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Page 10 of 15 Wang et al. Hepatoma Res 2020;6:61 I http://dx.doi.org/10.20517/2394-5079.2020.55

curve (AUC) value than AFP alone. This study demonstrated the clinical significance of using CTC panel
[63]
in diagnosis and real-time risk evaluation for HCC .

Increasing efforts have been made to investigate the correlation between different molecular phenotypes
of CTCs and corresponding clinical outcomes. The stem-like phenotype of CTC has been explored as a
-
strong predictor of the clinical outcome of patients with HCC. For instance, circulating CD45 intercellular
+
cell adhesion molecule-1 (+) (ICAM-1 ) cells were regarded as HCC CTCs with stem cell-like properties.
+
Liu et al. showed that patients with a higher burden of ICAM-1 CTCs had significantly shorter disease-
[46]
+
+
−
[86]
free survival and OS. Fan et al. also reported that circulating cancer stem cells (CD45 CD90 CD44 )
predicted post-hepatectomy HCC recurrence with high accuracy. Moreover, EMT subtypes of CTCs have
been studied for the correlation to clinicopathological features and prognosis of HCC patients. It is reported
that a presence or dominance of mesenchymal-like CTCs represented worse clinical outcomes for HCC
TM
patients due to earlier tumor relapse and metastasis [73,87] . The majority of these studies used the CanPatrol
platform for CTC analysis [73,88-94] . In a cohort of 113 HCC patients (65% BCLC 0/A) and 57 non-malignant
liver diseases patients, the system presented a higher diagnostic value (AUC = 0.774, 95%CI: 0.704-0.834)
of HCC than AFP [0.669 (AUC = 0.669, 95%CI: 0.587-0.750)]. A further combination of CTCs and AFP
[92]
showed the highest diagnostic capability (AUC = 0.821, 95%CI: 0.756-0.886) . The proportion of mixed
EMT status CTCs or mesenchymal CTCs was associated with advanced BCLC stages, higher metastatic
[90]
tendency, and elevated serum levels of AFP [88,89] . Yin et al. reported that twist expression in CTCs could
[93]
serve as a biomarker for evaluating HCC metastasis and prognosis. Similarly, Wang et al. studied 62 HCC
patients undergoing surgical resection and found that mesenchymal CTC positivity was an independent
risk factor for early recurrence. A similar study using CanPatrol platform also found that CTCs
TM
undergoing EMT were significantly associated with early recurrence, multi-intrahepatic recurrence, and
[94]
lung metastasis . However, a recent study reported that CTCs undergoing EMT were poorly correlated
[95]
with clinical stages or predictive of recurrence of HCC using the platform . Another study using this
platform also failed to uncover significant associations between change in total CTCs or CTC subtypes and
[96]
HCC recurrence in a cohort consisting of 47 patients who underwent liver transplantation . Nevertheless,
[97]
Xue et al. utilized an iFISH® platform to detect CTCs in patients undergoing liver transplantation
and found that patients with preoperative iFISH-CTCs ≥ 5 in 7.5 mL of blood had significantly shorter
recurrence-free survival than those with lower CTCs. Further large, multicenter studies are still needed to
confirm the association between different molecular phenotypes of CTCs and HCC prognosis.

TUMOR MONITORING AND GUIDING PERSONALIZED THERAPEUTIC INTERVENTION IN HCC
Surgical resection remains the most effective therapy for HCC. CTCs could serve as a complementary tool
[98]
to assess the efficacy of surgical resection and monitor tumor progression [8,14] . Qi et al. recently compared
the outcomes of patients undergoing anatomical or non-anatomical resection according to the number
and EMT phenotype of CTCs. They suggested that anatomic resection may improve the survival of HCC
patients, for those with low CTC count, negative epithelial/mesenchymal hybrid CTCs, and mesenchymal
CTCs. Thus, CTC analysis before surgery can be used to better guide the resection method for HCC.
[99]
Meanwhile, the decrease of CTC count after surgical treatment often reflects therapeutic efficacy. Fan et al.
investigated the effect of liver tumor resection on CTC dynamics using in vivo flow cytometry (IVFC) in
a green fluorescent protein-transfected HCC orthotopic metastatic mouse model. Their preliminary study
found that the number of CTCs and early metastases rates decreased significantly after the resection of
the primary tumor. Several clinical studies obtained similar results that CTC load decreased significantly
after tumor resection, while increased CTC numbers after surgery were associated with a worse prognosis
in patients with HCC [17,63,71,79,100] . Besides, Jin et al. [101] explored the clinical value of serial postsurgical
observation (at 0, 3, 6, 9, and 12 months) of AFP mRNA level of CTCs in assessing the therapeutic
effectiveness of hepatectomy.