Reduced expression of Raf-1 kinase inhibitory protein is a significant prognostic marker in patients with gallbladder carcinoma

Gallbladder carcinoma is one of the most aggressive malignancies. It is usually diagnosed at an advanced stage, and the prognosis remains poor despite advances in imaging techniques and aggressive surgical treatment. Because of the lack of reliable prognostic markers, the aim of this study was to investigate the prognostic significance of Raf-1 kinase inhibitory protein expression in gallbladder carcinomas. Immunostaining for Raf-1 kinase inhibitory protein was performed on chronic cholecystitis, adenoma, carcinoma in situ, and primary and nodal metastatic gallbladder carcinoma. Raf-1 kinase inhibitory protein expression was reduced in 68.8% (11/16) and 42.3% (44/104) of nodal metastatic and primary gallbladder carcinoma cases, respectively, but in no case of carcinoma in situ, adenoma, or chronic cholecystitis. The differences in Raf-1 kinase inhibitory protein expression in gallbladder carcinoma versus nongallbladder carcinoma tissues (P < .001), and in nodal metastatic gallbladder carcinoma versus primary gallbladder carcinoma (P = .009), were statistically significant. Kaplan-Meier curves showed that patients with Raf-1 kinase inhibitory protein-negative or weakly positive gallbladder carcinoma had a significantly shorter overall survival than did patients with Raf-1 kinase inhibitory protein-positive gallbladder carcinoma (median, 14 versus 120 months; P = .011). Multivariate survival analysis showed that reduced Raf-1 kinase inhibitory protein expression was an independent prognostic predictor for overall survival (P = .020). Our results suggest that reduction in Raf-1 kinase inhibitory protein expression in gallbladder carcinoma contributes to invasion and metastasis and is a significant prognostic marker in patients with gallbladder carcinoma.