Low Frequency of HIF-1α Overexpression in Germ Cell Tumors of the Testis

Cellular hypoxia is a hallmark of cancer. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) and von Hippel-Lindau protein (pVHL) are the key mediators of cellular response to hypoxia. Little is known about their role in germ cell tumors of the testis. We therefore examined their status in a cohort of germ cell tumors of the testis. Thirty-six primary germ cell tumors of the testis (11 seminomas, 24 mixed germ cell tumors, and 1 case of pure intratubular germ cell neoplasia) were included in the study. HIF-1 alpha and pVHL expression were studied using immunohistochemical (IHC) methods in the tumor and adjacent benign tissue. Selected cases with a low pVHL expression were further tested for genetic alterations using polymerase chain reaction. HIF-1 alpha protein expression was not detectable in adjacent atrophic seminiferous tubules. In contrast, HIF-1 alpha was expressed in one third of the malignancies, but in a low percentage of cells (mean, 3%; range, 0% to 20%). No difference in HIF-1 alpha expression was observed between seminomas and nonseminomas (P = 0.71). pVHL was expressed in atrophic tubular epithelium and in the Leydig cells, whereas a substantial loss of pVHL expression was observed in germ cell tumors regardless of the histologic type (mean, 45.6%; range, 0% to 100%). No genetic alterations of the VHL gene were observed in the cases with low pVHL expression. No significant correlation between HIF-1 alpha and pVHL expression was observed (P = 0.16). Germ cell tumors of the testis, regardless of the histologic type, are characterized by consistently low HIF-1 alpha protein overexpression and a partial loss of pVHL without underlying VHL gene alterations. Further studies are necessary to clarify the functional importance of such alterations in testicular germ cell tumors.