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Circulating tumor cells are associated with poor outcomes in early-stage hepatocellular carcinoma: a prospective study

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Abstract

Background

Previous studies evaluating association between circulating tumor cells (CTCs) and clinical outcomes in hepatocellular carcinoma (HCC) have shown inconsistent results due to suboptimal detection methods and patient heterogeneity.

Methods

Patients undergoing surgery for early-stage HCC were prospectively enrolled. The CTC numbers were determined using a tapered slit platform, which detects CTCs based on the cell size and morphology. Survival and recurrence were evaluated, and Cox proportional hazards models were used to demonstrate the prognostic significance of CTC.

Results

Of 105 patients, 25 had increased CTC numbers after surgery (ΔCTC > 0, defined as positive) and a significantly higher level of recurrence (p = 0.042). A positive ΔCTC was seen to be an independent predictor of recurrence (hazard ratio 2.28), along with hepatitis B virus infection, alanine aminotransferase level, and the presence of satellite nodules (all p < 0.05). Subgroup analyses showed that a positive ΔCTC was associated with lower survival and higher recurrence among patients with low alpha-fetoprotein levels and cirrhosis (all p < 0.05).

Conclusion

Calculation of ΔCTC based on the physical properties of the cells is predictive of recurrence in patients with early HCC undergoing surgery.

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Abbreviations

CTC:

Circulating tumor cell

HCC:

Hepatocellular carcinoma

AFP:

Alpha-fetoprotein

EpCAM:

Epithelial cell adhesion molecule

TSF:

Tapered slit filter

CK:

Cytokeratin

CD:

Cluster of differentiation

OS:

Overall survival

RFS:

Recurrence-free survival

SD:

Standard deviation

HBV:

Hepatitis B virus

AST:

Aspartate aminotransferase

MELD:

Model for end-stage liver disease

IQR:

Interquartile range

CI:

Confidence interval

HR:

Hazard ratio

ALT:

Alanine aminotransferase

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Funding

This work was supported in full by the Fundamental R&D Programs for Core Technology of Materials, Ministry of Trade, Industry and Energy (Grant Number: 10078295). The funder had no role in study design, data collection, analysis, and interpretation, writing of the report, or decision to submit the article for publication.

Author information

Authors and Affiliations

  1. Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea

    Yeonjung Ha & Han Chu Lee

  2. Department of Gastroenterology, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13496, South Korea

    Yeonjung Ha

  3. Department of Gastroenterology, Ewha Womans University Mokdong Hospital, Ewha Womans University, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul, 07985, South Korea

    Tae Hun Kim

  4. Department of Bio and Brain Engineering, Cell Bench Research Center, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea

    Jae Eul Shim, Sunghyun Yoon & Young-Ho Cho

  5. Good Gang-An Hospital, 40-1, Namcheondong, Suyoung-gu, Busan, 48365, South Korea

    Mi Jung Jun

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  1. Yeonjung Ha
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Correspondence to Han Chu Lee.

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Conflict of interest

Yeonjung Ha, Tae Hun Kim, Jae Eul Shim, Sunghyun Yoon, Mi Jung Jun, Young-Ho Cho, Han Chu Lee declare no conflicts of interest.

Informed consent in studies with human subjects

The study design was approved by the institutional review board of the Asan Medical Center (Approval Number: 20140766), the Ewha Womans University Mokdong Hospital (Approval Number: 2014-08-004), and the Korea Advanced Institute of Science and Technology (Approval Number: KH2012-02). The study was performed in accordance with the Declaration of Helsinki. All the participants provided written informed consent.

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12072_2019_9994_MOESM1_ESM.tif

Supplementary material 1 Schematic image of the tapered slit filter used for the isolation of circulating tumor cells (TIFF 356 kb)

Supplementary material 2 Experimental flow diagram (TIFF 40 kb)

Supplementary material 3 Inclusion criteria (TIFF 61 kb)

12072_2019_9994_MOESM4_ESM.tif

Supplementary material 4 a Representative images of EpCAM-positive (upper panel) and EpCAM-negative (lower panel) circulating tumor cells detected in the same patient. Scale bars, 20 µm. b Haematoxylin & eosin-stained tumor sections showing mixed histology—trabecular and scirrhous feature (TIFF 6148 kb)

12072_2019_9994_MOESM5_ESM.tif

Supplementary material 5 a Representative images of circulating tumor cell cluster partially positive for EpCAM. b Haematoxylin & eosin-stained tumor sections showing scirrhous feature (TIFF 6148 kb)

Supplementary material 6 (DOCX 19 kb)

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Ha, Y., Kim, T.H., Shim, J.E. et al. Circulating tumor cells are associated with poor outcomes in early-stage hepatocellular carcinoma: a prospective study. Hepatol Int 13, 726–735 (2019). https://doi.org/10.1007/s12072-019-09994-9

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