Short- and long-term outcomes after laparoscopic and open liver resection for combined hepatocellular-cholangiocarcinoma patients: a propensity score-matched study

Introduction

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) represents a rare primary liver neoplasm demonstrating dual differentiation along both hepatocellular and biliary epithelial lineages. cHCC-CCA demonstrates significantly lower incidence compared to hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), representing only 0.4–14.2% of all primary liver cancer (PLC) (1-3). Similar to other liver cancers, cHCC-CCA shows a male predominance, with peak incidence occurring at 60–65 years (1-3). The latest 5th edition of the World Health Organization (WHO) Classification of Tumors of the Digestive System (published in 2019) categorizes cHCC-CCA as a distinct primary liver malignancy requiring definitive histological evidence of dual hepatocellular and cholangiocellular differentiation in a single neoplastic lesion, exclusion of separated or independent HCC and ICC occurring simultaneously in the same liver (4).

Unlike HCC and ICC which have established treatment protocols, cHCC-CCA lacks consensus guidelines, with multiple therapeutic approaches currently under investigation. Radical surgical resection is the best treatment option for patients with cHCC-CCA (2,3,5-7). In addition, chemotherapy, radiotherapy, targeted therapy and immunotherapy are also effective (8-10). In general, cHCC-CCA demonstrates an intermediate prognosis between HCC and ICC, typically exhibiting worse outcomes than HCC but better or equal to those of ICC (3,6,11,12).

This study retrospectively analyzed the clinicopathological and follow-up data of patients with cHCC-CCA who underwent laparoscopic liver resection (LLR) or open liver resection (OLR) at our institution. The aim was to compare both short-term treatment outcomes and long-term survival between these surgical approaches, thereby providing evidence to inform future clinical decision-making. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-716/rc).

Methods

Patients

In this study, we retrospectively analyzed the clinicopathological and follow-up data of cHCC-CCA patients who underwent LLR or OLR between 2010 and 2022 at Shandong Provincial Hospital Affiliated to Shandong First Medical University. The patients were divided into the LLR group and the OLR group based on the surgical approach. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Medical Ethics Committee of Shandong Provincial Hospital (No. SWYX2024 − 695) and informed consent was obtained from all individual participants.

The inclusion and exclusion criteria

The inclusion criteria were: (I) underwent pathological confirmation of cHCC-CCA diagnosis; (II) underwent curative LLR or OLR; (III) with an American Society of Anesthesiologists (ASA) grade I–III; (IV) without a history of major upper abdominal surgery. The exclusion criteria were: (I) with other malignancies or distant metastases; (II) data missing or lost to follow-up; (III) preoperative neoadjuvant therapy.

Patient variables and follow-up

Data were obtained through electronic medical records. Preoperative investigations included complete blood count, liver function tests, coagulation indices, alpha-fetoprotein (AFP), carcinoma embryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9). Imaging comprised chest radiography and contrast-enhanced abdominal computed tomography (CT) or magnetic resonance imaging (MRI). Intraoperative and postoperative data included: operative time (OT), estimated blood loss (EBL), blood transfusion, tumor size, multiple tumors, tumor differentiation grade, predominant tumor component, lymph node metastasis, neural invasion, vessel carcinoma embolus, R0 resection, and postoperative complications.

OT was defined as the time from the first incision to the placement of the final dressing. The severity of postoperative complications was graded according to the Clavien-Dindo classification system. EBL was calculated as the sum of the suction volume (minus irrigation fluid) and the weight of soaked surgical gauzes (wet weight minus dry weight). This measurment methodology remained consistent throughout the study period (2010–2022) and was applied uniformly to both laparoscopic and open surgical procedures.

Patients were followed up regularly after surgery. Follow-up included abdominal ultrasound, CT or MRI and laboratory tests to check liver function and tumor indicators. These include checking levels of AFP, CEA and CA19-9 every 3 months for the first 2 years after surgery and every 6 months thereafter until death or loss to follow-up. Overall survival (OS) was measured from surgery to death or last follow-up. Patient follow-up continued until April 30, 2025.

