CLONAL ANALYSIS OF MACRONODULES IN CIRRHOSIS

Several arguments suggest that most hepatocellular carcinomas (HCCs) o ccurring in human cirrhotic livers arise from large hepatocellular nod ules or macronodules. Except for nodules with obvious features of HCC, there exist no consistent criteria enabling the differentiation betwe en benign regenerative and neoplastic, potentially malignant macronodu les, Surrogate markers able to accurately discriminate those lesions t hat will evolve toward a HCC are required. In this study, we investiga ted the clonality of 26 macronodules isolated from eight cases of expl anted cirrhotic livers in women by analyzing X-chromosome inactivation , as indicated by the methylation status of the human androgen recepto r gene (HUMARA). For each macronodule, a large set of pathological fea tures was evaluated and used to classify the macronodules into four gr oups: entirely benign-looking nodule (type 1), low-grade dysplastic no dule (type 2), high-grade dysplastic nodule (type 3), and HCC (type 4) . Clonal analysis showed that 14 macronodules (54%) were monoclonal an d 12 (46%) were polyclonal. Monoclonality was detected in 5 of 11 (45% ) nodules from groups of entirely benign-looking and low-grade dysplas tic nodules (types 1 and 2) and in 9 of 14 (60%) nodules from the grou p of high-grade dysplastic nodule and HCC (types 3 and 4). Neither the etiology of cirrhosis nor the size or histological classification of macronodules was correlated with the clonal status, In conclusion, clo nal analysis of macronodules enables the differentiation between mono- and polyclonal macronodules in cirrhosis, Because monoclonal macronod ules are prone to evolve to HCC, the determination of the clonal statu s of a macronodule could provide additional information for evaluating the prognosis of these lesions.