Trends in Hepatocellular Carcinoma Incidences in Japan Between 1996 and 2019

Background: While the proportion of hepatocellular carcinoma (HCC) cases with non-viral etiology continues to increase in Japan, the epidemiological trends in the sex and age distribution of new HCC cases remain unclear. This study examines the epidemiological trends, including the distribution of sex, age, and disease etiology, in HCC incidence over 24 years. Methods: Data of 20,547 newly diagnosed HCC patients in 1996–2019 at 19 institutions participating in the Liver Cancer Study Group of Kyushu were analyzed in this prospective study. We divided the study period into four 6-year quarters. HCC etiology was categorized as hepatitis B virus (HBV) infection, HBV+hepatitis C virus (HCV) infection, HCV infection, and both negative (non-BC). Results: The incidences of HCC per quarter of the study period were 4,311 (21.0%), 5,505 (26.8%), 5,776 (28.1%), and 4,955 (24.1%) cases, sequentially. Overall, 14,020 (68.2%) patients were male. The number of HCC cases in patients ≤ 50 years, 60–69 years, 70–79 years, and ≥ 80 years were 3,711 (18.1%), 6,652 (32.4%), 7,448 (36.2%), and 2,736 (13.3%), respectively. The average age of newly diagnosed patients increased in each quarter. HCC was associated with HBV, HBV+HCV, and HCV infections and non-BC in 2,997 (14.6%), 187 (0.9%), and 12,019 (58.5%), and 5,344 (26.0%) cases, respectively. The number of HCV-associated cases decreased in each quarter, while that of non-BC-associated cases increased. Conclusions: HCC incidence tends to increase in the elderly and in non-BC patients; in contrast, HCC incidence due to HCV tends to decrease. In countries where HCV infection is likely the predominant cause of HCC, similar trends in HCC incidence are anticipated in


Introduction
In 2018, liver cancer was the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related deaths worldwide, following lung, colorectal, and stomach cancers, with an estimated 841,000 new cases and 782,000 deaths annually. (1)(2)(3)(4) Primary liver cancer includes hepatocellular carcinoma (HCC, comprising 75-85% of cases) and intrahepatic cholangiocarcinoma (comprising 10-15% of cases), as well as some rare disease types. (1,2) The main risk factors for HCC, are chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), high alcohol intake, obesity, and type 2 diabetes. (1,2,(5)(6)(7)(8)(9)(10) Globally, HBV infection is the leading cause of incident liver cancer and associated mortality, followed by alcohol consumption, HCV infection, and other causes, which account for 33%, 30%, 21%, and 16% of the total burden of this disease, respectively.(2) The major risk factors associated with HCC vary between regions. In areas considered "high-risk" for HCC, for example, China and East Africa, the critical disease determinant is chronic HBV infection; in contrast, in countries such as Egypt or Japan, HCV infection is likely the predominant cause. (1,2) Recent developments in HCV treatment suggest that a large proportion of liver cancer cases can be prevented. (1,11,12) An interferon (IFN)-free direct-acting antiviral agent (DAA, daclatasvir plus asunaprevir) was approved for use in Japanese patients with HCV infection in July 2014. Therefore, high rates of sustained virological response (SVR) have been achieved in patients with chronic HCV infection. (13)(14)(15)(16) Recently, DAAs have been introduced as an easy and safe antiviral oral therapy for HCV infection. (16) In Japan, viral hepatitis remains the leading cause of HCC; however, the decrease in the prevalence of HCV-related HCC has changed the distribution of the disease etiology.(7) Speci cally, while the proportion of HCC cases with non-viral etiology continues to increase in Japan,(17) epidemiological trends in sex and age distribution of new HCC cases remain unclear. Therefore, this study aimed to examine the epidemiological trends in HCC incidence in Japan over the past 24 years (1996-2019

Diagnosis
We diagnosed HCC by measuring alpha-fetoprotein and des-gamma-carboxy prothrombin serum levels and via imaging techniques, including ultrasonography, contrast-enhanced computerized tomography, magnetic resonance, and/or tumor biopsies.

Etiology
The etiology of HCC was categorized as follows: HBsAg positive and HCV-antibody negative (HBV), both HBsAg and HCV-antibody positive (HBV + HCV), HBsAg negative and HCV-antibody positive (HCV), and both HBsAg and HCV-antibody negative (non-BC).

Statistical analysis
Inter-quarter differences in sex and disease etiology frequencies were calculated using the chi-square test, and age differences were examined using the one-way analysis of variance (ANOVA) and post-hoc analysis (Bonferroni) methods. All the statistical analyses were performed using JMP software version 15 (SAS Institute, Inc., Cary, NC, USA). P-values of < 0.05 were considered signi cantly different.
Abbreviations; non BC=both hepatitis B surface antigen and HCV−antibody negative.  Data are presented as counts (%) or mean ± standard deviation.  Fig. 1, 2). There were more female patients in the second quarter than in the rst (P = 0.0020, Table 2); concurrently, there were more male patients in the fourth quarter than in the third (P = 0.0231, Table 2). Therefore, there was no noticeable change in the sex distribution of HCC incidence throughout the study period (Fig. 1).

