Nucleolar hypertrophy correlates with hepatocellular carcinoma development in cirrhosis due to HBV infection

Abstract

Patients with cirrhosis are at significant risk for hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the relationship between the percentage of hepatocytes showing nucleolar hypertrophy and the development of HCC in cirrhosis of different causes. A total of 111 cirrhotic patients were studied, with a mean follow-up period of 83.3 months. Histologic sections from liver biopsy specimens were silver stained for selective visualization of the nucleolus; the nucleolar area was measured by image cytometry. Nucleoli with a size of 7 m 2 or greater were considered to be hypertrophic. The nucleolar index was obtained by calculating the percentage of hepatocytes disclosing a nucleolar area of 7 m 2 or greater. During the observation time, HCC was diagnosed in 39 of 111 patients. The incidence rate of HCC was greater in patients with nucleolar indexes of 2.5 or greater than in patients with nucleolar indexes of less than 2.5 (16.49%/y vs. 3.41%/y, respectively; P < .0001). The capacity of the nucleolar index to predict HCC development was separately tested in groups of patients divided by etiology, and it was found to be particularly relevant in hepatitis B virus (HBV)-related cirrhosis (P ‫؍‬ .0006). Among patients with hepatitis C virus (HCV) infection, high nucleolar-index values were associated with a greater risk for HCC development, but the difference in the incidence rate of HCC between groups with a nucleolar index of 2.5 or greater and less than 2.5 was not statistically significant (P ‫؍‬ .0944). In conclusion, our results have shown that high percentages of hepatocytes showing nucleolar hypertrophy significantly predict HCC development in patients with HBV infection, whereas their predictive value in HCV-related cirrhosis seems to be lower. (HEPATOLOGY 2003;37:72-78.) H epatocellular carcinoma (HCC) is one of the most prevalent tumors in humans. It is particularly common in certain regions of Asia and sub-Saharan Africa, but over the past decades its incidence has been increasing also in Western countries. 1 The prognosis of HCC is poor, and the application of various screening and treatment protocols during the past 25 years does not appear to have significantly improved the chances of survival of HCC patients. 2 Most HCCs occur in association with underlying chronic liver disease and, in more than 80% of cases, arise in cirrhotic liver. 3 The major risk factors affecting HCC development in cirrhotic patients are reported to be male sex, old age (over 60 years), alcohol abuse, and viral infection caused by hepatitis B virus (HBV) and hepatitis C virus (HCV). In addition to these well-established factors, hepatocyte proliferation rate 4-7 and the presence of large cell changes (LCC) 8,9 have been suggested as predictors of HCC occurrence in cirrhosis.Nucleolar hypertrophy or prominence, as frequently referred by pathologists, represents a morphologic feature that characterizes both proliferating and dysplastic hepatocytes. It is well known that after hematoxylin-eosin staining, nucleo...

Nucleolus, Ribosomes, and Cancer

“…59 Interestingly, there is evidence that, as far as chronic liver diseases from viral infections are concerned, an up-regulation of hepatocyte ribosome biogenesis is constantly associated with later onset of HCC. 60,61 Both hepatitis B (HBV) and hepatitis C (HCV) viruses, which are responsible for the development of chronic liver disease, have been shown to up-regulate the activity of the RNA polymerase I and III. 62,63 The HBV X protein, required for viral replication and correlated with the hepatocarcinogenesis of individuals chronically infected with HBV, modulates RNA polymerase I-dependent rRNA transcription by enhancing the rRNA promoter activity, 62 and activates specific RNA polymerase III-dependent promoters.…”

“…A series of studies performed to define whether nucleolar changes might be related to neoplastic transformation in chronic liver disease from viral infection demonstrated that the presence of abnormally enlarged hepatocyte nucleoli represent a very strong risk factor for developing HCC, mainly in the HBV-related cirrhotic livers. 61 In other words, only those chronic liver lesions in which the viral infection induced hypertrophy, and consequently a functional up-regulation of nucleoli, would be susceptible to cancer development.…”

Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress

“…The 5-year cumulative HCC incidence in cirrhosis is between 10% and 30% in HBV and HCV infection, depending on the geographic region, approximately 20% in hereditary hemochromatosis and 8% in alcoholic cirrhosis (Fattovich et al, 2004). Predictors of HCC in cirrhosis include the severity of liver disease determined by the ChildPugh score (Bolondi et al, 2001), the disease activity, reflected by serum transaminase activities (Benvegnu et al, 1994;Tarao et al, 1999), and some histological criteria, such as the presence of large cell changes (LCC) (Borzio et al, 1995;Ganne-Carrié et al, 1996), macronodules (Borzio et al, 2003) and markers for hyperregeneration (Donato et al, 2001;Trerè et al, 2003).…”

Research Article: Correlation of nucleolar morphology to transformed properties of Simian Virus 40 T antigen expressing cells

“…The findings reported here, using a T antigen transformed cell model, lay the groundwork for determining the cellular activities that are involved in increased nucleolar size and determining the relationship of nucleolar hypertrophy to transformation. Trere et al (2003) suggest that the nucleolar hypertrophy may be the result of transactivation of the RNA Polymerase I promoters by the HBX protein. However, we have shown that SV40 T antigen transactivates ribosomal promoters yet several mutants that are compromised in this activity are competent in cellular transformation (Cavender et al, 1999).…”

“…For instance, the tumor virus Hepatitis B (HBV) is known to enhance rRNA promoter activity, increase ribosome production, and in some cases lead to cancer (Wang et al, 1998;Cavender et al, 1999). Studies have shown that chronic viral liver diseases, such as HBV, up-regulate and enlarge nucleoli and are associated with the eventual development of hepatocellular carcinomas (Trere et al, 2003). Thus, several of these investigations suggest that increased numbers of nucleoli represent the key variable in tumor cell growth; others suggest that the predominant factor is increased nucleolar size ).…”