Jia XQ, Han S, Shang YS, Kong FG, Qi L, Wang CL, Xiong WJ. Expression of liver cancer stem cell markers and association with recurrence and survival in hepatocellular carcinoma. World J Stem Cells 2026; 18(5): 119123 [DOI: 10.4252/wjsc.v18.i5.119123]
Corresponding Author of This Article
Wu-Jun Xiong, MD, Chief Physician, Department of Gastroenterology, Fudan University Affiliated Pudong Hospital, No. 2800 Gongwei Road, Huinan Town, Pudong New Area, Shanghai 201399, China. xiongwujun25@163.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Study
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Jia XQ, Han S, Shang YS, Kong FG, Qi L, Wang CL, Xiong WJ. Expression of liver cancer stem cell markers and association with recurrence and survival in hepatocellular carcinoma. World J Stem Cells 2026; 18(5): 119123 [DOI: 10.4252/wjsc.v18.i5.119123]
Author contributions: Jia XQ conceived and designed the study, collected clinical data, performed immunohistochemical experiments, conducted statistical analyses, and drafted the manuscript; Han S and Shang YS participated in the data acquisition, pathological evaluation, and follow-up data collection; Kong FG and Qi L were responsible for patient enrollment, clinical data verification, and the interpretation of clinical variables; Wang CL contributed to the immunohistochemical staining procedures and quality control of pathological assessments; Xiong WJ supervised the entire study, critically revised the manuscript for important intellectual content, obtained funding support, and approved the final version for publication. All the authors have read and approved the final version of the manuscript.
AI contribution statement: We confirm that no artificial intelligence tools were used in writing this manuscript. No part of the Main Text of the manuscript (including Abstract, Introduction, Materials and Methods, Results, Discussion, and Conclusion) was generated by AI. All content was written independently by the authors. No AI tools were used for language polishing, translation, data analysis, or any form of writing assistance. No AI tools were involved in the design of the study, data interpretation, or formulation of the results and conclusions. No images, figures, or graphical materials in this manuscript were generated by AI. All authors take full responsibility for the originality, integrity, and accuracy of the work.
Supported by Clinical Medicine Emerging Specialty (or Specific Disease) Program of the Pudong New Area Health Commission, No. 2025-PWXZ-05; and Science and Technology Development Fund of Shanghai Pudong New Area, No. PKJ2024-Y54.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Jinan People’s Hospital, No. 20240530009.
Informed consent statement: Owing to the retrospective nature of the study, the Ethics Committee waived the requirement for informed consent.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
Corresponding author: Wu-Jun Xiong, MD, Chief Physician, Department of Gastroenterology, Fudan University Affiliated Pudong Hospital, No. 2800 Gongwei Road, Huinan Town, Pudong New Area, Shanghai 201399, China. xiongwujun25@163.com
Received: January 27, 2026 Revised: March 2, 2026 Accepted: April 7, 2026 Published online: May 26, 2026 Processing time: 117 Days and 23 Hours
Abstract
BACKGROUND
Postoperative recurrence and cancer-related mortality remain significant challenges following curative resection for hepatocellular carcinoma (HCC). Conventional clinicopathological parameters inadequately capture tumor biological heterogeneity; therefore, reliable tissue biomarkers that reflect stemness-associated aggressiveness are required for early postoperative risk stratification.
AIM
To evaluate liver cancer stem cell (CSC) markers (EpCAM, CD133, CK19, and CD44) in HCC and their prognostic value for recurrence and survival.
METHODS
A total of 132 patients with pathologically confirmed HCC who underwent radical resection at Jinan City People’s Hospital (January 2019 to December 2023) were retrospectively included. Tumor expression of EpCAM, CD133, CK19, and CD44 was assessed by immunohistochemistry using predefined thresholds. High CSC expression was defined as positivity for at least two markers. The primary outcomes were relapse-free survival and overall survival. Survival was analyzed using the Kaplan-Meier method and the log-rank test. Independent prognostic factors and risk scores were identified by Cox regression. Predictive performance for 3-year outcomes was assessed using receiver operating characteristic curves and the C-index.
