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Chen et al. Hepatoma Res 2018;4:72 I http://dx.doi.org/10.20517/2394-5079.2018.103 Page 11 of 16

Liquid biopsy refers to the sampling of bodily fluid instead of solid tissue for the genetic material of cancer.
The most common sampling markers are cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), circu-
lating tumor cells (CTCs), and cell-free RNAs (e.g., miRNA), which are the byproducts of tumor cells. In
contrast to solid tumor biopsy, liquid biopsy is less invasive and allows repeated sampling for dynamic evalu-
ation of disease status and prediction of clinical outcomes. Solid tumour biopsy is infrequently done now as
it is painful, carries risks of bleeding and iatrogenic tumor seeding. Liquid biopsy has been shown to have
higher sensitivity in the early tumor detection and prognostication. The application of liquid biopsy in HCC
is still under evaluation.

[42]
Liao et al. conducted a meta-analysis to evaluate the use of cfDNA in HCC diagnosis. By quantitatively
and qualitatively analysing the concentrations of circulating cfDNA, as well as single-gene methylation al-
terations, they found that the combination of AFP and cfDNA can attain an optimal sensitivity of 81% and
specificity of 96% in the diagnosis of HCC in at-risk patients.

CTCs are mainly studied for its role in cancer recurrence, prognosis, and response to treatments. It has not
been investigated in the context of HCC surveillance.

[43]
Data on the role of ctDNA in HCC are limited. Zhou et al. studied the size profiles of plasma DNA in 90
HCC patients, and found aberrantly short DNA molecules in HCC patients as well as elevated amounts of
mitochondrial DNA. Their presence raises the suspicion of early HCC during surveillance process. The de-
tection of ctDNA can also predict metastasis in 86% of the HCC patients.

Several studies were done on quantification of circulating miRNA to facilitate the diagnosis of HCC in
[44]
[47]
chronic hepatitis [44-46] and hepatitis C patients . Li et al. studied the serum miRNA levels of control, HBV
and HBV-positive HCC patients. They found that miR-375 alone has a high diagnostic accuracy of HCC
compared to control patients, and miRNA expression profiles can differentiate HBV patients from control,
and HBV-positive HCC patients from HBV patients. The study suggested that serum miRNAs can be used
[45]
as noninvasive biomarkers for the diagnosis of HBV infection and HBV-positive HCC. Hung et al. dem-
onstrated that serum circulating miRNAs, miR-122 and miR-let-7b, can differentiate dysplastic nodules from
early HCC in chronic hepatitis B patients. A recently published paper by the Vietnamese group collected all
the published data on miRNAs in HCC, and established a miRNA panel for HCC diagnosis. Three miRNAs,
[46]
mir-21, 122, and 192, together with AFP can be combined to diagnose early HCC in hepatitis B patients .
In the current clinical setting, liquid biopsy has limited applications in HCC surveillance owing to the lack
of standardized methodology and the high cost of genetic sequencing, which needs to be improved with
more studies and standardization of assays. The high cost of genetic sequencing also precludes its use as a
surveillance modality for HCC. However, liquid biopsy offers a noninvasive method of characterizing HCC
tumor cells’ genomic mutations and molecular pathways, hence offers opportunities for further studies on
the therapeutic targets in HCC. It is promising as a non-invasive, accurate and convenient surveillance tool
for HCC in the future.

DISCUSSION
This study reviewed the current status of the literature on the efficacy, benefit and harm of HCC surveil-
lance, as well as new developments in surveillance modalities. The benefit of HCC surveillance was demon-
strated in one RCT and supported by a significant number of cohort studies. Although significant bias may
[15]
be present, it is not feasible to conduct further randomized trials due to ethical concerns . Cohort studies
demonstrated earlier tumor detection and longer survival in HCC patients diagnosed from surveillance.
However, the proportion of patients diagnosed at early-stage and length of survival differs significantly in