The frequency of the EHPM site in HCC patients varies according to the geographical setting of the study. Genitourinary (mainly prostate) and colorectal tumors are described as the most prevalent sites in Western series [1
]. Previous Japanese studies consistently reported gastric cancer as the most frequent EHPM in HCC patients [2
]. In fact, gastric cancer is occasionally detected during clinical followup for HCC, and thus this theme was focused in the present study.
Chronic infection with HBV and/or HCV is a risk factor and the most influential determinant for HCC. However, the relationship between EHPM and viral hepatitis in patients with HCC has not been thoroughly examined in previous studies. The systemic effects of viral infection may play a role in development of EHPM. Bruno et al. hypothesized that HCV infection could play an important role not only in the development of HCC, but also of EHPM, based on the finding that all five of their EHPM cases were HCV Ab-positive [13
]. Several studies have noted HCV infection might be involved in the pathogenesis of B-cell lymphomas [17
]. Di Stasi et al. reported that the most common EHPM in their HCC cohort was B-cell lymphoproliferative disorders, with a higher incidence than expected in the reference population, and that 50% of patients with B-cell lymphoproliferative disorders had an HCV infection [9
]. However, most other series reported relatively low incidence of B-cell lymphoproliferative disorders in HCC patients [1
The prevalence of hepatitis virus infection also varies geographically; the prevalence of chronic hepatitis B infection is particularly high (10–20%) in China and in sub-Saharan Africa, while it is low (0.2–0.5%) in North America, Northern, Western, and Central Europe, and Australia [19
]. HCV also has clear differences in genotype prevalence in different geographic regions [20
]. Around 80% of HCC cases in Japan are related to HCV infection (approximately 70% of infections are caused by genotype 1b), but the prevalence of HBV is relatively low [21
]. The incidence of gastric cancer in Japan is extremely high in comparison to that in Western countries [22
]; therefore, the reported high incidence of gastric cancer among Japanese patients with HCC may simply reflect the high incidence of gastric cancer in general in the Japanese population. However, the current study found that most of these gastric cancers were not associated with Helicobacter pylori
infection which is considered as one of the main cause of the gastric cancer. A study from Taiwan has also reported gastric cancer as the most common EHPM among HCC patients [7
]. The most common HCV genotype in Taiwan is 1b (50% to 70%), which is similar to the situation in Japan [23
]. This may suggest a relationship between gastric cancer and HCV, especially for infection with genotype 1b.
One unexpected finding was that HBV infection showed the tendency of correlation with urinary tract cancer (urothelial carcinoma) in this study. The association between HBV and urothelial carcinoma has not been thoroughly investigated. A few reports presented suggestive evidence for a relationship of HBV infection and urothelial carcinoma. A report from Taiwan documented that the most common postrenal transplantation malignancies are HCC and urothelial carcinoma and that the high rate of HBV and HCV in Taiwan may explain this finding [24
]. One case report describes HCC and urothelial carcinoma that synchronously developed in a patient with a chronic hepatitis B infection [25
]. Identification of a relationship between HBV infection and the pathogenesis of urothelial carcinoma would be clinically important. Cohort studies from other countries, especially from areas with a high prevalence of chronic hepatitis B infection, such as China and sub-Saharan Africa, would provide important data to help this potential relationship.
Another unexpected finding was that breast cancer showed the tendency of correlation with a lack of infection with hepatitis B or C. It is interesting that two of five breast cancer cases were identified as having NASH. Although the incidence of breast cancer in nonalcoholic fatty liver disease (NAFLD) including NASH patients has not been clarified, there is a well-established link between obesity and postmenopausal breast cancer. One hypothesis is that this is because of an increase in the serum concentration of bioavailable estradiol [26
In conclusion, this study analyzed EHPM status in HCC patients with regard to infection with HBV and/or HCV. The results suggested that gastric cancer, the most common EHPM based on previous Japanese reports, was associated with HCV-infection in this Japanese cohort. In addition, relationships between HBV infection and urothelial carcinoma and a lack of infection with hepatitis virus and breast cancer were also suggested. However, this study involved following limitations. The information about viral activity (HBV-DNA and HCV-RNA) was not available in this cohort and the sample size was too small especially in the urothelial carcinoma and the breast cancer patients. A community-based cohort study would be appropriate for this kind of association study. Therefore, the current results should be verified by well-designed large cohort studies in the future.