RESULTS
A total of 45 cases (34.09%) were positive for EpCAM, 42 (31.82%) for CD133, 31 (23.48%) for CK19, and 62 (46.97%) for CD44. High expression was observed in 56 cases (42.42%) of CSC. The median follow-up time was 42 months. Relapse occurred in 66 cases (50.00%), and 43 patients (32.58%) died. The 3-year overall survival rate in CK19-positive patients was 51.61%, which was lower than 78.22% in CK19-negative patients (Log-rank χ2 = 10.564, P = 0.001). Multivariate Cox regression analysis revealed that CK19 positivity and microvascular invasion were independent factors for poor prognosis. The area under the curve for 3-year mortality increased from 0.726 to 0.788, while the C-index rose from 0.684 to 0.725 after the addition of the CSC marker.
CONCLUSION
The CSC-associated markers in HCC (CK19 and CD133 in particular) are closely related to postoperative recurrence and survival, and their combined assessment enhances risk stratification.
Core Tip: Postoperative recurrence is common after curative resection of hepatocellular carcinoma, highlighting the need for improved tissue-based risk stratification. We assessed four cancer stem cell-associated markers (EpCAM, CD133, CK19, and CD44) by immunohistochemistry in resected hepatocellular carcinoma. CK19 and CD133 were identified to carry prognostic information, and combined multi-marker assessment improved risk discrimination beyond routine clinicopathological factors. immunohistochemistry-based cancer stem cell profiling may help identify patients who require intensified surveillance and individualized postoperative management.
Citation: Jia XQ, Han S, Shang YS, Kong FG, Qi L, Wang CL, Xiong WJ. Expression of liver cancer stem cell markers and association with recurrence and survival in hepatocellular carcinoma. World J Stem Cells 2026; 18(5): 119123
Hepatocellular carcinoma (HCC) is a common malignancy of the digestive system, and curative hepatectomy remains a primary treatment option for patients with resectable disease[1]. Nevertheless, postoperative recurrence is frequent, with long-term recurrence rates reported to reach 60%-70% within 5 years in many studies, substantially limiting survival benefits[1]. Current prognostic assessments primarily consider tumor size, microvascular invasion (MVI), histological differentiation, and alpha-fetoprotein (AFP); however, these variables do not fully explain the biological heterogeneity or accurately identify patients at high risk of early relapse[2]. The cancer stem cell (CSC) concept suggests that a small subset of tumor cells with self-renewal and multilineage capacity can survive therapeutic pressure, regenerate tumors, and facilitate micrometastatic dissemination, thereby driving recurrence and progression[3]. EpCAM, CD133, CK19, and CD44 are commonly utilized tissue markers linked to stem cell/precursor-like phenotypes in HCC[4]. Although prior studies have suggested associations between CSC-related markers and aggressive pathological features, as well as recurrence and survival, results vary across cohorts and scoring thresholds, and single-marker assessments may not fully capture the prognostic spectrum[5]. Therefore, using retrospective patients who underwent radical resection, we systematically characterized the expression profiles of these markers, analyzed their relationships with recurrence-free survival (RFS) and overall survival (OS), and evaluated the incremental prognostic value of multi-marker combinations in postoperative risk stratification.
MATERIALS AND METHODS
Study design and ethics
This was a single-center, retrospective study. The protocol was reviewed and approved by the Ethics Committee of Jinan City People’s Hospital, and the requirement for written informed consent was waived due to the retrospective design and anonymized data processing. All the procedures were conducted in accordance with the principles of the Declaration of Helsinki.
Research participants
Patients with HCC who underwent radical hepatectomy at Jinan City People’s Hospital between January 2019 and December 2023 were included in the study. Radical resection was defined as R0 resection (negative under a resectoscope) with no residual lesions on postoperative imaging. The inclusion criteria comprised: (1) HCC confirmed by postoperative pathology; (2) First radical hepatectomy; (3) Patients who did not receive antitumor treatments such as transarterial chemoembolization (TACE), radiotherapy, targeted therapy, or immunotherapy; (4) Complete clinical data and pathological specimens obtained, with tumor tissue suitable for immunohistochemistry (IHC); and (5) At least one postoperative follow-up evaluation completed. Exclusion criteria: (1) Mixed HCC/cholangiocarcinoma or non-HCC; (2) Presence of other malignant tumors; (3) Death during the perioperative period (≤ 30 days) or missing key variables; and (4) Outcomes indeterminable due to lack of follow-up information. A total of 158 cases were screened. Of these, 26 cases were excluded (six cases of non-HCC/mixed cancer, eight with preoperative antitumor treatment, and 12 cases with incomplete information or loss to follow-up), resulting in 132 cases included in the study.
