Elsevier

Journal of Hepatology

Volume 51, Issue 5, November 2009, Pages 890-897
Journal of Hepatology

Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma

https://doi.org/10.1016/j.jhep.2009.07.009Get rights and content

Background/Aims

Hepatitis B virus (HBV) levels correlate with the development of hepatocellular carcinoma (HCC), but the role of viral load in HCC recurrence after tumor resection remains unclear. Herein we aimed to investigate the role of viral load in HCC recurrence following tumor resection.

Methods

From 1990 to 2002, 193 HBV-related HCC patients who underwent tumor resection in Taipei Veterans General Hospital were enrolled. Serum HBV DNA level and mutations were analyzed for association with early and late recurrence, together with other clinical variables.

Results

During a follow-up of 58.2 ± 44 months, 134 patients had HCC recurrence. Multivariate analysis showed that multinodularity (Hazard ratio [HR], 95% confidence interval [CI]; 2.232, 1.021–4.878), macroscopic venous invasion (4.693, 1.645–13.391), AFP >20 ng/ml (3.891, 1.795–8.475), and cut margin ⩽1 cm (3.333, 1.487–7.470) were correlated with early recurrence (within two years of operation) of HCC. In addition, multivariate analysis determined that Ishak hepatic inflammatory activity >6 (4.658, 1.970–11.017), multinodularity (3.266, 1.417–7.526), ICG-15 >10% (2.487, 1.095–5.650) and HBV DNA level >106 copies/ml (2.548, 1.040–6.240) were significantly associated with late recurrence (>two years after resection). Patients with high viral loads tended to have higher Ishak inflammatory (7.00 ± 3.07 vs. 5.33 ± 2.96, p = 0.001) and fibrosis scores (4.17 ± 2.01 vs. 3.20 ± 2.41, p = 0.007) than those with lower loads.

Conclusions

Tumor factors were associated with early HCC recurrence while high viral loads and hepatic inflammatory activity were associated with late recurrence. Pre- and post-operative antiviral and anti-inflammatory therapies may be crucial in reducing late recurrence.

Introduction

Chronic hepatitis B and C (HBV and HCV) viral infections are the two major etiologies of hepatocellular carcinoma (HCC) [1], [2], [3], with chronic HBV predominating in Taiwan. HCC is the third leading cause of cancer mortality in the world and the most important one in Taiwan [3]. Post-operative recurrence is common and is the main cause of death in HCC patients after resection [4], [5], [6]. Most recurrences occur within two years of surgery (early recurrence) [7]. Tumor size, number and venous invasion are known to be closely associated with post-operative tumor recurrence [6], [7], [8], [9], [10].

Of the eight HBV genotypes (A–H) [11], [12], B and C are the most prevalent in Asia and Taiwan [13], [14], [15]. Time to immune clearance is usually longer and hepatitis e antigen (HBeAg) seroconversion occurs relatively later in genotype C HBV infection compared to genotype B [15], [16], [17]. In hospital- and community-based studies, genotype C HBV infection is associated with a higher risk of HCC than genotype B [18], [19]. Dual mutations of A1762T and G1764A at the basic core promoter (BCP), more frequently found in genotype C HBV isolates, are associated with a higher risk of HCC [19], [20], [21]. Previous studies suggest that higher incidence of HCC in genotype C HBV infection may be due to higher prevalence of BCP mutation in this genotype [22], [23].

In previous studies [24], tumors that recurred two years after resection often showed clonal origins different from the original tumors, suggesting a de novo second primary HCC (late recurrence). Tumors occurring within two years of surgery were more likely to show the same clonal origins as the original tumor, suggesting that they had their metastatic origin shortly after the operation. Factors linked to late recurrence may be more closely related to those predisposing to hepatocarcinogenesis, whereas factors linked to early recurrence may be more closely related to those predisposing to tumor progression or metastasis [7]. The impact of viral factors on the prognosis of HCC after surgery may be overshadowed by tumor-related factors in early tumor recurrence. Understanding the respective role of tumor and viral factors in HCC recurrence may provoke new treatment strategies to prevent recurrence after tumor resection.

Section snippets

Patients and follow-up

A total of 193 HBV-related HCC patients who underwent partial hepatectomy at the Taipei Veterans General Hospital during 1990–2002 with pre-operative serum and post-operative pathology-verified HCC samples available for analysis were enrolled in this study. Criteria for HCC resection were: (A) Child’s classification of liver function of A or B with an indocyanine green (ICG) 15-min retention rate (ICG-15) <30%; (B) tumors involved no more than three Healey’s segments, without portal vein main

Clinical demographics, biochemical, surgical, virological and pathological data of HCC patients

Of the 193 cases, 94 (48.7%) were infected with genotype B HBV, 89 (46.1%) with genotype C, one (0.5%) with genotype A, and the remaining 9 (4.7%) with unclassified genotypes. Among the unclassified HBV genotypes, 2 were due to undetectable viral genomes and 7 were due to weak signals. Compared to genotype B HBV (Table 1), genotype C HBV isolates were associated with a higher prevalence of dual BCP mutations (86.4% vs. 55.9%, p < 0.001), triple mutations (30.7% vs. 11.8%, p = 0.003), and a lower

Discussion

This study clarifies that tumor factors and viral factors play different roles in early and late recurrence of HCC after tumor resection. As the impact of viral factors on the recurrence of HCC after surgery may be overwhelmed by tumor-related factors during the early phase, a characteristic approach in this study was to analyze factors associated with early or late recurrence separately.

Tumor factors such as unfree cut-margin, large tumor size, multinodularity of tumors, venous invasion, tumor

Acknowledgements

The authors acknowledge the technical support of the Sequencing Core, National Yang-Ming University Genome Research Center (YMGC). The Sequencing Core Facility is supported by the National Research Program for Genome Medicine (NRPGM), National Science Council, Taiwan.

This study was supported by grants from the National Science Council (NSC93-2321-B-010-012, NSC94-2321-B-010-010, NSC95-2321-B-010-005), Taipei Veterans General Hospital (V95C1-014, V97ER2-016), and Yang-Ming University

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    The authors who have taken part in this study declared that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript.

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    These authors contributed equally to this work.

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