Hepatocellular carcinoma: Recent trends in Japan

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During the past 20 years, primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), has ranked third in men and fifth in women as a cause of death from malignant neoplasm in Japan. The numbers of deaths and death rate from HCC showed a sharp increase beginning in 1975. Although both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are important causes, HCV-related HCC has accounted for most of the recent increase and now represents 75% of all HCC in Japan. Geographically, HCC is more frequent in western than eastern Japan, and the death rate of HCC in each prefecture correlates with prevalence of anti-HCV. Among patients with HCV-related HCC, a history of blood transfusion was a relatively important source of infection in the 1990s, whereas community-acquired infections increased after 2000. There was a negative correlation between the duration from onset of infection to development of HCC and the age at onset. Interferon therapy for chronic hepatitis C has reduced the risk for HCC, indicating that early detection of HCV carriers and better treatment will contribute to improved outcomes. Nationwide screening for HCV and HBV began in 2002 in Japan, and reduction of HCC is anticipated. Further research should focus on mechanisms of carcinogenesis by HCV and HBV, development of more effective treatments, and establishment of early detection and treatment approaches. Better understanding of HCC unrelated to HCV and HBV and possibly because of steatohepatitis and diabetes should also be a major concern in future studies.

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Changes in deaths and the death rate of primary liver cancer in the past 44 years

Changes in annual death totals of primary liver cancer in different age groups between 1958 and 2001 are shown in Figure 1. The total number of deaths from HCC was stable and less than 10,000 people per year until 1975 when numbers increased sharply. The increase in 1995 was probably due to the change in International Classification of Disease (ICD) codes from ICD9 to ICD10. Peak numbers of deaths from HCC were in patients below the age of 69 years until 1999, when the peak age rose to over 70

Changes in prevalence of HBV-related and HCV-related HCC in the past 14 years

A nationwide survey of primary liver cancer has been conducted every 2 years since 1968 by the Liver Cancer Study Group of Japan. The results of survey up to 1999 have been reported in several publications.3, 4, 5 A total of 99,196 patients have been entered in this registry between 1980 and 1999. Of the total, 95% (93,901) were diagnosed as HCC histologically and clinically, indicating that the majority of primary liver cancer in Japan is HCC.

Five serologic surveys performed between 1990 and

Geographic variation in liver cancer and HBV/HCV infection

Although Japan is a relatively small country with a homogenous population, the incidence of HCC varies greatly among different regions. The Vital Statistics of Japan for 2001 published in 2003 by the Japanese Ministry of Health, Labor, and Welfare on the incidence of deaths as a result of HCC in its 48 prefectures shows a gradient increase of death rates for HCC along the axis of Japan from east to west (Figure 3).8 The average age-adjusted death rate of HCC among the 48 prefectures was 27.3

Changes in clinical characteristics of HBV- and HCV-related HCC

Results of cross-sectional studies of HCC conducted at Shinshu University are shown in Table 1.6, 7 Men accounted for the majority of cases of both HBV- and HCV-related HCC for all age groups. The proportion of cases of HCC in men was 81% in 1982, 90% in 1990, but only 72% in 2003, indicating a recent relative increase in cases among women in recent years. The average age of diagnosis of HBV-related HCC was similar in all 3 time periods. In contrast, the average age of patients with HCV-related

Risk factors for HCC

There are 3 major categories of risk factors that appear to influence the incidence of HCC: host, viral, and environmental factors. Host factors include gender, age, ethnicity, stage of liver disease, diabetes mellitus, and hepatic steatosis. Viral factors include genotype, viral levels, DNA integration, rates of mutation, and coinfection with other agents. Environmental factors include toxins such as aflatoxin B1, medications and hormones, and nicotine or smoking.

Treatment of HCC and survival between 1988 and 1999

The report of the 15th follow-up survey of primary liver cancer conducted by the Liver Society Study Group of Japan provided information on the survival rates of patients who underwent hepatic resection (N = 21,711), ethanol injection therapy (N = 12,876), transcatheter arterial embolization (TAE) (N = 22,869), and microwave coagulation therapy (N = 1751).5 All patients were registered between 1988 and 1999, excepting those undergoing microwave coagulation who were registered only after 1992.

Measures to reduce the occurrence of HCC

In 1999, the Japan Society of Hepatology published the “Liver Cancer White Paper” aimed at promoting a national effort to eradicate liver cancer. The White Paper proposed 4 steps: (1) improve sanitary conditions and better patient information on means to prevent hepatitis virus infection; (2) routine screening for HBsAg and anti-HCV of the general population as well as in high-risk groups, including those having a history of blood transfusion, major surgery, tattooing, and injection drug use to

Antiviral therapy suppresses the incidence of HCC

A summary of different studies on the incidence of HCC among patients with HCV-related cirrhosis who were treated with interferon in Japan is noted in Table 2. Nishigutchi et al41 conducted a prospective, randomized controlled trial that examined the effects of therapy on development of HCC. In that study, 100 patients with compensated cirrhosis were randomized to receive 6 million units (MU) of interferon alfa 3 times weekly for 3 to 6 months or prospective monitoring without treatment. After

Future research needs

The origin of the majority of cases of HCC in Japan is HBV and HCV infection. The molecular mechanisms responsible for carcinogenesis with HCV and HBV infection have not been elucidated. Such clarification is urgently needed in that it may provide insights into new approaches to therapy and prevention of HCC.

With the introduction of passive and active immunization against HBV infection, especially in the case of perinatal transmission by carrier mothers to their infants, the prevalence of

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    Supported in part by a grant from the Ministry of Health, Labor and Welfare of Japan and a grant from the Ministry of Education, Culture, Sport, Science and Technology of Japan (No. 15590633).

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