INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, the sixth most common cancer worldwide, and the fourth leading cause of cancer-related mortality.^1-3 HCC is mainly associated with chronic viral hepatitis including hepatitis B virus (HBV) or hepatitis C virus (HCV).⁴ In South Korea, HBV infection is 65-75% of HCC cases diagnosed, while HCV infection is associated with 8.6-13.2% of cases.^5,6 Recently, non-B non-C (NBNC) HCC has gradually increased and been reported to be 15-18% in Korea.⁶

Various factors influence the development of HCC through different mechanisms.⁷ HBV is a DNA-based virus that can be incorporated into the host genome. Random insertions cause chromosomal instability that drives carcinogenesis.^8,9 HCV is an RNA virus that does not integrate into host DNA. Due to the absence of reverse transcription activity of the HCV RNA virus, its viral genome does not integrate into the genome of the infected cell. HCV causes HCC through an indirect pathway by causing chronic inflammation, cell death, proliferation and cirrhosis.⁸ In addition, tumorigenesis is associated with non-viral risk factors such as fatty liver disease or heavy alcohol consumption.¹⁰ NBNC population constitutes a substantial proportion of patients with HCC and has become the main cause of liver transplantation.

Most HCC cases develop in patients with cirrhosis. Generally, genetic and epigenetic mechanisms play an important role in the malignant transformation of dysplastic nodules.¹¹ Given the different etiologies and characteristics of HCC, the prognosis may vary between HBV, HCV, and NBNC patients. However, the earlier results are somewhat controversial. In a recent study, HBV-related patients showed favorable survival compared with other etiologies.¹² Some studies found significant survival differences between groups with different risk factors for HCC,^13-18 while others did not.^19-23 Furthermore, most studies only compared virus-infected groups (HBV vs. HCV) or combined both viral groups when compared to patients with NBNC.

However, the profiles of patients with HCC are changing. Remarkable treatment advances include immunotherapy, tyrosine kinase inhibitor, and transarterial radioembolization, which increase survival and quality of life but remain under evaluation. The NBNC-HCC population is increasing and currently outnumbers the HCV-HCC population in some regions.²⁴ Therefore, it is crucial to explore the role of etiology in HCC prognosis. In this study, we analyzed the characteristics of patients with HCC and their prognosis according to the etiology of the disease in Korea.

METHODS

1. Study population

Between 2010 and 2014, 1,900 patients who were first diagnosed with HCC at Severance Hospital, Yonsei University College of Medicine, South Korea, were enrolled. HCC was diagnosed histologically or radiologically according to the guidelines of the Korean Liver Cancer Association, American Association for the Study of Liver Disease or the European Association for the Study of the Liver.²³ Patients aged <19 years, those who had coinfection with other viral hepatitis, those who had missing follow-up data, or those who died before 1 month were excluded (Supplementary Fig. 1). Additionally, patients with Barcelona Clinic Liver Cancer (BCLC) stage D were excluded.

The patients were divided according to the etiology of the disease into three groups (HBV, HCV, and NBNC). Patients with HBsAg-positivity for ≥6 months, previous history of chronic HBV infection, and anti-HCV antibody-negative sera were assigned to the HBV group, those with anti-HCV antibody positive and HBsAg-negative sera were assigned to the HCV group. The remaining patients negative for HBV and HCV were assigned to the NBNC group; therefore, this was a heterogeneous group and included those whose HCC was attributable to alcoholic liver disease.

This retrospective observational study followed the STROBE guidelines (Supplementary Table 1). This study adhered to the ethical guidelines of the Declaration of Helsinki (1975). This study was approved by the Severance Hospital Institutional Review Board (IRB No. 4-2020-1081).

2. Variables and outcomes

All clinical, serological, and histological data were obtained from electronic medical records. Clinical variables included age, hypertension, type 2 diabetes mellitus (DM), sex, smoking, alcohol consumption (social drinking), BCLC stage, Child-Pugh score, and initial treatment (transarterial chemoembolization, transarterial radioembolization, radiofrequency ablation, cryoablation, systemic or intra-arterial chemotherapy, radiation, concurrent chemoradiation, surgical resection, etc.). Computed tomography and magnetic resonance imaging were used to explore tumor size, macrovascular invasion (MVI), and extrahepatic metastasis. We recorded the following serologic variables: albumin, total bilirubin, alpha-fetoprotein (AFP), prothrombin induced by the absence of vitamin K or antagonist-II (PIVKA-II), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and prothrombin time expressed as the international normalized ratio. All data were obtained using routine methods. The primary outcome was overall survival (OS), determined from the date of initial diagnosis to death or the last follow-up date.