Surgery and perioperative management
The surgical approach was determined by the hepatobiliary surgery team based on tumor location, vascular anatomy, and liver functional reserve, performing either an anatomic or non-anatomic hepatectomy. All patients underwent routine preoperative assessments [contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI) for staging, liver function tests, coagulation profiles, and indocyanine green clearance, when indicated]. Hepatectomy was performed under general anesthesia using standard open or laparoscopic techniques. Intraoperative ultrasound was used as needed to confirm the resection plane, and the intermittent Pringle maneuver was applied at the surgeon’s discretion. R0 resection was achieved, with negative pathological margins and no residual lesions detected on early postoperative imaging. Postoperatively, the patients received standardized care, including liver function monitoring, fluid and nutritional support, infection prevention, analgesia, and management of ascites or bile leakage. Antiviral therapy for hepatitis B virus (HBV)-related disease and other hepatoprotective treatments were administered according to current guidelines and each patient’s liver status. After discharge, all patients were enrolled in a structured surveillance program, as described in the follow-up section.
Collection and definition of clinical variables
General data (age, sex), liver disease background (HBV infection, cirrhosis), laboratory parameters (AFP), and oncological and pathological information (maximum tumor diameter, number of lesions, Edmondson classification, and MVI) were extracted from the electronic medical record system. Variable definition: AFP was stratified at 400 ng/mL (AFP ≥ 400 ng/mL vs < 400 ng/mL). Tumors were classified by maximum diameter at 5 cm (> 5 cm vs ≤ 5 cm). Edmondson III-IV was defined as moderate to poor differentiation. Multifocal lesions were defined as ≥ 2 tumor nodules indicated by imaging or pathology. MVI was determined from the pathological report (the tumor thrombus located within small vessels surrounding the tumor)[6].
IHC detection and interpretation
Paraffin-embedded tumor tissue blocks from surgical specimens were used, and conventional sections were cut at a thickness of 4 μm. The antigen was retrieved following xylene dewaxing and gradient ethanol rehydration (citric acid or ethylenediaminetetraacetic acid buffer, according to the manufacturer’s instructions). Endogenous peroxidase was blocked with 3% hydrogen peroxide, followed by incubation with the primary antibody, then the secondary antibody. Immunoreactivity was visualized using 3,3’-diaminobenzidine staining, counterstained with hematoxylin, and sections were subsequently sealed.
The following primary antibodies were used: EpCAM (mouse monoclonal, Abcam, Cambridge, United Kingdom; catalog ab71916; dilution 1:200), CD133 (rabbit polyclonal, Abcam, Cambridge, United Kingdom; catalog ab19898; dilution 1:100), CK19 (mouse monoclonal, Abcam, Cambridge, United Kingdom; catalog ab52625; dilution 1:200), and CD44 (rabbit monoclonal, Abcam, Cambridge, United Kingdom; catalog ab51037; dilution 1:500). Antigen retrieval was performed using citrate buffer (pH = 6.0) for EpCAM and CK19 and ethylenediaminetetraacetic acid buffer (pH = 9.0) for CD133 and CD44, followed by incubation at 4 °C overnight. A polymer-based horseradish peroxidase detection system was used, and signals were visualized with 3,3’-diaminobenzidine.
Interpretation method: A semi-quantitative scoring system was employed. Staining intensity was scored from 0 to 3 (0: No staining, 1 means light, 2 means medium, 3 means strong staining), and the proportion of positive cells was graded from 0 to 4 (0 = < 5%, 1 = 5%-25%, 2 = 26%-50%, 3 = 51%-75% and 4 = > 75%). A comprehensive score was calculated as intensity × proportion, with a score ≥ 3 defined as positive[7].
