2. Hepatocellular carcinoma (HCC) is the fifth most frequent cancer in the world and the third most common cause of cancer mortality.

3. The early stages of hepatocarcinogenesis in human chronic liver diseases are characterized by the emergence of preneoplastic lesions of which some will eventually develop into hepatocellular carcinoma (HCC).

4. Basic studies on the genetic and epigenetic alterations of these preneoplastic lesions may eventually lead to new therapeutic strategies.

5. Clinicopathological studies are also important in order to determine optimal management of patients with apreneoplastic lesion.

6. The microscopical small-cell dysplastic focus is the smallest morphologically recognizable precursor lesion of HCC and therefore is a logical target of study to elucidate the earliest events in hepatocarcinogenesis.

7. In contrast, large-cell dysplasia is not a precursor lesion, but appears to be of clinical value because of its good predictive value for development of HCC.

8. Dysplastic nodules (DNs) are macroscopically recognizable precursor lesions of HCC and high- grade DNs (HGDNs) have a risk of malignant transformation.

9. Detection of DNs and correct differentiation from small HCC (0.2 cm) is sometimes difficult, especially when only imaging techniques are used.

10. Additional clinicopathological studies on identification and optimal treatment of DNs are necessary.

11. Molecular studies on HGDNs and small HCCs may yield much information on the genetic mechanisms involved in the transition from severe dysplasia to early malignancy

12. In contrast, currently available data indicate that (large) regenerative nodules do not represent a distinct step in hepatocarcinogenesis.

13. HCCs mostly develop in patients with chronic liver disease caused by viral hepatitis, alcohol abuse and inborn metabolic errors.

14. Eighty percent of all HCCs worldwide occur when the underlying chronic liver disease has reached the cirrhotic stage.

15. These numbers and percentages clearly illustrate the important impact of this malignant tumor on public health and underscore the relevance of studies focusing on the development and evolution of HCC

16. The development and progression of a HCC in a chronically diseased liver, frequently referred to as ‘hepatocarcinogenesis’, is a multistep and long-term process characterized by the progressive accumulation and interplay of genetic alterations

17. causing aberrant growth and malignant transformation of liver parenchymal cells, followed by vascular invasion and metastasis (3). Hepatitis B virus (HBV), hepatitis C virus (HCV) and alcohol

18. a large geographic variation ranging from 120 in Eastern Asia to two in Australia. The incidence of HCC in Europe and the USA is rather low but steadily increasing, The annual rate of HCC per 100 000 person-years shows are some of the most frequent hepatocarcinogens in humans and they probably cause direct damage to the DNA.

19. Recent studies of gene expression patterns using microarray analysis suggest that each HCC has its own unique profile and history of genetic alterations

20. These carcinogens also cause indirect damage and impaired repair of DNA via chronic necro-inflammation, intensive regeneration and fibrogenesis

21. To render things even more complex, there isnot only heterogeneity between HCCs, but oftenalso within a given tumor: the growth and progressionof a well- differentiated HCCs usuallyoccurs via the emergence of less differentiated clonal areas within the tumor resulting in a tumoral mosaic of multiple differentiation stages.

22. Although a numberof general pathways have been discovered the types of genetic alterations and their sequence of occurrence are very variable

23. at least partly because of the high number of persons infected with HCV in recent decades. At the turn of the millennium, the annual incidence of HCC in the United States has reached 5.9/100 000 inhabitants