Modalities for Screening and Imaging Diagnosis of HCC

Abstract and Introduction

Abstract

Background: Hepatocellular carcinoma (HCC) incidence and mortality continue to rise worldwide. Society guidelines recommend HCC screening for patients with chronic hepatitis B (CHB) or cirrhosis. Unfortunately, HCC screening rates remain relatively low, and the performance characteristics of current screening modalities are suboptimal.

Aim: The aim of the study was to discuss the current state of HCC screening and imaging diagnosis utilising standard and emerging imaging modalities in addition to outlining areas of need and ongoing study.

Methods: A review of the field was performed combining literature searches and expert opinion.

Results: The development of the Liver Imaging Reporting and Data System (LI-RADS version 2018) algorithms have advanced and standardised the imaging diagnosis of HCC. While guidelines recommend US for HCC screening, the sensitivity of ultrasound is highly variable for the detection of early-stage HCC with sensitivity reports ranging from 40% to 80%. Biomarker-based scores such as GALAD and alternative imaging modalities such as abbreviated MRI are promising tools to improve HCC early detection. Patients with non-alcoholic fatty liver disease (NAFLD) and patients hepatitis C (HCV) who have achieved sustained virologic response (SVR) can present a clinical dilemma regarding the need for HCC screening. Biomarkers and elastography can aid in identification of individuals at high risk for HCC in these populations.

Conclusions: The LI-RADS system has standardised the imaging interpretation and diagnosis of HCC. Work remains regarding screening in special populations and optimization of screening modalities.

Introduction

Despite advancements in the treatment of viral hepatitis, the incidence of hepatocellular carcinoma (HCC) has risen significantly over recent decades making it one of the most common cancers worldwide.^[1] In the United States the incidence of liver cancer, of which 75%–90% is HCC, has more than tripled since 1980.^[2] While rates in men have stabilised, incidence continues to rise in women.^[2] These data are taken in light of the ongoing COVID-19 pandemic which may limit or influence both data collection and patient behaviour patterns making recent trends difficult to accurately report and interpret. Globally, chronic hepatitis B (CHB) accounts for the majority of HCC despite the demonstrated efficacy of newborn vaccination programmes. For example, a study in Thailand found the standardised incidence rate of HCC in nonvaccinated children older than age 10 was 0.88 per million compared with 0.07 per million in vaccinated children.^[3] Patients with cirrhosis from all aetiologies have a very high risk of HCC with an incidence estimated at 2%–4% per year.^[4] American Association for the Study of Liver Disease (AASLD) guidelines recommend HCC screening in all patients with cirrhosis and at-risk individuals with CHB.^[5] The delayed identification of HCC and the discovery of advanced malignancy is associated with limited treatment options and poor outcomes. Conversely, the detection of HCC at early stage as a result of effective screening can result in potentially curative treatments and excellent outcomes. This review aims to outline available screening modalities as well as key gaps in care and knowledge while highlighting emerging data and areas for future research and growth.

Table 1. LI-RADS categories according to the CT/MRI LI-RADS v2018 system.
LR 1	Definitely benign
LR 2	Probably benign
LR 3	Intermediate probability of malignancy
LR 4	Probably HCC
LR 5	Definitely HCC
LR M	Probable or definite malignancy with imaging features that are not specific to HCC
LR TIV	Definite tumour in vein
LR- NC	Observations that cannot be categorised due to image degradation or omission

Note: LI-RADS diagnostic categories reflect the relative probability of benignity, HCC, or overall malignancy. Observations categorised LR-M have high likelihood of being malignant but may not be HCC. These lesions usually require biopsy for further evaluation prior to treatment. The development and implementation of LI-RADS represents a major milestone in HCC screening, but even with this system there remain areas of growth and need for further research.

Table 2. Suggested populations for HCC Screening
Populations recommended for screening based on major guidelines
Patients with chronic hepatitis B	Benefit is uncertain in men younger than 40 and women younger than 50 without cirrhosis or a family history of HCC
Patients with cirrhosis	Except those with Child's C cirrhosis who are not transplant candidates
Additional populations to consider for screening
Patients with NAFLD and advanced fibrosis	Advanced fibrosis as defined by FIB-4 > 2.67, VCTE > 16.1 kPa, or MRE > 5 kPa
Patients with HCV following SVR with advanced fibrosis and elevated HCC risk	Advanced fibrosis and elevated HCC risk as defined by FIB-4 > 3.25, aMAP score > 60, MRE > 4.5 kPa, etc.

Note: Guidelines from major societies recommend that patients with chronic hepatitis B and patients with cirrhosis, excluding those with Child's C disease, should undergo routine HCC screening. In addition to these populations, data are emerging that sufficient risk of HCC is present in patients with NAFLD and advanced fibrosis and select patients with HCV following SVR that screening is likely warranted. A number of metrics and scores are available to estimate HCC risk in these populations with varying degrees of clinical use and validation. These tools can be used in addition to clinical presentation and patient preferences to guide the decision to initiate or defer screening.

Authors and Disclosures

Abbey Barnard Giustini¹, George N. Ioannou¹, Claude Sirlin² and Rohit Loomba³

¹Division of Gastroenterology, Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle, Washington, USA
²Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, California, USA
³NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA

Correspondence
Rohit Loomba, ACTRI Building, 1W202, 9452 Medical Center Drive, La Jolla, CA 92037, USA. Email: roloomba@ucsd.edu

Author Contributions
Abbey Barnard Giustini: Writing – original draft (lead); writing – review and editing (equal). George N. Ioannou: Writing – review and editing (equal). Claude Sirlin: Writing – review and editing (equal). Rohit Loomba: Conceptualization (lead); supervision (lead); writing – review and editing (equal). All authors approved the final version of the manuscript.

Conflict of Interest Statement
Dr. Rohit Loomba serves as a consultant for Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Inipharm, Intercept, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Sagimet, 89 bio, and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Pfizer and Siemens. He is also co-founder of Liponexus, Inc. Dr. Sirlin reports research grants from ACR, Bayer, Foundation of NIH, GE, Gilead, Pfizer, Philips, Siemens; lab service agreements with Enata, Gilead, ICON, Intercept, Nusirt, Shire, Synageva, Takeda; institutional consulting for BMS, Exact Sicences, IBM-Watson, Pfizer; Personal consulting for Altimmune Ascelia Pharma, Blade, Boehringer, Epigenomics, and Guerbet; receipet of royalities and/or honoraria from Medscape and Wolters Kluwer; ownership of stock options in Livivos; unpaid advisory board position in Quantix Bio. Dr. Sirlin serves as Chief Medical Officer for Livivos (unsalaried position with stock options), an appointment approved by his university. Doctors Barnard Giustini and Ioannou have nothing to disclose.

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