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Page 2 of 13 Best et al. Hepatoma Res 2020;6:62 I http://dx.doi.org/10.20517/2394-5079.2020.56

INTRODUCTION
Globally, hepatocellular carcinoma (HCC) is the sixth most frequent malignancy and the second most
[1]
[2]
common cause of cancer-related death . The global incidence of HCC has tripled since the 1980s . Despite
the availability of numerous locoregional therapies and a plethora of novel systemic treatment options, the
[3]
overall survival of HCC remains relatively poor . Furthermore, incidence of HCC in the western world is
rising with hepatic steatosis being seen as the major risk factor [Figure 1]. Nonalcoholic fatty liver (NAFL;
i.e., hepatic steatosis without significant inflammation) and nonalcoholic steatohepatitis (NASH; i.e.,
hepatic steatosis associated with hepatic inflammation and hepatocellular ballooning) in particular have
increasingly been recognized as risk factors for HCC. Previously, these cases have frequently been classified
[5]
as cryptogenic cirrhosis . Moreover, a significant proportion of patients develops HCC in the absence
[6]
of liver cirrhosis predominantly in the case of predisposing chronic hepatitis B or NASH . Nevertheless,
multiple HCC surveillance guidelines do not sufficiently recognize NASH as major risk factor of
hepatocarcinogenesis. Additionally, ultrasound for detection of smaller lesions, such as in early stage HCC,
lacks sensitivity and is further impaired when there is underlying cirrhosis, steatosis, or obesity. To address
those aforementioned insufficiencies, the definition of patients at risk has to be more concisely defined and
further prospective trials have to elucidate whether ultrasound alone has potential to detect a sufficient
proportion of HCC at stages when curative treatment options are still available. Several recent trials clearly
indicate that biomarker-based surveillance algorithms have potential to complement or even surpass
ultrasound as a surveillance strategy. This review aims to provide an overview of current biomarkers with
utility in HCC detection and how they could be implemented into current HCC early detection programs.

EARLY HCC DIAGNOSIS DETERMINES PATIENT PROGNOSIS
In patients participating in HCC early detection programs, an initial diagnosis is made in less advanced
stages, which results in a clear survival benefit. Successful surveillance, however, requires a reliable
screening method and a definition of the risk population based on medical needs.

Targeted HCC monitoring anticipates offering curative intended therapeutic procedures, such as liver
resection or transplantation, to the highest possible proportion of patients upon their initial HCC diagnosis.
[7]
Unfortunately, HCC is diagnosed in these early stages only in a minority of patients . In a representative
German singlecenter cohort, between 1998 and 2009, only 23.5% of over a thousand HCC patients were in
an early stage of HCC [Barcelona Clinic Liver Cancer (BCLC) 0/A] at initial diagnosis. Accordingly, less
[8]
than half of the patients received curative therapies and the median overall survival was only 16 months .
The above-mentioned data are consistent with large international trials where only 10%-23% of the patients
were curatively treatable at first diagnosis [9-12] . Consequently, only 10%-39% of those patients survived at
least one year after diagnosis [9-14] .

Since HCC is better suited for early detection programs than most other cancers, and since the risk
population to be screened could be well defined, the currently available data is particularly discouraging.
International guidelines recommend regular examinations of symptom-free risk patients according to
certain criteria.

INTERNATIONAL GUIDELINES PROVIDE DIFFERENT HCC SURVEILLANCE
RECOMMENDATIONS
Globally, there are marked regional variations in the algorithms for HCC early detection [Table 1]. The
guideline of the German Society for Digestive and Metabolic Diseases (DGVS) recommends that patients
with liver cirrhosis of any etiology, as well as patients with chronic hepatitis B or NASH in the absence
of cirrhosis, undergo liver ultrasound. Optionally, the liver tumor marker α-fetoprotein (AFP) can be