3. Statistical methods

Pearson’s chi-square test was used to compare baseline categorical variables. Analysis of variance or the Kruskal–Wallis test was used to compare continuous variables. OS was calculated using the Kaplan–Meier method. The association between each baseline variable and survival was tested using univariate analysis (log-rank test). Significant variables (P<0.05) in the univariate analysis were included in the multivariate analysis. All statistical analyses were performed with SPSS software ver. 22.0 (SPSS Inc, Chicago, IL, USA). Two-sided P<0.05 were considered statistically significant.

RESULTS

1. Baseline characteristics of the study population

The baseline characteristics of the study population are summarized in Table 1. Finally, 1,595 patients with HCC were analyzed. Of the 1,595 patients, 1,183 (74.2%) were in the HBV group, 146 (9.2%) were in the HCV group, and 266 (16.7%) were in the NBNC group. The HCV group had the highest proportion of female patients. The NBNC group had more elderly patients and metabolic comorbidities, including hypertension or type 2 DM than the viral hepatitis group. The HCV group had the lowest serum albumin level (3.5 g/dL vs. 3.8 g/dL and 3.7 g/dL, P<0.001) and the highest AST level (60.0 U/L vs. 45.0 U/L and 39.5 U/L, P<0.001) compared to the HBV and NBNC groups. The HBV group had the highest ALT level (36.0 U/L) compared to the HCV group (32.0 U/L) and the NBNC group (26.0 U/L) (P<0.001).

The NBNC group had the largest mean tumor size (3.6 cm vs. 3.5 cm in the HBV group and 3.3 cm in the HCV group, P=0.005). MVI was the least common in the HCV group (19.9% vs. 30.0% in the HBV group and 24.8% in the NBNC group, P=0.015). However, the extrahepatic metastasis rate did not differ between the three groups. The proportion of BCLC stage C patients was lower in the HCV group (23.3%) than in the HBV (35.2%) and NBNC groups (33.1%). The most common initial treatment in all groups was transarterial chemoembolization, followed by surgical resection.

2. OS according to the etiology

The median OS of all patients was 74 months. The survival rates at 1, 3, and 5 years were 78.8%, 62%, and 54.9% in the HBV group; 86.0%, 64.0%, and 48.6% in the HCV group; and 78.4%, 56.5%, and 45.9% in the NBNC group, respectively, and were comparable between the groups (Fig. 1A). However, in the BCLC stage 0 or A subgroup, HBV patients had significantly longer OS than NBNC patients (Fig. 1B-E).

3. Risk factors for mortality in patients with HCC

The log-rank test was used to identify factors that predicting prognosis. Univariate analysis identified the following factors: NBNC etiology, albumin, total bilirubin, prothrombin time, AST, tumor size, MVI, extrahepatic metastasis, AFP, and PIVKA-II (Table 2). Factors with P<0.05 were included in the multivariate analysis, which identified the following significant risk factors for mortality: NBNC etiology (hazard ratio [HR], 1.245; 95% confidence interval [CI], 1.020-1.518; P=0.031), low albumin level (HR, 0.629; 95% CI, 0.538-0.734; P<0.001), high prothrombin time (HR <2.314; 95% CI, 1.280-4.182; P=0.005), MVI (HR, 2.682; 95% CI, 2.278-3.158; P<0.001), extrahepatic metastasis status (HR, 2.882; 95% CI, 2.233-3.720; P<0.001), high AFP (HR, 1.000; 95% CI, 1.000-1.000; P<0.001), and PIVKA-II (HR, 1.000; 95% CI, 1.000-1.000; P<0.001) levels (Table 2). We also analyzed the risk factors for mortality in each stage of BCLC (Supplementary Tables 2-5).

4. The effects of DM on the risk of mortality

We explored the effect of type 2 DM on OS (Fig. 2A). Overall, DM was a risk factor for mortality in patients with early-stage HCC, including BCLC stage 0 or A, but not B or C (Fig. 2B-D). Similar results were obtained when the HBV and NBNC sub-groups were analyzed (Table 3). DM increased the risk of mortality in HCC patients with BCLC 0 (HR, 2.06; 95% CI, 1.00-4.22; P=0.049) and BCLC A (HR, 1.65; 95% CI, 1.17-2.31; P=0.004) in overall population. In HBV-HCC and NBNC-HCC only, DM similarly increased the risk of mortality in HCC patients with BCLC 0 (HR, 2.97; 95% CI, 1.40-6.30; P=0.005) and BCLC A (HR, 1.78; 95% CI, 1.25-2.53; P=0.002) in overall population.