Quality control: A positive control (known positive tissue) and a negative control (phosphate-buffered saline instead of the primary antibody) were included. Independent interpretation was performed by two qualified pathologists using a blinded method. Discrepancies of greater than 1 point in the comprehensive score or inconsistent positive/negative determinations were resolved through joint review until consensus was reached.
High CSC expression was defined as positivity for at least two of the four markers (EpCAM, CD133, CK19, CD44). This definition was used for combined multi-marker analysis and risk stratification[8].
Follow-up and outcome definition
The follow-up methods included outpatient follow-up, telephone follow-up, and electronic medical record review. The recommended follow-up frequency was once every 3 months at 0-24 months after surgery and once every 6 months at 24-60 months after surgery. Each visit included assessments of liver function, AFP, and imaging (enhanced CT or MRI, and chest CT or bone imaging, if necessary). Recurrence was determined based on a combination of imaging findings (new typical enhancement-elution lesions or clear metastases on dynamic contrast-enhanced CT/MRI) or pathological evidence. RFS was defined as the interval from the date of surgery to the first documented recurrence or death, whichever occurred first. OS was defined as the interval from the date of surgery to death from any cause. Patients with no events were censored at the last follow-up visit. The mean follow-up period was 42 months.
Statistical analysis
Statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, United States) and R software version 4.3.1. The Shapiro-Wilk test was conducted for measurement data, and the conforming normal distribution was expressed as mean ± SD. Comparisons between groups were performed using Welch’s t-test, with the t statistic and degrees of freedom reported. Non-normally distributed data are expressed as median (interquartile range). The Mann-Whitney U test was used to determine the U value for intergroup comparisons. The count data were expressed as n (%) using the χ2 test. The Fisher’s exact test was used when the theoretical frequency did not meet the conditions. The Kaplan-Meier method was employed to generate survival curves, and the log-rank test was used for inter-group comparison, reporting log-rank χ2 and P values. Single-factor and multivariate analyses were performed using Cox proportional hazards regression. A risk score was constructed based on regression coefficients from a multivariable model. Receiver operating characteristic curves were plotted using 3-year outcomes as the endpoint, and the area under the curve (AUC) was calculated. All tests were two-sided, and P < 0.05 was considered statistically significant.
RESULTS
Entry process and overall outcomes
Among the 132 patients, the mean age was 54.59 ± 9.56 years; this overall mean represents the weighted average of the CSC-low and CSC-high subgroups reported in Table 1 (55.05 ± 9.46 vs 53.96 ± 9.76), with minor differences attributable to rounding. The study included 99 males (75.00%) and 33 females (25.00%). The median follow-up time was 42 months. During follow-up, 66 patients (50.00%) developed recurrence, while 43 patients (32.58%) died.
Table 1 Baseline characteristics of patients stratified by different levels of cancer stem cell expression, n (%).
Expression profile of CSC markers and relationship with baseline characteristics
IHC revealed EpCAM positivity in 45 (34.09%), CD133 positivity in 42 (31.82%), CK19 positivity in 31 (23.48%), and CD44 positivity in 62 (46.97%) patients. Overall, 56 patients (42.42%) met the criteria for high CSC expression (at least two positive markers). As summarized in Table 1, patients in the CSC high-expression group more frequently had tumors > 5 cm (62.50% vs 44.74%, P = 0.037) and Edmondson grade III-IV differentiation (55.36% vs 35.53%, P = 0.023) than those in the CSC low-expression group, whereas age, sex, HBV infection, cirrhosis, AFP category, multifocality, and MVI did not differ significantly between groups (all P > 0.05).
Positive rate of CSC markers and correlation with invasive characteristics
As presented in Table 2, CK19 positivity was significantly associated with MVI (61.29% in CK19-positive vs 32.67% in CK19-negative, χ2 = 6.982, P = 0.008). For EpCAM, no significant associations were observed with MVI (37.78% vs 40.23%, P = 0.505), Edmondson III-IV (48.89% vs 41.38%, P = 0.168), or AFP ≥ 400 ng/mL (11.11% vs 10.34%, P = 0.794). For CD133, the difference in Edmondson III-IV exhibited a borderline trend (59.52% vs 36.67%, P = 0.057), while MVI (40.48% vs 38.89%, P = 0.986) and AFP ≥ 400 ng/mL (14.29% vs 8.89%, P = 0.392) were not significant. For CD44, trends were toward higher rates of MVI (48.39% vs 31.43%, P = 0.070) and Edmondson III-IV (53.23% vs 35.71%, P = 0.135); however, statistical significance was not reached. The proportion of patients with AFP ≥ 400 ng/mL was also comparable between groups (12.90% vs 8.57%, P = 0.491).
