Associations between antibody to hepatitis B core antigen positivity and outcomes in hepatocellular carcinoma patients undergoing hepatic resection

We aimed to evaluate the effect of antibody to hepatitis B core antigen (HBcAb) positivity on clinical outcomes after hepatic resection in hepatocellular carcinoma (HCC) patients with negative hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb), termed non‐B, non‐C HCC (NBNC‐HCC), or with HCV‐related HCC.


INTRODUCTION
H EPATOCELLULAR CARCINOMA (HCC) is the most prevalent epithelial cancer of the liver, and one of the most common causes of cancer-related death in many countries, especially in Japan. 1,2 Hepatic resection has been established as a safe and effective treatment for HCC. 3,4 There is a high prevalence of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in the general population of Japan; however, the proportion of HCC cases negative for hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb), termed non-B, non-C HCC (NBNC-HCC), is currently increasing. 5,6 Patents with antibody to hepatitis B core antigen (HBcAb) positivity and HBsAg negativity are considered to have occult HBV infection. 7 Antibody to hepatitis B core antigen is present in approximately 20% of healthy individuals. 8,9 Moreover, the HBcAb-positive rate has been reported as 53.6% in HCV-related chronic liver disease, 10 and a recent study reported that the positive rate of HBcAb in patients with NBNC-HCC reached 40%. 6 However, because measurement of HBcAb is not included in the regular screening protocol for HBV infection at many institutions, the actual prognostic influence of HBcAb positivity in HCC patients remains unclear. Thus, given the apparently high proportion of patients with a history of HBV, the clinical features of the HBcAb-positive subgroup of NBNC-HCC or HCV-related HCC patients need to be explored to allow for better clinical management of HCC. The aim of the present study was, therefore, to investigate the relationship between HBcAb positivity and clinical outcome in patients with NBNC-HCC or HCV-related HCC undergoing hepatic resection.

Patients
B ETWEEN JULY 2000 and December 2015, 510 patients underwent hepatic resection for HCC at the Department of Surgery and Science, Kyushu University Hospital (Fukuoka, Japan). We excluded 241 patients because HBcAb was not measured, and 6 patients who were both HBsAg-and HCVAb-positive were further excluded from this analysis. The data of the remaining 263 patients were studied in detail. This study was approved by the Ethics Committee of Kyushu University (approval code: 28-212).

Surgical procedures
The details of our surgical techniques and patient selection criteria for hepatic resection for HCC have been previously reported. 11 The resection volume was decided based on the patients' indocyanine green dye retention rate at 15 min (ICGR15). Patients with an ICGR15 ≥35% were generally selected for limited resection. Parenchymal transection was carried out using the Cavitron Ultrasonic Surgical Aspirator (Valleylab, Boulder, CO, USA). Inflow vascular control was carried out with intermittent hemior total Glisson's sheath occlusion (Pringle maneuver) and, if required, with a selective hepatic vein-clamping method. Inflow occlusion was applied intermittently with 15 min of occlusion alternating with 5 min of reperfusion.

Histological examinations
The histologic grade of tumor differentiation, degree of fibrosis in the background liver, and presence or absence of vascular invasion were assessed microscopically based on the classification system proposed by the Liver Cancer Study Group of Japan. 12 Fibrosis staging was scored using the Scheuer classification 13 on a scale of 0-4 as follows: F0, no fibrosis; F1, enlarged fibrotic portal tracts; F2, periportal or portal-portal septa but intact architecture; F3, fibrosis with architectural distortion but no obvious cirrhosis; and F4, probable or definite cirrhosis.

Follow-up assessment
The patients were strictly followed after the hepatic resection, with monthly measurements of the levels of α-fetoprotein and des-γ-carboxy prothrombin, as well as monthly ultrasonography. Dynamic computed tomography was carried out every 3 months by radiologists, and angiographic examination was undertaken on admission if there was a strong suspicion of disease recurrence. 14 We treated recurrent HCC by repeat hepatic resection, local ablation therapy, or transcatheter arterial chemoembolization. 15

Statistical analysis
The data are expressed as the median and range. Continuous variables without normal distribution were compared by the Mann-Whitney U-test. Categorical variables were compared by the χ 2 -test or Fisher's exact test. The overall survival (OS) and recurrence-free survival (RFS) rates were calculated by the Kaplan-Meier (product limit) method and compared by the log-rank test. All statistical analyses were carried out using JMP software (SAS Institute, Cary, NC, USA), with P < 0.05 considered statistically significant. HBcAb-negative (47.7%) patients. Significant differences were observed in a number of factors among patients with HBV-or HCV-related HCC, and NBNC-HCC (data not shown). There were no significant differences in RFS and OS between HBcAb-positive and -negative patients who had NBNC-or HCV-related HCC (P = 0.873 and 0.856, respectively; Fig. 1).

T HE MEDIAN OBSERVATION
The clinicopathological characteristics of the 109 patients with NBNC-HCC are shown in Table 1. The percentage of multiple tumors was significantly greater in patients with HBcAb positivity compared to HBcAb negativity (P = 0.028). However, there were no significant differences in other factors between positive and negative patients.
The RFS and OS curves for NBNC-HCC patients after hepatic resection are shown in Figure 2. The RFS rates were similar between HBcAb-positive and -negative patients (P = 0.461). The 5-year RFS rates in the positive and negative patients were 44.9% and 34.9%, respectively. There was no significant difference in OS between the patients with HBcAb positivity and negativity (P = 0.190). patients with NBNC-HCC were 82.5% versus 75.4% and 54.6% versus 52.8%, respectively. Table 2 summarizes the baseline characteristics of the 116 patients with HCV-related HCC. There were no significant differences in the baseline factors between positive and negative HBcAb patients, except for in the percentage of anatomical resection. The RFS and OS curves of HCV-related HCC patients after hepatic resection are     In this study, the proportion of anatomical resection of the liver for HBcAb-positive patients with HCV-related HCC was significantly greater than that in HBcAb-negative patients. There were no significant differences in RFS or OS between patients undergoing anatomical resection and partial hepatic resection for HCV-related HCC (data not shown). Anatomical resection is one of the curative treatments for HCC, and yields a better RFS than partial hepatic resection, especially for tumors between 2 and 5 cm in diameter. 25 Hence, further investigations of a greater number of patients are needed to confirm the advantage of anatomical resection.
There are several limitations to the present study. This was a single-center retrospective study. In addition, the number of patients was relatively small, and data on the HBV DNA findings were missing. Further multi-institutional studies with a greater number of patients and additional data are required to confirm these results.
In conclusion, the presence of occult HBV infection had no effect on the oncological outcomes for patients with NBNC-or HCV-related HCC following hepatic resection.