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Epidemiology and surveillance for hepatocellular carcinoma: New trends

  • Amit G. Singal
    Correspondence
    Corresponding author. Address: Division of Digestive and Liver Diseases, UT Southwestern Medical Center, 5959 Harry Hines Blvd, POB 1, Suite 420, Dallas TX 75390-8887, USA. Tel.: +1 214 645 6111; fax: +1 214 645 6114.
    Affiliations
    Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
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  • Pietro Lampertico
    Affiliations
    CRC “A. M. and A. Migliavacca” Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
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  • Pierre Nahon
    Affiliations
    Centre de Recherche des Cordeliers, Sorbonne Universités, Université Paris Descartes, Université Paris Diderot, Université Paris, Paris, France

    Functional Genomics of Solid Tumors, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris, Paris, France

    Service d'hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France

    Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France
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      Summary

      The burden of hepatocellular carcinoma (HCC) is highest in East Asia and Africa, although its incidence and mortality are rapidly rising in the United States and Europe. With the implementation of hepatitis B vaccination and hepatitis C treatment programmes worldwide, the epidemiology of HCC is shifting away from a disease predominated by viral hepatitis – an increasing proportion of cases are now attributable to non-alcoholic steatohepatitis. Surveillance using ultrasound, with or without alpha-fetoprotein, every 6 months has been associated with improved early detection and improved overall survival; however, limitations in implementation lead to a high proportion of HCC being detected at late stages in clinical practice. Herein, we review the current state of HCC surveillance and highlight areas for future research, including improved risk stratification of at-risk patients, surveillance tools with higher sensitivity and specificity for early HCC, and interventions to increase surveillance utilisation.

      Linked Article

      Introduction

      Liver cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide, after lung, colorectal, and stomach cancer.
      • Wang H.
      • Naghavi M.
      • Allen C.
      • Barber R.M.
      • Bhutta Z.A.
      • et al.
      Global Burden of Disease Liver Cancer Collaboration 2015
      Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015.
      Liver cancer is a highly fatal tumour, with most cases detected at late stages and an incidence-to-mortality ratio that approaches 1. For example, there were approximately 854,000 new liver cancer cases in 2015, compared to an estimated 810,000 liver cancer-related deaths per year.
      • Global Burden of Disease Liver Cancer Collaboration
      • Akinyemiju T.
      • Abera S.
      • Ahmed M.
      • Alam N.
      • Alemayohu M.A.
      • et al.
      The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015.
      Hepatocellular carcinoma (HCC) represents about 75–85% of primary liver cancers
      • Bray F.
      • Ferlay J.
      • Soerjomataram I.
      • Siegel R.L.
      • Torre L.A.
      • Jemal A.
      Global Cancer Statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      and constitutes a major health problem worldwide.

      Incidence

      The worldwide incidence of HCC is heterogeneous because of the variable prevalence of underlying risk factors. It is estimated that 72% of cases occur in Asia (more than 50% in China), 10% in Europe, 7.8% in Africa, 5.1% in North America, 4.6% Latin America and 0.5% in Oceania. Fig. 1 shows the estimated age-standardised incidence rates (ASIRs) for liver cancer in the world in 2018. The highest ASIRs per 100,000 occur in Eastern Asia (17.7), with Mongolia (93.4) having the highest ASIR in this region and the world, followed by South-East Asia (13.3), and Africa (8.4), with Egypt (32.2) and Gambia (23.9) having the highest ASIRs in Africa. The lowest ASIRs are observed in South Central Asia (2.5), followed by Central and Eastern Europe and Western Asia (equally about 4.0).
      Figure thumbnail gr1
      Fig. 1Worldwide age-standardized HCC incidence rates, 2018. Data source: GLOBOCAN 2018. Graph production: IARC (http://gco.iarc.fr/today), World Health Organization. Accessed 24 October 2019. ASIR, age-standardized incidence rate; HCC, hepatocellular carcinoma.

      Mortality

      Age-standardised mortality rates (ASMRs) from HCC in 2018 are also highest in Eastern Asia (16.0) and Northern Africa (13.9), followed by South Eastern Asia (13.2). The lowest ASMR is observed in South Central Asia (2.3), followed by Central, Northern, and Eastern Europe and Western Asia (around 3.8–4.0). Mongolia and Egypt have the highest ASMRs, while the lowest are in Morocco and Nepal, countries with low ASIRs. Worldwide the ASMR is close to ASIR, reflecting the fact that HCC is a deadly disease.

      Aetiology

      The large majority of HCC cases occur in the setting of chronic liver disease, with cirrhosis being the primary risk factor for HCC, independent of liver disease aetiology. It is estimated that one-third of cirrhotic patients will develop liver cancer during their lifetime,
      • Sangiovanni A.
      • Prati G.M.
      • Fasani P.
      • Ronchi G.
      • Romeo R.
      • Manini M.
      • et al.
      The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 patients.
      with a 1–8% annual incidence reported in long-term follow-up studies (e.g. 2% in HBV-infected cirrhotic patients and 3–8% in HCV-infected cirrhotic patients).
      • Ioannou G.N.
      • Splan M.F.
      • Weiss N.S.
      • McDonald G.B.
      • Beretta L.
      • Lee S.P.
      Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis.
      The incidence of HCC appears lower in alcohol-related and non-alcohol steatohepatitis (NASH)-related cirrhosis than active viral hepatitis but the incidence appears to be greater than 1.5% across cirrhosis aetiologies.
      The large majority of HCC cases occur in patients with chronic liver disease, with cirrhosis being the main risk factor.
      Hepatitis B virus (HBV) is the leading cause of incident cases of liver cancer and deaths in the world (33%), followed by alcohol (30%), hepatitis C virus (HCV) (21%) and other causes (16%). The contribution of different aetiologies to HCC incidence varies markedly between countries and regions and is summarised in Table 1. In Africa and East Asia, the largest population attributable fraction is caused by HBV (60%); however, in the Western world only 20% of cases can be attributed to HBV infection, and chronic HCV is the most common underlying liver disease aetiology.
      • Global Burden of Disease Liver Cancer Collaboration
      • Akinyemiju T.
      • Abera S.
      • Ahmed M.
      • Alam N.
      • Alemayohu M.A.
      • et al.
      The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015.
      Among HBV-infected individuals, HBeAg seropositivity,
      • Yang H.I.
      • Lu S.N.
      • Liaw Y.F.
      • You S.L.
      • Sun C.A.
      • Wang L.Y.
      • et al.
      Hepatitis B e antigen and the risk of hepatocellular carcinoma.
      high viral load
      • Chen C.J.
      • Yang H.I.
      • Su J.
      • Jen C.L.
      • You S.L.
      • Lu S.N.
      • et al.
      Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.
      and genotype C
      • Yu M.-W.
      • Yeh S.-H.
      • Chen P.-J.
      • Liaw Y.-F.
      • Lin C.-L.
      • Liu C.-J.
      • et al.
      Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men.
      are independent predictors of HCC development. Although prior studies among HCV-infected patients reported similar risk factors, e.g. HCV genotype, the strongest determinants of HCC risk in these patients are currently the presence (vs. absence) of cirrhosis and attaining sustained virological response (SVR). Guidelines uniformly recommend surveillance in patients with HCV-related cirrhosis but differ on HCC risk and recommendations for HCC surveillance in HCV-infected patients with F3 fibrosis;
      • Heimbach J.K.
      • Kulik L.M.
      • Finn R.S.
      • et al.
      AASLD guidelines for the treatment of hepatocellular carcinoma.
      • EASL Clinical Practice Guidelines
      Management of hepatocellular carcinoma.
      • Omata M.
      • Cheng A.L.
      • Kokudo N.
      • et al.
      Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.
      however, a recent cost-effectiveness analysis suggests that this practice is likely not cost-effective in those without cirrhosis.
      • Zangneh F.
      • Wong W.W.L.
      • Sander B.
      • et al.
      Cost effectiveness of hepatocellular carcinoma surveillance after a sustained virologic response to therapy in patients with hepatitis c virus infection and advanced fibrosis.
      Table 1Geographical distribution of risk factors for primary liver cancer.
      VariablesAlcohol (%)Hepatitis B (%)Hepatitis C (%)Others (%)
      Global30332116
      Europe
       Western32134410
       Central46152910
       Eastern5315248
      America
       North America3793123
       Andean Latin America23451220
       South Latin America4264111
      Asia
       East Asia3241918
       Asia-Pacific1822556
       South-East Asia31262221
      Africa
       North Africa, Middle East13274416
       Southern (sub-Saharan)40292011
       Western (sub-Saharan)29451115
       Oceania16381927
      Contribution of hepatitis B, C, alcohol and others causes on absolute liver cancer deaths, both sexes, globally and by region 2015 (3). Data refer to all primary liver cancers (hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver cancer of mixed differentiation).
      Implementation of infant HBV immunisation programmes in many countries in East Asia is expected to lower HBV-related HCC in the future, as demonstrated in Taiwan where annual HCC incidence significantly decreased from 0.92 per 105 persons in an unvaccinated cohort of patients to 0.23 per 105 persons in a vaccinated birth cohort.
      • Chang M.H.
      • You S.L.
      • Chen C.J.
      • Liu C.J.
      • Lai M.W.
      • Wu T.C.
      • et al.
      Long-term effects of hepatitis B immunization of infants in preventing liver cancer.
      However, there are several countries which have yet to implement universal HBV vaccination, so many individuals are still infected with HBV (approximately 257 million in 2015), mostly in Asia and sub-Saharan Africa.
      • Yuen M.-F.
      • Chen D.-S.
      • Dusheiko G.M.
      • et al.
      Hepatitis B virus infection.
      Unfortunately, a vaccine for HCV does not exist, so primary prevention of HCV-related HCC is not possible. Among those with active infection, antiviral therapies are effective in reducing HCC incidence although they do not eradicate the risk, in both HBV- and HCV-infected patients.
      • Liaw Y.-F.
      • Sung J.J.Y.
      • Cheng Chow W.
      • et al.
      Lamivudine for patients with chronic hepatitis B and advanced liver disease.
      • Morgan R.L.
      • Baack B.
      • Smith B.D.
      • Yartel A.
      • Pitasi M.
      • Falck-Ytter Y.
      Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies.
      • Kanwal F.
      • Kramer J.
      • Asch S.M.
      • Chayanupatkul M.
      • Cao Y.
      • El-Serag H.B.
      Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.
      Among HCV-infected patients the risk of developing HCC significantly declined from 6.2% to 1.5% with interferon-based SVR
      • Morgan R.L.
      • Baack B.
      • Smith B.D.
      • Yartel A.
      • Pitasi M.
      • Falck-Ytter Y.
      Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies.
      and a similar reduction is observed for SVR from direct-acting antiviral agents.
      • Kanwal F.
      • Kramer J.
      • Asch S.M.
      • Chayanupatkul M.
      • Cao Y.
      • El-Serag H.B.
      Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.
      Despite improvement, patients with cirrhosis prior to SVR remain at high risk of HCC, so surveillance should be continued.
      • Ioannou G.
      • Beste L.A.
      • Green P.K.
      • Singal A.G.
      • Tapper E.B.
      • Waljee A.K.
      • et al.
      Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores.
      Alcohol consumption and the resulting cirrhosis seem to have a causal relationship in the development of HCC.
      • McKillop I.
      • Schrum L.
      Role of alcohol in liver carcinogenesis.
      In France, the estimated HCC incidence in patients with alcoholic cirrhosis was 2.9 per 100 patient-years in a cohort of 652 French patients during a median follow-up of 29 months.
      • Ganne-Carrié N.
      • Chaffaut C.
      • Bourcier V.
      • Archambeaud I.
      • Perarnau J.M.
      • Oberti F.
      • et al.
      for CIRRAL Group. Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis.
      An increased risk of developing HCC has been reported for most parts of the world (with the exception of Northern Europe), including France
      • Nahon P.
      • Sutton A.
      • Rufat P.
      • Ziol M.
      • Akouche H.
      • Laguillier C.
      • et al.
      Myeloperoxidase and superoxide dismutase 2 polymorphisms comodulate the risk of hepatocellular carcinoma and death in alcoholic cirrhosis.
      and Spain.
      • Mancebo A.
      • Gonzalez-Dieguez M.L.
      • Cadahia V.
      • Varela M.
      • Perez R.
      • Navascues C.A.
      • et al.
      Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups.
      There is growing evidence that non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) contribute to HCC development, and are becoming an increasingly common cause of HCC worldwide. It is estimated that about 10–30% of NAFLD cases progress to cirrhosis, and in the United States alone approximately 6 million people have NASH.

