Hepatocellular carcinoma (HCC) is one of the most common malignant
tumors in some areas of the world with an extremely poor prognosis. The major etiologic risk factors for HCC development include toxins (alcohol,
aflatoxin B1),
androgens and
estrogens, hepatitis B virus (HBV) and hepatitis C virus (HCV)
infection as well as various inherited metabolic disorders, such as alpha-1-antitrypsin deficiency and
hemochromatosis. The molecular pathogenesis of HCC development is very complex and involves alterations in the structure or expression of several tumor suppressor genes, oncogenes and, possibly, mechanisms leading to a genetic instability due to
mismatch repair deficiency or
chromosomal instability and
aneuploidy due to defective chromosomal segregation. Central to the molecular pathogenesis of HCCs are mutations of various genes and a genetic instability which in most cases result from chronic
liver disease and the associated enhanced liver cell regeneration and mitotic activity. The prognosis of HCC patients is generally very poor. Most studies report a five year survival rate of less than 5% in symptomatic HCC patients. Furthermore, these
tumors have been shown to be quite resistant to radio- or
chemotherapy. Investigations of the natural history and
clinical course of HCCs revealed long-term survival of patients only with small asymptomatic HCCs that could be treated surgically or by non-surgical interventions. Apart from exploring and refining new HCC treatment strategies, the implementation of existing and the development of novel measures to prevent HCC development are most important. Primary HCC prevention includes among others universal
hepatitis B vaccination,
antiviral therapy of patients with
chronic hepatitis B or C, reduction of food contamination with
aflatoxins, elimination of excessive alcohol etc. Also for some
genetic diseases there is the potential for HCC prevention by identifying affected family members at risk, such as patients with precirrhotic
hemochromatosis. Reduction of
iron overload by phlebotomy has been shown to eliminate the progression
hemochromatosis to
liver cirrhosis and HCC. Preventive measures, therefore, should have a major impact on the incidence of HCCs in patients with acquired and inherited
liver diseases. Further, the prevention of a local recurrence or the development of new HCC lesions in patients after successful surgical or non-surgical HCC treatment (
secondary prevention) is of paramount importance and is expected to significantly improve disease-free and overall patient survival. Based on rapid scientific advances, molecular diagnosis, gene therapy and molecular prevention are becoming increasingly part of our patient management and will eventually
complement and in part replace existing diagnostic, therapeutic and preventive strategies. Overall, this should result in a reduction of the incidence of HCCs, one of the most devastating
malignancies worldwide.