VHL and nonpapillary renal cell carcinoma: Loss or mutation of the von Hippel-Lindau (VHL) gene is one of the primary characteristics of ccRCC that leads to the constitutive activation of the hypoxia-inducible factor, which further activates the vascular endothelial growth factor (VEGF) and increases angiogenesis in the ccRCC tumor microenvironment (7–12).