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Small fish models have been used for decades in carcinogenicity testing. Demonstration of common morphological changes associated with specific mechanisms is a clear avenue by which data can be compared across divergent phyletic levels. Dimethylnitrosamine, used in rats to model human alcoholic cirrhosis and hepatic neoplasia, is also a potent hepatotoxin and carcinogen in fish. We recently reported some striking differences in the mutagenicity of DMN in lambda cII transgenic medaka fish vs. Big Blue(®) rats, but the pre-neoplastic and neoplastic commonalities between the two models are largely unknown. Here, we focus on these commonalities, with special emphasis on the TGF-β pathway and its corresponding role in DMN-induced hepatic neoplasia. Similar to mammals, hepatocellular necrosis, regeneration, and dysplasia; hepatic stellate cell and "spindle cell" proliferation; hepatocellular and biliary carcinomas; and TGF-β1 expression by dysplastic hepatocytes all occurred in DMN-exposed medaka. Positive TGF-β1 staining increased with increasing DMN exposure in bile preductular epithelial cells, intermediate cells, immature hepatocytes and fewer mature hepatocytes. Muscle specific actin identified hepatic stellate cells in DMN-exposed fish. Additional mechanistic comparisons between animal models at different phyletic levels will continue to facilitate the interspecies extrapolations that are so critical to toxicological risk assessments.

A 14-year-old Maltese dog presented for complete medical examination due to intermittent vomiting and diarrhea observed during the previous two days. A single, solitary, lobulated cystic mass was observed in the liver upon ultrasonographic and computed tomographic examination. After surgical hepatic resection to remove the mass, histological examination revealed a multilocular cyst lined by cuboidal to columnar epithelial cells, which is consistent with biliary cystadenoma. Here, we report the clinical, clinicopathological, histopathological, and diagnostic imaging findings of biliary cystadenoma in a dog.

A 13-year-old male lion (Panthera leo) from Dae Jeon Zoo, Republic of Korea, presented with clinical signs of lethargy and anorexia. Despite treatment with antibiotics and fluid therapy, the lion died 6 days after initial presentation. Postmortem examination revealed multiple masses measuring 5-10 cm in diameter and cysts throughout the liver. A diagnosis of spontaneous peribiliary cysts was made on the basis of microscopic lesions as well as special staining and immunohistochemical characteristics. Histologically, the neoplasm was surrounded and composed of compact collagenous tissue. The inner cystic single layer resembled biliary mucosa and was composed of cuboidal or flattened epithelial lining that was strongly immunopositive for cytokeratin AE1/AE3. This layer was surrounded by fibrous tissue that stained blue by Masson's trichrome staining. Given the presence of multiple organized cysts in the liver, the lesion was consistent with peribiliary cysts. To the authors' knowledge, this is the first report of peribiliary cysts in an animal.

Hepatobiliary neuroendocrine carcinoma was diagnosed in 17 cats in a period of 10 years. Seven tumors were of intrahepatic origin, one of which was a composite containing components of epithelial and neuroendocrine carcinoma. Nine tumors were of extrahepatic origin, and one tumor was located in the gall-bladder. The cats were adult and geriatric, and the male : female ratio varied according to tumor group. Hepatomegaly, anorexia, weight loss, and vomiting were the most common clinical signs observed in the cats with hepatic neuroendocrine carcinoma. The cats with extrahepatic neuroendocrine carcinoma showed these signs plus icterus (5/9) and high concentrations of hepatic enzymes. Histologically, the hepatic neuroendocrine carcinomas had two patterns, one with acinar structures separated by vascular stroma lined by cuboidal or columnar cells and the other solid with groups of anaplastic cells separated by vascular stroma. The composite tumor consisted of both bile duct carcinoma and neuroendocrine carcinoma. The extrahepatic neuroendocrine carcinomas and the gallbladder neuroendocrine carcinoma were characterized by solid sheets or groups of round to oval cells with vascular or fibrovascular stroma. Immunohistochemical examination of 10 of the neuroendocrine carcinomas revealed that all 10 stained with neuron-specific enolase; one bile duct carcinoma and the gallbladder carcinoma stained with chromogranin; four of five bile duct carcinomas and the gall bladder carcinoma stained with synaptophysin; and one bile duct carcinoma stained with gastrin. One cat with hepatic carcinoma had duodenal ulcer; in this cat, ultrastructural studies showed neurosecretory granules leading to the diagnosis of Zollinger-Ellison syndrome. In four cats in which necropsy was permitted, carcinomatosis (4/4), lymph nodes (4/4), lungs (2/4), and intestines (1/4) were the metastatic sites. Fourteen of the 17 cats were euthanatized during or immediately after surgery.

