Clonality of nodular lesions in liver cirrhosis and chromosomal abnormalities in monoclonal nodules of altered hepatocytes.

AIMS: To investigate the clonality and chromosome abnormalities of nodules of altered hepatocytes (NAH) in liver cirrhosis and determine whether there is a genetic link between monoclonal NAH and hepatocellular carcinoma (HCC). METHODS AND RESULTS: First, 93 nodules from nine hepatitis B virus (HBV)-related liver cirrhosis patients were dissected by laser microdissection. Next, genomic DNA was extracted, pretreated with Hpa II or Hha I, and amplified via nested polymerase chain reaction for the phosphoglycerate kinase and androgen receptor genes. Finally, the chromosomal aberrations of 12 monoclonal NAH were studied using array-based comparative genomic hybridization (array-CGH). Loss of X chromosomal inactivation mosaicism was demonstrated in three large regenerative nodules and 12 NAH with small cell change (SCC), indicating their neoplastic nature. Among the 60 NAH without SCC, 29 (48.33%) were shown to be monoclonal, whereas four glycogen-storing foci and 14 regenerative nodules were found to be polyclonal. Array-CGH analysis revealed chromosomal abnormalities in one NAH with SCC. Moreover, a part of chromosomal abnormalities in the NAH with SCC coincided with those in HCC. CONCLUSIONS: Some (48.33%) NAH in HBV-associated cirrhosis, particularly all those with SCC, are already neoplastic lesions. Occurrence of SCC is a late event during NAH progression, suggesting a premalignant phenotype.

Nodular regenerative hyperplasia is a new cause of chronic liver disease in HIV-infected patients.

OBJECTIVE: To describe and explain the syndrome of HIV-associated cryptogenic liver disease in eight consecutive patients suffering from portal hypertension. METHODS: The study was undertaken at a liver disease centre in Paris and involved eight of 97 consecutive HIV-infected patients presenting abnormal liver function tests and/or symptomatic portal hypertension of unknown origin. Serology, pathology, and liver function tests were performed. RESULTS: A clear nodular architecture corresponding to nodular regenerative hyperplasia was observed in seven patients and suggested in one, based on the presence of sinusoidal dilatation in a clinical context of portal hypertension, without overt liver disease. CONCLUSIONS: Nodular regenerative hyperplasia appears to be a new cause of portal hypertension in HIV-infected patients. This syndrome can be of critical importance as patients can be exposed to the significant complications of portal hypertension and to refractory ascites which may require liver transplantation.

Immunohistochemical detection of hcv in cirrhosis, dysplastic nodules, and hepatocellular carcinomas with parallel-tissue quantitative RT-PCR.

Hepatitis C virus is a major risk factor for hepatocarcinogenesis in humans. In situ detection of the virus in early sequential lesions of hepatocarcinogenesis could provide information about the role of the virus in the transformation and promotion process. Parallel in situ detection of HCV proteins and RNA in human tissues were performed in 55 posthepatitis C cirrhosis, 17 dysplastic nodules (DN), and 25 hepatocellular carcinomas (HCC), using immunohistochemistry and tissue quantitative RT-PCR. A consistent cytoplasmic hepatocellular staining was obtained in 73% of cirrhosis cases (with or without HCC) and in 55% DN cases. A few tumoral hepatocytes were unambiguously stained in 28% HCC. The percentage of positive cells and the intensity of immunostaining significantly decreased from cirrhosis to HCC through DN, whereas there was no difference in the prevalence of positivity or the number of viral copies between cirrhosis and HCC using tissue-quantitative RT-PCR. Finally, RT-PCR levels were found parallel with the immunostaining in cirrhosis but not in HCC. These results suggest that HCV protein synthesis may persist but be down-regulated during sequential hepatocarcinogenesis. A putative role of HCV proteins on cell proliferation and differentiation during the early steps of carcinogenesis cannot therefore be excluded.

Outcomes of dysplastic nodules in human cirrhotic liver: a clinicopathological study.

The number of dysplastic nodules detected clinically has increased since patients with hepatitis virus-associated cirrhosis, who are at increased risk for hepatocellular carcinoma (HCC), began to undergo regular cancer surveillance. Although it is potentially important to determine which type(s) of nodule may be prone to progress to HCC, outcomes of dysplastic nodules have not been fully investigated. This prompted us to examine the outcomes of dysplastic nodules in cirrhotic patients clinicopathologically. We studied 33 dysplastic nodules of <20 mm in maximum diameter, diagnosed by fine needle aspiration biopsy under ultrasonography (US). These nodules were clinically followed, mainly by US examination, for up to 70 months. When the nodules enlarged or exhibited changes on US, they were histologically reexamined by second biopsy. Surprisingly, 15 of the 33 nodules (45.5%) disappeared, 14 nodules (42.4%) remained unchanged, and only 4 nodules (12.1%) progressed to HCC. The latter 4 nodules were all hyperechoic on US and were composed of clear cells with fatty change or small cells with increased nuclear density, and in all 4 patients serum was positive for hepatitis C virus antibody. Univariate analyses revealed that, although not significant, the hyperechoic nodules or nodules with small cell change showed a higher HCC progression rate in comparison with the hypoechoic nodules or the nodules without small cell change. In summary, most of the dysplastic nodules we followed disappeared or remained unchanged, but some progressed to HCC. Hyperechoic nodules in patients with hepatitis C virus-associated cirrhosis, which show small cell change with increased nuclear density, may be prone to progress to HCC.