Comparisons of Viral Etiology and Outcomes of Hepatocellular Carcinoma Undergoing Liver Resection between Taiwan and Vietnam

Epidemiologic data have suggested that etiologic variations of hepatocellular carcinoma (HCC) exist in different geographic areas, and might be associated with different outcomes. We compared the viral etiology, clinicopathological characteristics and surgical outcomes between 706 Taiwanese and 1704 Vietnamese patients with HCC undergoing liver resection. Vietnamese patients had a significantly higher ratio of hepatitis B virus (HBV) (p < 0.001) and a lower ratio of hepatitis C virus (HCV) (p < 0.001) and non-B non-C than Taiwanese patients. Among patients with HBV or non-B non-C, the mean age was younger in Vietnam than in Taiwan (p < 0.001, p = 0.001, respectively). The HCC patients in Vietnam had significantly higher serum alpha-fetoprotein (AFP) levels (p < 0.001), larger tumors (p < 0.001), and a higher ratio of macrovascular invasion (p < 0.001) and extrahepatic metastasis (p < 0.001), compared to those in Taiwan. Patients treated in Vietnam had a higher tumor recurrent rate (p < 0.001), but no difference in overall survival was found between both groups. In subgroup analysis, the recurrent rate of HCC was the highest in patients with dual HBV/HCV, followed by HCV or HBV, and non-B non-C (p < 0.001). In conclusion, although the viral etiology and clinicopathological characteristics of HCC differed, postoperative overall survival was comparable between patients in Taiwan and Vietnam.


Introduction
Hepatocellular carcinoma (HCC) is the sixth most commonly occurring malignancy, and one of the largest contributors of cancer-related death in the world [1]. Despite recent advances in surgical technique and diagnostic modality, the overall five-year survival rate of HCC is still unsatisfactory [2]. In some developing countries of Asia and Africa, the annual incidence and mortality of HCC have been increasing [3]. Currently, chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) remains the most important risk factors for HCC [4]. Nevertheless, some other factors, include alcohol consumption, metabolic diseases, such as diabetes mellitus and obesity, and environmental toxins, such as alfatoxin, have become increasingly important etiologic factors [5][6][7].
Several epidemiologic studies have suggested that HCC in different geographic areas of the world may represent different forms of the disease [3]. It is worth investigating whether the regional differences in HCC characteristics and outcomes are due to different etiologies and underlying liver damage. HCC is highly prevalent in the Asia-Pacific region, where HBV infection plays the predominant role in the development of HCC [8]. In The comparison of baseline characteristics of patients and tumors between Taiwan and Vietnam are shown in Table 1. There was a male predominance in both groups; whereas patients in Vietnam had a higher male to female ratio than those in Taiwan (p < 0.001). The HCC patients in Vietnam were younger (p < 0.001), and had significantly higher serum AFP level (p < 0.001), larger size of tumor (p < 0.001) and tended to have a single tumor (p < 0.001), having macrovascular invasion (p < 0.001) and extrahepatic metastasis (p < 0.001), compared to those in Taiwan. The most common viral etiology was HBV in both groups, but Vietnamese patients had a significantly higher ratio of HBV (p < 0.001) and a lower ratio of HCV (p < 0.001) and non-B non-C than Taiwanese patients.  Table 2 shows the differences in age and gender according to viral etiology of HCC between Taiwan and Vietnam. The mean age of HBV patients was significantly younger than that of patients with HCV (both p < 0.001) or non-B non-C (both p < 0.001) in both groups. Among patients with HBV or non-B non-C, the mean age was younger in Vietnam than in Taiwan (p < 0.001, p = 0.001, respectively), whereas there was no difference among those with HCV. The male-to-female ratio was higher in HBV than in HCV patients (p < 0.001) only in the Taiwanese group. * Mean ± SD; p-value by one-way ANOVA test with least significant difference (LSD) post-hoc correction or x 2 test. a Significant differences between HBV and HCV; b Significant differences HBV and B + C; c Significant differences between HBV and Non-B, Non-C; d Significant differences between HCV and B + C; e Significant differences HCV and Non-B, Non-C; f Significant differences between Taiwan and Vietnam HBV-HCC; g Significant differences between Taiwan and Vietnam HCV-HCC; h Significant differences between Taiwan and Vietnam NBNC-HCC.
In regard to the viral etiology contributing to tumor recurrence, we, therefore, analyzed the patients who were classified into four groups accordingly. As shown in Figure 2, the incidence of HCC recurrence was the highest in patients with dual HBV/HCV infection, followed by HCV or HBV mono-infection, and non-B non-C (p < 0.001).  (11) 168/38 (4.4) 0.206 * Mean ± SD; p-value by one-way ANOVA test with least significant difference (LSD) post-hoc correction or x 2 test. a Significant differences between HBV and HCV; b Significant differences HBV and B + C; c Significant differences between HBV and Non-B, Non-C; d Significant differences between HCV and B + C; e Significant differences HCV and Non-B, Non-C; f Significant differences between Taiwan and Vietnam HBV-HCC; g Significant differences between Taiwan and Vietnam HCV-HCC; h Significant differences between Taiwan and Vietnam NBNC-HCC.

