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See article in J. Gastroenterol. Hepatol. 2002; 17: 1229–35

Chronic hepatitis C virus (HCV) infection is a predominant cause of chronic liver diseases that progresses to hepatocellular carcinoma (HCC) at a high rate in Japan. In fact, 84% of Japanese HCC patients were reported to be seropositive for anti-HCV antibody.1 Since 1992, patients with chronic HCV infection have been treated with interferon (IFN)-α or -β covered by the public health insurance in Japan. Recently, the IFN monotherapy has been replaced by IFN-α-2b plus ribavirin therapy.

The risk factors for HCC development in patients with chronic HCV infection were reported to be male sex, excessive alcohol intake, older age, sporadic infection, advanced histological staging, and lower platelet counts.2–5 In IFN-treated chronic hepatitis C patients, advanced hepatic fibrosis and decreased platelet counts, reflecting the stage of liver disease, were the significant independent factors for HCC development.6,7 Interestingly, higher hepatic expression of Fas protein before IFN therapy is also associated with HCC development.6 Ikeda et al.8 reported that the hepatocellular carcinogenesis rates in the IFN-treated and -untreated chronic hepatitis C patients were 7.6% and 12.6% at the 10th year, respectively. In particular, the incidence of HCC in sustained responders (SR) was significantly decreased as compared with that in non-responders or patients without IFN therapy.9–13 In this point, the efficacy of IFN therapy on chronic hepatitis C is superior to that on chronic hepatitis B, because contradictory results exist concerning the efficacy of IFN therapy on hepatocellular carcinogenesis in chronic hepatitis B patients.14–17

Although a significant decrease in the incidence of HCC in SR to IFN therapy has been observed in addition to improving liver biochemistries,9–13 HCC is detected in some cases of complete responders (CR) even several years after successful IFN therapy.18–24 In the previous volume of the Journal, Yamaura et al. reported a case of a CR who developed a small HCC 77 months after the completion of IFN therapy.21 In this case, interestingly, eradication of HCV was confirmed in the HCC tissue along with the non-tumorous liver tissue or the serum as examined by reverse transcription–polymerase chain reaction for HCV RNA. A similar CR case showing no detectable HCV RNA in the HCC tissue was also reported by Yamaguchi et al.19 It is reasonable to consider that HCC found in successfully IFN-treated chronic hepatitis C patients after finishing IFN may have already existed in the HCV-infected liver prior to IFN therapy.

Then, how long do the CR/SR patients have to be followed after IFN therapy? More than 40 cases of HCC in CR/SR patients have been reported in Japan, and the interval between the end of IFN therapy and the detection of HCC did not exceed 5 years in 43/46 (93%) of CR/SR24 or 22/24 (92%) of CR21 patients. A similar result was observed in our study (unpubl. data, 2000). Therefore, all chronic hepatitis C patients, particularly the male, need to be followed carefully for at least 5 years, even after a successful IFN therapy. In addition, SR/CR patients with moderate or severe liver fibrosis should be followed for at least 10 years because HCC can be detected more than 5 years after finishing IFN therapy.19,21

It is generally believed that small HCC, particularly those smaller than 1 cm in diameter, are composed of well-differentiated tumor cells, which are often indistinguishable from adenomateous regenerative nodules.25 When the HCC increases in size, dedifferentiated tumor cells grow in the nodule replacing the well-differentiated tumor cells and progressing to the ‘advanced tumor’.26 In Japan, Majima27 reported that the doubling time (DT) of HCC less than 3 cm in diameter varied from 14 days to 230 days with the average of 93.0 days by measuring the diameter of the tumor with ultrasonography. This author also commented that dedifferentiated tumors tended to grow rapidly, which was consistent with another report showing that well-differentiated and hypovascular HCC had a significantly longer DT than hypervascular HCC.28 Ebara et al.29 reported that the mean DT of HCC less than 3 cm in diameter was 6.5 ± 5.7 months, approximately 195 ± 171 days. Barbara et al.,30 in an Italian population, reported that the mean DT of HCC less than 5 cm in diameter was 204 ± 135 days. Although the DT of HCC varies considerably from case to case, it can be speculated that the mean DT of small, well-differentiated HCC probably exceeds 90 days.

In the process of the development of HCC, many factors affect the growth rate of the tumor, including the apoptosis-inducing agents. We calculated the growth interval between a single HCC cell and a HCC tumor 1 cm in diameter on the assumption that the DT of HCC was 90 days and concluded that it might be more than 6 years.10 Apart from inhibiting the intrahepatic production of growth-promoting factors for HCC in CR/SR patients, IFN itself may delay the growth of HCC, because IFN has a growth-inhibitory effect. Therefore, the actual mean time for the tumor formation of HCC 1 cm in diameter may be longer than 6 years, and it is reasonable to consider that almost all HCC detected within 10 years of the follow-up period after IFN therapy had already developed prior to IFN therapy.

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