Chronic idiopathic myelofibrosis: Independent prognostic importance of bone marrow microvascular density evaluated by CD105 (endoglin) immunostaining

Department of Pathology and Laboratory Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States
Modern Pathology (Impact Factor: 6.19). 01/2005; 17(12):1513-20. DOI: 10.1038/modpathol.3800224
Source: PubMed


Microvascular density (MVD) is substantially increased in bone marrow biopsies of patients with chronic idiopathic myelofibrosis (CIMF). CD105, a useful molecule for assessing MVD in various malignancies, is preferentially expressed by recently formed microvessels. Increased serum-soluble CD105 in patients with chronic myeloproliferative disorders, including CIMF, was documented. CD105 MVD has not so far been investigated in CIMF: to this end, the results in 55 patients with CIMF and 21 controls were compared with the conventional CD34 immunostaining as well as traditional histological and clinical disease features. The MVD mean values estimated by both CD105 and CD34 were significantly higher in CIMF patients than in controls (P<0.00001). In addition, the proportion of CD105-positive megakaryocytes was significantly higher in CIMF than in controls (P<0.0001). A degree of reticulin fibrosis >2 correlated with increased CD105 MVD (P=0.05). A multivariate analysis confirmed that CD105-positive MVD was an independent adverse prognosticator. This study demonstrates that while MVD, as assessed by both CD34 and CD105 immunostaining, is significantly increased in CIMF, only CD105-determined MVD correlates with the degree of fibrosis and is prognostically relevant. These findings provide a rationale for the investigational use of anti-CD105-targeted drugs in CIMF.

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Available from: Giuseppe Viale, Jun 15, 2014
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    • "The available data on angiogenesis and expression of VEGF and its receptors in the bone marrow of patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN) suggest that MVD is increased, especially in primary myelofibrosis (PMF), and that increased angiogenesis might inversely correlate with survival [55-58]. In a recent study, we found a significantly increased MVD and VEGF expression in MPN compared to controls especially in cases with high JAK2-V617F mutant allele burdens [17]. "
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    ABSTRACT: New blood vessel formation (angiogenesis) is not only essential for the growth of solid tumors but there is also emerging evidence that progression of hematological malignancies like multiple myeloma, acute leukemias, and myeloproliferative neoplasms, also depends on new blood vessel formation. Anti-angiogenic strategies have become an important therapeutic modality for solid tumors. Several anti-angiogenic agents targeting angiogenesis-related pathways like monoclonal antibodies, receptor tyrosine kinase inhibitors, immunomodulatory drugs, and proteasome inhibitors have been entered clinical trials or have been already approved for the treatment of hematological malignancies as well and in some instances these pathways have emerged as promising therapeutic targets. This review summarizes recent advances in the basic understanding of the role of angiogenesis in hematological malignancies and clinical trials with novel therapeutic approaches targeting angiogenesis.
    Full-text · Article · Jun 2010 · Journal of Angiogenesis Research
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    • "g . Lundberg et al , 2000 ; Ponzoni et al , 2004 ; Zetterberg et al , 2004 ; Steurer et al , 2007 ) . An important new aspect of our study is the significant differences found in the CD105 - MVD of the MPN group compared to controls . "
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    ABSTRACT: Data on angiogenesis in the bone marrow of BCR-ABL1-negative myeloproliferative neoplasm (MPN) patients suggest an increase of the microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression, but relations to the JAK2-V617F status remain controversial. We performed immunohistochemical studies of MVD and VEGF-expression in 100 MPN, including 24 essential thrombocythemia- (ET), 46 polycythemia vera- (PV), 26 primary myelofibrosis- (PMF), four myelodysplastic (MDS)/MPN- and 20 control reactive bone marrow cases, and correlated these findings with biological and clinical key data and the JAK2-V617F status. We found significantly increased MVD, particularly that assessed by CD105, and VEGF expression in MPN compared to controls (PMF > PV > MDS/MPN > ET). We observed stronger association between CD105-MVD and VEGF expression, fibrosis, and JAK2-V617F mutant allele burden, compared to CD34-MVD. MVD was strongly increased in MPN with high JAK2-V617F mutant allele burden. Our study highlights the importance of newly formed CD105+ vessels in the bone marrow of MPN patients, and indicates that assessment of CD105-MVD better reflects angiogenic activity in MPN. In addition, it provides evidence that despite the fact that angiogenesis is generally independent of the JAK2-V617F status in MPN, new vessel formation might be linked to Jak2 effects in some cases with high JAK2-V617F mutant allele burden.
    Full-text · Article · May 2009 · British Journal of Haematology
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    • "From a clinical standpoint, the assessment of MVD may provide useful prognostic information for survival in patients with PMF (Mesa et al, 2000; Ponzoni et al, 2004). The presence of angiogenesis in PMF represents the rationale for treating these patients with anti-angiogenetic drugs, such as thalidomide (Elliott et al, 2002; Mesa et al, 2003) or lenalidomide (Tefferi et al, 2006a). "
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    ABSTRACT: Philadelphia-negative chronic myeloproliferative disorders (CMD) include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Angiogenesis is critical in the pathogenesis of PMF. We studied angiogenesis in 115 patients with CMD (23 PV, 24 ET, 46 PMF, 12 post-PV and 10 post-ET myelofibrosis) by assessment of microvessel density (MVD) in bone marrow (BM). Kruskall-Wallis analysis of variance showed that patients with PMF had significantly higher values of MVD than those with PV (P < 0.001), ET (P < 0.001) and controls (P < 0.001). Mann-Whitney U-test demonstrated that patients with PMF at the prefibrotic stage had significantly higher MVD values than those with ET (P = 0.02). Patients with post-PV myelofibrosis showed significantly higher MVD values than those with PV (P < 0.001), as did patients with post-ET myelofibrosis compared with ET (P < 0.001). In patients with CMD, the multivariate generalized linear regression model showed that the JAK2 (V617F) mutational burden (P = 0.01), serum lactate dehydrogenase level (P = 0.003), and anaemia (P < 0.001) independently correlated with MVD. In summary, this study indicates that assessment of BM angiogenesis, as measured by MVD, may be a useful additional tool in the histopathological definition of CMD.
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