An Occurrence of Multiple Carcinomas in Both Kidneys of a 5-year-old Female Cynomolgus Monkey ( Macaca fascicularis )

Abstract

An occurrence of multiple carcinoma in both kidneys of a 5-year-old female cynomolgus monkey is described in the present paper. Macroscopically, the kidneys were enlarged with multiple solid and grayish-white masses and cysts mainly in the cortex and outer medulla. Light microscopically, carcinomas showed either tubulopapillary or tubulosolid growth patterns. Carcinoma cells were pleomorphic cuboidal to columnar cells. Cytoplasm was abundant and either granular and eosinophilic or clear, and nuclei were large and vesicular with prominent nucleoli. Electron microscopy revealed the existence of a brush border-like structure on the cell surface of carcinoma cells, suggesting that carcinoma cells arose from proximal tubular epithelial cells. Small foci of tubular epithelial cell hyperplasia and adenomas were also observed independently of carcinomas. There was no evidence of transition from adenoma to carcinoma, and no metastases were detected.

Introduction

Nonhuman primates are frequently used laboratory animals in the field of toxicology and pharmacology, and therefore, it is important to collect and analyze their physiological as well as pathological background data including spontaneous lesions. With regard to spontaneous renal tumors in nonhuman primates, there have been reports of renal cell carcinoma (Chapman et al., 1968; Kaur et al., 1968; Greene et al., 1973; McClure, 1973; Kommineni et al., 1978; Jones et al., 1981; Brack et al., 1985; Witt et al., 1989) transitional cell carcinoma (Jones et al., 1981) and sarcoma (Anderson et al., 1994; Chrisp et al., 1985). Most of them were reported before 1990, and only limited literature is available after 1990 when monkeys became more commonly used in toxicological studies. In addition, most of the cases of spontaneous renal tumors in nonhuman primates were reported in rhesus monkeys (Macaca mulatta) (Jones et al., 1981), whereas only 1 case of renal cell carcinoma (Kommineni et al., 1978), malignant nephroblastoma (Bennett et al., 1982) and renal lymphosarcoma (Anderson et al., 1994) were reported in cynomolgus monkeys (Macaca fascicularis), which are now the most commonly used primates in toxicological studies in Japan. In this report, we describe the pathological characteristics of a case of bilateral, multiple renal cell carcinoma found in a 5-year-old female cynomolgus monkey.

Case Report

The animal purchased from the Institute of Laboratory Animal Science of Chinese Academy of Medical Sciences (Republic of China) at 4 years of age had been maintained under laboratory conditions for approximately 1 year. The animal was already in the late stage of pregnancy when delivered to our laboratory and gave birth 1 month later. The animal was not subjected to any toxicological studies, and was sacrificed at 5 years of age by exsanguination from the axillary artery under ketamine hydrochloride anesthesia (Ketalar 50: Sankyo Co., Ltd., Japan). There were no abnormal clinical findings observed except for a transient elevation of white blood cell count (193 × 10² /μl) at 1 month before sacrifice.

At necropsy, the left kidney was markedly enlarged (56 g) with 8 masses (8–20 mm in diameter) and six cysts (1–40 mm in diameter), and the right kidney was also slightly enlarged (16.4 g) with three nodules (3–10 mm in diameter) and a few cysts (1 mm in diameter) (see Figure 1). The masses were solid and grayish-white in color, and the cysts contained transparent fluid. In addition, slight enlargement of the liver and spleen and a small focus of discoloration at the apex of the heart were also observed. Renal and mesenteric lymph nodes were normal and ascites was not observed.

For light microscopic examination, the kidneys and mesenteric lymph nodes, heart, liver, spleen and lungs were fixed with 10% phosphate-buffered formalin (pH 7.2). Two-μm paraffin sections were stained with hematoxylin and eosin (HE). Additional paraffin sections of the kidney were stained by periodic acid-Schiff (PAS). For electron microscopic examination, formalin-fixed renal tissues were refixed with 2.5% glutaraldehyde and 1% osmium tetroxide, and embedded in Epok 812. Ultrathin sections were double-stained with uranyl acetate and lead citrate and observed under a JEM-100 CX II electron microscope (JEOL, Tokyo).

Light microscopically, varying-sized multiple neoplastic foci which were generally demarcated from the surrounding tissues by fibrous septa were observed in both kidneys. Most of them were located in the cortex but some large ones extended from the cortex into the outer medulla. The neoplastic tissues showed either tubulopapillary (Figure 2) or tubulosolid growth patterns. Most neoplastic cells were pleomorphic cuboidal to columnar cells. Cytoplasm was abundant and either granular and eosinophilic or clear, and nuclei generally were large and vesicular with prominent nucleoli. In addition, in some neoplastic foci showing tubulosolid growth pattern, neoplastic cells were observed which had markedly swollen cytoplasm containing either large amounts of weakly to strongly eosinophilic and PAS-negative material or large vacuoles (Figure 3).

The nuclei of these cells were highly pleomorphic, had prominent nucleoli, and were eccentrically located along the cell membrane. Mitotic figures were rarely seen in neoplastic cells, and there were neither hemorrhagic nor necrotic foci within the neoplastic tissues. Electron microscopic examination revealed that some neoplastic cells had brush border-like structures on the cell surface (Figure 4). This strongly suggests that the neoplastic cells originated from proximal tubular epithelial cells. Similar electron microscopic findings were also reported in chemically induced renal cell carcinoma in rats (Bannasch et al., 1994).

From the above-mentioned light and electron microscopic findings, we diagnosed the neoplasms as renal cell carcinomas. However, neither intrarenal vascular invasion by carcinoma cells nor metastasis of carcinoma cells to extrarenal tissues including renal and mesenteric lymph nodes was observed. This suggests that renal cell carcinomas may occur in both kidneys independently of each other.

In both kidneys, several foci of tubular epithelial cell hyperplasia and adenomas (Figure 5) and multiple cysts with various sizes were observed independently of carcinomas, not only in the cortex but also in the medulla. Adenoma cells were relatively uniform cuboidal cells with smaller nuclei than in the carcinomas. There was no evidence of transition from adenoma to carcinoma. Cysts were generally lined by flattened tubular epithelial cells, and partially by hyperplastic tubular epithelial cells. As to the microscopic changes in organs other than the kidneys, small foci of fibrosis were observed in the apex of the heart corresponding to macroscopic findings.

As mentioned before, the present case of renal tumors observed in a 5-year-old female cynomolgus monkey was considered to be bilateral multiple renal cell carcinoma. In nonhuman primates, although the incidence of renal cell carcinoma is somewhat higher than that of other renal tumors, an occurrence of multiple carcinomas in both kidneys is very rare (Jones et al., 1981). In addition, there are only a few reports of renal tumors in nonhuman primates of 5 years and under (Jones et al., 1981).