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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 2  |  Page : 452-460

Prognostic value of circulating tumor cells and analysis of clinicopathological factors in liver cancer


1 Department of Hepatobiliary Surgery, Shandong Cancer Hospital, Cheeloo College of Medicine, Shandong University; Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China, China, People's Republic of China
2 Department of General Surgery, The Fifth People's Hospital of Jinan, Jinan, Shandong, People's Republic of China, China, People's Republic of China
3 Hepatobiliary Surgery, Shandong Cancer Hospital, Cheeloo College of Medicine, Shandong University; Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China, China, People's Republic of China
4 Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China, China, People's Republic of China

Date of Submission21-Dec-2021
Date of Decision11-Feb-2022
Date of Acceptance24-Feb-2022
Date of Web Publication20-May-2022

Correspondence Address:
Sheng Li
Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250200; Shandong Cancer Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250117
People's Republic of China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_2311_21

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 > Abstract 


Objective and Aims: The number of circulating tumor cells (CTCs) and the presence of circulating tumor microemboli (CTM) were determined in the peripheral blood of patients with liver cancer (LC). The relationship between CTCs, CTM, clinicopathologic features, and prognosis of LC was analyzed. The objective of this study was to determine the diagnostic and prognostic value of CTCs/CTM in LC.
Subjects and Methods: Patients with LC were enrolled between May 2013 and August 2017, and 67 patients were included in the study. Overall survival curves were built using the Kaplan–Meier method and the log-rank test to identify risk factors. The results were analyzed using a Cox proportional hazards model and expressed as hazard ratio and 95% confidence interval (95% CI).
Results: CTCs and either CTCs or CTM were detected in 27 patients (40.3%) and 29 patients (43.3%). CTM were found in four patients. One-year, 3-year, and 5-year survival rates were 42%, 20%, and 15%, respectively. Univariate Cox regression analysis showed that alpha-fetoprotein (AFP), number of CTCs, presence of CTM, and positive CTC/CTM were associated with survival time. Multivariate Cox regression analysis showed that alpha fetoprotein (AFP), number of CTCs, and presence of CTM were independent risk factors for survival in patients with LC.
Conclusion: There was no significant correlation between the number of CTCs, the presence of CTM, and clinicopathologic factors. AFP, number of CTCs, and presence of CTM were independent risk factors for survival in patients with LC.

Keywords: Alpha-fetoprotein (AFP), circulating tumor cells (CTCs), circulating tumor microemboli (CTM), clinicopathological correlation, liver cancer, prognosis


How to cite this article:
Cui K, Ou Y, Ning D, Li H, Xi Y, Li S. Prognostic value of circulating tumor cells and analysis of clinicopathological factors in liver cancer. J Can Res Ther 2022;18:452-60

How to cite this URL:
Cui K, Ou Y, Ning D, Li H, Xi Y, Li S. Prognostic value of circulating tumor cells and analysis of clinicopathological factors in liver cancer. J Can Res Ther [serial online] 2022 [cited 2022 Jul 7];18:452-60. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/452/345538




 > Introduction Top


Primary liver cancer (LC) is a common malignant tumor. High morbidity and mortality in patients with LC is a significant public health problem.[1],[2] High-risk factors for LC include hepatitis B and C, aflatoxin treatment, cirrhosis, long-term alcoholism, non-alcoholic fatty liver disease, and family history of LC.[3]

Although the incidence and mortality of LC have decreased because of hepatitis B vaccination,[4] a National Cancer Center report showed that LC incidence and mortality rates are increasing in China. The early stage of LC is not easily detected, and treatment during the middle and late stages of LC is less effective than during the early stage. Therefore, the regular screening of high-risk groups is essential. Early diagnosis and treatment prolong the survival of patients with LC. Although treatments are being continuously improved, the 5-year survival is low,[5] especially for intermediate and advanced LC.

