Hepatocellular carcinoma (HCC) makes up 75%-85% of all primary liver cancers and is the fourth most common cause of cancer related death worldwide. Chronic liver disease is the most significant risk factor for HCC with 80%-90% of new cases occurring in the background of cirrhosis. Studies have shown that early diagnosis of HCC through surveillance programs improve prognosis and availability of curative therapies. All patients with cirrhosis and high-risk hepatitis B patients are at risk for HCC and should undergo surveillance. The recommended surveillance modality is abdominal ultrasound (US) given that it is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with non-alcoholic fatty liver disease (NAFLD). With the current obesity epidemic and rise in the prevalence of NAFLD, abdominal computed tomography or magnetic resonance imaging may be indicated as the primary screening modality in these patients. The addition of alpha-fetoprotein to a surveillance regimen is thought to improve the sensitivity of HCC detection. Further investigation of serum biomarkers is needed. Semiannual screening is the suggested surveillance interval. Surveillance for HCC is underutilized and low adherence disproportionately affects certain demographics such as non-Caucasian race and low socioeconomic status.

Primary liver cancer is projected to be the sixth most commonly diagnosed and fourth most common cause of cancer death worldwide in 2018 with hepatocellular carcinoma (HCC) making up 75%-85% of all primary liver cancers[1]. HCC has a higher incidence in developing countries with > 80% of HCC cases occurring in either sub-Saharan Africa or Eastern Asia. HCC is three times more prevalent among men than women. The mean age at diagnosis varies among geographical location depending on the local burden of disease. While the incidence of HCC is decreasing in some Chinese and Japanese populations due to vaccination and treatment programs for viral hepatitis, HCC cases are increasing in the United States. In fact, HCC is the fastest growing cause of cancer-related deaths in the United States, with a decrease in the mean age at diagnosis[2-4]. Chronic liver disease of any etiology remains the most significant risk factor, with 80% to 90% of new HCC cases occurring in this population[4-6]. Given the international burden of disease, surveillance programs have been developed for earlier detection and mortality reduction. Current guidelines recommend enrollment in surveillance programs for adults with cirrhosis and high-risk patients without cirrhosis using ultrasound (US) with or without alpha-fetoprotein (AFP) at six-month intervals. These guidelines are largely unanimous among major international societies including the American Association for the Study of Liver Disease (AASLD), the European Association for the Study of the Liver (EASL) and the Asian Pacific Association for the Study of the Liver (APASL)[7-9]. Our objective is to summarize the current literature regarding utility of HCC surveillance, high-risk populations, surveillance modalities and adherence and recall.

A comprehensive literature search was performed using PubMed and Google Scholar for research papers regarding HCC surveillance and related literature was analyzed to prepare this review article. We did not restrict the search to a certain period of time. Articles written in English and published in peer-reviewed journal were included.

Optimal screening tests are designed to detect an asymptomatic or subclinical disease and must meet several criteria including high sensitivity, cost effectiveness and availability. Diseases suitable for screening include those that are of high burden in selected populations with a proven treatment strategy and outcomes that improve with early detection[10]. When screening tests are used at regular intervals in at-risk populations, this is considered surveillance[11].

A randomized clinical trial (RCT) is the optimal way to measure the effectiveness of cancer surveillance programs but unfortunately there is limited RCT data available to address whether HCC surveillance programs reduce disease-related mortality. A key study that is often cited was performed by Zhang et al[12] in China and included 18816 patients with current or previous evidence of hepatitis B infection. The selected patients were randomly assigned to surveillance group (n = 9373) or control group (n = 9443). Surveillance in this study consisted of measurement of serum AFP levels and US imaging every 6 mo. Study adherence was poor (60%) but showed a significant reduction (37%) in mortality related to HCC in the surveillance group. While this landmark study is the basis for many of the surveillance recommendations, it is not without its criticisms and limitations. Limitations of this study include lack of outcome data other than death and lack of information regarding all-cause mortality. The authors also failed to account for clustering which could produce misleading statistical significance. Additionally, the study population included only HBV patients. With these points in mind, some have argued that there is limited ability to extrapolate this data and its conclusions to Western countries[13]. However, any attempts to affirm these conclusions with an RCT in North America or Europe is largely impractical due to ethical concerns in randomizing patients at risk for HCC to a no surveillance group and the sheer difficulty of enrolling patients who are informed of the potential risks and benefits of HCC surveillance[14].