      World Gastroenterology Organisation Global Guidelines. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. 2012 Available from: http://www.worldgastroenterology.org/assets/export/userfiles/2012_NASH%20and%20NAFLD_Final_long.pdf. (accessed: 25.05.2018).

      Although patients with NASH appear to have a lower risk of HCC than patients with HCV-related cirrhosis, the annual incidence is likely between 1–2%. In a large cohort study of 4,235 patients with NASH cirrhosis from the Veterans Affairs health system in the United States, the incidence of HCC was determined to be 1.06 per 100 person-years.
      • Kanwal F.
      • Kramer J.R.
      • Mapakshi S.
      • Natarajan Y.
      • Chayanupatkul M.
      • Richardson P.A.
      • et al.
      Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.
      Although patients with NAFLD are at a lower risk of developing liver cancer than those with NASH cirrhosis, the high number of people with NAFLD make it one of the major causes of HCC. There have now been several cohort studies that have shown over one-fourth of NASH-related HCC can occur in the absence of cirrhosis,
      • Mittal S.
      • El_Serag H.B.
      • Sada Y.H.
      • Kanwal F.
      • Duan Z.
      • Temple S.
      • et al.
      Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease.
      • Dyson J.
      • Jaques B.
      • Chattopadyhay D.
      • Lochan R.
      • Graham J.
      • Das D.
      • et al.
      Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.
      which is significantly higher than proportions seen in other liver diseases.
      • Stine J.G.
      • Wentworth B.J.
      • Zimmet A.
      • Rinella M.E.
      • Loomba R.
      • Caldwell S.H.
      • et al.
      Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases..
      However, the annual incidence rate of HCC in non-cirrhotic NASH appears to be low. Data from the Veterans Affairs health system demonstrated an incidence of HCC of only 0.008 per 100 person-years among a cohort of 292,366 patients with non-cirrhotic NAFLD.
      • Kanwal F.
      • Kramer J.R.
      • Mapakshi S.
      • Natarajan Y.
      • Chayanupatkul M.
      • Richardson P.A.
      • et al.
      Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.
      Similarly, data from Taiwan demonstrated 1-, 3-, and 5-year cumulative incidences of only 0.2%, 0.8%, and 1.0%.
      • Lee T.Y.
      • Wu J.C.
      • Yu S.H.
      • Lin J.T.
      • Wu M.S.
      • Wu C.Y.
      • et al.
      The occurrence of hepatocellular carcinoma in different risk stratifications of clinically noncirrhotic nonalcoholic fatty liver disease.
      However, a recent systematic review of this literature highlighted several notable limitations of the current literature including heterogeneous definitions for NAFLD, differential proportions of patients with metabolic syndrome, heterogeneous definitions for cirrhosis, ascertainment bias given intermittent surveillance and selection/referral bias.
      • Reig M.
      • Gambato M.
      • Man N.
      Should patients with NAFLD/NASH be surveyed for HCC?.
      Therefore, the impact of metabolic liver disease on the epidemiology of HCC is likely to be underestimated. Components of the metabolic syndrome, such as diabetes and/or obesity, are emerging risk factors for HCC and may increase HCC risk if present with other chronic liver diseases, even in the absence of a NAFLD diagnosis. Obesity might account for about 16% of HCC cases in Europe, according to the EPIC study,
      • Schlesinger S.
      • Aleksandrova K.
      • Pischon T.
      • Jenab M.
      • Fedirko V.
      • Trepo E.
      • et al.
      Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort.
      while both obesity and/or diabetes account for about 37% of HCC in the US.
      • Welzel T.M.
      • Graubard B.I.
      • Quraishi S.
      • Zeuzem S.
      • Davila J.A.
      • El-Serag H.B.
      • et al.
      Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States.
      Based on current data, HCC risk is sufficient to justify HCC surveillance in patients with NASH cirrhosis; however, HCC surveillance is not recommended in those with non-cirrhotic NAFLD given the low annual incidence rate.
      Patients with other, less common causes of cirrhosis including primary biliary cirrhosis, autoimmune hepatitis, and haemochromatosis are also at an increased risk of HCC. Patients with haemochromatosis who progressed to advanced fibrosis/cirrhosis are at extremely high risk and develop HCC in up to 45% of cases
      • Deugnier Y.M.
      • Guyader D.
      • Crantock L.
      • Lopez J.M.
      • Turlin B.
      • Yaouanq J.
      • et al.
      Primary liver cancer in genetic hemochromatosis: a clinical, pathological, and pathogenetic study of 54 cases.
      • Fracanzani A.L.
      • Conte D.
      • Fraquelli M.
      • Taioli E.
      • Mattioli M.
      • Losco A.
      • et al.
      Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with noniron-related chronic liver disease.
      , with a higher incidence in those with acute hepatic porphyria and porphyria cutanea tarda.
      • Andant C.
      • Puy H.
      • Bogard C.
      • Faivre J.
      • Soulé J.C.
      • Nordmann Y.
      • et al.
      Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors.
      • Fracanzani A.L.
      • Taioli E.
      • Sampietro M.
      • Fatta E.
      • Bertelli C.
      • Fiorelli G.
      • et al.
      Liver cancer risk is increased in patients with porphyria cutanea tarda in comparison to matched control patients with chronic liver disease.
      Among patients with cirrhosis, there is a differential distribution of cases by several sociodemographic factors. HCC has a strong male predominance for incidence and mortality, with a male-to-female ratio exceeding 2.5 for both.
      • Global Burden of Disease Liver Cancer Collaboration
      • Akinyemiju T.
      • Abera S.
      • Ahmed M.
      • Alam N.
      • Alemayohu M.A.
      • et al.
      The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015.
      This differential distribution by sex is believed to be related to a clustering of risk factors among men, as well as a potential effect of androgens on HCC risk. Similarly, several studies have reported higher incidence and mortality rates among racial/ethnic minorities in the United States, with higher incidence rates among racial/ethnic minorities than non-Hispanic whites.
      • Rich N.E.
      • Hester C.
      • Odewole M.
      • Murphy C.C.
      • Parikh N.D.
      • Marrero J.A.
      • et al.
      Racial and ethnic differences in hepatocellular carcinoma presentation and outcomes.
      Finally, there are important environmental risk factors for HCC. For example, dietary intake of aflatoxin B1, which originate from fungal contaminations of staple foodstuffs, is a relevant co-factor for HCC development in parts of Africa and Asia. Aflatoxin B1 exposure is strongly correlated with TP53 mutations (codon 249) and HCC development in HBV-infected individuals.
      • Hsu I.C.
      • Metcalf R.A.
      • Sun T.
      • Welsh J.A.
      • Wang N.J.
      • Harris C.C.
      Mutational hotspot in the p53 gene in human hepatocellular carcinomas.
      Several epidemiological studies have also revealed an increased risk of developing HCC among smokers, with a meta-analysis reporting an adjusted RR of 1.5 (95% CI 1.37–1.67) compared to non-smokers.
      • Lee Y.-C.A.
      • Cohet C.
      • Yang Y.-C.
      • Stayner L.
      • Hashibe M.
      • Straif K.
      Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer.
      Several epidemiological studies have addressed the topic of HCC prevention in the general population and in patients with chronic liver disease. Coffee consumption, aspirin use and metformin treatment have consistently been shown to reduce the HCC incidence in patients with diabetes.
      • EASL Clinical Practice Guidelines
      Management of hepatocellular carcinoma.
      • Tseng C.-H.
      Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes.
      • Simon T.G.
      • Ma Y.
      • Ludvigsson J.F.
      • Chong D.Q.
      • Giovannucci E.L.
      • Fuchs C.S.
      • et al.
      Association between aspirin use and risk of hepatocellular carcinoma.
      The highest evidence has been produced for coffee consumption by means of case-control studies in Japanese patients with HCV and a hospital-based control study among Italian patients with a variety of liver disease aetiologies. These findings have also been confirmed in cohort studies performed in Japan and Southern Europe, as well as a meta-analysis.
      • EASL Clinical Practice Guidelines
      Management of hepatocellular carcinoma.
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • Tsugane S.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • et al.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study.
      • Bravi F.
      • Bosetti C.
      • Tavani A.
      • Bagnardi V.
      • Gallus S.
      • Negri E.
      • et al.
      Coffee drinking and hepatocellular carcinoma risk: a meta-analysis.
      • Bravi F.
      • Tavani A.
      • Bosetti C.
      • Boffetta P.
      • La Vecchia C.
      Coffee and the risk of hepatocellular carcinoma and chronic liver disease: a systematic review and meta-analysis of prospective studies.
      In epidemiological studies, coffee consumption, aspirin use, and metformin treatment have been shown to reduce the incidence of HCC in patients with diabetes.

      Trends

      Between 1990 and 2015, liver cancer incidence increased by 75% worldwide. These data reflect changes in aetiology, population age distribution, population growth, and ASIRs.
      • Global Burden of Disease Liver Cancer Collaboration
      • Akinyemiju T.
      • Abera S.
      • Ahmed M.
      • Alam N.
      • Alemayohu M.A.
      • et al.
      The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015.
      During this period a significant increase in HCC age-standardised incidence (per 100,000 persons) due to HCV (+15.7%) was observed, while HBV-related HCC significantly decreased (−18.9%) and no significant changes were observed for HCC due to alcohol (+13.5%) and other causes (−12.3%).
      • Global Burden of Disease Liver Cancer Collaboration
      • Akinyemiju T.
      • Abera S.
      • Ahmed M.
      • Alam N.
      • Alemayohu M.A.
      • et al.
      The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015.
      Despite a decrease in ASIRs for HCC related to HBV and other causes, overall incident HCC cases have increased because of demographic changes, namely population growth and aging.
      • Global Burden of Disease Liver Cancer Collaboration
      • Akinyemiju T.
      • Abera S.
      • Ahmed M.
      • Alam N.
      • Alemayohu M.A.
      • et al.
      The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015.
      Based on current trends, the number of new cases of, and deaths caused by, liver cancer are projected to increase from 841,080 and 781,631 in 2018, to 1,361,836 and 1,284,252 in 2040, representing changes of +62% and +64%, respectively.

      Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Tomorrow. International Agency for Research on Cancer, Lyon 2018. Available from: https://gco.iarc.fr/tomorrow (accessed:29.09.2018).

