VHL and nonpapillary renal cell carcinoma: Since this enzyme is a downstream target of the VHL-HIF pathway[64-66], it is reported to exhibit diffuse, strong membranous reactivity by immunohistochemistry in CCRCC, in contrast to other subtypes of renal tumors, which typically exhibit focal or multifocal reactivity[63], sometimes juxtaposed to areas of ischemia or necrosis.