The insulinlike growth factor signaling axis (factors I and II and their receptor) has been implicated in hepatocarcinogenesis. Previous studies on insulinlike growth factor I receptor using resected hepatocellular carcinoma generated mixed results; however, the distribution and clinical significance of insulinlike growth factor I receptor β expression in hepatocellular carcinoma in the setting of liver transplantation have not been evaluated. Immunohistochemical staining for insulinlike growth factor I receptor β was performed in 72 liver explants from patients with hepatocellular carcinoma undergoing liver transplantation. Expression of insulinlike growth factor I receptor β in hepatocytes was noted in 59.7% of tumors but only 6.9% of adjacent, nontumorous liver tissues (P.001). Compared with subjects with tumors within Milan criteria, those who fell beyond had 3.1 times higher odds of having insulinlike growth factor I receptor β-positive tumors (95% confidence interval, 1.003-9.8). Poorly differentiated hepatocellular carcinomas had 10.3 times higher odds of insulinlike growth factor I receptor β positivity compared with well- or moderately differentiated tumors (95% confidence interval, 1.3-85.2). Subjects with nonalcoholic steatohepatitis were less likely to have insulinlike growth factor I receptor β-positive tumors (P = .015). Finally, higher arteriolar insulinlike growth factor I receptor β scores in the tumor and adjacent liver were significantly associated with insulinlike growth factor I receptor β expression in tumor cells (P = .015 and .043 for intratumoral and adjacent arterioles, respectively) in a subset of 26 randomly chosen hepatocellular carcinoma. Our results suggest that synchronized up-regulation of the insulinlike growth factor I receptor axis in tumor cells and intratumoral and adjacent arterioles could represent a mechanism of hepatocarcinogenesis and progression as manifest by poor differentiation and tumors beyond Milan criteria. Targeted therapies against insulinlike growth factor receptors may be justifiable in the treatment of hepatocellular carcinoma.