      There is geographic variation in these temporal trends. ASIRs have increased in many high socio-demographic index countries like North America (USA, Canada), Australia, New Zealand and most European countries (i.e. Austria, Denmark, Germany, Greece, Ireland, Portugal, Norway, Spain, Switzerland, and United Kingdom); conversely, some countries with high incidence rates like China and countries in Eastern and Western sub-Saharan Africa have experienced a more than 20% decrease.
      • Global Burden of Disease Liver Cancer Collaboration
      • Akinyemiju T.
      • Abera S.
      • Ahmed M.
      • Alam N.
      • Alemayohu M.A.
      • et al.
      The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015.
      Declines in ASIRs have also been observed in Japan, where a decline in HCC incidence has been noted for the first time since 1990,
      • Tanaka H.
      • Imai Y.
      • Hiramatsu N.
      • Ito Y.
      • Imanaka K.
      • Oshita M.
      • et al.
      Declining incidence of hepatocellular carcinoma in Osaka, Japan, from 1990 to 2003.
      • Qiu D.
      • Katanoda K.
      • Marugame T.
      • Sobue T.
      A Joinpoint regression analysis of long-term trends in cancer mortality in Japan (1958–2004).
      and in some countries in Europe (i.e. Finland, France, Italy, the Netherlands, and Sweden).
      • Bosetti C.
      • Levi F.
      • Boffetta P.
      • Lucchini F.
      • Negri E.
      • La Vecchia C.
      Trends in mortality from hepatocellular carcinoma in Europe, 1980–2004.
      Along the same line is a recent report evaluating projections of primary liver cancer occurrence in 30 countries worldwide,
      • Valery P.C.
      • Laversanne M.
      • Clark P.J.
      • Petrick J.L.
      • McGlynn K.A.
      • Bray F.
      Projections of primary liver cancer to 2030 in 30 countries worldwide.
      which predicts the percentage change in ASIR over a 25-year period, from 2005 to 2030, increasing >30% among men in 15 countries and among women in 8 countries. The largest rate increases among men are predicted in Norway (2.9% per annum), US whites (2.6%), Canada (2.4%), and the Russian Federation (2.2%). Equivalent increases in primary liver cancer among women are predicted in fewer countries, with the greatest increases expected among US blacks (4.0%), Switzerland (3.4%), and Germany (3.0%). In contrast, a decrease in liver cancer among men is predicted in Japan (23.1%), China (22.1%), Singapore (21.6%), Slovakia (21.4%), the Czech Republic (21.0%), and Estonia (20.6%), while the largest decreases among women are predicted in Japan (22.3%) and Denmark (21.8%).
      The predicted increases in incidence mainly reflect population growth and aging in most countries, as well as changes in risk factors. Changing distributions of risk factors, especially HBV, HCV, alcohol consumption, and obesity, could alter future trends and projections. Based on the predicted declines in the prevalence of HBV and HCV infections, mainly due to HBV immunisation and increased efforts to screen and treat patients with active HCV, the importance of non-viral risk factors for HCC is expected to increase in the future, mainly due to NAFLD. In the United States, it was estimated that the incidence of HCC due to NAFLD would increase by 122% between 2016 and 2030, from 5,510 to 12,240 cases.
      • Estes C.
      • Anstee Q.M.
      • Arias-Loste M.T.
      • et al.
      Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030.
      The incidence of HCC is expected to increase in the coming years, reflecting population growth and aging.

      HCC surveillance data and intervals

      Cancer surveillance programmes aim to detect tumours at an early stage when they are amenable to curative therapy that is known to improve survival,
      • Prasad V.
      • Lenzer J.
      • Newman D.H.
      Why cancer screening has never been shown to “save lives” – and what we do about it.
      The evidence highlighting a survival benefit associated with HCC screening in patients with cirrhosis remains controversial.
      • Kansagara D.
      • Papak J.
      • Pasha A.S.
      • et al.
      Screening for hepatocellular carcinoma in chronic liver disease: a systematic review.
      Apart from numerous methodological biases discussed below, analysis of the literature shows that negative studies often underscore inappropriate or suboptimal implementation of screening procedures rather than failure of surveillance programmes to be translated into survival benefit.
      • Moon A.M.
      • Weiss N.S.
      • Beste L.A.
      • et al.
      No association between screening for hepatocellular carcinoma and reduced cancer-related mortality in patients with cirrhosis.
      The only randomised controlled trial supporting HCC surveillance with 6-monthly abdominal ultrasound was performed in more than 18,000 Chinese patients and showed a 37% reduction in mortality risk in screened patients.
      • Zhang B.H.
      • Yang B.H.
      • Tang Z.Y.
      Randomized controlled trial of screening for hepatocellular carcinoma.
      However, this trial was conducted in an HBV-infected patient population and it is unclear if these results would apply to patients with cirrhosis given increased nodularity, which could impact surveillance effectiveness, as well as a higher competing risk of liver-related mortality. Because the implementation of trials comparing screening versus no surveillance would not be ethical,
      • Poustchi H.
      • Farrell G.C.
      • Strasser S.I.
      • Lee A.U.
      • McCaughan G.W.
      • George J.
      Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed?.
      the level of evidence mostly relies on retrospective observational studies which have concluded that surveillance for HCC was an independent predictor of survival.
      • Singal A.G.
      • Pillai A.
      • Tiro J.
      Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis.
      • Van Meer S.
      • de Man R.A.
      • Coenraad M.J.
      • Sprengers D.
      • van Nieuwkerk K.M.
      • Klümpen H.J.
      • et al.
      Surveillance for hepatocellular carcinoma is associated with increased survival: results from a large cohort in the Netherlands.
      • Wu C.Y.
      • Hsu Y.C.
      • Ho H.J.
      • Chen Y.J.
      • Lee T.Y.
      • Lin J.T.
      Association between ultrasonography screening and mortality in patients with hepatocellular carcinoma: a nationwide cohort study.
      • Mittal S.
      • Kanwal F.
      • Ying J.
      • Chung R.
      • Sada Y.H.
      • Temple S.
      • et al.
      Effectiveness of surveillance for hepatocellular carcinoma in clinical practice: a United States cohort.
      • Choi D.T.
      • Kum H.
      • Park S.
      • Ohsfeldt R.L.
      • Parikh N.D.
      • Singal A.G.
      Hepatocellular carcinoma screening is associated with increased survival of patients with cirrhosis.
      More recently, the long prospective follow-up of patients with compensated viral cirrhosis showed that patients who respected the recommended 6-month screening interval had a higher proportion of HCC detected at an early stage, which translated into a survival benefit due to more frequent implementation of first-line curative procedures.
      • Costentin C.E.
      • Layese R.
      • Bourcier V.
      • Cagnot C.
      • Marcellin P.
      • Guyader D.
      • et al.
      Compliance with hepatocellular carcinoma surveillance guidelines associated with increased lead-time adjusted survival of patients with compensated viral cirrhosis: a multi-center cohort study.
      However, numerous limitations and biases affecting observational studies dedicated to cancer screening must be acknowledged. Among them, lead-time bias suggests that a given proportion of the survival benefit could be ascribed to earlier diagnosis due to surveillance. In addition, length time bias supports that tumours diagnosed early in the setting of surveillance programmes might differ in their prognosis from tumours diagnosed later. The most recent studies assessing the impact of HCC screening on outcomes usually considered these biases in an attempt to reinforce the strength of their conclusions.
      • Duffy S.W.
      • Nagtegaal I.D.
      • Wallis M.
      • Cafferty F.H.
      • Houssami N.
      • Warwick J.
      • et al.
      Correcting for lead time and length bias in estimating the effect of screen detection on cancer survival.
      Western recommendations support a 6-month screening interval, based on HCC volume doubling-time, which is estimated to be around 6 months.
      • Barbara L.
      • Benzi G.
      • Gaiani S.
      • Fusconi F.
      • Zironi G.
      • Siringo S.
      • et al.
      Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival.
      In order to minimise the risk of detecting HCC at an advanced stage, a 3-month interval has been proposed by Japanese guidelines for specific groups considered at higher risk.
      • Kudo M.
      • Izumi N.
      • Kokudo N.
      • Matsui O.
      • Sakamoto M.
      • Nakashima O.
      • et al.
      Management of hepatocellular carcinoma in Japan: consensus-based clinical practice guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version.
      However, a French randomised trial had previously compared intervals of 3 and 6 months in more than 1,200 cirrhotic patients, and concluded that surveillance performed every 3 months, detected increased small-size focal lesions compared with ultrasound every 6 months but did not improve detection of early HCC and did not translate into survival benefits.
      • Trinchet J.C.
      • Chaffaut C.
      • Bourcier V.
      • Degos F.
      • Henrion J.
      • Fontaine H.
      • et al.
      Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities.
      Similarly, a large retrospective study assessed the impact of different surveillance intervals in patients at risk of HCC.
      • Wu C.Y.
      • Hsu Y.C.
      • Ho H.J.
      • Chen Y.J.
      • Lee T.Y.
      • Lin J.T.
      Association between ultrasonography screening and mortality in patients with hepatocellular carcinoma: a nationwide cohort study.
      Shorter ultrasound screening intervals were associated with reduced overall mortality in these patients, and as a whole provided additional arguments to support the 6-month screening interval as the optimal cut-off for HCC surveillance.

      Surveillance tests

      Abdominal ultrasound has been the historic cornerstone of HCC surveillance and continues to be recommended as the primary surveillance test by the AASLD, EASL, and APASL. It has several advantages including being cheap, readily available, and safe with minimal direct physical harms. Although ultrasound has an acceptable sensitivity of 84% (95% CI 76–92%) for detecting HCC at any stage, its sensitivity for detection of early stage HCC is significantly lower at only 47% (95% CI 33–61%).
      • Tzartzeva K.
      • Obi J.
      • Rich N.E.
      • Parikh N.D.
      • Marrero J.A.
      • Yopp A.
      • et al.
      Surveillance Imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis.
      Further, its effectiveness can be affected by operator expertise as well as several patient-level factors such as obesity and liver disease severity, leading to wide variations in its sensitivity between centres and patients.
      • Simmons O.
      • Fetzer D.T.
      • Yokoo T.
      • et al.
      Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis.
      • Del Poggio P.
      • Olmi S.
      • Ciccarese F.
      • Di Marco M.
      • Rapaccini G.L.
      • Benvegnù L.
      • et al.
      Factors that affect efficacy of ultrasound surveillance for early stage hepatocellular carcinoma in patients with cirrhosis.
      • Singal A.G.
      • Nehra M.
      • Adams-Huet B.
      • Yopp A.C.
      • Tiro J.A.
      • Marrero J.A.
      • et al.
      Detection of hepatocellular carcinoma at advanced stages among patients in the HALT-C trial: where did surveillance fail?.
      The reported lower sensitivity of ultrasound in patients with obesity and non-viral liver disease is particularly concerning in light of epidemiologic shifts, with an increasing proportion of HCC related to underlying NASH. However, there are few data specifically evaluating surveillance effectiveness among cohorts with emerging risk factors, such as those with NASH and post-SVR HCV infection.
      Given these concerns, alternative imaging modalities, such as CT or MRI, are increasingly being used in clinical practice;
      • Joshi K.
      • Mendler M.
      • Gish R.
      • Loomba R.
      • Kuo A.
      • Patton H.
      • et al.
      Hepatocellular carcinoma surveillance: a national survey of current practices in the USA.
      however, there are currently limited data supporting routine use of cross-sectional imaging for HCC surveillance. A small single-centre randomised trial comparing CT and ultrasound-based surveillance among 163 patients with cirrhosis failed to find a significant difference in early detection (62.5.5% vs. 55.5%, p = 0.93) or HCC-related mortality (8.8% vs. 6.0%, p = 0.46) despite significantly higher costs in the surveillance CT group ($57,383 vs. $17,041 per HCC detected).
      • Pocha C.
      • Dieperink E.
      • McMaken K.A.
      • Knott A.
      • Thuras P.
      • Ho S.B.
      Surveillance for hepatocellular cancer with ultrasonography vs. computed tomography – a randomised study.
      Subsequently, a recent retrospective cohort study including 636 HBV-infected patients found that patients who underwent surveillance using alternating CT and ultrasound every 6 months had improved early HCC detection compared to those who underwent ultrasound-based surveillance (HR 2.52, 95%CI 1.41–4.51); however, these data are limited by potential selection bias and residual confounding so still require prospective validation.
      • Lee M.
      • Kim J.H.
      • Kang S.
      • Jun B.G.
      • Kim T.S.
      • et al.
      Alternate dynamic computed tomography and ultrasonography for surveillance of chronic hepatitis B patients with cirrhosis at high risk for hepatocellular carcinoma.
      Finally, Kim and colleagues conducted a prospective cohort study comparing MRI-based and ultrasound-based surveillance among 407 patients with cirrhosis (predominantly HBV-related) and found MRI-based surveillance had a significantly higher sensitivity for early HCC detection than ultrasound (83.7% vs. 25.6%).
      • Kim S.Y.
      • An J.
      • Lim Y.S.
      • Han S.
      • Lee J.Y.
      • Byun J.H.
      • et al.
      MRI with liver-specific contrast for surveillance of patients with cirrhosis at high risk of hepatocellular carcinoma.
      However, further data about MRI performance in non-HBV patients and its cost-effectiveness are still needed prior to routine use of surveillance MRI in clinical practice. Other concerns about potential physical harms (radiation and contrast exposure), financial harms (costs), and limited radiologic capacity may also limit routine use of CT or MRI for HCC surveillance in all patients with cirrhosis. Early studies evaluating alternative imaging strategies, such as abbreviated MRI protocols, have suggested high sensitivity for early HCC detection, approaching that of diagnostic MRI;
      • Besa C.
      • Lewis S.
      • Pandharipande P.V.
      • Chhatwal J.
      • Kamath A.
      • et al.
      Hepatocellular carcinoma detection: diagnostic performance of a simulated abbreviated MRI protocol combining diffusion-weighted and T1-weighted imaging at the delayed phase post gadoxetic acid.
      • Marks R.M.
      • Ryan A.
      • Heba E.R.
      • Tang A.
      • Wolfson T.J.
      • et al.
      Diagnostic per-patient accuracy of an abbreviated hepatobiliary phase gadoxetic acid-enhanced MRI for hepatocellular carcinoma surveillance.

