Vascular endothelial growth factor, its receptor Flk-1, and hypoxia inducible factor-1alpha are involved in malignant transformation in dysplastic nodules of the liver

Dysplastic nodules (DNs) are regarded as a premalignant lesion of hepatocellular carcinoma (HCC). Sinusoidal capillarization and unpaired arteries are reported in HCC and also to a lesser degree in DN. However, the mechanism and significance of these vascular alterations remain unclear. In this study, these vascular changes were examined with respect to vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and Flk-1), hypoxia inducible factor-1alpha (HIF-1alpha), and CD34, by using 20 surgically resected cases of DNs and 36 cases of conventional HCC. The expression of these molecules was examined immunohistochemically. Although sinusoidal capillarization characterized by CD34 expression was found diffusely in HCC, such changes were found mainly in the areas around the portal tracts and also in other areas in DNs (focal in 6 cases, zonal in 7 cases, and extensive distribution in 7 cases). These capillarized areas were frequently associated with unpaired arteries, and the infiltration of neoplastic hepatocytes into the portal tracts and loss of reticulin fibers in DNs, particularly those with a zonal and extensive distribution. VEGF was diffusely expressed in neoplastic hepatocytes of DNs and HCC. Interestingly, Flk-1 and HIF-1alpha were mostly expressed in endothelial cells and neoplastic hepatocytes in the capillarized areas around portal tracts in DNs, respectively. In conclusion, the capillarized areas with increased numbers of unpaired arteries in DNs may represent an early malignant transformation. Increased expression of Flk-1 and HIF-1alpha associated with VEGF may be involved in sinusoidal capillarization and the increased numbers of unpaired arteries in these areas.