Although the RCT data is of limited quality and unable to be replicated, this does not disprove the effectiveness of HCC surveillance and there is observational data available to support a survival benefit from HCC surveillance. A 2014 meta-analysis of forty-seven cohort and case-controlled studies looked at the effect of HCC surveillance on early tumor stage detection, receipt of curative therapy and overall survival in patients with cirrhosis. Of the 15158 patients analyzed, 6284 (41.4 %) had HCC detected by surveillance while 8874 (58.6%) had HCC detected incidentally or due to presence of symptoms. Rates of HCC detected by surveillance were higher among studies in the United States (51%) and Europe (45%). Of the studies that included data on tumor stage and curative treatment, HCC surveillance was associated with improved early stage detection, curative treatment rates and prolonged survival. The pooled 3-year survival rate was 50.8% among patients undergoing surveillance compared to 27.9% among those without surveillance. Overall the data is encouraging, however, limitations include short duration of follow up and failure to adjust for liver function or lead-time bias. This data suggests that given the association of HCC surveillance with significant improvements in early tumor detection, these patients are more likely to receive curative treatment and thus overall survival benefit providing evidence to support regular HCC surveillance guidelines[15].

Given the poor 1-year and 3-year survival rates in patients with HCC (36% and 17%, respectively), early detection may provide curative treatment options including surgical resection, transplantation and percutaneous ablation. Finding late stage or advanced HCC removes these options and leaves only palliation[16-18].

HCC surveillance has also been shown to be cost effective. Both Lin et al[19] and Arguedas et al[20] found that HCC screening using either biannual AFP and annual abdominal US or triple phase computed tomography (CT) were cost effective compared to no surveillance, with cost effectiveness ratio less than $50000 quality-adjusted life year. This is comparable to other frequently used screening strategies including colonoscopy and mammography[19,20].

The AASLD recommends offering surveillance when the risk of HCC is at least 1.5% per year and the incidence is greater than 0.2% per year, which includes patients with cirrhosis and some non-cirrhotic hepatitis B carriers[7]. The risk for HCC in chronic liver disease differs based on the underlying etiology of disease. Chronic hepatitis C virus (HCV) infection is associated with a 15- to 20-fold higher risk of HCC compared to those without HCV and patients with HCV related cirrhosis have a 3.5% annual rate of HCC development[4]. While HCC can develop in HCV infected patients in the absence of cirrhosis, the odds decrease significantly when elastography shows a lack of advanced fibrosis (< 10 kPa)[21]. Currently, HCC surveillance is not recommend in patients with chronic hepatitis C without cirrhosis[7]. Eradication of HCV with sustained viral response (SVR) has been shown to decrease the risk for HCC. Morgan et al[22] previously showed that in the interferon era, eradication of HCV with SVR resulted in a reduced risk for HCC (relative risk = 0.24).

The landscape of HCV treatment has evolved with the availability of effective direct antiviral agents (DAAs). As opposed to IFN-based therapies, DAAs are better tolerated in patients with advanced liver disease and can provide SVR rates > 95%[23-25]. Despite the utility of DAAs, there has been a debate regarding increased incidence of HCC (recurrence or de novo) in contrast to IFN-based treatment. There are conflicting results from various retrospective studies looking at DAA therapy and HCC. An initial small cohort study by Reig et al[25] suggested an increase in rates of HCC following DAA therapy, however a large meta-analysis subsequently found no difference in HCC occurrence in patients following SVR from DAA vs IFN-based treatment[26]. Kwong et al[27] recently showed that although the incidence of de novo HCC in patients with HCV cirrhosis has increased in the DAA era, these changes may be explained by changes in the rates of liver transplantation among HCV patients and wait list mortality. Increasing age and severity of liver disease likely contributes to a higher incidence of HCC in transplant candidates as well[23,27]. Current guidelines continue to recommend HCC surveillance in patients with cirrhosis even after eradication of HCV with DAA therapy[7].

