Clear Cell Renal Cancer, a Tumour with Neuroendocrine Features Originating from the Erythropoietin-Producing Cell

Abstract

The dominating type of kidney cancer is the clear cell renal cell cancer (ccRCC), hitherto been thought to develop from proximal tubule cells. However, the ability of tubule cells to proliferate is at best controversial. ccRCCs show many peculiarities like erythrocytosis due to erythropoietin overproduction and a combination of early metastases and sometimes apparent dormancy and late recurrence, features in common with neuroendocrine tumours (NETs). We have shown that most ccRCCs express erythropoietin and the neuroendocrine marker neuron-specific enolase, and other neuroendocrine markers in a percentage of the cancers. Missense mutation in von Hippel–Lindau (VHL) factor is rather specific for ccRCC found in familial and sporadic forms. The function of VHL factor is together with other proteins to destroy hypoxia-inducible factors (HIFs), central in adaptation to hypoxia. Lack of functioning VHL factor results in continuous overstimulation of the erythropoietin-producing cell to release erythropoietin and parallelly to proliferate, and in long-term mutations and malignant transformation. Thus, ccRCC occurs about 30 years later in sporadic cases compared with familial von Hippel–Lindau syndrome, reflecting the time necessary for two versus one genetic change. Embryologically, there are many arguments favouring neural crest origin of the erythropoietin-producing cell.