The presence of circulating tumor cells (CTCs) was first reported by Professor Thomas Ashworth in 1869,[6] and technological advancements have improved their detection and isolation. A few CTCs form metastatic foci because most of these cells undergo apoptosis and phagocytosis in early-stage cancer. Therefore, isolating and identifying CTCs are crucial, CTC single-cell sorting is found not only in the blood circulation system but also in the cerebrospinal fluid.[7] CTCs are present in the circulatory system as single cells or cell clusters, known as circulating tumor microemboli (CTM). CTM have a mesenchymal phenotype.[8] Therefore, CTM are better prognostic indicators than CTCs, and the presence of CTM in the blood predicts distant metastasis.[9] In this respect, changes in hepatocellular carcinoma can be predicted by the number of CTCs, presence of CTM, and positive CTC/CTM.[10]

This study analyzes the correlation between the number of CTCs, the presence of CTM, clinicopathological characteristics, and prognosis of LC.


 > Patients and Methods Top


Patient selection and general data

Sixty-seven patients diagnosed with primary LC at our hospital between May 2014 and August 2017 were enrolled. None of the patients were treated, and all patients gave written informed consent. The diagnostic criteria for primary LC were based on tumor staging according to the guidelines of the Chinese Society of Liver Cancer.[3] The patients were in good general condition and had no surgical contraindications. The exclusion criteria were distant metastases confirmed clinically, other primary malignancies associated with LC, intellectual or mental disorders, and non-compliance with the study protocols. Fasting blood samples (5 mL) were collected from the median cubital vein and analyzed in the CTC-biopsy system. The number of CTCs was determined according to the manufacturer's instructions. The results were independently analyzed by two researchers and reviewed by a third examiner. The experimental group was followed up until June 2019. Patient information on survival and treatment status was obtained, and overall survival (OS) was calculated.

Statistical analysis

Data on the number of CTCs, the presence of CTM, and clinicopathological factors were analyzed using the SPSS software version 17.0. Data normality was assessed using the Shapiro–Wilk test. Normally distributed data are shown as means and standard deviations. Continuous variables are expressed as median and interquartile ranges. Differences between the groups were compared using t-test, non-parametric Mann–Whitney test, Chi-square test, or Fisher's exact test. Qualitative data are expressed as ratios. The correlation between the number of CTCs, the presence of CTM, and clinicopathological characteristics was evaluated.

OS and prognostic factors were evaluated using the Kaplan–Meier test and log-rank test. Risk factors were analyzed using the Cox proportional hazards model, and the results were expressed as hazard ratio (HR) and 95% confidence interval (95% CI). Two-tailed P values of less than 0.05 were considered statistically significant.


 > Results Top


Clinicopathological factors

Sixty-seven patients with LC (61 men [91.0%] and 6 women [9.0%]) admitted to the Shandong Cancer Hospital from May 2014 to August 2017 were included in the study. The average age was 55.1 ± 10.4 years (range: 33–75 years). The number of participants with LC stages I, II, III, and IV was 11, 9, 28, and 19, respectively.

Twenty-seven patients (40.3%) presented CTCs in the peripheral blood. The number of CTCs ranged from 1 to 15, and the number of patients with one, two, or three CTCs was 6, 5, and 3, respectively [Figure 1]. CTM were present in 4 patients (with one, one, two, and four clusters, respectively) and absent in 63 patients. CTCs or CTM were present in 29 patients and absent in 38 patients.
Figure 1: Number of circulating tumor cells in the peripheral blood of 67 patients with liver cancer

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Number of CTCs and presence of CTM according to clinicopathological factors

The number of CTCs in our cohort according to clinicopathological factors is shown in [Table 1]. The percentage of men and women with CTCs was 39.3% (24/61) and 50.0% (3/6), respectively. The percentage of CTC-positive patients with stages I, II, III, and IV was 27.2% (3/11), 55.6% (5/9), 46.4% (13/28), and 31.6% (6/19), respectively, and the percentage of CTC-positive patients with AFP ≥400 μg/L or <400 μg/L was 39.3% (11/28) and 41.0% (16/39), respectively. The average age of CTC-positive and CTC-negative patients was 55.0 ± 11.4 and 55.3 ± 9.1 years, respectively. The average D-dimer level of CTC-positive and CTC-negative patients was 1.2 mg/L and 0.7 mg/L, respectively, and these values were higher than normal. The average platelet count (×109/L) in CTC-positive and CTC-negative patients was 158.0 and 119.5, respectively, and these values were within the normal range. Lymphocytes, neutrophils, and monocyte count, neutrophil-to-lymphocyte ratio (NLR), prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), international normalized ratio (INR), and fibrinogen were within the normal range in both CTC-positive and CTC-negative patients [Table 1].
Table 1: Correlation between circulating tumor cells (CTCs) and clinicopathological factors in patients with liver cancer