Patients with chronic hepatitis B virus (HBV) represent a unique population who require HCC surveillance outside of the setting of cirrhosis. Specific recommendations for surveillance in patients with chronic hepatitis B without cirrhosis include Asian and black males > age 40, Asian females > age 50, African/North African blacks with hepatitis B > age 20, patients with hepatitis D co-infection, and patients with a first-degree relative with HCC[7,28]. High levels of HBV DNA are associated with a higher risk of developing HCC and worse prognosis in those with HCC[29]. It is thought that active HBV viral proliferation promotes carcinogenesis through both direct and indirect mechanisms and therefore antiviral treatment can lower the risk for HCC occurrence in these patients[30]. A previous study showed that patients with advanced fibrosis or cirrhosis who received lamivudine had a significantly lower risk (3.9%) of developing HCC compared to placebo (7.4%)[30]. Despite the reduced risk, these patients still require routine monitoring for HCC occurrence. Alanine aminotransferase (ALT) is a marker of liver injury and can be used in conjunction with other host factors such as age and duration of infection to identify high-risk HBV carriers[28,29]. Other important risk factors include environmental exposures such as alcohol, cigarettes and the mycotoxin aflatoxin[31] as well as a family history of HCC[32].

Heavy alcohol use and subsequent alcohol related liver disease has also been associated with the development of HCC. The incidence of HCC in patients with alcohol related cirrhosis (Child-Pugh A or B) has been previously reported to be 2.5%[33]. A previous review found that alcohol use greater than 80 g/d for more than 10 years led to a 5-fold increase in risk for development of HCC[34]. A synergistic effect can occur between alcohol use and other risk factors for HCC, most prominently viral hepatitis. It has been suggested that screening patients younger than age 55 with platelet counts > 125000 mm³ may not be cost effective[34], however current guidelines still recommend surveillance for all patients with cirrhosis[7].

Non-alcoholic fatty liver disease (NAFLD) and its complications are of increasing clinical significance, particularly in Western nations due to a rising burden of metabolic syndrome[35]. A prior retrospective analysis has shown that cumulative incidence of HCC is slightly lower in NAFLD related cirrhosis compared to HCV cirrhosis (2.6% vs 4%)[36], however surveillance is still recommended in this population. A very low incidence of HCC has been described in patients with NAFLD without cirrhosis, however incidence rates do not meet surveillance criteria at this time[37,38]. Continued investigation of these relationships is of utmost importance given the increasing prevalence and incidence of NAFLD[7].

Less common etiologies of cirrhosis that can also increase the risk for HCC include hereditary hemochromatosis (HH), primary biliary cholangitis (PBC), autoimmune hepatitis (AIH) and alpha 1-antitrypsin deficiency (A1AT). Patients with HH have been shown to have a 20-fold higher risk of HCC without an increased risk for non-hepatic malignancies in a large Swedish based population cohort study[39]. While the incidence of HCC in HH patients with cirrhosis is unknown, the AASLD endorses a surveillance benefit in these patients[7]. HCC also occurs with increased frequency in patients with cirrhosis secondary to PBC[40]. The risk of HCC in these patients has been shown to be similar to the risk of HCC in patients with HCV cirrhosis[41], and therefore the AASLD recommends routine surveillance[7]. Although there are no formal recommendations regarding surveillance in patients with cirrhosis secondary to AIH, several studies note an annual incidence rate > 1.5% and therefore it is reasonable to include these patients in standard surveillance protocols[42]. The incidence of HCC in patients with cirrhosis secondary to A1AT deficiency has been previously shown to be 0.88%/year in one small retrospective study[43], however guidelines still recommend biannual surveillance at this time[7]. Additional studies would be helpful in these less common causes of cirrhosis to more accurately determine annual incidence and suitability for surveillance programs.

As mentioned, the mortality benefit in HCC surveillance lies in the advantages of early detection so that curative therapies, including liver transplantation, can be considered. As such, patients with Childs Pugh C cirrhosis who are not eligible for HCC treatments and are not candidates for liver transplantation should not be offered surveillance programs. Liver transplant candidates should continue to undergo surveillance up until the time of transplantation[7].

The AASLD recommends surveillance using US with or without AFP every 6 mo. We will look at the evidence behind the surveillance methods including imaging techniques and biomarkers as well as the time intervals when they should be performed.

To summarize, there is sufficient evidence to support the importance and survival benefit of HCC surveillance (Table 1). Early identification through surveillance provides more curative treatment options. Surveillance programs are indicated for all cirrhotic patients and high-risk HBV patients without cirrhosis. Surveillance for obese and NAFLD patients is of increasing interest as this population continues to rise in the United States. Semiannual US (with or without AFP) is the recommended imaging modality for surveillance but clinicians must consider alternative imaging if the US is limited. Surveillance rates are low and disproportionately affect certain populations. Clinicians must recognize the importance of adherence to surveillance and continue to explore options to improve surveillance rates through systems based approaches and awareness.

The authors would like to recognize and thank Dr. Frederick Weber for his contributions to this work.