Mutations in the von Hippel-Lindau (VHL) gene refine differential diagnostic criteria in renal cell carcinoma

Background and Objectives: Renal cell carcinomas (RCC) with abundant granular cytoplasm include oncocytomas, eosinophillic variants of chromophobe RCC, papillary RCC, collecting duct carcinoma, and sonic conventional (clear cell) RCC. Tumors with predominantly clear cell cytoplasm include typical chromophobe RCC and conventional (clear cell) RCC. The objective of this study was to determine if mutations in the VHL gone can serve as auxiliary diagnostic criteria in refining histology based subtyping of renal epithelial neoplasia. Methods: The study cohort of 67 cases included 24 conventional RCC, 14 chromophobe RCC, 14 papillary RCC, and 15 oncocytomas. Single strand conformational polymorphism (SSCP) was used as a screening procedure for mutations followed by automated sequencing to identify mutations. Results: Thirteen of the 14 mutations identified were novel, seven of which were in the coding region. In chromophobe RCC, mutations clustered in the 5'UTR/promoter region and have not been previously reported. Exon 3 appeared to favor conventional (clear cell) RCC and correlated with a more aggressive phenotype. Mutations were absent in the papillary and oncocytoma RCC subtypes. Conclusions: Exon 3 mutations permitted a morphological distinction between conventional (clear cell) RCC and chromophobe RCC with clear cells. Mutations in the VHL gene refine histologic diagnostic criteria in RCC serving as adjuncts to the present morphology based diagnosis of RCC. (C) 2002 Wiley-Liss, Inc.