      Khatri G, Pedrosa I, Xi Y, Singal AG, Yopp A, Yokoo T. Abbreviated-protocol screening MRI versus complete-protocol diagnostic MRI for detection of hepatocellular carcinoma in patients with cirrhosis – an equivalence study using LI-RADS v2018. J Magnet. Resonance Imaging (in press). https://doi.org/10.1002/jmri.26835.

      however, these data are limited by selection bias and verification bias, which may overestimate the accuracy of abbreviated MRI. Until data evaluating these novel imaging techniques in larger cohorts mature, ultrasound remains the standard radiographic surveillance modality.
      Therefore, there has been increasing interest in serum biomarkers that may improve sensitivity for early HCC detection. The best studied biomarker to date remains alpha-fetoprotein (AFP), which has garnered limited enthusiasm given poor sensitivity for HCC when used alone. However, a meta-analysis of studies that directly compared the performance of ultrasound alone versus ultrasound plus AFP for early HCC detection found concomitant use of ultrasound and AFP improved early HCC detection compared to ultrasound alone, with sensitivities of 63% (95% CI 48–75%) and 45%, (95% CI 30–62%), respectively.
      • Tzartzeva K.
      • Obi J.
      • Rich N.E.
      • Parikh N.D.
      • Marrero J.A.
      • Yopp A.
      • et al.
      Surveillance Imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis.
      The improved sensitivity was offset by a decrease in specificity (84% vs. 92%, RR 1.08, 95% CI 1.05–1.09), although the clinical significance of this decrease is thought to be minimal. The diagnostic odds ratio, which accounts for sensitivity and specificity, of the 2 tests in combination was higher than that of ultrasound alone. Further, several methods have been proposed to minimise false-positive results of AFP. First, using the trend of AFP values, rather than a single test result at a fixed threshold, better reflects how AFP is interpreted in clinical practice and can more accurately identify patients with early stage HCC.
      • Tayob N.
      • Lok A.S.
      • Do K.A.
      • Feng Z.
      Improved detection of hepatocellular carcinoma by using a longitudinal alpha-fetoprotein screening algorithm.
      • Lee E.
      • Edward S.
      • Singal A.G.
      • Lavieri M.S.
      • Volk M.
      Improving screening for hepatocellular carcinoma by incorporating data on levels of alpha-fetoprotein, over time.
      Patients with consistent increases in AFP level, even if below 20 ng/ml, can be concerning and prompt cross-sectional imaging, whereas stable to decreasing AFP levels, even if greater than 20 ng/ml, would be reassuring and may be monitored instead of requiring diagnostic evaluation. Second, AFP is traditionally interpreted at a cut-off of 20 ng/ml for all patients with cirrhosis, despite recognition that it is often elevated in the absence of HCC among patients with viral hepatitis.
      • Di Bisceglie A.M.
      • Sterling R.K.
      • Chung R.T.
      • Everhart J.E.
      • Dienstag J.L.
      • Bonkovsky H.L.
      • et al.
      Serum alpha- fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C Trial.
      Therefore, use of different AFP cut-offs by liver disease aetiology can improve specificity, with 1 study suggesting a higher cut-off of 59 ng/ml in patients with cirrhosis caused by viral hepatitis and a lower cut-off of 11 ng/ml in those with non-viral cirrhosis.
      • Gopal P.
      • Yopp A.C.
      • Waljee A.K.
      • Chiang J.
      • Nehra M.
      • Kandunoori P.
      • et al.
      Factors that affect accuracy of alpha-fetoprotein test in detection of hepatocellular carcinoma in patients with cirrhosis.
      Finally, there has been increasing interest in developing AFP-adjusted algorithms to improve its accuracy for early HCC detection. For example, an HCC early detection screening (HES) model that incorporates the rate of AFP change along with the most recent value of AFP, age of the patient, alanine aminotransferase blood level, and platelet count is associated with improved sensitivity for early HCC detection compared to the current standard of care.
      • White D.L.
      • Richardson P.
      • Tayoub N.
      • Davila J.A.
      • Kanwal F.
      • El-Serag H.B.
      The updated model: an adjusted serum alpha-fetoprotein-based algorithm for hepatocellular carcinoma detection with hepatitis c virus-related cirrhosis.
      Due to intra-tumoral heterogenicity in HCC, there has been increasing recognition that a single biomarker may not be sufficient, and that a combination of biomarkers may be needed to optimise sensitivity for early HCC detection. GALAD, which includes gender, age, lectin-bound AFP % (AFP-L3%), AFP, and des-gamma carboxy prothrombin (DCP), is one of the best studied biomarker panels to date. In a multinational phase II study with 6,834 patients (2,430 HCC and 4,404 chronic liver disease), GALAD achieved sensitivities ranging from 60% to 80% for early HCC detection.
      • Berhane S.
      • Toyoda H.
      • Tada T.
      • Kumada T.
      • Kagebayashi C.
      • et al.
      Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients.
      Another panel including AFP, fucosylated kininogen, age, gender, alkaline phosphatase, and alanine aminotransferase demonstrated a c-statistic of 0.97 (95% CI 0.95–0.99) for early HCC detection in a small phase II biomarker study of 162 patients (69 early HCC, 93 cirrhosis).
      • Wang M.
      • Sanda M.
      • Comunale M.A.
      • Harrera H.
      • Swindell C.
      • et al.
      Changes in the glycosylation of kininogen and the development of a kininogen-based algorithm for the early detection of HCC.
      Finally, a methylated DNA marker panel had a c-statistic of 0.96 (95% CI 0.93–0.99), with a sensitivity exceeding 90%, for early HCC detection in a phase II study with 146 patients (95 HCC and 51 cirrhosis).
      • Kisiel J.B.
      • Dukek B.A.
      • V S R Kanipakam R.
      • Ghoz H.M.
      • Yab T.C.
      • Berger C.K.
      • et al.
      Hepatocellular carcinoma detection by plasma methylated DNA: discovery, phase I pilot, and phase II clinical validation.
      Similar to individual biomarker studies, these data are promising but still require validation in large phase III biomarker studies.
      There has been an increasing interest in serum biomarkers for early HCC detection, although it is accepted that a combination of markers may be required for optimal diagnostic accuracy.

      Potential surveillance harms

      As for all screening programmes, HCC surveillance might cause objective or subjective discomfort encompassing: i) depression or anxiety during the screening process, ii) financial or physical harms resulting from investigation of false-positive or indeterminate results and iii) overdiagnosis and overtreatment of a tumour that never would have progressed to clinical attention in the absence of screening, although the latter is likely a rare situation in the case of HCC.
      • Harris R.P.
      • Sheridan S.L.
      • Lewis C.L.
      • Barclay C.
      • Vu M.B.
      • et al.
      The harms of screening: a proposed taxonomy and application to lung cancer screening.
      • Heleno B.
      • Thomsen M.F.
      • Rodrigues D.S.
      • Jorgensen K.J.
      • Brodersen J.
      Quantification of harms in cancer screening trials: literature review.
      • Rich N.E.
      • Singal A.G.
      Overdiagnosis: an understudied issue in hepatocellular carcinoma surveillance.
      The potential benefits of surveillance programmes must be weighed against the potential harms of screening, while also considering the severe consequences of late HCC diagnosis.
      Overall, the risk of these potential harms when deciding to perform recall procedures for a focal lesion and/or elevated serum biomarker has to be weighed against the dismal prognosis in the case of unscreened liver cancer and the possibility of remission from curative procedures of a tumour detected during surveillance.
      All guidelines recommend the performance of contrast-enhanced imaging techniques when a focal lesion, larger than 1 cm, is detected by ultrasound.
      • Heimbach J.K.
      • Kulik L.M.
      • Finn R.S.
      • et al.
      AASLD guidelines for the treatment of hepatocellular carcinoma.
      • EASL Clinical Practice Guidelines
      Management of hepatocellular carcinoma.
      • Omata M.
      • Cheng A.L.
      • Kokudo N.
      • et al.
      Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.
      CT scans lead to radiation exposure and might be responsible for potential renal toxicity due to contrast injection.
      • Sangiovanni A.
      • Manini M.A.
      • Iavarone M.
      • Romeo R.
      • Forzenigo L.V.
      • Fraquelli M.
      • et al.
      The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis.
      While MRI scans cause no radiation exposure, the test is costly, a contrast injection is still required, and it can be a particular cause of distress for patients.
      • Geh D.
      • Rana F.A.
      • Reeves H.L.
      Weighing the benefits of hepatocellular carcinoma surveillance against potential harms.
      Recent data suggest a risk of gadolinium accumulation, although the long-term clinical consequences of this phenomenon are currently unknown. In cases of an atypical radiologic finding, a liver biopsy of the lesion is recommended. The risk of false negative biopsies are common in clinical practice, particularly in the case of small lesions, and may lead to delays in both diagnosis and treatment.
      • Forner A.
      • Vilana R.
      • Ayuso C.
      • Bianchi L.
      • Solé M.
      • Ayuso J.R.
      • et al.
      Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.
      Tumour seeding along the biopsy tract is a rare event (1–5%), with important consequences as it may preclude the implementation of subsequent curative procedures such as ablation, resection or transplantation.
      • Maturen K.E.
      • Nghiem H.V.
      • Marrero J.A.
      • Hussain H.K.
      • Higgins E.G.
      • Fox G.A.
      • et al.
      Lack of tumor seeding of hepatocellular carcinoma after percutaneous needle biopsy using coaxial cutting needle technique.
      Finally, the risk of bleeding is considered low but can be life-threatening.
      • Buscarini L.
      • Fornari F.
      • Bolondi L.
      • et al.
      Ultrasound-guided fine-needle biopsy of focal liver lesions: techniques, diagnostic accuracy and complications.
      A recent report suggested that false-positive or indeterminate results are likely frequently observed among patients included in HCC surveillance programmes.
      • Atiq O.
      • Tiro J.
      • Yopp A.C.
      • Muffler A.
      • Marrero J.A.
      • Parikh N.D.
      • et al.
      An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis.
      This study included 680 cirrhotic patients, among whom 78 (11.5%) developed HCC over a 3-year period. As a measure of screening benefit, it was noted that 48 (61.5%) of the HCCs were identified by surveillance ultrasound and/or AFP. However, surveillance harm events over the same period, defined largely as “unnecessary testing”, were identified in 187 (27.5%) patients and nearly 10% had moderate-to-severe harm, defined as repeated imaging and/or invasive testing such as a biopsy. Of note, some patients in this study had diagnostic evaluation for indeterminate surveillance tests, such as sub-centimetre lesions on ultrasound, suggesting surveillance harm could have been mitigated by closer observation of guideline recommendations. These data were recently confirmed in another single-centre study, which similarly found nearly 20% of patients underwent diagnostic testing for indeterminate lesions detected as part of an HCC surveillance programme.
      • Konerman M.
      • Verma A.
      • Zhao B.
      • Singal A.G.
      • Lok A.S.
      • Parikh N.D.
      Frequency and outcome of abnormal imaging impact in patients with cirrhosis enrolled in a hepatocellular carcinoma surveillance program.
      Although subjective discomfort was not assessed in these studies, the results compensate for the lack of data regarding surveillance-related harms highlighted by most reports, which have mostly focused on the potential benefits of HCC surveillance.

