Prognostic Value of MET, RON and Histoprognostic Factors for Urothelial Carcinoma in the Upper Urinary Tract

Abstract

RON (recepteur d'origine Nantais) (Santa Cruz Technology, Santa Cruz, California) and c-met (Dako, Glostrup, Denmark) are members of the c-met proto-oncogene family. c-met encodes a receptor tyrosine kinase and has a role in oncogenesis. RON has a role in cell transformation and epithelial tumorigenesis. Over expression of the 2 genes has been demonstrated in human bladder cancer. We explored whether over expression of the 2 proteins has a role in the tumorigenesis and defined histoprognostic factors of poor clinical outcomes in patients with these tumors. We reviewed the records of 42 patients with upper urinary tract urothelial carcinoma. A total of 24 tumors were localized in the renal pelvis and 18 were in the ureter. Immunohistochemical staining for RON and c-met was performed using tissue microarrays. Patient age was 46 to 100 years (mean 70.6). Of the patients 23 (54%) died of disease. Over expression of c-met was associated with a higher risk of embolism (p = 0.0002), while over expression of RON was not significantly associated with emboli (p = 0.5). Univariate analysis showed that relapse was significantly associated with ureteral localization (p = 0.02), vascular invasion (p = 0.003), and high grade (p = 0.04) and high stage (0.02) urothelial carcinoma. The association with vascular invasion, and high grade and high stage urothelial carcinoma was also statistically significant (p <0.0001). Notably superficial tumors showed an important relapse rate (p = 0.003). Independent prognostic factors of relapse in upper urinary tract urothelial carcinoma are ureteral localization, vascular invasion, high grade and high stage. c-met seems to influence the development of vascular invasion via an unknown mechanism. Nevertheless, to our knowledge an association between c-met over expression and aggressive clinical behavior in upper urinary tract carcinomas has not been previously reported.