HEPATIC STELLATE CELL ACTIVATION IN DYSPLASTIC NODULES - EVIDENCE FORAN ALTERNATE HYPOTHESIS CONCERNING HUMAN HEPATOCARCINOGENESIS

We have previously suggested that dysplastic nodules (also referred to as ''adenomatous hyperplasia'' or ''macroregenerative nodules''), lik ely precursors of hepatocellular carcinoma (HCC), develop as an infilt rating clonal expansion, in advance of or parallel to cirrhosis. As pa rt of this hypothesis, to explain aspects of their gross and microscop ic appearance, we suggested that dysplastic nodules are resistant to t he scarring process affecting the rest of the liver. We sought to test this hypothesis by examining the distribution of activated hepatic st ellate cells (HSCs), the hallmark of hepatic scarring, in cirrhotic no dules, dysplastic nodules and HCC. We immunohistochemically stained 56 cirrhotic nodules, 20 low grade dysplastic nodules, 27 high grade dys plastic nodules, and 20 HCCs with monoclonal antibodies against alpha- smooth muscle actin to identify activated HSCs. Distribution and numbe r of HSCs were graded semiquantitatively (0 to 4+). In our results, HS Cs were significantly less widespread in dysplastic nodules than in ci rrhotic nodules or in HCCs (both: p<0.00001). HSCs were also more prom inent in the periphery of dysplastic nodules than in the center, thoug h still fewer in number than in cirrhotic nodules. In conclusion, the low number of activated HSCs in dysplastic nodules, compared to both c irrhotic nodules and HCC, supports our hypothesis concerning dysplasti c nodule development: that they arise as clonal expansions of neoplast ic hepatocytes in advance of, or parallel to, the development of cirrh osis.