      Implementation of and compliance to surveillance programmes

      Numerous studies from the West suggest that less than 30% of patients with cirrhosis are included in HCC surveillance programmes and actually receive semi-annual screening.
      • Singal A.G.
      • Yopp A.
      • Skinner C.S.
      • Packer M.
      • Lee W.M.
      • Tiro J.A.
      Utilization of hepatocellular carcinoma surveillance among American patients: a systematic review.
      • Goldberg D.S.
      • Taddei T.H.
      • Serper M.
      • Mehta R.
      • Dieperink E.
      • Aytaman A.
      • et al.
      Identifying barriers to hepatocellular carcinoma surveillance in a national sample of patients with cirrhosis.
      • Davila J.A.
      • Henderson L.
      • Kramer J.R.
      • Kanwal F.
      • Richardson P.A.
      • Duan Z.
      • et al.
      Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States.
      Factors explaining low adherence to HCC screening are multiple. Access to care seems to impact HCC screening, in particular for uninsured patients and African Americans in the US.
      • Singal A.G.
      • Li X.
      • Tiro J.A.
      • Kandunoori P.
      • Huet B.
      • Nehra M.
      • Yopp A.C.
      Racial, social, and clinical determinants of hepatocellular carcinoma surveillance.
      In addition, it is suspected that only 20–50% of cirrhotic patients are seen by hepatologists or gastroenterologists, who are usually inclined to include their patients in screening programmes. In this setting, the majority of cirrhotic patients are followed by primary care providers, in whom knowledge and beliefs regarding HCC surveillance are usually less developed.
      • Palmer L.
      • Kappelman M.
      • Sandler R.S.
      • Hayashi P.
      Surveillance for hepatocellular carcinoma in a medicaid cirrhotic population.
      • Singal A.G.
      • Tiro J.
      • Li X.
      • Adams-Huet B.
      • Chubak J.
      Hepatocellular carcinoma surveillance among patients with cirrhosis in a population based integrated healthcare delivery system.
      • Simmons O.L.
      • Feng Y.
      • Parikh N.D.
      • Singal A.G.
      Primary care provider practice patterns and barriers to hepatocellular carcinoma surveillance.
      In a recent US study, a survey of 1,000 primary care providers showed that most practitioners see patients with cirrhosis, but only a minority enrol them in surveillance protocols, which could be related to suboptimal knowledge of effective HCC therapy options.
      • McGowan C.
      • Edwards T.
      • Luong M.
      • Hayashi P.
      Suboptimal surveillance for and knowledge of hepatocellular carcinoma among primary care providers.
      Patient adherence and compliance to surveillance also seem to be a determinant. In this setting, based on the prospective follow-up of a large cohort of 1,671 patients with compensated viral-induced cirrhosis included in protocolised screening procedures, an impaired compliance to the 6-month rule was observed in nearly 40% of the 216 patients who were diagnosed with HCC during a nearly 60-month follow-up.
      • Costentin C.E.
      • Layese R.
      • Bourcier V.
      • Cagnot C.
      • Marcellin P.
      • Guyader D.
      • et al.
      Compliance with hepatocellular carcinoma surveillance guidelines associated with increased lead-time adjusted survival of patients with compensated viral cirrhosis: a multi-center cohort study.
      Such an observation is particularly worrisome when considering that only patients with viral-related cirrhosis (usually more prone to be compliant) who accepted long-term, periodical follow-up, were recruited. It is possible, if not likely, that adherence to surveillance regimens may be lower in patients with alcohol- or NASH-related cirrhosis.
      • Singal A.G.
      • Yopp A.
      • Gupta S.
      • Skinner C.S.
      • Halm E.A.
      • et al.
      Failure rates in the hepatocellular carcinoma surveillance process.
      Similarly, patients with a history of HCV-related cirrhosis remain at risk of HCC after SVR but may not be followed as closely and may therefore be more prone to lapses in surveillance. Further data characterising surveillance utilisation and barriers to surveillance in cohorts with these emerging risk factors are needed.
      HCC surveillance is underutilised in clinical practice, which can decrease its effectiveness – thus, improving utilisation is a target for intervention efforts.
      Overall these prospective analyses revealed a survival advantage associated with compliance with HCC screening guidelines after correction for lead-time bias. Indeed, respect for the 6-month screening rule was associated with early HCC diagnosis, allocation of curative treatment and longer lead-time adjusted overall survival. In this context, deciphering the mechanisms explaining lower compliance in some patients is pivotal. Patient knowledge, attitudes, and perceived barriers were recently assessed through a survey performed in a tertiary American centre and were correlated with receipt of surveillance during a 1-year period.
      • Farvardin S.
      • Patel J.
      • Khambaty M.
      • Yerokun O.
      • Mok H.
      • Tiro J.A.
      • et al.
      Patient-reported barriers are associated with lower HCC surveillance rates in patients with cirrhosis.
      Overall, this study demonstrated that surveillance rates were higher in patients displaying high levels of cirrhosis/HCC-related knowledge; conversely, the quality of screening was impaired by several pragmatic aspects reported as “barriers” including difficulty with the scheduling process, costs of surveillance testing, and transportation difficulties. Finally, the strongest argument highlighting the impact of patient knowledge is derived from an aborted surveillance trial, in which it was demonstrated that a randomised study comparing HCC screening versus no surveillance was not feasible once informed consent had been provided.
      • Poustchi H.
      • Farrell G.C.
      • Strasser S.I.
      • Lee A.U.
      • McCaughan G.W.
      • George J.
      Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed?.

      Perspectives and areas of research

      Optimising HCC surveillance is one of the major challenges our community will have to deal with in order to improve the dismal prognosis of this cancer. Increasing uptake and refining strategies to tailor personalised management are the cornerstones that must guide our action (Fig. 2). The latter must be scientifically implemented and evaluated in the forthcoming years; furthermore, the evolution of healthcare and medico-economic contexts characterised by limited resources must be accounted for.
      Figure thumbnail gr2
      Fig. 2Potential interventions to increase HCC surveillance effectiveness. HCC, hepatocellular carcinoma.

      Risk stratification, cost-effectiveness and personalised screening

      All patients with cirrhosis do not have the same risk of developing HCC and it remains difficult to assess the specific risk at an individual level.
      • Nahon P.
      • Zucman-Rossi J.
      Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis.
      Furthermore, and as mentioned earlier, despite enrolment in surveillance programmes, some patients are diagnosed with advanced HCC irrespective of their compliance, particularly because of the poor sensitivity of ultrasound. Such pitfalls could be overcome by using more sophisticated contrast-enhanced imaging techniques such as MRI or new circulating biomarkers, which are useful for HCC prediction as well as early detection. However, implementing such costly surveillance programmes may not be cost-effective in certain subsets of cirrhotic patients because of their particularly low annual incidence of HCC, for example in the case of cirrhotic patients with controlled or eradicated HBV-/HCV-infection.
      • McGowan C.
      • Edwards T.
      • Luong M.
      • Hayashi P.
      Suboptimal surveillance for and knowledge of hepatocellular carcinoma among primary care providers.
      • Costentin C.E.
      • Layese R.
      • Bourcier V.
      • Cagnot C.
      • Marcellin P.
      • Guyader D.
      • et al.
      Compliance with hepatocellular carcinoma surveillance guidelines associated with increased lead-time adjusted survival of patients with compensated viral cirrhosis: a multi-center cohort study.
      • Singal A.G.
      • Yopp A.
      • Gupta S.
      • Skinner C.S.
      • Halm E.A.
      • et al.
      Failure rates in the hepatocellular carcinoma surveillance process.
      • Farvardin S.
      • Patel J.
      • Khambaty M.
      • Yerokun O.
      • Mok H.
      • Tiro J.A.
      • et al.
      Patient-reported barriers are associated with lower HCC surveillance rates in patients with cirrhosis.
      • Poustchi H.
      • Farrell G.C.
      • Strasser S.I.
      • Lee A.U.
      • McCaughan G.W.
      • George J.
      Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed?.
      • Nahon P.
      • Zucman-Rossi J.
      Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis.
      • Papatheodoridis G.
      • Lampertico P.
      • Manolakopoulos S.
      • Lok A.S.
      Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review.
      In this setting, personalised assessment of the individual risk of HCC and refinement of screening policies might be discussed. Until now, various HCC scoring systems have been based on the combination of routine clinical features to stratify cirrhotic patients into various HCC risk classes.
      • Papatheodoridis G.V.
      • Idilman R.
      • Dalekos G.N.
      • Buti M.
      • Chi H.
      The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B.
      However, it is unclear if clinical features can accurately risk stratify patients in isolation or if other features such as genomics or molecular signatures are needed.
      • Nahon P.
      • Bourcier V.
      • Layese R.
      • Audureau E.
      • Cagnot C.
      • et al.
      Eradication of hepatitis c virus infection in patients with cirrhosis reduces risk of liver and non-liver complications.
      • Singal A.G.
      • Mukherjee A.
      • Elmunzer B.J.
      • Higgins P.D.
      • Lok A.S.
      • Zhu J.
      • et al.
      Machine learning algorithms outperform conventional regression models in predicting development of hepatocellular carcinoma.
      • Hoshida Y.
      • Villanueva A.
      • Kobayashi M.
      • Peix J.
      • Chiang D.Y.
      • Camargo A.
      • et al.
      Gene expression in fixed tissues and outcome in hepatocellular carcinoma.
      Further, it is unclear if these risk stratification tools could be applied to patients with non-cirrhotic NAFLD to identify a subgroup in whom HCC surveillance may be cost-effective. Based on the stratification into low-, intermediate- or high-HCC risk groups, it is tempting to speculate that adaptation of screening strategies might optimise both cost-effectiveness and the allocation of limited medical resources. In this context, the intensification of screening programmes in intermediate- or high-risk groups is a timely challenge in view of the changing epidemiology of chronic liver disease: using expensive but highly sensitive imaging techniques such as MRI or performing sequential assessment of circulating biomarkers yet to be discovered might then be justified in populations at the highest risk of HCC.
      • Goosens N.
      • Singal A.G.
      • King L.
      • Andersson K.L.
      • Fuchs B.
      • Besa-Correa C.
      • et al.
      Cost-effectiveness of risk score-stratified hepatocellular carcinoma screening in patients with cirrhosis.

      Development of new biomarkers for early diagnosis

      Despite improved accuracy compared to ultrasound alone, it is clear that a surveillance strategy of ultrasound and AFP remains far from where we need to be. In fact, the surveillance strategy of ultrasound with AFP still misses approximately one-third of HCC at an early stage. A number of novel biomarkers, such as DCP and AFP-L3, have been promising in phase II studies but still require validation in larger phase III cohort studies.
      • Berhane S.
      • Toyoda H.
      • Tada T.
      • Kumada T.
      • Kagebayashi C.
      • et al.
      Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients.
      Cell free DNA released from tumour cells may be detected in peripheral blood samples and is another promising biomarker; however, it is also in the early phases of evaluation for surveillance, as its unclear if it will be found in sufficient quantities in patients with early stage tumours.
      • Tang J.C.
      • Feng Y.
      • Guo T.
      • Xie A.
      • Cai X.
      Circulating tumor DNA in hepatocellular carcinoma: trends and challenges.
      The development of large prospective cohorts with stored biobanks of longitudinal serum and plasma samples, such as the Early Detection Research Network (EDRN) Hepatocellular cancer Early Detection Study (HEDS) and Cancer Prevention Research Institute of Texas (CPRIT) Texas HCC Consortium (THCCC) cohorts, should facilitate phase III validation of these biomarkers in the near future.
      • Feng Z.
      • Marrero J.A.
      • Khaderi S.
      • Singal A.G.
      • Kanwal F.
      • Loo N.
      • et al.
      Design of the Texas hepatocellular carcinoma consortium cohort study.
      Such efforts are also being initiated in Europe, with the constitution of the STHEPBIO consortium, which will encompass several prospective cohorts of cirrhotic patients with adjoining sequential biobanks from France, Italy, Belgium and Spain.