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CTM were detected in three men (4.9%), one woman (16.7%), patients with LC stage III (2, 7.1%) or stage IV (2, 10.5%), as well as patients with AFP ≥400 μg/L (4, 14.3%), HBV-DNA <500 cps/mL (1/21, 4.7%), and HBV-DNA ≥500 cps/mL (3/35, 8.6%). The average age of patients with and without CTM was 48.0 ± 14.6 and 55.5 ± 10.1 years, respectively. The clinicopathological characteristics of patients with and without CTM are shown in [Table 2].
Table 2: Correlation between circulating tumor microemboli (CTM) and clinicopathological factors in patients with liver cancer

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CTCs or CTM were present in 26 men (42.6%) and 3 women (50.0%). The percentage of CTC-positive or CTM-positive patients with stages I, II, III, and IV was 27.3% (3/11), 55.6% (5/9), 50.0% (14/28), and 36.8% (7/19), respectively. CTCs or CTM were present in patients with AFP ≥400 μg/L (13, 46.4%), AFP <400 μg/L (16, 41.0%), HBV-DNA <500 cps/mL (9/21, 42.9%), and HBV-DNA ≥500 cps/mL (15/35, 42.9%). The average age of patients with and without CTM was 54. 0 ± 10.1 and 55.9 ± 10.8 years, respectively. The average D-dimer level in patients with and without CTM was 1.20 mg/L and 0.65 mg/L, respectively, and these values were higher than normal. The average levels of platelets, lymphocytes, neutrophils, monocytes, NLR, PT, TT, INR, APTT, and fibrinogen in patients with and without CTM were within normal limits [Table 3].
Table 3: Correlation between the presence of circulating tumor cells (CTCs) and/or circulating tumor microemboli (CTM) and clinicopathological factors in patients with liver cancer

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Data normality was assessed using the Shapiro–Wilk test. D-dimer, platelets, lymphocytes, neutrophils, monocytes, NLR, TT, and fibrinogen had a non-normal distribution.

The number of CTCs and the presence of CTM were correlated with clinicopathological factors. There was a significant correlation between the number of CTCs, the presence of CTM, and fibrinogen. In turn, gender, age, clinical stage, AFP, HBV-DNA, D-dimer, platelets, lymphocytes, neutrophils, monocytes, NLR, PT, TT, APTT, number of CTCs, presence of CTM, and fibrinogen were not significantly correlated with clinicopathological factors.

Correlation between CTCs, CTM, and clinicopathological characteristics

The correlation between the number of CTCs, the presence of CTM, and clinicopathological characteristics was analyzed. Spearman correlation analysis was performed because the distribution of these two variables was non-normal. D-dimer, lymphocyte and monocyte count, and TT were negatively correlated with the number of CTCs, whereas the remaining variables were positively correlated with the number of CTCs. However, these correlations were not statistically significant [Table 4]. Four CTM-positive patients presented AFP ≥400. Lymphocyte count and APTT were positively correlated with the presence of CTM, whereas the remaining variables were negatively correlated with CTM. Nonetheless, these correlations were not statistically significant [Table 5].
Table 4: Correlation between the number of circulating tumor cells and clinicopathological factors in patients with liver cancer

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Table 5: Correlation between the number of circulating tumor microemboli and clinicopathological factors in patients with liver cancer

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Patient survival

Survival was analyzed until June 2019. Eleven patients survived, and 56 patients died or were lost to follow-up. The median survival time in our cohort was 9 months (range: 1–61 months), and the 1-year, 2-year, 3-year, 4-year, and 5-year survival rates were 42%, 28%, 20%, 15%, and 15%, respectively [Figure 2].
Figure 2: Overall survival of 67 patients with liver cancer

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The independent variables were CTCs, CTM, CTCs or CTM, age, gender, clinical stage, and AFP. AFP, CTCs, CTM, and CTC or CTM were significantly associated with OS (HR: 2.27 [95% CI: 1.33–3.89], 1.845 [95% CI: 1.07–3.17], 5.40 [95% CI: 1.80–16.18], and 2.06 [95% CI: 1.20–3.54], respectively) [Table 6].
Table 6: Univariate analysis of overall survival in 67 patients with liver cancer

