Expression of VHL and HIF-1α and Their Clinicopathologic Significance in Benign and Malignant Lesions of the Gallbladder

Background: The Von Hippel-Lindau (VHL) gene is a tumor-suppressor gene. Recent studies have shown that low expression of VHL has a close relationship with tumor formation, progression, and prognosis. Hypoxia-inducible factor (HIF)-1 alpha is a transcription factor, which exists universally in mammals including humans under states of hypoxia. Some studies have also shown that expression of HIF-1 alpha closely correlates with tumor progression, angiogenesis, metastasis, and invasion. This molecule is also an important cytokine, which may be used to evaluate the prognosis of some malignant tumors. In this study, we studied the expression of VHL and HIF-1 alpha and evaluated their clinicopathologic significance and relationship in benign and malignant lesions of the gallbladder. Methods: EnVision immunohistochemistry was used for detecting the expression level of VHL and HIF-1 alpha in routinely paraffin-embedded sections from specimens of gallbladder adenocarcinoma (n = 108), peritumoral tissues (n = 46), adenomatous polyps (n = 15), and chronic cholecystitis (n = 35). Results: The frequency of positive VHL expression was significantly lower in adenocarcinoma of gallbladder (48.1%) than that in peritumoral tissues (80.4%), adenomatous polyps (80.0%), and chronic cholecystitis (88.6%) (P < 0.05 or P < 0.01). In contrast, the positive HIF-1 alpha expression was significantly higher in adenocarcinoma (53.7%) than that in peritumoral tissues (34.8%), adenomatous polyps (26.7%), and chronic cholecystitis (14.3%) (P < 0.05 or P < 0.01). The benign lesions with positive VHL and/or negative HIF-1 alpha expression showed atypical hyperplasia in gallbladder epithelium. The positive expression of VHL and negative expression of HIF-1 alpha were significantly associated with differentiation, tumor mass, lymph node metastasis, and invasion of adenocarcinoma (P < 0.05 or P < 0.01). The highly inconsistent expression of VHL and HIF-1 alpha in gallbladder adenocarcinoma was found P < 0.01). Univariate Kaplan-Meier analysis showed that elevated expression of VHL (P = 0.023) or lowered expression of HIF-1 alpha (P = 0.020) was closely associated with decreased overall survival. Multivariate Cox regression analysis showed that positive expression of VHL (P = 0.013) and/or negative expression of HIF-1 alpha (P = 0.005) was an independent poor-prognostic predictor in gallbladder adenocarcinoma. Conclusions: The lowered expression of HIF-1 alpha and elevated expression of VHL in gallbladder adenocarcinoma are important markers for the progression, clinical biological behavior, and prognosis. Measurement of VHL and HIF-1 alpha expression could be a tool for early detection of gallbladder cancer in benign lesions and in population screening. The highly inconsistent expression of VHL and HIF-1 alpha in gallbladder may require further study to see whether they are intrinsically related.