      Intervention to increase surveillance rates

      Optimising HCC surveillance will likely necessitate the creation of specific networks involving physicians, patients and healthcare systems. Improving patient education using dedicated tools encompassing the intervention of trained personnel, websites, patient group sessions, education screencasts, and smart phone applications must be encouraged. Involving patients in the decision-making process, in the setting of the aforementioned personalisation of screening programmes, is also strongly recommended. Integrating HCC surveillance into complete work-up sessions mixing diverse interventions (nutritionists, alcohol liaison service, portal hypertension screening) into one-stop clinics might facilitate clinical pathways and ultimately favour compliance in the long term. The intensification of specific interventions aimed at improving compliance are also needed. For instance, mailed outreach strategies and patient navigation have been proven to successfully increase HCC surveillance uptake.
      • Singal A.G.
      • Tiro J.A.
      • Marrero J.A.
      • McCallister K.
      • Mejias C.
      • Sanders J.
      • et al.
      Mailed outreach program increases ultrasound screening of patients with cirrhosis for hepatocellular carcinoma.
      • Singal A.G.
      • Tiro J.A.
      • Murphy C.C.
      • Marrero J.A.
      • McCallister K.
      • Fullington H.
      • et al.
      Mailed outreach invitations significantly improve HCC surveillance rates in patients with cirrhosis: a randomized clinical trial.
      In the same line, implementing clinical reminder systems for physicians seems to positively impact the respect for surveillance timeframes in routine practice
      • Beste L.A.
      • Ioannou G.N.
      • Yang Y.
      • Chang M.F.
      • Ross D.
      • Dominitz J.A.
      Improved surveillance for hepatocellular carcinoma with a primary care-oriented clinical reminder.
      . Finally, enlisting primary care providers in HCC surveillance through reinforced partnership and training programmes might also facilitate screening uptake
      • McGowan C.
      • Edwards T.
      • Luong M.
      • Hayashi P.
      Suboptimal surveillance for and knowledge of hepatocellular carcinoma among primary care providers.
      . However, these interventions, particularly when implemented in broad populations followed by primary care providers alone, still have surveillance rates below 50%, highlighting the need for more intensive intervention strategies in the future.

      Conclusions

      The global incidence and mortality of HCC is rising, particularly in the US and Europe. Given the strong association between early detection and survival, improving uptake and performance of HCC surveillance must be defined as a priority for our community. Our actions will benefit from improved risk stratification of at-risk patients, discovery of more sensitive and specific surveillance tools (e.g. circulating blood-based biomarkers and new imaging techniques) and implementation of interventions to increase surveillance utilisation that involve a broader range of physicians and patient participation. Healthcare systems will need to adapt to the changing epidemiology of chronic liver disease and the associated economic burden, in order to move towards a personalised approach aimed at increasing the percentage of patients with HCC eligible for curative procedures. This could be the most effective action to improve the prognosis of this difficult-to-treat cancer.

      Abbreviations

      AFP, alpha-fetoprotein; ASIRs, age-standardised incidence rates; ASMRs, age-standardised mortality rates; DCP, des-gamma carboxy prothrombin; HCC, hepatocellular carcinoma; HR, hazard ratio; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; SVR, sustained virological response.

      Financial support

      Dr. Singal’s research is supported by National Cancer Institute (NCI) R01 CA212008 and CA222900 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation of the manuscript. Dr Nahon’s research is sponsored by the ANRS (France REcherche Nord & sud SIDA-HIV Hépatites: FRENSH) and Banque Publique d’Investissement. The funding sponsors had no role in the design and conduct of the study, the collection, management, analysis, interpretation of data, or the preparation, review, or approval of the manuscript.

      Conflict of interest

      Amit G. Singal has has served on advisory boards for Gilead, Abbvie, Bayer, Eisai, Bristol Meyers Squibb, Wako Diagnostics, and Exact Sciences. He serves as a consultant to Bayer, Eisai, Exelixis, Roche, Exact Sciences, Glycotest, and TARGET. He has received research funding from Gilead and Abbvie. Pierre Nahon has received honoraria from and/or consults for Abbvie, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Gilead, Ipsen and MSD. He received research grants from Abbvie and Bristol-Myers Squibb. Pietro Lampertico has served on speakers' bureau/advisory boards for BMS, Roche, Gilead Sciences, GSK, MSD, Abbvie and Janssen, Eiger, Myr pharma.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors' contributions

      All authors contributed significantly to the work and reviewed the final version.

      Acknowledgments

      We thank Dr. Angelo Sangiovanni for contributing to the paper.

      Supplementary data

      The following are the Supplementary data to this article:

      References

      Author names in bold designate shared co-first authorship

        • Wang H.
        • Naghavi M.
        • Allen C.
        • Barber R.M.
        • Bhutta Z.A.
        • et al.
        • Global Burden of Disease Liver Cancer Collaboration 2015
        Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015.
        Lancet. 2016; 388: 1459-1544
        • Global Burden of Disease Liver Cancer Collaboration
        • Akinyemiju T.
        • Abera S.
        • Ahmed M.
        • Alam N.
        • Alemayohu M.A.
        • et al.
        The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015.
        JAMA Oncol. 2017; 3: 1683-1691
        • Bray F.
        • Ferlay J.
        • Soerjomataram I.
        • Siegel R.L.
        • Torre L.A.
        • Jemal A.
        Global Cancer Statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68: 394-424
      1. https://gco.iarc.fr/today/online-analysis-treemap?v=2018&mode=cancer&mode_ population=continents&population=900&populations=900&key=asr&sex=0&cancer=39&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&nb_items=5&group_cancer=1&include_nmsc=1&include_nmsc_other=1&reloaded. Access on 06/04/2019.

      2. https://gco.iarc.fr/today/online-analysis-map?v=2018&mode=population&mode _population=continents&population=900&populations=900&key=asr&sex=0&cancer=11&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&nb_items=5&group_cancer=1&include_nmsc=1&include_nmsc_other=1&projection=natural-earth&color_palette=default&map_scale=quantile&map_nb_colors=5&continent=0&rotate=%255B10%252C0%255D. Access on 06/04/2019.

      3. https://gco.iarc.fr/today/online-analysis-map?v=2018&mode=population&mode _population=continents&population=900&populations=900&key=asr&sex=0&cancer=11&type=1&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&nb_items=5&group_cancer=1&include_nmsc=1&include_nmsc_other=1&projection=natural-earth&color_palette=default&map_scale=quantile&map_nb_colors= 5&continent=0&rotate=%255B10%252C0%255D. Access on 06/04/2019.

        • Sangiovanni A.
        • Prati G.M.
        • Fasani P.
        • Ronchi G.
        • Romeo R.
        • Manini M.
        • et al.
        The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 patients.
        Hepatology. 2006; 43: 1303-1310
        • Ioannou G.N.
        • Splan M.F.
        • Weiss N.S.
        • McDonald G.B.
        • Beretta L.
        • Lee S.P.
        Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis.
        Clin Gastroenterol Hepatol. 2007; 5: 938-945
        • Yang H.I.
        • Lu S.N.
        • Liaw Y.F.
        • You S.L.
        • Sun C.A.
        • Wang L.Y.
        • et al.
        Hepatitis B e antigen and the risk of hepatocellular carcinoma.
        N Engl J Med. 2002; 347: 168-174
        • Chen C.J.
        • Yang H.I.
        • Su J.
        • Jen C.L.
        • You S.L.
        • Lu S.N.
        • et al.
        Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.
        JAMA. 2006; 295: 65-73
        • Yu M.-W.
        • Yeh S.-H.
        • Chen P.-J.
        • Liaw Y.-F.
        • Lin C.-L.
        • Liu C.-J.
        • et al.
        Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men.
        J Natl Cancer Inst. 2005; 97: 265-272
        • Heimbach J.K.
        • Kulik L.M.
        • Finn R.S.
        • et al.
        AASLD guidelines for the treatment of hepatocellular carcinoma.
        Hepatology (Baltimore, MD). 2018; 67: 358-380
        • EASL Clinical Practice Guidelines
        Management of hepatocellular carcinoma.
        J Hepatol. 2018; 69: 182-236
        • Omata M.
        • Cheng A.L.
        • Kokudo N.
        • et al.
        Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.
        Hep Intl. 2017; 11: 317-370
        • Zangneh F.
        • Wong W.W.L.
        • Sander B.
        • et al.
        Cost effectiveness of hepatocellular carcinoma surveillance after a sustained virologic response to therapy in patients with hepatitis c virus infection and advanced fibrosis.
        Clin Gastroenterol Hepatol. 2018; (pii: S1542–3565(18)-6): 31394https://doi.org/10.1016/j.cgh.2018.12.018
        • Chang M.H.
        • You S.L.
        • Chen C.J.
        • Liu C.J.
        • Lai M.W.
        • Wu T.C.
        • et al.
        Long-term effects of hepatitis B immunization of infants in preventing liver cancer.
        Gastroenterology. 2016; 151: 472-480
        • Yuen M.-F.
        • Chen D.-S.
        • Dusheiko G.M.
        • et al.
        Hepatitis B virus infection.
        Nat Rev Dis Primers. 2018; 4: 18035
        • Liaw Y.-F.
        • Sung J.J.Y.
        • Cheng Chow W.
        • et al.
        Lamivudine for patients with chronic hepatitis B and advanced liver disease.
        N Engl J Med. 2004; 351: 1521-1531
        • Morgan R.L.
        • Baack B.
        • Smith B.D.
        • Yartel A.
        • Pitasi M.
        • Falck-Ytter Y.
        Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies.
        Ann Intern Med. 2013; 158: 329-337
        • Kanwal F.
        • Kramer J.
        • Asch S.M.
        • Chayanupatkul M.
        • Cao Y.
        • El-Serag H.B.
        Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.
        Gastroenterology. 2017; 153: 996-1005
        • Ioannou G.
        • Beste L.A.
        • Green P.K.
        • Singal A.G.
        • Tapper E.B.
        • Waljee A.K.
        • et al.
        Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores.
        Gastroenterology. 2019; 157 (1264–1278.e4)
        • McKillop I.
        • Schrum L.
        Role of alcohol in liver carcinogenesis.
        Semin Liver Dis. 2009; 29: 222-232
        • Ganne-Carrié N.
        • Chaffaut C.
        • Bourcier V.
        • Archambeaud I.
        • Perarnau J.M.
        • Oberti F.
        • et al.
        for CIRRAL Group. Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis.
        J Hepatol. 2018; 69: 1274-1283
        • Nahon P.
        • Sutton A.
        • Rufat P.
        • Ziol M.
        • Akouche H.
        • Laguillier C.
        • et al.
        Myeloperoxidase and superoxide dismutase 2 polymorphisms comodulate the risk of hepatocellular carcinoma and death in alcoholic cirrhosis.
        Hepatology. 2009; 50: 1484-1493
        • Mancebo A.
        • Gonzalez-Dieguez M.L.
        • Cadahia V.
        • Varela M.
        • Perez R.
        • Navascues C.A.
        • et al.
        Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups.
        Clin Gastroenterol Hepatol. 2012; 11: 95-101
      4. World Gastroenterology Organisation Global Guidelines. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. 2012 Available from: http://www.worldgastroenterology.org/assets/export/userfiles/2012_NASH%20and%20NAFLD_Final_long.pdf. (accessed: 25.05.2018).

