Noncirrhotic hepatocellular carcinoma: derivation from hepatocellular adenoma? Clinicopathologic analysis

The majority of hepatocellular carcinomas arise in background chronic liver disease, particularly cirrhosis. The pathogenesis of noncirrhotic hepatocellular carcinomas remains unclear. While malignant transformation reportedly occurs in <15% of hepatocellular adenoma, the prevalence of noncirrhotic hepatocellular carcinomas arising from a pre-existing adenoma is a challenge to study. Cirrhotic hepatocellular carcinoma and hepatocellular adenoma may be subclassified by molecular pathways, but little is known in noncirrhotic hepatocellular carcinoma. We aim to delineate clinical, morphologic and immunohistochemical features of noncirrhotic hepatocellular carcinoma to evaluate for possible derivation from hepatocellular adenoma. We evaluated the clinicopathologic features of 74 noncirrhotic hepatocellular carcinomas from 72 patients for underlying clinical conditions and immunohistochemical markers known to be associated with hepatocellular adenoma. Men were more commonly affected (59%); however, in the <50-year-old group, women predominated (8:1). The age range was wide: 18-83 years; median-64 years. Underlying liver diseases were identified in only 7%; however, 25% had diabetes mellitus, 69% were overweight or obese and 58% had metabolic syndrome. Only 50% of the noncirrhotic hepatocellular carcinoma were encapsulated. As published in hepatocellular adenoma, multifocality and larger tumor size were more common in liver fatty acid-binding protein-negative noncirrhotic hepatocellular carcinoma. Beta-catenin nuclear positivity was uncommon (5%), and was restricted to hepatocellular carcinomas in older men. Serum amyloid A positivity was not restricted to any subtype. In summary, we present the largest series to date examining noncirrhotic hepatocellular carcinoma. We evaluated these with current hepatocellular adenoma subclassification markers for possible associations. Thirty percent of the 74 noncirrhotic hepatocellular carcinoma had some clinical, morphological or immunophenotypical associations currently described in hepatocellular adenoma. Our data also confirm the association of noncirrhotic hepatocellular carcinoma in middle-aged to elderly men, an association with metabolic syndrome, and, as with hepatocellular adenoma, that women predominated in the noncirrhotic hepatocellular carcinoma subjects <50 years of age.