A stranded adult female northern elephant seal (Mirounga angustirostris) was admitted to a rehabilitation hospital grossly underweight and lethargic in April 2001. The animal was icteric, had severe bilirubinemia, and elevated serum gamma glutamyl transferase concentrations. Laparoscopy under anesthesia revealed multiple masses up to 3 cm diameter throughout the liver and spleen and the animal was euthanized. Abnormal gross postmortem findings included green serous fluid in the abdominal cavity and 0.5 to 3 cm diameter yellow nodules scattered throughout the liver, spleen, and lymph nodes. Histopathology revealed a biliary adenocarcinoma with metastases to the liver, spleen, lymph nodes, adrenal gland, and pancreas. This is believed to be the first reported case of neoplasia in a northern elephant seal.

Medical records of 5 cats with hepatobiliary cystadenomas treated by means of surgical excision were reviewed. All cats were examined because of lethargy or abdominal enlargement. A cystic liver mass was seen in each cat ultrasonographically. Postoperative complications did not develop, and none of the cats developed evidence of tumor recurrence. Four cats died 12 to 44 months after surgery. Two cats were euthanatized for unrelated problems, and 2 cats died suddenly 25 and 44 months after surgery; the causes of death were not determined in either case. One cat was alive and considered clinically normal on physical examination 42 months after surgery.

A retrospective study was done of 47 neoplasms of the hepatic and biliary systems from 47 cats brought to The Animal Medical Center over a period of 10 years (1980 to 1989). Histologic examination of specimens taken at necropsy revealed that 87% (41/47) of the hepatic neoplasms were epithelial and 13% (6/47) were nonepithelial. Of the epithelial tumors, 25/47 (53%) were of intrahepatic bile duct origin, 9/47 (19%) were of hepatocellular origin, 5/47 (11%) involved the extrahepatic bile ducts, and 2/47 (4%) were adenocarcinomas of the gall bladder. Of the nonepithelial neoplasms, hemangiosarcomas were more common, 5/47 (11%), than leiomyosarcomas, 1/47 (2%). Multiple liver lobes were involved in 21/34 (62%) of the epithelial and all six of the nonepithelial intrahepatic neoplasms. Most of the bile duct adenocarcinomas (6/9) were predominantly characterized by acinar structures with mucin production, diffuse necrosis, and little desmoplasia. The hepatocellular carcinomas were characterized by three patterns-trabecular (five tumors), pseudoglandular pattern (two tumors), and anaplastic (one tumor). The hepatic carcinoid was characterized by various-sized groups of acinar and rosettelike structures, some with lumens, separated by thin fibrovascular stroma. The extrahepatic bile duct adenocarcinomas (4/4) were acinopapillary with moderate desmosplasia, whereas the adenocarcinomas of the gall bladder had elongated tubular structures lined by anaplastic cells and a severe desmoplastic reaction. The neuroendocrine carcinoma of the extrahepatic bile duct, the hemangiosarcomas, and the leiomyosarcoma had morphologic features characteristic of these neoplasms. Two of the 16 (13%) bile duct adenomas had anaplastic and precancerous changes. Residual benign components were seen in 10/15 (67%) of the biliary adenocarcinomas, 4/9 (44%) of the intrahepatic bile duct adenocarcinomas, and all of the extrahepatic bile duct adenocarcinomas and gall bladder adenocarcinomas. Results of immunohistochemical studies of the biliary neoplasms were similar to those described in studies of biliary neoplasms in human beings. Results of this study revealed that the frequency of different types of hepatic neoplasms in cats varied from that seen in dogs and human beings, but the morphologic features were comparable.

The ultrastructure and histology of cholangiocellular carcinomas from feral English sole (Parophyrs vetulus) living in polluted waterways of Puget Sound, WA. are described. Electron microscopy confirmed that biliary epithelial cells were the main proliferative cell type composing this variety of neoplasm. The arrangement of these cells varied from well-organized multiple bile duct-like structures to disorganized multilayered sheets of poorly differentiated biliary epithelial cells. A fibrous stroma consisting of multiple layers of collagen fibers and fibroblasts, with macrophages and various blood cell types scattered among these layers occurred between bile duct-like structures or aggregates of biliary epithelial cells. Hepatocytes were not apparent in these neoplasms except within small necrotic regions surrounded by neoplastic biliary epithelial cells. No virus-like particles were observed among the cases examined in this study.