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Aim: Angiogenesis correlates with disease progression in various haematological malignancies. This study investigated the association between microvascular density (MVD) and the Ki-67 proliferation index (Ki-67 PI), bone marrow infiltration, and C reactive protein (CRP) in patients with multiple myeloma., Methods: Bone marrow MVD was examined in 44 biopsies at diagnosis and 15 in plateau phase by immunostaining the endothelial cells with a monoclonal antibody to CD34. The Ki-67 PI was evaluated by a double immunostaining technique using the monoclonal antibodies MIB-1 and CD38., Results: MVD, Ki-67 PI, bone marrow infiltration, and CRP were significantly higher in pretreatment patients than in controls and decreased in patients achieving plateau phase. MVD significantly correlated with Ki-67 PI and infiltration, and Ki-67 correlated with infiltration., Conclusion: In multiple myeloma, apart from being a marker of proliferative activity, Ki-67 is also associated with bone marrow angiogenesis and tumour burden.

There is evidence that angiogenesis plays an important role in the progression of multiple myeloma (MM). Hepatocyte growth factor (HGF) and tumor necrosis factor-alpha (TNF-alpha) are cytokines that potently stimulate angiogenesis. We evaluated the microvascular density (MVD) of bone marrow biopsies (after immunostaining with anti-CD34 antibodies) and serum levels of HGF and TNF-alpha in 43 patients with newly diagnosed MM. Twenty-four of these patients reached a plateau phase after treatment and were reevaluated for MVD, HGF and TNF-alpha. MVD values and serum levels of HGF and TNF-alpha were elevated in newly diagnosed MM patients in comparison with healthy controls. Pre-treatment MVD, HGF and TNF-alpha increased with advancing stage of MM disease. In patients reaching the plateau phase, a significant reduction in MVD, HGF and TNF-alpha levels occurred. A positive correlation was noted between pre-treatment MVD and serum levels of TNF-alpha and lactic dehydrogenase but not with HGF. However, HGF strongly correlated with beta2-microglobulin (beta2M), TNF-alpha and lactate dehydrogenase (LDH). We conclude that angiogenesis in MM, as expressed by the bone marrow MVD and the serum levels of angiogenic molecules such as HGF and TNF-alpha, increases with advancing clinical stage and decreases after effective chemotherapy.

The expression of proliferating cell nuclear antigen (PCNA) was studied in plasma cells in bone marrow biopsies from patients with multiple myeloma (MM) using a double immunostaining method. In the same samples, microvessel density (MVD), after staining with anti-CD34 antibodies, was determined before and after chemotherapy. The correlation of PCNA expression and MVD with other myeloma parameters (clinical stage, bone marrow plasma cell infiltration and serum interleukin-6 (IL-6)) was also investigated. The study population included 51 newly diagnosed MM patients, 15 patients in plateau phase after treatment and 15 normal controls. Pretreatment mean +/- SE values of PCNA, MVD, plasma cell infiltration and serum IL-6 were significantly higher than post treatment values and controls. Pretreatment PCNA expression correlated significantly with bone marrow MVD (p<0.05) plasma cell infiltration (p<0.01) and IL-6 (p<0.01). These findings show that the proliferative activity of plasma cells is related to the angiogenic activity in the bone marrow of multiple myeloma patients. Both PCNA and MVD correlate with markers of disease activity thus may provide additional information when included in the initial evaluation of myeloma bone marrow biopsies.