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Page 10 of 16 Chen et al. Hepatoma Res 2018;4:72 I http://dx.doi.org/10.20517/2394-5079.2018.103

[33]
A shortcoming of ultrasound in HCC surveillance is its relatively low sensitivity and specificity . A recent
[34]
retrospective cohort study by Samoylova et al. investigated the predictors for ultrasound failure of HCC
detection. It was found that the sensitivity of ultrasound to detect HCC for subjects with BMI ≥ 30 was sig-
nificantly lower (0.76) compared to those with BMI < 30 group (0.87). Patients with NASH had a ultrasound
sensitivity of only 0.59 compared to 0.84 in other etiologies, suggesting 41% of HCC would be missed in this
population. Thus we currently lack an ideal first-line imaging modality for surveillance of HCC in patients
with NASH despite the latter becoming an increasingly prevalent liver disease worldwide.

A recent systemic review and meta-analysis studied the use of surveillance imaging, with or without AFP,
for early detection of HCC in patients with cirrhosis. Thirty-two studies were reviewed and ultrasound was
found to have a good sensitivity for detecting any stage HCC. However it performs poorly in detecting early-
stage HCC with only 47% sensitivity. The combination of ultrasound with AFP increased the sensitivity (65%)
[33]
but also lowered the specificity for HCC detection .
[35]
Pocha et al. conducted a randomized trial comparing biannual ultrasound vs. annual CT in HCC sur-
veillance of cirrhotic patients. CT has a comparable sensitivity (62.5%) to ultrasound-based surveillance.
However, due to its high cost and repeated radiation exposure, no evidence so far supports the use of CT as
surveillance modality. Studies comparing MRI and ultrasound showed that MRI has a significantly higher
[36]
sensitivity than ultrasound (83.7% vs. 25.6%) for HCC detection in cirrhotic patients . However, the high
cost, limited availability of scanners and long scanning time make MRI not ideal as a surveillance tool.

Serum biomarkers
Serum biomarkers are cancer-related molecules or substances that are measurable in the peripheral blood,
enabling early cancer detection. They are attractive tools in cancer surveillance and diagnosis as they are
noninvasive with the convenience of repeated sample collections.

The most commonly used serum marker in HCC is AFP, which by itself has limited sensitivity and specific-
ity, and serves as an adjunct to imaging in HCC diagnosis. AFP-L3 measures the AFP isoform that is reac-
tive to lens culinaris agglutinin. It is widely used for HCC surveillance in Japan. A recent study on AFP-L3
[37]
by Kumada et al. involving 2,830 patients in a HCC surveillance program found that 34.3% of the patients
had elevated AFP-L3 1 year prior to the diagnosis of HCC, suggesting that it can be an earlier predictor of
HCC development.

DCP, also known as prothrombin-induced by vitamin K absence-II, is an abnormal prothrombin formed
in the presence of vitamin K antagonism. The performance of DCP varies among different studies [38,39] . One
[40]
study by Ji et al. studied DCP vs. AFP in HBV-related HCC, and concluded that DCP is complementary to
AFP in detecting AFP-negative HCC, and excluding HCC in cirrhotic patients with false positive AFP, sug-
gesting its complementary role in HCC surveillance. Similar conclusion was drawn in HCV cohorts by the
[41]
Italian group .
Other biomarkers studied were GPC3 (plasma membrane bound protein), Golgi protein 73, interleukin-6,
and squamous cell carcinoma antigen. These biomarkers have been studied for many years, but had incon-
sistent performance in different patient populations, precluding its wide use in HCC surveillance.

Liquid biopsy
Recent advances in genomics sequencing technologies allow identification and quantification of cancer ge-
netic material in the circulating blood. This has enabled the discovery of novel biomarkers and increased our
understanding of HCC cancer genomics.