1:27–31
Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186
Padro T, Ruiz S, Bieker R et al (2000) Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood 95:2637–2644
Hussong JW, Rodgers JM, Shami PJ (2000) Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 95:309–313
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 157:15–19
Mesa RA, Hanson CA, Rajkumar SV et al (2000) Evaluation and clinical correlations of bone marrow angiogenesis in myelofibrosis with myeloid metaplasia. Blood 96:3374–3380
Peterson L, Kini AR (2001) Angiogenesis is increased in B-cell chronic lymphocytic leukemia. Blood 97:2529
Rajkumar SV, Leong T, Roche PC et al (2000) Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 6:3111–3116
Aguayo A, Kantarjian H, Manshouri T et al (2000) Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 96:2240–2245
Pruneri G, Bertolini F, Soligo D et al (1999) Angiogenesis in myelodysplastic syndromes. Br J Cancer 81:1398–1401
Korkolopoulou P, Apostolidou E, Pavlopoulos PM et al (2001) Prognostic evaluation of the microvascular network in myelodysplastic syndromes. Leukemia 15:1369–1376
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 30:247–253
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 29:41–46
Gale NW, Yancopoulos GD (1999) Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 13:1055–1066
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 97:1427–1434
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 47:451–460
Bennett JM, Catovsky D, Daniel MT et al (1982) Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189–199
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 88–93
Greenberg P, Cox C, LeBeau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088
Thiele J, Kvasnicka HM, Facchetti F et al (2005) European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90:1128–1132
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 58:217–225
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 150:815–821
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 137:206–215
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 25:3503–3510
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 118:151–156
Gabrilove J (2001) Angiogenic growth factors: autocrine and paracrine regulation of survival in hematologic malignancies. Oncologist 6(Suppl 5):4–7
Dias S, Hattori K, Zhu Z et al (2000) Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest 106:511–521
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 16:1302–1310
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 19:2223–2231
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 80:272–277
Horny HP, Sotlar K, Valent P (2007) Diagnostic value of histology and immunohistochemistry in myelodysplastic syndromes. Leuk Res 31:1609–1616
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 31:727–736
Patsouris E, Katsarou O, Korkolopoulou P et al (2004) Increased microvascular network in bone marrow of HIV-positive haemophilic patients. HIV Med 5:18–25
List A, Dewald G, Bennett J et al (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355:1456–1465
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 111:86–93
Musto P (2004) Thalidomide therapy for myelodysplastic syndromes: current status and future perspectives. Leuk Res 28:325–332
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 102:795–801
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 30:801–811
Oh ST, Gotlib J (2008) Antiangiogenic therapy in myelodysplastic syndromes: is there a role? Curr Hematol Malig Rep 3:10–18
Acknowledgments
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Savic, A., Cemerikic-Martinovic, V., Dovat, S. et al. Angiogenesis and Survival in Patients with Myelodysplastic Syndrome. Pathol. Oncol. Res. 18, 681–690 (2012). https://doi.org/10.1007/s12253-012-9495-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12253-012-9495-y