Clonal analysis of macronodules in cirrhosis

Abstract

Several arguments suggest that most hepatocellular carcinomas (HCCs) occurring in human cirrhotic livers arise from large hepatocellular nodules or macronodules. Except for nodules with obvious features of HCC, there exist no consistent criteria enabling the differentiation between benign regenerative and neoplastic, potentially malignant macronodules. Surrogate markers able to accurately discriminate those lesions that will evolve toward a HCC are required. In this study, we investigated the clonality of 26 macronodules isolated from eight cases of explanted cirrhotic livers in women by analyzing X-chromosome inactivation, as indicated by the methylation status of the human androgen receptor gene (HUMARA). For each macronodule, a large set of pathological features was evaluated and used to classify the macronodules into four groups: entirely benignlooking nodule (type 1), low-grade dysplastic nodule (type 2), high-grade dysplastic nodule (type 3), and HCC (type 4). Clonal analysis showed that 14 macronodules (54%) were monoclonal and 12 (46%) were polyclonal. Monoclonality was detected in 5 of 11 (45%) nodules from groups of entirely benign-looking and low-grade dysplastic nodules (types 1 and 2) and in 9 of 15 (60%) nodules from the group 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, clonal analysis of macronodules enables the differentiation between mono-and polyclonal macronodules in cirrhosis. Because monoclonal macronodules are prone to evolve to HCC, the determination of the clonal status of a macronodule could provide additional information for evaluating the prognosis of these lesions. (HEPATOLOGY 1998;28:953-958.)

Pathologic diagnosis of early hepatocellular carcinoma: A report of the international consensus group for hepatocellular neoplasia # †

“…Evidence accumulated in the last two decades strongly favors the existence of a sequence of events in hepatic nodules that precedes the emergence of hepatocellular carcinoma (HCC), [1][2][3][4][5][6][7][8][9][10] and these lesions are recognized as precursors of HCC. However, from the beginning of their recognition, there has been considerable confusion concerning nomenclature and diagnostic approaches to these hepatic nodules.…”

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

“…Cirrhosis is the histological end point of this chronic inflammatory and fibrotic process, and liver cell DNA synthesis is indeed increased in cirrhotic, as compared to normal, livers. Clonal analysis of some cirrhotic nodules clearly indicates monoclonal cell expansion (Paradis et al, 1998;Kojiro and Roskams, 2005); however, the underlying chronic active hepatitis is the main driving carcinogenic factor and this accounts for the higher risk of tumor occurrence in patients with active cirrhosis. Animal models for Hepadna virus infection have provided fundamentally important information on these issues.…”

Fractional allelic loss in non-end-stage cirrhosis: Correlations with hepatocellular carcinoma development during follow-up

“…When a distinct pattern of genetic abnormalities is acquired, then it is likely to expand in morphologically recognizable hepatocellular preneoplastic/ dysplastic and neoplastic nodules, as already suggested. 13,27,33 In the current clinical management of cirrhotic patients, predictive markers of neoplastic transformation are urgently needed for proper follow-up and therapeutic options. Some of these have already been proposed, such as the serological alpha-fetoprotein value, the morphological detection of large cell changes, and the hepatocellular growth fraction.…”