Discussion
In the present study, we examined epidemiological trends in HCC incidence, including the distribution of sex, age, and disease etiology over 24 years. Although there was no noticeable change in the sex distribution of HCC incidence throughout the study period, the average age of newly diagnosed HCC patients increased along the quarters. The number of HCV-associated cases decreased over time, while non-BC-associated cases increased over time. Moreover, there was a signi cant association between patient age and disease etiology.
In July 2014, DAAs were approved for Japanese patients with HCV infection. The development of DAAs has made it easier to treat HCV infections in the elderly and cirrhotic patients, and not only at specialized high-volume centers but also at general practice clinics.(16) As a result, the eradication of HCV infection has been reported to reduce HCC risk. (19) In the present study, the number of new HCC cases increased from the rst to the third quarter (1996-2013), decreasing, after that, from the third to the fourth quarter (2014-2019). This relative reduction in HCC cases observed in the fourth quarter (2014-2019) may be associated with improved management of HCV infections with DAAs.
HCC incidence is 2-3-fold higher among men than women in most regions worldwide, while liver cancer ranks fth and second in the global number of cases and associated deaths among men, respectively. (1) Meanwhile, liver cancer incidence is forecasted to decrease among men in Japan and China and women in Japan and Denmark. (2) In the present study, there was no association between sex and HCC incidence over time. Therefore, while the incidence of HCC is expected to decrease among both men and women in Japan, a sex gap in the burden of this disease remains.
In the present study, patient age among newly diagnosed HCC cases increased over time. Meanwhile, the number of HCV-associated HCC cases decreased over time, in contrast to non-BC-associated cases, which increased over time. Additionally, we observed an association between patients' age and disease etiology. Overall, HBV-associated HCC patients tended to be younger (mean age ± SD at onset 60.2 ± 10.9 years) than HCV-associated HCC patients (mean age ± SD at onset 69.7 ± 8.8 years). Therefore, it was predicted that the age of new-onset HCC patients would decrease by the decrease in new-onset HCVassociated HCC cases; however, the age of new-onset HCC patients has instead increased. This is because in the present study, the proportion of non-BC-associated HCC cases (mean age ± SD at onset 71.0 ± 9.9 years) was higher than that of HCV-associated HCC cases (mean age ± SD at onset 69.7 ± 8.8 years), and it continued to increase. In the future, as the incidence of non-BC-associated HCC increases, the age of the incidence of HCC will also increase.
The use of DAAs in HCV-infected patients has been shown to lower the risk of liver-related events, including HCC. (20) However, despite an SVR of > 95%, the HCC risk in DAA-treated HCV-infected patientswith advanced brosis or cirrhosis-was shown to remain between 0.3 and 1.8% per year. (21,22) The current European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD) guidelines recommend lifetime surveillance of HCV-cured patients with cirrhosis. (23,24) Identifying clinical and molecular markers associated with HCC risk among these patients may improve the treatment effectiveness and resource allocation. (23,24) Studies on epidemiology and precision medicine may help inform, re ne, and customize clinical guidelines for disease surveillance in this context. (25) In the present study, the average age of patients newly diagnosed with HCC and those newly diagnosed with non-BC-associated HCC increased over time, while the patients newly diagnosed with HCVassociated HCC decreased over time. The increasing age of patients newly diagnosed with non-BCassociated HCC is likely to become a public health concern in the future. Recent studies have reported an association between metabolic syndrome (diabetes and obesity), excessive alcohol consumption (alcoholic fatty liver disease), and high-calorie intake (nonalcoholic fatty liver disease), and HCC risk in This study had some limitations. Firstly, while the hepatic reserve effect in liver carcinogenesis was known, in the present study, we focused mainly on three factors, sex, age, and disease etiology. Secondly, we did not investigate the size or number of HCC incidences, namely, its stages. Future studies investigating the correlation between the HCC stage and sex, age, or disease etiology are required.
In conclusion, the present study suggests that HCC incidence in the elderly and due to non-BC tended to increase, while the incidence of HCV-associated HCC tended to decrease between quarters. In countries where HCV infection is likely the predominant cause of HCC, like Japan, similar trends in HCC incidence are anticipated in the future.

Declarations
Con ict of interest and Ethical Standards: The authors have no con icts of interest to declare.
Informed Consent: Informed consent was obtained from all individual participants included in the study.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ethics Committee of the National Hospital Organization Nagasaki Medical Center, no. 2020053) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Data Availability: The data that support the ndings of this study are available from the corresponding author, HY, on reasonable request. The authors have no con icts of interest to declare. Funding: Not applicable  Correlation between patient age and disease etiology. 60.2 ± 10.9 years in HBV to 63.6 ± 10.0 years in HBV+HCV, P<0.0001; 63.6 ± 10.0 years in HBV+HCV to 69.7 ± 8.8 years in HCV, P<0.0001; 69.7 ± 8.8 years in HCV to 71.0 ± 9.9 years in non-BC, P<0.0001, respectively (mean ± standard deviation).

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