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Wang et al. Hepatoma Res 2020;6:61 I http://dx.doi.org/10.20517/2394-5079.2020.55 Page 9 of 15

2019 FISH analysis 155 HCC patients Value of serum dickkopf-1 CTCs levels can predict the efficacy and ●○○○ [102]
and CTCs in predicting the prognosis of TACE treatment in patients Very Low
efficacy and prognosis of with HCC
TACE treatment in HCC
2020 CanPatrol 136 HCC patients Relationship between CTC Anatomic resection might improve ●●○○ [98]
platform status and outcomes of the survival of HCC patients, but Low
different surgical methods only those with low CTC count and
in HCC negative mesenchymal and epithelial/
mesenchymal-CTC phenotypes
2020 PowerMag 30 HCC patients Longitudinal monitoring Sequential CTC enumeration during ●○○○ [104]
negative the treatment response treatment can benefit the management Very Low
selection of patients with locally of patients with locally advanced or
system advanced HCC using CTCs metastatic HCC, in particular for the
AFP-low cases
CTC: circulating tumor cells; HCC: hepatocellular carcinoma; EpCAM: epithelial cell adhesion molecule; OS: overall survival; ICAM-
1: intercellular cell adhesion molecule-1; EMT: epithelial-to-mesenchymal transition; ASGPR: asialoglycoprotein receptor; TACE:
transcatheter arterial chemoembolization; qRT-PCR: quantitative reverse transcription polymerase chain reaction; AFP: alpha-
fetoprotein; pERK: phosphorylated ERK; pAkt: phosphorylated Akt; PFS: progression-free survival; HBV: hepatitis B virus; FISH:
fluorescence in situ hybridization; EGFR: epidermal growth factor receptor

(SII), a novel index based on peripheral lymphocyte, neutrophil, and platelet counts. HCC patients who
experienced unfavorable internal inflammatory alterations after radical hepatic resection suffered an earlier
recurrence and distant metastasis. Thus, they proposed that the dissemination and colonization of CTCs
[27]
may be influenced by host inflammatory and immune response status [75,76] . In 2018, Sun et al. showed
that CTC and circulating tumor cluster burden in hepatic veins and peripheral circulation prognosticated
postoperative lung metastasis and intrahepatic recurrence in HCC patients by multi-vascular sites
sampling, respectively. This study provided new insight that multi-vascular measurement of CTCs could
facilitate precise prediction of postoperative relapse or metastasis patterns in HCC. Other studies using
+
TM
CellSearch also demonstrated that patients who had EpCAM CTCs were associated with vascular
[78]
[77]
invasion [77,78] , significantly elevated AFP , more advanced BCLC stage , higher recurrence rate [79,80] ,
and shorter OS [77,79] . High EpCAM-positive CTC count also predicted poor survival of patients with
unresectable HCC treated with transcatheter arterial chemoembolization (TACE) .
[81]
PCR-based methods can detect tumor-specific mRNA in blood cells with high sensitivity and specificity.
[82]
Yao et al. reported the combination of positive/negative cell sorting methods and RT-PCR could
[71]
effectively detect AFP mRNA-positive CTCs in HCC patients. Guo et al. established an optimized
platform based on negative enrichment and qRT-PCR for the detection of EpCAM mRNA-positive CTCs
in HCC. Using their platform, they reported good sensitivity and specificity of PCR-based CTC detection
TM
in a cohort of 299 HCC patients. The novel platform exhibited 76.6% consistency with the CellSearch
system while required a reduced blood volume (5 mL). They also reported that low pretreatment CTC
levels were significantly correlated to a better prognosis after curative resection, TACE, or radiotherapy for
patients with HCC. Using the same platform, Zhou et al. discovered that patients with high CTC/Treg
[83]
levels exhibited higher recurrence rates than those with low CTC/Treg counterparts (66.7% vs. 10.3%, P <
0.001) by combining the measurement of EpCAM mRNA+ CTCs and CD4 CD25 Foxp3 Treg cells. Currently,
+
+
+
AFP examination remains the most extensively used screening method to indicate early HCC. However,
about 30%-40% of HCC patients are AFP negative and the specificity of AFP may be flawed by false-positive
results [84,85] . CTC enumeration can be useful in the early detection of HCC since tumor dissemination can
occur at the early stage of tumor development . In 2018, the same group developed a qRT-PCR-based
[2]
multimarker (EpCAM, CD90, CD133, and CK19) diagnostic CTC panel for the identification of CTCs
with stem-like phenotypes. They obtained a sensitivity of over 70.0% and specificity of over 90.0% in a
well-designed multicenter cohort (n = 1,006). This panel performed equally well in detecting early-stage
and AFP-negative HCC as in differentiating HCC from patients with benign liver diseases. The CTC panel
outperformed AFP as a biomarker in terms of differential diagnostic capability, yielding higher area under