Table 2 Positive rate of cancer stem cell markers and correlation with invasive characteristics.
Analysis of the survival status of patients with high and low expression of CSC
Kaplan-Meier analysis demonstrated that the RFS rate of patients in the CSC high-expression group was significantly lower than that in the CSC low-expression group (Log-rank χ2 = 10.735, P = 0.001), as illustrated in Figure 1.
Figure 1 Kaplan-Meier curve of recurrence-free survival of patients with high-expression and low-expression cancer stem cells.
CSC: Cancer stem cell.
Comparison of OS/RFS rates in patients with positive and negative CK19 expression
The 3-year OS rate in CK19-positive patients was 51.61%, which was lower than 78.22% in CK19-negative patients (Log-rank χ2 = 10.564, P = 0.001) (Figure 2A). The 3-year RFS rate in CK19-positive patients was 32.26%, which was lower than 63.37% in CK19-negative patients (Log-rank χ2 = 14.181, P = 0.000) (Figure 2B).
Figure 2 Kaplan-Meier curves of CK19 expression and overall survival rate.
A: Overall survival; B: Recurrence-free survival.
Multi-factor Cox regression analysis affecting the prognosis of patients with liver cancer
Multivariate Cox regression analysis identified EpCAM-positivity, CK19 positivity, and MVI as independent factors affecting RFS, while the relevant factors affecting OS included CK19 positivity and a maximum tumor diameter > 5 cm, as demonstrated in Tables 3 and 4.
Comparison of predictive performance between the clinical model alone and the combined clinical + CSC marker model
For 3-year recurrence prediction, the AUC of the clinical model (including MVI, tumor maximum diameter > 5 cm, multifocal, AFP ≥ 400 ng/mL, and Edmondson III-IV) was 0.695; AUC increased to 0.761 after the addition of the CSC marker (Figure 3A). For the prediction of 3-year mortality, the clinical model AUC was 0.726, while the clinical + CSC model AUC was 0.788 (Figure 3B).
Figure 3 Comparison of prediction performance of the clinical model and the combined clinical + cancer stem cell marker model.
A: For 3-year recurrence prediction; B: For 3-year mortality prediction. CSC: Cancer stem cell; AUC: Area under the curve.
DISCUSSION
In this study, we evaluated four CSC-associated markers (EpCAM, CD133, CK19, and CD44) in a uniform cohort of patients undergoing curative resection for HCC, and assessed their prognostic relevance using both RFS and OS endpoints. Our findings suggest that CK19 served as a robust indicator of aggressive biology and adverse postoperative outcomes, whereas CD133 appeared to be more closely linked to survival, potentially reflecting treatment resistance and disease progression after relapse. Importantly, the combination of multiple markers provided incremental prognostic information beyond conventional clinicopathological factors, suggesting a practical role for IHC-based stemness profiling in postoperative risk stratification[9].
CK19 is a marker of biliary epithelial cells and hepatic progenitor cell lineages[10]. CK19-positive HCC is often characterized by precursor-like characteristics and is histologically associated with poor differentiation, pronounced interstitial responses, and an increased propensity for vascular invasion[11,12]. This may be biologically related to bile duct-like differentiation or the lineage reprogramming of tumor cells. Conversely, precursor-like cells are more likely to activate epithelial-mesenchymal transition programs (such as down-regulation of E-cadherin and up-regulation of vimentin), thereby enhancing migration and invasion[13,14]. On the other hand, abnormal activation of transforming growth factor-β, Notch, and Wnt/β-catenin pathways can promote dry maintenance and micrometastasis dissemination[15,16]. In this study, CK19 positivity was significantly associated with MVI and with significantly reduced 3-year OS and RFS, suggesting that it may more closely reflect the histological window of “early recurrence/micrometastasis” risk following surgery. For these patients, clinical management should place greater emphasis on intensive surveillance (shorter interval between image reviews and interpretation of dynamic AFP trends) during the first two years. Furthermore, clinical studies including adjuvant therapy or intensive follow-up should be prioritized[17,18]. In addition, treatment strategies after recurrence should consider early evaluation of combined systemic and local therapies to avoid missing a potentially actionable intervention window[19,20].
