Spontaneous Occurrence of a Distinctive Renal Tubule Tumor Phenotype in Rat Carcinogenicity Studies Conducted by the National Toxicology Program

Abstract

The Toxicology Data Management System (TDMS) of the National Toxicology Program, National Institutes of Environmental Health Sciences, National Institutes of Health, was surveyed for occurrence and distribution of a distinctive renal tubule tumor type in rats. The hallmark features of this tumor included eosinophilic/amphophilic staining, large finely granular cells, and numerous vacuoles and/or minilumens. It is referred to here as the amphophilic-vacuolar (AV) variant of renal tubule tumor. Of 154 studies in which renal tubule tumors had been recorded in the standard single sections of kidney in the TDMS, there were collectively 1012 rats with renal adenomas, carcinomas, or adenocarcinomas, and of these, 100 displayed the distinctive AV morphology, representing 74 studies involving mostly the F344 rat, but also the Sprague-Dawley and Wistar strains. The AV tumors (mainly adenomas but also some carcinomas) occurred usually as solitary lesions in the affected animals. However, they were multiple and bilateral in a few cases. They were equally distributed between the sexes, did not metastasize (at least to the lung), and were not associated with chronic progressive nephropathy. The distribution of this renal tumor type was random across studies and dose groups, underscoring the likelihood that it was of spontaneous origin and not chemically induced. Accordingly, it is suggested that this distinctive renal tumor phenotype be recorded as a separate category from conventional RTT when assessing the carcinogenic potential of a test compound.

Renal Tumors in 26-Week Tg.Rash2 Mice Carcinogenicity Studies

“…Each study was administered a different control and test article; the test articles in individual studies were not related or members of a particular family of compounds. All tumors described in this article were amphophilic with lobular appearance and morphologically similar to AV tumors noted in Sprague-Dawley and Fischer 344 rats, which are considered familial in nature (Crabbs et al 2013;Hard et al 2008). However, none of the tumors exhibited both amphophilic and vacuolar patterns.…”

“…The mice with renal tumors reached terminal sacrifice and were less than 9 months old at the time of terminal sacrifice. Similar to the rats, there was no sex predilection (Hard et al 2008).…”

Regulatory Forum Opinion Piece*

“…Tumors are distinctly identified by their typically solid lobular growth, intervening tracts of fibrovascular stroma, and often lymphoid cell infiltration. Cystic and more basophilic variants are more uncommon (Hard et al 2008).…”

Renal Cell Carcinoma in Humans and Animals: A Brief Literature Review

“…Various renal tubular tumors including RCC are reported and described as familial in laboratory rat, Long-Evans derived Eker rats and the Nihon rat [35][36][37][38][39][40]. Furthermore, familial renal cell tumors are also suspected in F344 and Sprague-Dawley rats [41][42][43].…”

“…Apparently some animals are genetically predisposed to certain neoplasms. Renal neoplasm is reported to be an inherited genetic disease in various species of rats [35][36][37][38][39][40][41][42][43]. Hereditary renal cystadenocarcinoma is reported in German shepherd dogs [17].…”