Clinicopathological characteristics and prognostic markers in canine and feline primary liver tumours

Abstract

Over the past decade, many advances have been made in the characterization of primary liver tumours in humans, in particular relating to the identification and role of Hepatic Progenitor Cells (HPCs), which has resulted in a new classification. In view of the similarities in cell biological mechanisms involved in regeneration and tumour development between the human liver and the liver in small domestic animals, it is conceivable that the observations made in human hepatic tumour pathology may also be true for canine or feline liver tumours. Therefore, we investigated the presence and relative frequency of morphological types of canine and feline primary hepatic neoplasms and determined whether the classification is similar to the new human classification. Canine and feline primary liver tumours were examined histologically and with a series of immunohistochemical markers including the HPC marker keratin 19 (K19). K19 positive hepatocellular neoplasias in dogs were highly comparable to man and constituted 12% of canine hepatocellular tumours. Like in man the canine hepatocellular tumours could be subdivided in hepatocellular tumours with 0–5% positivity for K19, which were well differentiated and had no evidence of metastasis, tumours with >5% positivity for K19, which were poorly differentiated and had intrahepatic and/or distant metastasis, and a scirrhous subgroup with an intermediate position with regard to K19 staining and malignancy. Also cholangiocellular carcinomas and a cholangiolocarcinomas well as neuroendocrine carcinomas were found, which all had intrahepatic and/or distant metastases. The histopathological and immunohistochemical examination of canine primary hepatic neoplasms can differentiate hepatocellular, cholangiocellular and neuroendocrine tumours in accordance with the most recent human classification system. Histological and immunohistochemical examination of primary hepatic neoplasms in the cat revealed marked differences between canine and feline primary hepatic neoplasms justifying a separate new classification scheme for the cat. This comprised hepatocellular adenomas and carcinomas, cholangiocellular carcinomas as well as small cell carcinomas / carcinoids. In contrast to the dog, feline hepatocellular carcinomas showed no HPC characteristics but maintained their hepatocellular characteristics. Instead, within the small cell carcinomas or carcinoids a K19 negative group of true neuroendocrine carcinomas and a K19 positive group with HPC characteristics were recognized. To better understand the aggressive behaviour of K19-positive hepatocellular tumours, K19-positive and K19-negative canine hepatocellular tumours were immunohistochemically stained and compared for the presence of proteins known to be crucial in tumour development. The differential expression of for instance malignancy markers PDGAFRα and GPC-3 explain the malignant phenotype of carcinomas versus adenomas. The proposed classification of the primary liver tumours in dogs and cats provides a basis for a standardized diagnosis that allows more patient specific treatment modalities. In addition, functional immunohistochemical characterisation of the canine hepatocellular tumours suggested pathways for malignant transformation and may present possibilities for new diagnostic and future personalized therapies.