P04: Histopathological features of the Bhd gene mutant (Nihon) rat

We have reported that the Nihon rat, a rat model of hereditary renal cell carcinoma (RCC), carries a single germline nucleotide insertion in the rat counterpart of human Birt–Hogg–Dube gene ( BHD ). In heterozygotes, RCC develops from early preneoplastic lesions, which began to appear as early as 3 weeks of age, to adenocarcinomas by the age of 6 months. The present work was conducted to further characterize aspect of RCC and to investigate extra-renal lesions of the Nihon rat. A total of 492 rats obtained from a colony of the Nihon rats were assigned at an age of 4 weeks to studies to evaluate the histopathological features of RCC and extra renal lesions. All rats were maintained in a barrier facility for up to 12 or 16 months, then the rats were euthanized and necropsied. All organs were fixed in 10% buffered formalin, and routinely processed for embedding in paraffin. Histopathological examination was performed using sections stained with hematoxylin and eosin, special stainings, and immunohistochemical methods, and electron-microscopy. Two out of 4 abdominal nodules were subjected to genomic analysis to detect mutations or loss of heterozygosity. The primary cell types of the RCC were of the clear/acidophilic cell type where some similarities were evident to RCCs in BHD syndrome. Heterotopic ossification was occasionally found within RCCs. As the extra-renal lesions, the Nihon rats also showed clear cell hyperplasia/adenoma of the endometrium, clear cell change of the epithelium of striated portions of salivary glands, cardiac rhabdomyomatosis and postoperative abdominal desmoid tumor(s). This rat model provides a useful tool for analyzing the series of events leading to renal tumorigenesis and for studying BHD gene functions.