Factors Associated with RFS
As shown in Figure 1A, 332 patients in Taiwan and 1049 patients in Vietnam had tumor recurrence during the follow-up period (p < 0.001). In Table 3 In regard to the viral etiology contributing to tumor recurrence, we, therefore, analyzed the patients who were classified into four groups accordingly. As shown in Figure  2, the incidence of HCC recurrence was the highest in patients with dual HBV/HCV infection, followed by HCV or HBV mono-infection, and non-B non-C (p < 0.001).

Discussion
This present study compared the viral etiology, clinicopathological characteristics and surgical outcomes of HCC patients receiving liver resection between Taiwan and Vietnam in the Asia-Pacific region, where the prevalence of HCC is the highest worldwide. We demonstrated that HCC patients in Vietnam were younger, and had more aggressive tumor characteristics, such as higher serum AFP level, larger size of tumor, more macrovascular invasion and more extrahepatic metastasis, compared to those in Taiwan. The patients treated in Vietnam had a significant tumor recurrent rate after resection by multivariate analysis, in addition to other common risk factors, including male gender, higher AFP, larger tumor size, multiple tumors, macrovascular invasion and extrahepatic metastasis. However, despite these differences, the postoperative OS was compatible between Taiwan and Vietnam. Although the definite reason was unclear, this might be explained by the shorter mean follow-up period in Vietnam than in Taiwan.
Globally, the male-to-female ratio of HCC patients has been reported to range from 2:1 to 5:1, with the variations associated with dominant hepatitis virus in the population and the existence of other risk factors [15]. In this study, the male-to-female ratio was higher in HBV than in HCV patients in the Taiwanese group, but not in the Vietnamese group. This finding could be partially explained by the fact that Vietnamese patients had a lower ratio of HCV infection than those in Taiwan. On the other hand, we found that HBV patients was significantly younger than patients with HCV or non-B non-C among both Taiwanese and Vietnamese patients. These data were compatible with those reported in previous studies [12,13], suggesting that age distribution of HCC depended on gender, etiology and region. However, in particular, the mean age was younger in Vietnam than in Taiwan among patients with HBV or non-B non-C, indicating that some risk factors, other than the hepatitis virus, such as agricultural use of organophosphorous pesticides or alfatoxin, should be considered in Vietnam [16,17].
Several clinicopathological factors have been constantly reported to have prognostic value following liver resection of HCC [12,18,19]. In this study, we demonstrated that male gender, higher AFP (≥400 ng/mL), larger tumor size (≥5 cm), multiple tumors, macrovascular invasion and extrahepatic metastasis were independent factors associated Viruses 2022, 14, 2571 7 of 9 with poorer OS. Our data were consistent with those reported in most studies. In contrast, there was no significant difference in OS between Taiwan and Vietnam.
Whether different viral etiologies have an impact on long-term outcomes in patients undergoing liver resection for HCC is unclear. Cescon et al. reported that RFS was significantly higher in non-B non-C patients compared with those with HBV [20]. A recent study demonstrated that non-B non-C HCC occurs mostly in elderly patients, and OS rate is significantly higher than that of HBV-HCC patients [21]. In regard to dual HBV/HCV infection, previous meta-analyses have confirmed that patients with dual HBV/HCV infection have an increased risk of HCC, whereas data about dual HBV/HCV infection in association with surgical outcomes in HCC patients remain limited. Our data showed that the recurrent rate of HCC after liver resection was the highest in patients with dual HBV/HCV infection, followed by HCV or HBV mono-infection, and NBNC. This result was consistent with a recent report showing that the RFS rates in patients with HBV/HCV-HCC were significantly poorer than those with HBV-HCC in a propensity score matching cohort [22]. The reason why different etiologies impact on the HCC recurrence after liver resection remains unclear. A recent report indicated the key role of regulatory T cells in the HCC immune microenvironment and their presence has been correlated with tumor progression, and invasiveness, as well as metastasis [23]. However, our study did not confirm the association of viral etiology with OS. This issue should be further clarified due to limited cases of dual HBV/HCV infection in our study.
The strength of this study was our large sample size of patients who were enrolled from two large tertiary referral centers. However, our study has the common limitations associated with its retrospective study design with some incomplete patient records and potential selection bias. In addition, our study did not analyze the treatment effect of antivirals such as nucleos(t)ide analogs for HBV, and interferon-based therapies or direct acting antivirals for HCV. Moreover, our data, such as the data on two-year recurrence and three-year survival, were compatible with those previously reported in a meta-analysis of single HCV-untreated studies, evaluating outcomes after curative treatments of HCVrelated HCC [24,25]. Our study also did not analyze the effect of other treatment procedures for recurrent lesions on OS. Further studies are necessary to clarify these weak points.

Conclusions
This study identified the differences in viral etiology and clinicopathological characteristics, as well as surgical outcomes, between Taiwan and Vietnam. Although HCC patients in Vietnam had more aggressive tumor characteristics and higher tumor recurrence rates after resection, there was no significance in postoperative OS between Taiwan and Vietnam.  Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Data Availability Statement:
The data presented in this study are available on reasonable request to the first author and corresponding author.