Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 28, 2021; 27(24): 3466-3482
Published online Jun 28, 2021. doi: 10.3748/wjg.v27.i24.3466
Non-cirrhotic hepatocellular carcinoma in chronic viral hepatitis: Current insights and advancements
Abhilash Perisetti, Hemant Goyal, Rachana Yendala, Ragesh B Thandassery, Emmanouil Giorgakis
Abhilash Perisetti, Department of Internal Medicine, Division of Gastroenterology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
Hemant Goyal, Department of Internal Medicine, Macon University School of Medicine, Macon, GA 31207, United States
Rachana Yendala, Department of Hematology and Oncology, Conway Regional Health System (CRHS), Conway, AR 72034, United States
Ragesh B Thandassery, Department of Gastroenterology and Hepatology, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, United States
Emmanouil Giorgakis, Department of Transplant, University of Arkansas for Medical Sciences Little Rock, AR 72205, United States
Author contributions: Perisetti A, Thandassery R, and Giorgakis E contributed to conception and design; Perisetti A and Yendala R contributed to literature search; Perisetti A did the first draft; Perisetti A, Thandassery R, Giorgakis E, Yendala R and Goyal H contributed to critical revision and editing; all authors have read and approved the final manuscript.
Conflict-of-interest statement: None of the authors have no conflicts of interest
Open-Access: This article is an open-access article that 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:
Corresponding author: Emmanouil Giorgakis, FRCS, MD, MSc, Assistant Professor, Department of Transplant, University of Arkansas for Medical Sciences, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, United States.
Received: January 26, 2021
Peer-review started: January 26, 2021
First decision: February 24, 2021
Revised: March 13, 2021
Accepted: May 25, 2021
Article in press: May 25, 2021
Published online: June 28, 2021

Primary liver cancers carry significant morbidity and mortality. Hepatocellular carcinoma (HCC) develops within the hepatic parenchyma and is the most common malignancy originating from the liver. Although 80% of HCCs develop within background cirrhosis, 20% may arise in a non-cirrhotic milieu and are referred to non-cirrhotic-HCC (NCHCC). NCHCC is often diagnosed late due to lack of surveillance. In addition, the rising prevalence of non-alcoholic fatty liver disease and diabetes mellitus have increased the risk of developing HCC on non-cirrhotic patients. Viral infections such as chronic Hepatitis B and less often chronic hepatitis C with advance fibrosis are associated with NCHCC. NCHCC individuals may have Hepatitis B core antibodies and occult HBV infection, signifying the role of Hepatitis B infection in NCHCC. Given the effectiveness of current antiviral therapies, surgical techniques and locoregional treatment options, nowadays such patients have more options and potential for cure. However, these lesions need early identification with diagnostic models and multiple surveillance strategies to improve overall outcomes. Better understanding of the NCHCC risk factors, tumorigenesis, diagnostic tools and treatment options are critical to improving prognosis and overall outcomes on these patients. In this review, we aim to discuss NCHCC epidemiology, risk factors, and pathogenesis, and elaborate on NCHCC diagnosis and treatment strategies.

Keywords: Cirrhosis, Hepatic fibrosis, Non-alcoholic liver disease, Primary liver cancer, Hepatocellular carcinoma, Hepatoma, Liver cancer, Hepatitis B virus, Hepatitis C virus, Liver resection, Liver transplantation

Core Tip: Non-cirrhotic hepatocellular carcinoma (HCC) accounts for 20% of reported HCCs. Such tumors are typically diagnosed late, compromising the outcome. The discovery of direct antivirals, loco-regional treatments and systemic novel immune-chemotherapies, along with advancements of complex hepatobiliary surgery, and the genesis of transplant oncology have revolutionized the management of these aggressive primary liver tumors. Coordinated care at tertiary high-volume HCC, preferably liver transplant centers, remains critical. It is time the stakeholders pursued a consensus approach in developing universal HCC surveillance and treatment strategies on non-cirrhotic patients at risk, such as patients with non-alcoholic steatohepatitis and/or patients with advanced fibrosis.