Contribution of Hepatitis B Virus Infection to the Aggressiveness of Primary Liver Cancer: A Clinical Epidemiological Study in Eastern China

Fan Yang,Feng Shen,Mengchao Wang,Hongwei Zhang,Hongyang Wang,Shuqun Cheng,Guangwen Cao,Xi Chen,Yuan Yang,Weiping Zhou,Jun Zhao,Longteng Ma,Wenbin Liu

doi:10.3389/fonc.2019.00370

Abstract

Background and aims: The contribution of hepatitis B virus (HBV) infection to the aggressiveness of primary liver cancer (PLC) remains controversial. We aimed to characterize this in eastern China.Methods: We enrolled 8,515 PLC patients whose specimens were reserved at the BioBank of the hepatobiliary hospital (Shanghai, China) during 2007–2016. Of those, 3,124 who received primary radical resection were involved in survival analysis. A nomogram was constructed to predict the survivals using preoperative parameters.Results: Hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular cholangiocarcinoma (CHC) accounted for 94.6, 3.7, and 1.7%, respectively. The rates of HBV infection were 87.5, 49.2, and 80.6%, respectively. HBV infection was significantly associated with 10-year earlier onset, more cirrhosis, higher α-fetoprotein, higher carbohydrate antigen 19-9 (CA19-9), more microvascular invasion (MVI), lower neutrophil-to-lymphocyte ratio (NLR), and lower platelet-to-lymphocyte ratio (PLR) in HCC. HBV infection was also associated with 7-year earlier onset, more cirrhosis, higher α-fetoprotein, more MVI, and lower PLR in ICC. In the multivariate Cox analysis, high circulating HBV DNA, α-fetoprotein, CA19-9, NLR, tumor size, number, encapsulation, Barcelona Clinic Liver Cancer (BCLC) stage, and MVI predicted an unfavorable prognosis in HCC; only CA19-9 and BCLC stage, rather than HBV-related parameters, had prognostic values in ICC. A nomogram constructed with preoperative HBV-related parameters including HBV load, ultrasonic cirrhosis, and α-fetoprotein perform better than the current staging systems in predicting postoperative survival in HCC.Conclusion: HBV promotes the aggressiveness of HCC in Chinese population. The contributions of HBV to ICC and other etiological factors to HCC might be indirect via arousing non-resolving inflammation.

Highlights

Primary liver cancer (PLC), comprising hepatocellular carcinoma (HCC, 70–90%), intrahepatic cholangiocarcinoma (ICC, 10– 20%), and rare histotypes including combined hepatocellular cholangiocarcinoma (CHC), is the second leading cause of cancer death in men and the sixth leading cause of cancer death in women worldwide [1, 2]
Of global PLC, 56% were attributable to hepatitis B virus (HBV) and 20% to hepatitis C virus (HCV) [3]
To evaluate if HBV-related clinical parameters harvested preoperatively could predict postoperative prognosis, we developed a nomogram using the independent prognostic factors

Summary

Introduction

Primary liver cancer (PLC), comprising hepatocellular carcinoma (HCC, 70–90%), intrahepatic cholangiocarcinoma (ICC, 10– 20%), and rare histotypes including combined hepatocellular cholangiocarcinoma (CHC), is the second leading cause of cancer death in men and the sixth leading cause of cancer death in women worldwide [1, 2]. HCV infection is the leading cause of HCC in most European and American countries, the contribution of HBV is increasing possibly because of immigration. Aflatoxin B1 exposure or smoking increases the occurrence of HCC caused by other factors [6, 7]. Chronic infection with HBV or HCV increase the risk of ICC [9, 10]. It remains to be identified whether the risk factors promote the development of HCC or ICC directly or indirectly via inducing inflammation. The contribution of hepatitis B virus (HBV) infection to the aggressiveness of primary liver cancer (PLC) remains controversial.

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