The incidence of hepatocellular carcinoma (HCC) appears to be increasing across the globe. Well-established protocols for screening are available, and the most common underlying liver problem associated with the development of HCC is cirrhosis. However, with few exceptions, patients without cirrhosis are generally not screened for HCC. Nodular regenerative hyperplasia (NRH) is not associated with the development of significant fibrosis or impaired liver synthetic function. The major clinical impact of NRH appears to be in the development of portal hypertension. Patients with NRH are also not recommended to undergo routine screening for the development of HCC. This report describes a case of a 44-year-old woman with NRH found to have de novo HCC. Emerging evidence suggest a possible pathogenetic relationship between NRH and HCC. The case described here and our review of the published work suggests that additional studies regarding the epidemiological association between NRH and HCC may change the current notion that NRH is not a premalignant lesion, and further studies assessing the utility of routine screening of NRH patients for HCC should be considered.

To evaluate the relationship between expression of ras, p53 and bcl-2 gene products and hepatocarcinogenesis since the endotoxemia produced from lipopolysaccharide administration and/or the hypophagocytic state of splenectomy significantly accelerated hepatocarcinogenesis induced by thioacetamide.

The hepatocarcinoma model was induced by 6-mo oral intake of 0.03% thioacetamide. During the hepatocarcinoma modeling process, rats were additionally treated with splenectomy and/or lipopolysaccharide administration. The techniques of flow cytometry, immunohistochemistry and immunoelectronmicroscopy were applied for quantitative analysis of the expression of oncogene proteins.

In this model system, overexpression of ras p21 protein mainly occurred in the precancerous cell population or in cells in the early stage of hepatocyte transformation. The levels of ras p21 declined when nuclear DNA aneuploidy increased. Expression of bcl-2 protein slowly and steadily rose, with more hepatocytes staying in S + G2M phases, as the hepatocarcinoma became more malignant. p53 was moderately expressed during hepatocarcinogenesis. There was no statistical correlation between endotoxemia levels and the changes in levels of ras, p53 and bcl-2 gene products.

Overexpression of oncogene ras p21 was considered likely to be a precursor of premalignant hepatocytes and possibly as responsible for the initiation of hepatocarcinogenesis. Bcl-2 protein expression is proportional to the severity of malignancy in hepatocarcinogenesis. p53 may be involved in a key pathway underlying the transformation and development processes of hepatocarcinoma. This study confirmed the hypothesis that there are multiple genes and multiple steps involved in hepatocarcinogenesis. Expression of oncogene proteins reflects the properties of the premalignant and malignant cells, but is not directly related to endotoxemia statistically.

In humans, the role of liver cell dysplasia as a preneoplastic lesion is still debated. A prospective, long-term, multicenter study was performed to establish whether liver cell dysplasia in cirrhosis is associated with an increased risk for hepatocellular carcinoma (HCC).

A cohort of 307 consecutive patients in whom liver cirrhosis was diagnosed by histology was investigated for development of HCC at 6-month intervals by ultrasonography and determination of alpha-fetoprotein levels.

At enrollment, liver cell dysplasia was found in 75 patients (24%) and in 53% (P < 0.01) of those positive for hepatitis B surface antigen (HBsAg). After a mean follow-up of 46 months, HCC was detected in 45 cases, and it was significantly more frequent in patients with liver cell dysplasia (P < 0.01) and HBsAg-serum positivity (P < 0.01). Multivariate analysis showed that liver cell dysplasia was the most important risk factor correlated with HCC development. HBsAg positivity and age over 60 years were also independent risk factors for HCC.

These results indicate that liver cell dysplasia is a major risk factor for HCC, and it should be looked for carefully by pathologists in liver biopsy specimens to identify patients requiring more intensive observation.

A proto-oncogene, bcl-2, encodes a protein that inhibits programmed cell death (apoptosis) and may play a role in cell and tissue differentiation. As bcl-2 appears to be involved in the turn-over of stem or precursor cells, it is thought to be operational in carcinogenesis pathways. However, apart from certain lymphomas, only limited data are available on the frequency of its expression in solid tumors. Immunohistochemical analysis with an antibody specific for bcl-2 protein was used to detect the protein in hepatocellular carcinomas and in one of the putative precursor lesions, liver cell dysplasia. We detected bcl-2 protein in 5 of 37 hepatocellular carcinomas. Immunoreactivity was not related to type, grade, or extent of PCNA staining of the tumours. No bcl-2 protein staining was observed in three types of liver cell dysplasia. Thus, bcl-2 is abnormally expressed in some hepatocellular carcinomas but not in potential tumour precursor cells.

The immunohistochemical determination of the accessory protein of DNA-polymerase delta (PCNA), a marker of an early S-phase of the cell cycle, was used to evaluate cell proliferation retrospectively in formalin-fixed, paraffin-embedded liver biopsy sections in a group of patients with cirrhosis of similar age and duration of follow up, and with no evidence of hepatocellular carcinoma (41), including 17 patients with and 24 without hepatocellular carcinoma appearance during follow up. Proliferation was expressed as total (PCNA-TOT) and strongly (PCNA-STRO) positive nuclei per 1000 hepatocytes. The presence of dysplasia was also recorded. Histological findings and biochemical data, at the time of liver biopsy, were compared in the two groups. While total PCNA positivities were not significantly different in the two groups, strong reactivity was significantly higher in patients who eventually developed hepato-cellular carcinoma (median 0.7 vs 2.6). Univariate analysis of histological and biochemical data at the time of biopsy, followed by a stepwise regression study, showed that the significant parameters for a time-dependent disease-free state were, in decreasing order: cholesterol, PCNA-STRO, PCNA-TOT and alpha foeto-protein. Other clinical, biochemical and histological parameters, including dysplasia, provided no further information. From these data, hepatocellular proliferation can be evaluated in patients with cirrhosis with a currently available technique. Patients with high cell proliferation are at increased risk of developing hepatocellular carcinoma and may require differentiated follow up.

The aim of this study was to determine the risk of developing primary liver cancer in patients with a diagnosis of alcoholism, liver cirrhosis, or both. Three population-based, mutually exclusive cohorts were defined on the basis of hospital discharge diagnosis between 1965 and 1983. Complete follow-up through 1984--excluding the first year of follow-up--showed that among 8,517 patients with a diagnosis of alcoholism, 13 cancers occurred, vs. 4.2 expected (standardized incidence ratio (SIR) = 3.1; 95% confidence interval (CI) = 1.6 to 5.3); among 3,589 patients with liver cirrhosis, 59 cancers occurred, vs. 1.7 expected (SIR = 35.1; 95% CI = 26.7 to 45.3), and among 836 patients with both diagnoses, 11 cancers occurred, vs. 0.3 expected (SIR = 34.3; 95% CI = 17.1 to 61.3). Thus, alcoholism alone entailed a moderately increased risk and alcoholism with liver cirrhosis did not increase the high relative risk for liver cancer more than cirrhosis alone. We conclude that alcohol intake may be a liver carcinogen only by being causally involved in the development of cirrhosis; and further, that the risk of developing liver cancer following cirrhosis in this population is similar to or higher than that after chronic hepatitis-B-virus infection in other Western countries.