DISCUSSION

We explored whether the etiology of HCC affected disease characteristics and prognosis. As previously reported, we found that the mean age of HCV and NBNC patients was approximately 10 years older than that of HBV patients.^14,16,21 The NBNC group had the lowest serum AST and ALT levels. Although liver enzyme levels differed between the groups, the Child–Pugh score, liver function, and prognosis did not show differences. The tumor size was the largest in the NBNC group. The frequency of MVI was the highest in the HBV group. When the groups were evaluated in terms of extrahepatic metastasis, BCLC stage distribution, and initial treatment, the aggressiveness of HCC did not show differences between the groups. The HBV group had significantly longer OS than the NBNC group in HCC patients with early stage. Therefore, we stratified the patients according to BCLC stage and found that HBV patients with BCLC stages 0 and A (but not B or C) survived significantly longer than those with NBNC. However, this should be interpreted with caution, as the proportion of patients with DM in the NBNC group was more than twice that of the HBV group.

We also speculate that DM may affect survival differently according to the HCC stage. The results of the univariate analysis, shown in Table 3 and Fig. 2, support this conclusion. DM was a significant independent predictor of poorer survival in patients with BCLC stages 0 and A, but not B or C. Others have reported that DM in patients with HCC is a prognostic factor. One study from Taiwan found that DM was a crucial predictor of survival in patients with early-stage HCC (BCLC 0 and A).²⁵ DM can enhance or reduce survival depending on the BCLC stage or treatment.^25-27 We did not consider other confounders (metabolic syndrome or insulin resistance) that could contribute to the apparent difference in survival between the HBV and NBNC groups.

A limitation of our study is that the etiologies of NBNC may have differed; they had either non-alcoholic fatty liver disease or alcoholic liver disease. Therefore, we were unable to explain the difference in survival rates between the HBV and NBNC groups. In addition, we did not have information on the cause of death; therefore, we could not distinguish liver-related death due to cancer from other causes. This would have helped to determine whether the high mortality rate in NBNC patients with early-stage cancer was attributable to DM. In addition, we used it as a prognostic indicator. Further studies should consider recurrence-free survival, progression-free survival, tumor response, and quality of life.²⁸ Finally, there were more patients in the HBV group than in the other groups. We initially considered using propensity score matching, but we would have lost a great deal of data if we had used method. Therefore, we decided to preserve the entire dataset.

In conclusion, the etiology of HCC affected clinical characteristics and prognosis to some extent. NBNC-HCC patients showed shorter OS than viral-related HCC patients. Additionally, the presence of DM is an additional important prognostic factor in patients with early-stage HCC.

Article information

Conflicts of Interest

Hye Won Lee currently serves on the editorial board of J Liver Cancer. She was not involved in the review process of this article. Otherwise, the authors have no conflicts of interest to disclose.

Ethics Statement

This study adhered to the ethical guidelines of the Declaration of Helsinki (1975). This study was approved by the Severance Hospital Institutional Review Board (IRB No. 4-2020-1081). The need for informed consent was waived due to the retrospective nature of this study.

Funding Statement

This study was supported by the Korean Liver Cancer Association Research Award (2022).

Data Availability

The datasets generated or analyzed during this study are available from the corresponding author on reasonable request.

Author Contribution

Conceptualization: DYK

Data acquisition: HWL, JSL, BKK, SUK, JYP, SHA, DYK

Data analysis and interpretation: WJJ, HWL, DYK

Writing – original draft: WJJ, HWL, DYK

Writing – review & editing: WJJ, HWL, DYK

Statistical analysis: WJJ, HYL, DYK

Study supervision: DYK

Approval of final manuscript: all authors

Supplementary Material

Figure 1.

Overall survival of patients with hepatocellular carcinoma according to cancer etiology and Barcelona Clinic Liver Cancer (BCLC) stages. (A) All patients (log-rank, P=0.132), (B) BCLC stage 0 patients (log-rank, P=0.040), (C) BCLC stage A (log-rank, P=0.013), (D) BCLC stage B patients (log-rank, P=0.384), and (E) BCLC stage C patients (log-rank, P=0.630). HBV, hepatitis B virus; HCV, hepatitis C virus; NBNC, non-B non-C.

Figure 2.

Survival of patients with hepatocellular carcinoma with different Barcelona Clinic Liver Cancer (BCLC) stages with or without diabetes mellitus. (A) BCLC stage 0 patients (P=0.045), (B) BCLC stage A patients (P=0.004), (C) BCLC stage B patients (P=0.513), (D) BCLC stage C patients (P=0.709).

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Figure & Data

References

Citations

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