        • Kanwal F.
        • Kramer J.R.
        • Mapakshi S.
        • Natarajan Y.
        • Chayanupatkul M.
        • Richardson P.A.
        • et al.
        Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.
        Gastroenterology. 2018; 155: 1828-1837
        • Mittal S.
        • El_Serag H.B.
        • Sada Y.H.
        • Kanwal F.
        • Duan Z.
        • Temple S.
        • et al.
        Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease.
        Clin Gastroenterol Hepatol. 2016; 14: 124-131
        • Dyson J.
        • Jaques B.
        • Chattopadyhay D.
        • Lochan R.
        • Graham J.
        • Das D.
        • et al.
        Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.
        J Hepatol. 2014; 60: 110-117
        • Stine J.G.
        • Wentworth B.J.
        • Zimmet A.
        • Rinella M.E.
        • Loomba R.
        • Caldwell S.H.
        • et al.
        Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases..
        Aliment Pharmacol Ther. 2018; 48: 696-703
        • Lee T.Y.
        • Wu J.C.
        • Yu S.H.
        • Lin J.T.
        • Wu M.S.
        • Wu C.Y.
        • et al.
        The occurrence of hepatocellular carcinoma in different risk stratifications of clinically noncirrhotic nonalcoholic fatty liver disease.
        Int J Cancer. 2017; 141: 1307-1314
        • Reig M.
        • Gambato M.
        • Man N.
        Should patients with NAFLD/NASH be surveyed for HCC?.
        Transplantation. 2019; 103: 39-44
        • Schlesinger S.
        • Aleksandrova K.
        • Pischon T.
        • Jenab M.
        • Fedirko V.
        • Trepo E.
        • et al.
        Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort.
        Ann Oncol. 2013; 24: 2449-2455
        • Welzel T.M.
        • Graubard B.I.
        • Quraishi S.
        • Zeuzem S.
        • Davila J.A.
        • El-Serag H.B.
        • et al.
        Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States.
        Am J Gastroenterol. 2013; 108: 1314-1321
        • Deugnier Y.M.
        • Guyader D.
        • Crantock L.
        • Lopez J.M.
        • Turlin B.
        • Yaouanq J.
        • et al.
        Primary liver cancer in genetic hemochromatosis: a clinical, pathological, and pathogenetic study of 54 cases.
        Gastroenterology. 1993; 104: 228-234
        • Fracanzani A.L.
        • Conte D.
        • Fraquelli M.
        • Taioli E.
        • Mattioli M.
        • Losco A.
        • et al.
        Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with noniron-related chronic liver disease.
        Hepatology. 2001; 33: 647-651
        • Andant C.
        • Puy H.
        • Bogard C.
        • Faivre J.
        • Soulé J.C.
        • Nordmann Y.
        • et al.
        Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors.
        J Hepatol. 2000; 32: 933-939
        • Fracanzani A.L.
        • Taioli E.
        • Sampietro M.
        • Fatta E.
        • Bertelli C.
        • Fiorelli G.
        • et al.
        Liver cancer risk is increased in patients with porphyria cutanea tarda in comparison to matched control patients with chronic liver disease.
        J Hepatol. 2001; 35: 498-503
        • Rich N.E.
        • Hester C.
        • Odewole M.
        • Murphy C.C.
        • Parikh N.D.
        • Marrero J.A.
        • et al.
        Racial and ethnic differences in hepatocellular carcinoma presentation and outcomes.
        Clin Gastroenterol Hepatol. 2019; 17: 551-559
        • Hsu I.C.
        • Metcalf R.A.
        • Sun T.
        • Welsh J.A.
        • Wang N.J.
        • Harris C.C.
        Mutational hotspot in the p53 gene in human hepatocellular carcinomas.
        Nature. 1991; 350: 427-428
        • Lee Y.-C.A.
        • Cohet C.
        • Yang Y.-C.
        • Stayner L.
        • Hashibe M.
        • Straif K.
        Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer.
        Int J Epidemiol. 2009; 38: 1497-1511
        • Tseng C.-H.
        Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes.
        Liver Int. 2018; 38: 2018-2027
        • Simon T.G.
        • Ma Y.
        • Ludvigsson J.F.
        • Chong D.Q.
        • Giovannucci E.L.
        • Fuchs C.S.
        • et al.
        Association between aspirin use and risk of hepatocellular carcinoma.
        JAMA Oncol. 2018; 4: 1683-1690
        • Inoue M.
        • Yoshimi I.
        • Sobue T.
        • Tsugane S.
        Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
        J Natl Cancer Inst. 2005; 97: 293-300
        • Gelatti U.
        • Covolo L.
        • Franceschini M.
        • Pirali F.
        • Tagger A.
        • Ribero M.L.
        • et al.
        Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study.
        J Hepatol. 2005; 42: 528-534
        • Bravi F.
        • Bosetti C.
        • Tavani A.
        • Bagnardi V.
        • Gallus S.
        • Negri E.
        • et al.
        Coffee drinking and hepatocellular carcinoma risk: a meta-analysis.
        Hepatology. 2007; 46: 430-435
        • Bravi F.
        • Tavani A.
        • Bosetti C.
        • Boffetta P.
        • La Vecchia C.
        Coffee and the risk of hepatocellular carcinoma and chronic liver disease: a systematic review and meta-analysis of prospective studies.
        Eur J Cancer Prev. 2017; 26: 368-377
      5. Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Tomorrow. International Agency for Research on Cancer, Lyon 2018. Available from: https://gco.iarc.fr/tomorrow (accessed:29.09.2018).

        • Tanaka H.
        • Imai Y.
        • Hiramatsu N.
        • Ito Y.
        • Imanaka K.
        • Oshita M.
        • et al.
        Declining incidence of hepatocellular carcinoma in Osaka, Japan, from 1990 to 2003.
        Ann Intern Med. 2008; 148: 820-826
        • Qiu D.
        • Katanoda K.
        • Marugame T.
        • Sobue T.
        A Joinpoint regression analysis of long-term trends in cancer mortality in Japan (1958–2004).
        Int J Cancer. 2009; 124: 443-448
        • Bosetti C.
        • Levi F.
        • Boffetta P.
        • Lucchini F.
        • Negri E.
        • La Vecchia C.
        Trends in mortality from hepatocellular carcinoma in Europe, 1980–2004.
        Hepatology. 2008; 48: 137-145
        • Valery P.C.
        • Laversanne M.
        • Clark P.J.
        • Petrick J.L.
        • McGlynn K.A.
        • Bray F.
        Projections of primary liver cancer to 2030 in 30 countries worldwide.
        Hepatology. 2018; 67: 600-611
        • Estes C.
        • Anstee Q.M.
        • Arias-Loste M.T.
        • et al.
        Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030.
        J Hepatol. 2018; 69: 896-904
        • Prasad V.
        • Lenzer J.
        • Newman D.H.
        Why cancer screening has never been shown to “save lives” – and what we do about it.
        BMJ. 2016; 352: h6080
        • Kansagara D.
        • Papak J.
        • Pasha A.S.
        • et al.
        Screening for hepatocellular carcinoma in chronic liver disease: a systematic review.
        Ann Intern Med. 2014; 161: 261-269
        • Moon A.M.
        • Weiss N.S.
        • Beste L.A.
        • et al.
        No association between screening for hepatocellular carcinoma and reduced cancer-related mortality in patients with cirrhosis.
        Gastroenterology. 2018; 155: 1128-1139
        • Zhang B.H.
        • Yang B.H.
        • Tang Z.Y.
        Randomized controlled trial of screening for hepatocellular carcinoma.
        J Cancer Res Clin Oncol. 2004; 130: 417-422
        • Poustchi H.
        • Farrell G.C.
        • Strasser S.I.
        • Lee A.U.
        • McCaughan G.W.
        • George J.
        Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed?.
        Hepatology (Baltimore, MD). 2011; 54: 1998-2004
        • Singal A.G.
        • Pillai A.
        • Tiro J.
        Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis.
        PLoS Med. 2014; 11e1001624
        • Van Meer S.
        • de Man R.A.
        • Coenraad M.J.
        • Sprengers D.
        • van Nieuwkerk K.M.
        • Klümpen H.J.
        • et al.
        Surveillance for hepatocellular carcinoma is associated with increased survival: results from a large cohort in the Netherlands.
        J Hepatol. 2015; 63: 1156-1163
        • Wu C.Y.
        • Hsu Y.C.
        • Ho H.J.
        • Chen Y.J.
        • Lee T.Y.
        • Lin J.T.
        Association between ultrasonography screening and mortality in patients with hepatocellular carcinoma: a nationwide cohort study.
        Gut. 2016; 65: 693-701
        • Mittal S.
        • Kanwal F.
        • Ying J.
        • Chung R.
        • Sada Y.H.
        • Temple S.
        • et al.
        Effectiveness of surveillance for hepatocellular carcinoma in clinical practice: a United States cohort.
        J Hepatol. 2016; 65: 1148-1154
        • Choi D.T.
        • Kum H.
        • Park S.
        • Ohsfeldt R.L.
        • Parikh N.D.
        • Singal A.G.
        Hepatocellular carcinoma screening is associated with increased survival of patients with cirrhosis.
        Clin Gastroenterol Hepatol. 2019; 17: 976-987
        • Costentin C.E.
        • Layese R.
        • Bourcier V.
        • Cagnot C.
        • Marcellin P.
        • Guyader D.
        • et al.
        Compliance with hepatocellular carcinoma surveillance guidelines associated with increased lead-time adjusted survival of patients with compensated viral cirrhosis: a multi-center cohort study.
        Gastroenterology. 2018; 155: 431-442
        • Duffy S.W.
        • Nagtegaal I.D.
        • Wallis M.
        • Cafferty F.H.
        • Houssami N.
        • Warwick J.
        • et al.
        Correcting for lead time and length bias in estimating the effect of screen detection on cancer survival.
        Am J Epidemiol. 2008; 168: 98-104
        • Barbara L.
        • Benzi G.
        • Gaiani S.
        • Fusconi F.
        • Zironi G.
        • Siringo S.
        • et al.
        Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival.
        Hepatology. 1992; 16: 132-137
        • Kudo M.
        • Izumi N.
        • Kokudo N.
        • Matsui O.
        • Sakamoto M.
        • Nakashima O.
        • et al.
        Management of hepatocellular carcinoma in Japan: consensus-based clinical practice guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version.
        Dig Dis. 2011; 29 (339.e64)
        • Trinchet J.C.
        • Chaffaut C.
        • Bourcier V.
        • Degos F.
        • Henrion J.
        • Fontaine H.
        • et al.
        Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities.
        Hepatology. 2011; 54: 1987-1997
        • Wu C.Y.
        • Hsu Y.C.
        • Ho H.J.
        • Chen Y.J.
        • Lee T.Y.
        • Lin J.T.
        Association between ultrasonography screening and mortality in patients with hepatocellular carcinoma: a nationwide cohort study.
        Gut. 2016; 65: 693-701
        • Tzartzeva K.
        • Obi J.
        • Rich N.E.
        • Parikh N.D.
        • Marrero J.A.
        • Yopp A.
        • et al.
        Surveillance Imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis.
        Gastroenterology. 2018; 154 (1706–1718.e1701)
        • Simmons O.
        • Fetzer D.T.
        • Yokoo T.
        • et al.
        Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis.
        Aliment Pharmacol Ther. 2017; 45: 169-177
        • Del Poggio P.
        • Olmi S.
        • Ciccarese F.
        • Di Marco M.
        • Rapaccini G.L.
        • Benvegnù L.
        • et al.
        Factors that affect efficacy of ultrasound surveillance for early stage hepatocellular carcinoma in patients with cirrhosis.
        Clin Gastroenterol Hepatol. 2014; 12 (1927–1933.e1922)
        • Singal A.G.
        • Nehra M.
        • Adams-Huet B.
        • Yopp A.C.
        • Tiro J.A.
        • Marrero J.A.
        • et al.
        Detection of hepatocellular carcinoma at advanced stages among patients in the HALT-C trial: where did surveillance fail?.
        Am J Gastroenterol. 2013; 108: 425-432
        • Joshi K.
        • Mendler M.
        • Gish R.
        • Loomba R.
        • Kuo A.
        • Patton H.
        • et al.
        Hepatocellular carcinoma surveillance: a national survey of current practices in the USA.
        Dig Dis Sci. 2014; 59: 3073-3077
        • Pocha C.
        • Dieperink E.
        • McMaken K.A.
        • Knott A.
        • Thuras P.
        • Ho S.B.
        Surveillance for hepatocellular cancer with ultrasonography vs. computed tomography – a randomised study.
        Aliment Pharmacol Ther. 2013; 38: 303-312
        • Lee M.
        • Kim J.H.
        • Kang S.
        • Jun B.G.
        • Kim T.S.
        • et al.
        Alternate dynamic computed tomography and ultrasonography for surveillance of chronic hepatitis B patients with cirrhosis at high risk for hepatocellular carcinoma.
        AASLD. 2018; (abstract 894)
        • Kim S.Y.
        • An J.
        • Lim Y.S.
        • Han S.
        • Lee J.Y.
        • Byun J.H.
        • et al.
        MRI with liver-specific contrast for surveillance of patients with cirrhosis at high risk of hepatocellular carcinoma.
        JAMA Oncol. 2017; 3: 456-463
        • Besa C.
        • Lewis S.
        • Pandharipande P.V.
        • Chhatwal J.
        • Kamath A.
        • et al.
        Hepatocellular carcinoma detection: diagnostic performance of a simulated abbreviated MRI protocol combining diffusion-weighted and T1-weighted imaging at the delayed phase post gadoxetic acid.
        Abdom Radiol (NY). 2017; 42: 179-190
        • Marks R.M.
        • Ryan A.
        • Heba E.R.
        • Tang A.
        • Wolfson T.J.
        • et al.
        Diagnostic per-patient accuracy of an abbreviated hepatobiliary phase gadoxetic acid-enhanced MRI for hepatocellular carcinoma surveillance.
        AJR Am J Roentgenol. 2015; 204: 527-535
      6. Khatri G, Pedrosa I, Xi Y, Singal AG, Yopp A, Yokoo T. Abbreviated-protocol screening MRI versus complete-protocol diagnostic MRI for detection of hepatocellular carcinoma in patients with cirrhosis – an equivalence study using LI-RADS v2018. J Magnet. Resonance Imaging (in press). https://doi.org/10.1002/jmri.26835.

