Hepatobiliary Neuroendocrine Carcinoma in Cats: A Clinicopathologic, Immunohistochemical, and Ultrastructural Study of 17 Cases

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 gallbladder 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.

Vascular Permeability Factor/Vascular Endothelial Growth Factor and Vascular Stroma Formation in Neoplasia: Insights from In Situ Hybridization Studies

The formation of vascular stroma plays an important role in the pathophysiology of malignancy. We describe the use of in situ hybridization in our laboratory as a tool to study the role of vascular permeability factor/vascular endothelial growth factor in the angiogenesis associated with malignancy.

Angiogenesis in Neoplasia; Insights from in Situ Hybridization Studies

The formation of vascular stroma (angiogenesis) is essential for tumor growth and may also influence invasion and metastasis. Quantitation of angiogenesis may serve as a prognostic marker in certain malignancies and novel therapies targeted at inhibiting angiogenesis may prove to play an important role in control of tumor growth.In situ hybridization (ISH) studies have helped to define some of the molecular and cellular events responsible for the formation of vascular stroma in malignancy.Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine associated with tumor angiogenesis. Vascular endothelial cells express at least two tyrosine kinase receptors for VPF, flt-1 and KDR. VPF acts as an angiogenic factor in several ways. It is an endothelial cell growth factor, alters endothelial cell gene expression, induces endothelial cell migration, and it is also a potent inducer of microvascular hyperpermeability (50,000 times as strong as histamine).