Natural history of hepatocellular carcinoma as viewed by the pathologist

The classical morphological criteria in the diagnosis of hepatocellular carcinoma (HCC) include: (a) the similarity of tumor cells to hepatic cord cells; (b) the trabecular nature of the growth with capillary and canaliculi formation, and (c) the intravascular growth of trabecular carcinoma. These criteria apply to the most common variants of HCC but they do not suffice in all cases. That makes additional criteria and certain refinements necessary. A promising approach to the diagnosis of HCC is that based upon consideration by the pathologist of some relevant aspects of the natural history of this tumor. A panel of tests exploring the various functions and properties of liver cells should be set up. Tests for bile and fibrinogen synthesis are most important because they reflect specific and exclusive properties of the original cell line. Bile synthesis in tumor tissue is reflected by the finding of cholecholatestasis, namely bilirubinostasis and retention of copper and copper-binding proteins. The positive immunostaining for fibrinogen may appear in the form of cytoplasmic granules occurring in 50% of HCC, or in the form of fibrinogen-ground-glass (G-G) inclusions, representing a specific feature of HCC. During neoplastic transformation oncofetal proteins may reappear, alpha-fetoprotein (AFP) being very common. Despite sensitivity of AFP, this test, similar to alpha-1-antitrypsin (AAT), has very low specificity, because of the widespread occurrence of these proteins in a variety of tumors. The selection of special 'clones' such as Mallory bodies and fibrinogen-G-G is of particular value, because of the specificity of these peculiar cytoplasmic changes. Although rare, the presence of HBV antigens in tumor tissue is virtually pathognomonic for HCC. The availability of nonneoplastic liver tissue for morphological examination is of great help, because it may carry key information or markers of the development stages of HCC: cirrhosis, liver cell dysplasia, HBV antigens, congenital metabolic disorders, such as hemochromatosis and AAT deficiency. The two latter conditions represent the link with the last working hypothesis of the present study, i.e. that during neoplastic transformation hepatocytes may 'switch' their 'phenotype' thus escaping the storage phenomena, which continue to occur in nonneoplastic hepatocytes. This study provides a guideline to a dynamic approach to the diagnosis of HCC. The rationale is listed in 5 points; among them, bile production, fibrinogen synthesis, Mallory body and fibrinogen-G-G selection, HBV antigen expression can be considered at present as confident markers for the morphological diagnosis of HCC.