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Patient survival according to AFP levels, number of CTCs, and presence of CTM were analyzed using the Kaplan–Meier method [Table 7] and [Figure 3] to [Figure 4], [Figure 5], [Figure 6]. The average survival in the group with AFP <400 μg/L was longer than that in the group with AF ≥400 μg/L. The average survival was significantly lower in patients with either CTCs or CTM than in those without CTCs and CTM.
Table 7: Kaplan-Meier analysis of alpha-fetoprotein, circulating tumor cells (CTCs), circulating tumor microemboli (CTM), and CTCs or CTM in 67 patients with liver cancer

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Figure 3: Overall survival of 67 patients with liver cancer according to alpha-fetoprotein levels

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Figure 4: Overall survival of 67 patients with liver cancer according to the number of circulating tumor cells

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Figure 5: Overall survival of 67 patients with liver cancer according to the number of circulating tumor microemboli

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Figure 6: Overall survival of 67 patients with liver cancer according to the presence of circulating tumor cells or circulating tumor microemboli

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Multivariate Cox regression analysis

Independent risk factors for survival, including AFP, CTCs, and CTM, were determined using multivariate Cox regression analysis (forward likelihood ratio). AFP, CTCs, and CTM were independent risk factors, and survival in LC patients with AFP >400 μg/L and positive CTC or CTM was shorter than that in LC patients with AFP <400 μg/L and negative CTC or CTM [Table 8].
Table 8: Multivariate Cox regression analysis of 67 patients with liver cancer

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 > Discussion Top


In 2012, the International Cancer Research Center reported that 50–55% of all LC cases occurred in China, and the incidence of LC in China and elsewhere was 9.4% and 6.1%, respectively. The mortality rate from LC in China and worldwide in 2012 was 13.94% and 9.42%, respectively.[2],[11] LC has a poor prognosis and a high rate of recurrence and metastasis, particularly blood metastasis. Cancer cells invade the portal vein, form tumor thrombus, and cause extrahepatic metastases.[12]

Early diagnosis and treatment strongly affect patient prognosis. Therefore, accurate predictors of LC survival and prognostic indicators of LC are urgently needed. In this respect, non-invasive liquid biopsy, high-throughput sequencing, and other techniques to detect tumor cells in the blood have better reproducibility and operability and less trauma than traditional biopsy, opening new directions in the clinical research of LC.[13] Studies have shown that the folate receptor-positive circulating tumor cells (FR + CTC) are a reliable biomarker for the early diagnosis of small-sized lung cancer.[14]

CTC and CTM quantification are used in non-invasive, liquid biopsy-based cancer diagnostics. CTCs and CTM are closely associated with the prognosis of malignant tumors, including prostate, ovarian, lung, breast, gastric, and colorectal cancers.[15],[16],[17],[18],[19],[20],[21],[22] The potential of CTCs to form distant metastases depends on the tumor microenvironment and the gene expression profile of tumor cells. Tumor cells with highly invasive phenotypes can invade other organs and tissues through the blood, escape the immune system, proliferate, and form larger tumors.[23]

As a new type of tumor index, CTCs are detectable by liquid biopsy because these cells migrate to distant sites before diagnosis or treatment. CTM have a high metastatic potential, and their detection in the blood may indicate distant metastasis. In addition, the presence of CTM indicates that the tumor is more aggressive and malignant, resulting in lower survival.[24] Therefore, the early detection of CTCs and CTM is fundamental for analyzing tumor metastasis and recurrence.

The detection and isolation of CTCs and CTM have improved in recent years, and the methods currently used for this purpose are immunomagnetic enrichment using epithelial cell adhesion molecule,[23] isolation by the size of epithelial tumor cells (ISET), density gradient centrifugation, immunomagnetic separation, CellSearch, laser scanning cytometry, enzyme-linked immunospot assay, CTC chip, optical fiber array scanning, and reverse transcription-polymerase chain reaction.[25],[26],[27] This study used the CTC-biopsy detection system (Wuhan Youzhiyou Medical Technology Co., Ltd.), which is an improvement of the Isolation by size of epithelial tumor cells (ISET) technology.[28] The basic principle of CTC biopsy is the enrichment of tumor cells by membrane filtration according to cell size. The operation includes blood sample pretreatment, cell staining, and qualitative analysis. The advantages of this system are the optimization of filtration and sample pretreatment and fully automated cell enrichment and identification, which improve CTC enrichment, staining, and collection.