        • Tayob N.
        • Lok A.S.
        • Do K.A.
        • Feng Z.
        Improved detection of hepatocellular carcinoma by using a longitudinal alpha-fetoprotein screening algorithm.
        Clin Gastroenterol Hepatol. 2016; 14 (469–475.e462)
        • Lee E.
        • Edward S.
        • Singal A.G.
        • Lavieri M.S.
        • Volk M.
        Improving screening for hepatocellular carcinoma by incorporating data on levels of alpha-fetoprotein, over time.
        Clin Gastroenterol Hepatol. 2013; 11: 437-440
        • Di Bisceglie A.M.
        • Sterling R.K.
        • Chung R.T.
        • Everhart J.E.
        • Dienstag J.L.
        • Bonkovsky H.L.
        • et al.
        Serum alpha- fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C Trial.
        J Hepatol. 2005; 43: 434-441
        • Gopal P.
        • Yopp A.C.
        • Waljee A.K.
        • Chiang J.
        • Nehra M.
        • Kandunoori P.
        • et al.
        Factors that affect accuracy of alpha-fetoprotein test in detection of hepatocellular carcinoma in patients with cirrhosis.
        Clin Gastroenterol Hepatol. 2014; 12: 870-877
        • White D.L.
        • Richardson P.
        • Tayoub N.
        • Davila J.A.
        • Kanwal F.
        • El-Serag H.B.
        The updated model: an adjusted serum alpha-fetoprotein-based algorithm for hepatocellular carcinoma detection with hepatitis c virus-related cirrhosis.
        Gastroenterology. 2015; 149: 1986-1987
        • Berhane S.
        • Toyoda H.
        • Tada T.
        • Kumada T.
        • Kagebayashi C.
        • et al.
        Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients.
        Clin Gastroenterol Hepatol. 2016; 14 (875–886.e6)
        • Wang M.
        • Sanda M.
        • Comunale M.A.
        • Harrera H.
        • Swindell C.
        • et al.
        Changes in the glycosylation of kininogen and the development of a kininogen-based algorithm for the early detection of HCC.
        Cancer Epidermol Biomarkers Prevention. 2017; 26: 795-803
        • Kisiel J.B.
        • Dukek B.A.
        • V S R Kanipakam R.
        • Ghoz H.M.
        • Yab T.C.
        • Berger C.K.
        • et al.
        Hepatocellular carcinoma detection by plasma methylated DNA: discovery, phase I pilot, and phase II clinical validation.
        Hepatology. 2019; 69: 1180-1192
        • Harris R.P.
        • Sheridan S.L.
        • Lewis C.L.
        • Barclay C.
        • Vu M.B.
        • et al.
        The harms of screening: a proposed taxonomy and application to lung cancer screening.
        JAMA Intern Med. 2014; 174: 281-285
        • Heleno B.
        • Thomsen M.F.
        • Rodrigues D.S.
        • Jorgensen K.J.
        • Brodersen J.
        Quantification of harms in cancer screening trials: literature review.
        BMJ. 2013; 347f5334
        • Rich N.E.
        • Singal A.G.
        Overdiagnosis: an understudied issue in hepatocellular carcinoma surveillance.
        Semin Liver Dis. 2017; 37: 296-304
        • Sangiovanni A.
        • Manini M.A.
        • Iavarone M.
        • Romeo R.
        • Forzenigo L.V.
        • Fraquelli M.
        • et al.
        The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis.
        Gut. 2010; 59: 638-644
        • Geh D.
        • Rana F.A.
        • Reeves H.L.
        Weighing the benefits of hepatocellular carcinoma surveillance against potential harms.
        J Hepatocellular Carcinoma. 2019; 6: 23-30
        • Forner A.
        • Vilana R.
        • Ayuso C.
        • Bianchi L.
        • Solé M.
        • Ayuso J.R.
        • et al.
        Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.
        Hepatology. 2008; 47: 97-104
        • Maturen K.E.
        • Nghiem H.V.
        • Marrero J.A.
        • Hussain H.K.
        • Higgins E.G.
        • Fox G.A.
        • et al.
        Lack of tumor seeding of hepatocellular carcinoma after percutaneous needle biopsy using coaxial cutting needle technique.
        AJR Am J Roentgenol. 2006; 187: 1184-1187
        • Buscarini L.
        • Fornari F.
        • Bolondi L.
        • et al.
        Ultrasound-guided fine-needle biopsy of focal liver lesions: techniques, diagnostic accuracy and complications.
        J Hepatol. 1990; 11: 344-348
        • Atiq O.
        • Tiro J.
        • Yopp A.C.
        • Muffler A.
        • Marrero J.A.
        • Parikh N.D.
        • et al.
        An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis.
        Hepatology. 2017; 65: 1196-1205
        • Konerman M.
        • Verma A.
        • Zhao B.
        • Singal A.G.
        • Lok A.S.
        • Parikh N.D.
        Frequency and outcome of abnormal imaging impact in patients with cirrhosis enrolled in a hepatocellular carcinoma surveillance program.
        Liver Transpl. 2019; 25: 369-379
        • Singal A.G.
        • Yopp A.
        • Skinner C.S.
        • Packer M.
        • Lee W.M.
        • Tiro J.A.
        Utilization of hepatocellular carcinoma surveillance among American patients: a systematic review.
        J General Internal Med. 2012; 27: 861-867
        • Goldberg D.S.
        • Taddei T.H.
        • Serper M.
        • Mehta R.
        • Dieperink E.
        • Aytaman A.
        • et al.
        Identifying barriers to hepatocellular carcinoma surveillance in a national sample of patients with cirrhosis.
        Hepatology. 2017; 65: 864-874
        • Davila J.A.
        • Henderson L.
        • Kramer J.R.
        • Kanwal F.
        • Richardson P.A.
        • Duan Z.
        • et al.
        Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States.
        Ann Intern Med. 2011; 154: 85-93
        • Singal A.G.
        • Li X.
        • Tiro J.A.
        • Kandunoori P.
        • Huet B.
        • Nehra M.
        • Yopp A.C.
        Racial, social, and clinical determinants of hepatocellular carcinoma surveillance.
        Am J Med. 2015; 128: 90e1-90e7
        • Palmer L.
        • Kappelman M.
        • Sandler R.S.
        • Hayashi P.
        Surveillance for hepatocellular carcinoma in a medicaid cirrhotic population.
        J Clin Gastroenterol. 2013; 47: 713-718
        • Singal A.G.
        • Tiro J.
        • Li X.
        • Adams-Huet B.
        • Chubak J.
        Hepatocellular carcinoma surveillance among patients with cirrhosis in a population based integrated healthcare delivery system.
        J Clin Gastrol. 2017; 51: 650-655
        • Simmons O.L.
        • Feng Y.
        • Parikh N.D.
        • Singal A.G.
        Primary care provider practice patterns and barriers to hepatocellular carcinoma surveillance.
        Clin Gastroenterol Hepatol. 2019; 17: 766-773
        • McGowan C.
        • Edwards T.
        • Luong M.
        • Hayashi P.
        Suboptimal surveillance for and knowledge of hepatocellular carcinoma among primary care providers.
        Clin Gastroenterol Hepatol. 2015; 13: 799-804
        • Singal A.G.
        • Yopp A.
        • Gupta S.
        • Skinner C.S.
        • Halm E.A.
        • et al.
        Failure rates in the hepatocellular carcinoma surveillance process.
        Cancer Prevention Res. 2012; 5: 1124-1130
        • Farvardin S.
        • Patel J.
        • Khambaty M.
        • Yerokun O.
        • Mok H.
        • Tiro J.A.
        • et al.
        Patient-reported barriers are associated with lower HCC surveillance rates in patients with cirrhosis.
        Hepatology. 2017; 65: 875-884
        • Nahon P.
        • Zucman-Rossi J.
        Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis.
        J Hepatol. 2012; 57: 663-674
        • Papatheodoridis G.
        • Lampertico P.
        • Manolakopoulos S.
        • Lok A.S.
        Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review.
        J Hepatol. 2010; 53: 348-356
        • Papatheodoridis G.V.
        • Idilman R.
        • Dalekos G.N.
        • Buti M.
        • Chi H.
        The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B.
        Hepatology. 2017; 66: 1444-1453
        • Nahon P.
        • Bourcier V.
        • Layese R.
        • Audureau E.
        • Cagnot C.
        • et al.
        Eradication of hepatitis c virus infection in patients with cirrhosis reduces risk of liver and non-liver complications.
        Gastroenterology. 2017; 152: 142-156
        • Singal A.G.
        • Mukherjee A.
        • Elmunzer B.J.
        • Higgins P.D.
        • Lok A.S.
        • Zhu J.
        • et al.
        Machine learning algorithms outperform conventional regression models in predicting development of hepatocellular carcinoma.
        Am J Gastroenterol. 2013; 108: 172-1730
        • Hoshida Y.
        • Villanueva A.
        • Kobayashi M.
        • Peix J.
        • Chiang D.Y.
        • Camargo A.
        • et al.
        Gene expression in fixed tissues and outcome in hepatocellular carcinoma.
        N Engl J Med. 2008; 359: 1995-2004
        • Goosens N.
        • Singal A.G.
        • King L.
        • Andersson K.L.
        • Fuchs B.
        • Besa-Correa C.
        • et al.
        Cost-effectiveness of risk score-stratified hepatocellular carcinoma screening in patients with cirrhosis.
        Clin Transl Gastroenterol. 2017; 8e101
        • Tang J.C.
        • Feng Y.
        • Guo T.
        • Xie A.
        • Cai X.
        Circulating tumor DNA in hepatocellular carcinoma: trends and challenges.
        Cell Biosci. 2016; 6: 32
        • Feng Z.
        • Marrero J.A.
        • Khaderi S.
        • Singal A.G.
        • Kanwal F.
        • Loo N.
        • et al.
        Design of the Texas hepatocellular carcinoma consortium cohort study.
        Am J Gastrol. 2019; 114: 530-532
        • Singal A.G.
        • Tiro J.A.
        • Marrero J.A.
        • McCallister K.
        • Mejias C.
        • Sanders J.
        • et al.
        Mailed outreach program increases ultrasound screening of patients with cirrhosis for hepatocellular carcinoma.
        Gastroenterology. 2017; 152: 608-615
        • Singal A.G.
        • Tiro J.A.
        • Murphy C.C.
        • Marrero J.A.
        • McCallister K.
        • Fullington H.
        • et al.
        Mailed outreach invitations significantly improve HCC surveillance rates in patients with cirrhosis: a randomized clinical trial.
        Hepatology. 2019; 69: 121-130
        • Beste L.A.
        • Ioannou G.N.
        • Yang Y.
        • Chang M.F.
        • Ross D.
        • Dominitz J.A.
        Improved surveillance for hepatocellular carcinoma with a primary care-oriented clinical reminder.
        Clin Gastroenterol Hepatol. 2015; 13: 172-179