Microvessel Density and Expression of Vascular Endothelial Growth Factor and Its Receptors in Diffuse Large B-Cell Lymphoma Subtypes

Abstract

Angiogenesis is known to play a major role in neoplasia, including hematolymphoid neoplasia. We assessed the relationships among angiogenesis and expression of vascular endothelial growth factor and its receptors in the context of clinically and biologically relevant subtypes of diffuse large B-cell lymphoma using immunohistochemical evaluation of tissue microarrays. We found that diffuse large B-cell lymphoma specimens showing higher local vascular endothelial growth factor expression showed correspondingly higher microvessel density, implying that lymphoma cells induce local tumor angiogenesis. In addition, local vascular endothelial growth factor expression was higher in those specimens showing higher expression of the receptors of the growth factor, suggesting an autocrine growth-promoting feedback loop. The germinal center-like and nongerminal center-like subtypes of diffuse large Bcell lymphoma were biologically and prognostically distinct. Interestingly, only in the more clinically aggressive nongerminal center-like subtype were microvessel densities significantly higher in specimens showing higher vascular endothelial growth factor expression; the same was true for the finding of higher vascular endothelial growth factor receptor-1 expression in conjunction with higher vascular endothelial growth factor expression. These differences may have important implications for the responsiveness of the two diffuse large B-cell lymphoma subtypes to anti-vascular endothelial growth factor and anti-an- Angiogenesis and the proangiogenic growth factor vascular endothelial growth factor (VEGF; also known as vascular permeability factor) have a known role in solid neoplasia, and there is increasing evidence that they also play a role in hematolymphoid neoplasia. Increased microvessel density has been noted in a range of hematolymphoid disorders, including multiple myeloma, nonHodgkin lymphoma, acute and chronic leukemias of myeloid and lymphoid lineages, and myelodysplastic disorders.

Vascularization predicts overall survival and risk of transformation in follicular lymphoma

“…Similar results have been reported in hematopoietic tumors, including multiple myeloma and lymphoma. 3,4,14,15 In murine lymphoma models and in lymphoma patients, circulating endothelial cells and serum vascular endothelial growth factor (VEGF) levels appear to correlate with lymphoma volume and increased angiogenesis. 16,17 In contrast, previous studies of MVD in FL have resulted in conflicting results.…”

“…Angiogenesis plays a crucial role in oncogenesis, promoting growth and progression of both solid and hematologic tumors. 3,4 The acquisition of an angiogenic phenotype, referred to as the "angiogenic switch", allows the formation of neovessels that are vital for tumor growth. 5 This "angiogenic switch" results not only from interactions between vessels and cancer cells, but also involves non-neoplastic cells in the microenvironment, including macrophages.…”

R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: final MAIN study outcomes

“…[6][7][8] High serum levels of VEGF and elevated expression of VEGF in tissue biopsies are associated with higher tumor burden, 9 microvessel density, 3,6 and inferior overall survival (OS). 4,7,8,10 In vitro and in vivo pre-clinical studies of DLBCL have shown that treatments targeting VEGF or its receptors reduce tumor growth by increasing apoptosis and decreasing vascularization.…”

“…Angiogenesis in general and vascular endothelial growth factor (VEGF) in particular are involved in the development, growth, and progression of a range of non-Hodgkin lymphoma (NHL) histological subtypes, [1][2][3][4][5] including diffuse large B-cell lymphoma (DLBCL). [6][7][8] High serum levels of VEGF and elevated expression of VEGF in tissue biopsies are associated with higher tumor burden, 9 microvessel density, 3,6 and inferior overall survival (OS).…”

Expression of HGAL in primary cutaneous large B-cell lymphomas: evidence for germinal center derivation of primary cutaneous follicular lymphoma

“…9 We chose to use 5% in our scoring system, consistent with previous criteria used by Sundram et al 12 This scoring system has also been used by other investigators. 12,17 Nevertheless, BCL2 expression was similar across studies in that it was positive in all the DLBCL-LT. The higher CD10 expression in our study was due to the cutoff used.…”