In this study, approximately 75% of LC cases were stages III or IV, and the clinical condition of most of these patients was severe.

The prognostic factors of LC include clinical stage, AFP, HBV-DNA, and age; nonetheless, the ability of these factors to predict disease varies across studies.[29],[30],[31] In the present study, gender, clinical stage, AFP, HBV-DNA, age, D-dimer, platelets, lymphocytes, neutrophils, monocytes, NLR, PT, TT, INR, APTT, and fibrinogen were not significantly correlated with the number of CTCs and detection of CTM in the peripheral blood of patients with LC. There was a significant correlation between the number of CTCs, the presence of CTM, and fibrinogen. The absence of a correlation between CTCs, CTM, and clinicopathological characteristics contradicts the findings of Baitang et al.[32] and may be due to the small sample size or short follow-up in our cohort. Further studies are necessary to confirm these results.

In our cohort, 11 patients survived and 56 died or were lost to follow-up. The 5-year survival rate was 15%, which agrees with a previous study (14.1%).[33] Cox regression analysis showed that AFP, CTCs, CTM, and CTCs or CTM were significantly associated with patient survival.

Log-rank analysis showed that the average survival time was longer in the group with AFP <400 μg/L than in the group with AFP ≥400 μg/L (15 months [95% CI, 7.66–22.34] vs. 4 months [95% CI, 2.06–5.95]) (χ2 = 10.04, P = 0.002), which agrees with the data from the Specifications for the Diagnosis and Treatment of Primary Liver Cancer (2019 edition). Therefore, AFP can be used for the early screening and prognosis of LC[3],[34] and as an indicator of the efficacy of LC treatment.[35],[36],[37]

Log-rank analysis indicated that the mean survival was shorter in the groups with CTC, CTM, and CTC/CTM than in their counterparts (7 months [95% CI: 3.18–10.82] vs. 12 months [95% CI: 5.80–18.20]) [χ2 = 5.40, P = 0.020]; 3 months [95% CI: 1.04–4.96] vs. 9 months [95% CI: 6.08–11.92) [χ2 = 12.592, P < 0.001]; 6 months [95% CI: 3.36–8.64] vs. 14 months [95% CI: 3.43–24.57]) [χ2 = 7.604, P = 0.006]), indicating that CTCs and CTM can serve as prognostic markers of LC, and their presence reduces survival.

Multivariate Cox regression analysis (forward likelihood ratio method) of the factors affecting prognosis, including AFP, CTCs, CTM, and CTC/CTM, showed that these parameters were independent risk factors for survival. The risk of death was significantly higher in the group with AFP ≥400 μg/L (2.35-fold; 95% CI, 1.32–4.17), CTCs (2.10-fold; 95% CI, 1.20–3.67), and CTM (3.42-fold; 95% CI, 1.11–10.53) than in their counterparts, demonstrating that AFP, CTCs, and CTM are independent factors for patient survival. AFP >400 μg/L in the presence of CTCs or CTM reduced survival, which agrees with the study by Wu et al.[38],[39] but not by Chen et al.,[40] which may be explained by differences in sample selection, follow-up time, and detection methods. Therefore, larger studies are necessary to confirm the correlation between CTCs, CTM, CTC/CTM, and LC prognosis. The limitation of this study is that the sample size was not enough, and the positive rate of CTC or CTM was low, which may lead to information bias.


 > Conclusion Top


The positive rate of CTC in LC detected by the CTC-biopsy detection system adopted by our team is 40%–45%, which has the greatest advantage of detecting CTM, especially in the middle and late stages. There was no significant correlation between the number of CTCs, the presence of CTM, and clinicopathological factors, including gender and clinical stage. AFP (≥400 μg/L), number of CTCs, and presence of CTM were independent risk factors for patient survival.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013), and was approved by the Ethics committee of Shandong Provincial Institute of Cancer Prevention and Treatment (201702019). All patients gave written informed consent.

Acknowledgments

This research was funded by the Shandong province key research and development plan (2017CXGC1204) and the Academic Promotion Program of Shandong First Medical University (2019QL004).

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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