Retrospective Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 28, 2016; 22(12): 3404-3411
Published online Mar 28, 2016. doi: 10.3748/wjg.v22.i12.3404
Intrahepatic distribution of hepatitis B virus antigens in patients with and without hepatocellular carcinoma
Parham Safaie, Mugilan Poongkunran, Ping-Ping Kuang, Asad Javaid, Carl Jacobs, Rebecca Pohlmann, Imad Nasser, Daryl TY Lau
Parham Safaie, Mugilan Poongkunran, Ping-Ping Kuang, Asad Javaid, Daryl TY Lau, Liver Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
Carl Jacobs, Rebecca Pohlmann, Imad Nasser, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
Author contributions: Safaie P, Poongkunran M, Nasser I and Lau DT designed, implemented and supervised the analysis, manuscript preparation of the study; Kuang PP performed the immunostains of HBV antigens in liver tissues, Javaid A contributed to the interpretations of the data and manuscript writing; Pohlmann R and Jacobs C contributed to the reading and interpretation of the pathology; all authors read and approved the final manuscript; Safaie P and Poongkunran M contributed equally to this manuscript.
Institutional review board statement: The Beth Israel Deaconess Medical Center (BIDMC) Committee on Clinical Investigations (CCI); the appropriately authorized Institutional Review Board (IRB); and Privacy Board appointed to review research involving human subjects, has referenced the protocol named “factors affecting the pathogenesis and progression of chronic liver disease” (IRB Protocol No: 2008P000299).
Informed consent statement: This study used only the excessive liver biopsy samples from the IRB Protocol No: 2008P000299. Hence no informed consent from the study subjects necessary.
Conflict-of-interest statement: Parham Safaie, Mugilan Poongkunran, Ping-Ping Kuang, Asad Javaid, C. Jacobs, Rebecca Pohlmann, Imad Nasser, Daryl TY Lau declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Daryl TY Lau, MD, Associate Professor, Liver Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite 4A, Boston, MA 02215, United States. dlau@bidmc.harvard.edu
Telephone: +1-617-6321098 Fax: +1-617-6321125
Received: September 18, 2015
Peer-review started: September 19, 2015
First decision: October 14, 2015
Revised: November 9, 2015
Accepted: December 30, 2015
Article in press: December 30, 2015
Published online: March 28, 2016
Processing time: 187 Days and 4.2 Hours
Abstract

AIM: To study the intrahepatic expression of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) in chronic hepatitis B patients with and without hepatocellular carcinoma.

METHODS: A total of 33 chronic hepatitis B patients (mean age of 40.3 ± 2.5 years), comprising of 14 HBeAg positive and 19 HBeAg negative patients; and 13 patients with hepatitis B virus related hepatocellular carcinoma (mean age of 49.6 ± 4.7 years), were included in our study. Immunohistochemical staining for HBcAg and HBsAg was done using standard streptavidin-biotin-immunoperoxidase technique on paraffin-embedded liver biopsies. The HBcAg and HBsAg staining distributions and patterns were described according to a modified classification system.

RESULTS: Compared to the HBeAg negative patients, the HBeAg positive patients were younger, had higher mean HBV DNA and alanine transaminases levels. All the HBeAg positive patients had intrahepatic HBcAg staining; predominantly with “diffuse” distribution (79%) and “mixed cytoplasmic/nuclear” pattern (79%). In comparison, only 5% of the HBeAg-negative patients had intrahepatic HBcAg staining. However, the intrahepatic HBsAg staining has wider distribution among the HBeAg negative patients, namely; majority of the HBeAg negative cases had “patchy” HBsAg distribution compared to “rare” distribution among the HBeAg positive cases. All but one patient with HCC were HBeAg negative with either undetectable HBV DNA or very low level of viremia. Intrahepatic HBcAg and HBsAg were seen in 13 (100%) and 10 (77%) of the HCC patients respectively. Interestingly, among the 9 HCC patients on anti-viral therapy with suppressed HBV DNA, HBcAg and HBsAg were detected in tumor tissues but not the adjacent liver in 4 (44%) and 1 (11%) patient respectively.

CONCLUSION: Isolated intrahepatic HBcAg and HBsAg can be present in tumors of patients with suppressed HBV DNA on antiviral therapy; that may predispose them to cancer development.

Keywords: Hepatitis B virus; Chronic hepatitis B; Hepatocellular carcinoma; Hepatitis B core antigen; Hepatitis B surface antigen

Core tip: This study described the distributions and patterns of intrahepatic hepatitis B core antigen and hepatitis B surface antigen (HBsAg) in patients with chronic hepatitis B using a novel, modified classification system. The HBeAg negative patients were found to have intense HBsAg in liver tissues despite their lower serum hepatitis B virus (HBV) DNA levels. For those with hepatocellular carcinoma (HCC), we observed high rate of HBV antigen detection in tumor tissues, but not in adjacent non-tumor livers, especially among those with optimal serum HBV DNA suppression. These data support that HCC can be derived from clonal expansion of infected hepatocytes with high carcinogenic potentials and selective resistance to antiviral agents.