Hepatocellular carcinoma in primary biliary cirrhosis at an early histologic stage: coincidental or causally related?

Recent studies have shown that hepatocellular carcinoma (HCC) arises relatively frequently at an advanced, cirrhotic stage of primary biliary cirrhosis (PBC) without evidence of hepatitis viral infection (1–3), though the precise incidence of such association remains unclarified. Shibuya et al reported that most HCC associated with PBC arise at the cir-rhotic stage and in males gender and the risk of HCC in patients with late stage PBC is relatively comparable to HCV-related cirrhosis (2). Long-standing hepatocellular damage and regeneration of hepatocytes seem to be causally related to hepatocarcinogenesis at the cirrhotic stage of PBC as speculated in other chronic liver diseases with eventual development of HCC (1, 2). In comparison with HCC in hepatitis virus-related cirrhosis, HCC detected in PBC cases was generally small and HCC itself was not always lethal in these cases (2, 3); rather, the majority of such patients died of hepatic failure due to advanced cirrhosis of PBC. In fact, small HCCs were detected incidentally at autopsy or transplanted livers (3). Shibuya et al reported that superimposition of hepatitis viral infection could be a synergistic factor for HCC development in PBC (2). Regarding preneoplastic lesions in the development of HCC in cirrhotic PBC, dysplastic nodules which are now proposed as a preneoplastic lesion of HCC in hepatitis virus related chronic liver diseases have also been reported in advanced stages of PBC (4). In fact, foci of classical HCC within dysplastic nodules are reported in cirrhotic PBC livers (4), suggesting that the dysplastic nodule-HCC sequence may be one type of HCC development in advanced PBC. As for HCC arising in the non-cirrhotic stage of PBC, there have been few cases in the literatures (5). The background liver pathology preceding or related to the occurrence of HCC has not been described in detail. However, according to the literature or based on our experience, the following candidate histologic lesions are considerable for the development of HCC. First, nodular regenerative hyperplasia of the hepatocytes (NRH) can be such a lesion. Occurrence of NRH is established in the non-cirrhotic liver of PBC including stage I (6), and NRH associated with PBC at early histo-logical stages may reflect an active hepatocellular proliferation (6). In non-PBC cases, there have been several studies suggesting that NRH is a preneoplastic lesion of HCC (7). Particularly, NRH with dysplastic changes can be a lesion associated with HCC development. That is, Nzeako et al reported that liver …