CD133, often considered representative of dry maintenance and tolerance phenotypes, is associated with drug efflux, anti-apoptosis, enhanced repair of DNA damage, and immune escape[21,22]. We observed that CD133 was strongly associated with OS but had a relatively weak effect on RFS, suggesting that it may play a greater role in post-recurrence disease progression, metastatic tendency, or variability in follow-up treatment response, rather than directly influencing the initial occurrence of recurrence. Clinically, once the disease recurs, CD133-positive patients are more likely to experience multifocal progression or limited benefit from TACE/targeted therapy/immunotherapy. Therefore, greater emphasis should be placed on the early identification of recurrence patterns, differentiating focal intrahepatic recurrence from extrahepatic metastasis, distinguishing oligometastasis from diffuse progression during follow-up, and incorporating post-recurrence treatment strategies (re-resection/ablation, TACE, and systematic treatment sequence) in the analysis of subsequent studies[23-25]. In the future, we can further use post-relapse OS as the endpoint and identify the key link of CD133 in the “relapse-progression-death” chain.
EpCAM is closely related to the liver precursor cell-like phenotype, cell adhesion, and signal transduction; however, previous studies have indicated that EpCAM contributes to tumor initiation ability, immune microenvironment remodeling, and early recurrence[26,27]. As an adhesion molecule and hyaluronic acid receptor, CD44 is involved in cell migration, matrix adhesion, and immune regulation, and may present the interweaving of “dry/invasion” and “inflammatory/fibrotic background” across various subtypes[28,29]. In a real-world cohort, the effect of a single marker is easily influenced by the sampling site, spatial heterogeneity within the tumor, and threshold setting, which explains the inconsistent results between different studies[30,31]. Therefore, the inclusion of EpCAM, CD133, CK19, and CD44 in a unified evaluation framework can mitigate variability among individual markers and more accurately reflect the overall status of the tumor network.
CSC overexpression was defined as “≥ 2 positive” in this study and was significantly associated with RFS and with an elevated AUC based on traditional clinical pathology factors. This implied that the CSC markers provided biological information for the model that was not fully captured by traditional factors[32]. Notably, emphasis should be placed on the clinical utility of these markers, which extends beyond the improvement in AUC and includes guiding management decisions, such as advancing high-risk groups to more intensive follow-up, exploring adjuvant therapies, or implementing more active comprehensive treatment after recurrence[33]. From the perspective of convertibility, IHC offers a controllable cost and a mature process, making it suitable for integration into routine pathological reports[34]. However, to ensure replicability, standardization of antibodies, staining platform, thresholds, and interpretation criteria, and adoption of digital pathology remain essential to quantify continuous variables, to reduce the information loss caused by the “positive/negative” dichotomy[35].
Limitations of this study: (1) This study had a single-center retrospective design, with selection bias and residual confounding. The upper limit of follow-up was 42 months, with limited characterization of further outcomes; and (2) Differences in IHC thresholds and antibody batches may impact repeatability, and key variables, such as molecular typing, immune infiltration, and perioperative and post-relapse treatment differences, were not included. Future efforts should focus on the development of a multicenter prospective cohort with external validation. Spatial heterogeneity was resolved through multiregional sampling and digital pathological quantification. A multimodal prognosis model can be constructed based on a combination of circulating tumor cells/circulating tumor DNA, radiomic features from medical imaging, and clinical treatment data. The net clinical benefits can be verified using decision curves and other methods.
CONCLUSION
Resected HCC tissues were proportionally positive for EpCAM, CD133, CK19, and CD44. CK19 and CD133 were closely associated with poor survival, while CK19 was linked with the risk of relapse. The inclusion of CSC-related markers in prognostic assessment can improve risk stratification based on traditional clinical factors and provide a basis for postoperative follow-up and individualized management.
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