Statistical analysis

To minimize potential confounding factors and selection bias, a propensity score matching (PSM) analysis was performed using 1:1 nearest-neighbor matching without replacement with a caliper width of 0.2. Covariates included in the propensity score model were: age, gender, body mass index (BMI), ASA grade, hepatitis B virus (HBV), hemoglobin (Hb), albumin (ALB), total bilirubin (TBIL), AFP, CEA, CA19-9, tumor size, multiple tumors, tumor differentiation grade, predominant tumor component, and surgical year. Standardized mean differences were used to assess the balance of covariates in the propensity-matched cohort. Continuous variables were expressed as medians and interquartile range (IQR). Student’s t-test and the Mann-Whitney U test were applied to analyze normally and non-normally distributed variables, respectively. The categorical variables were displayed as numbers and percentages and compared using the chi-square test or Fisher’s exact test. Kaplan-Meier (K-M) survival curves were generated and compared with the log-rank test to evaluate differences between the LLR and OLR groups. Univariate Cox proportional hazards regression was used to screen potential variables associated with OS. Significant variables (P<0.05) in the univariate analysis were then included in a multivariate Cox regression model to identify independent prognostic factors. Significance was defined as a P value of <0.05. All statistical analyses were performed using SPSS software (version 22.0).

Results

Patients’ characteristics

Figure 1 shows the progression of cHCC-CCA patients selected for this study who underwent curative liver resection between 2010 and 2022. Ten patients who underwent palliative surgery, three who received preoperative neoadjuvant therapy and six patients lost to follow-up were excluded. A total of 141 cHCC-CCA patients were enrolled in the study, with 78 patients undergoing LLR and 63 patients undergoing OLR. After 1:1 PSM, 47 patients were enrolled in each group, with balanced baseline characteristics between cohorts (Table 1).

Figure 1 Flow chart of this study showing the selection process of cHCC-CCA patients who underwent LLR or OLR. cHCC-CCA, combined hepatocellular-cholangiocarcinoma tumors; LLR, laparoscopic liver resection; OLR, open liver resection; PSM, propensity score matching.

Comparison of short-term outcomes between LLR and OLR groups before and after PSM

Table 2 details the perioperative outcomes for both cohorts. After PSM, there were no significant differences between the LLR group and the OLR group in OT (360.0 vs. 330.0, P=0.24), lymph node metastasis rate (36.2% vs. 21.3%, P=0.17), blood transfusion rate (48.9% vs. 36.2%, P=0.29), neural invasion rate (27.7% vs. 12.8%, P=0.12), vessel carcinoma embolus (34.0% vs. 38.3%, P=0.83), R0 resection rate (95.7% vs. 95.7%, P>0.99), serious complications (C–D grade ≥ III) (10.6% vs. 2.1%, P=0.20) and 3-year OS rate (42.6% vs. 53.2%, P=0.40). However, the LLR group had lower EBL (200.0 vs. 300.0 mL, P=0.004) and a shorter length of stay (LOS) (10.0 vs. 15.0 days, P<0.001) compared with the OLR group.

Long-term outcomes in cHCC-CCA patients before and after PSM

The 1-, 3-, and 5-year OS rates for all patients were 94.3%, 69.8%, and 56.0%, respectively. Before PSM, the 1-, 3-, and 5-year OS rates for patients in the LLR group were 96.0%, 62.5%, and 36.5%, respectively; and the median OS was 51 (42.0–60.0) months. The OLR group demonstrated 1-, 3-, and 5-year OS rates of 96.7%, 68.7%, and 60.9%, respectively, with a median OS of 66 (53.1–78.9) months. OS did not differ significantly between the groups (P=0.12; Figure 2A). After PSM, the 1-, 3-, and 5-year OS rates for patients in the LLR group were 93.6%, 73.2%, and 46.8%, respectively; and the median OS was 60 (46.5–73.5) months. The 1-, 3-, and 5-year OS rates for patients in the OLR group were 89.4%, 63.9%, and 51.4%, respectively; and the median OS was 69 (36.3–101.7) months. OS did not differ significantly between groups (P=0.54, Figure 2B).

Figure 2 Kaplan-Meier curves estimating OS in cHCC-CCA patients who underwent LLR or OLR before and after PSM. (A) OS of cHCC-CCA patients before PSM; (B) OS of cHCC-CCA patients after PSM. cHCC-CCA, combined hepatocellular-cholangiocarcinoma tumors; LLR, laparoscopic liver resection; OLR, open liver resection; OS, overall survival; PSM, propensity score matching.

Univariate and multivariate Cox regression analyses of OS

Univariate analysis showed that gender [male vs. female, hazard ratio (HR) =0.472; 95% confidence interval (CI): 0.231–0.965; P=0.03] and tumor main ingredients (HCC vs. ICC, HR=0.385, 95% CI: 0.192–0.775; P=0.007) were prognostic factors for OS. Multivariate analysis showed that only tumor main ingredients were HCC (HR =0.323, 95% CI: 0.151–0.693, P=0.004), significant predictors of OS. Detailed results are shown in Table 3.

Discussion

cHCC-CCA is a rare PLC. Currently, there are few studies analyzing the prognosis of cHCC-CCA patients comparing LLR and OLR using PSM. The current study, which compared both short- and long-term outcomes in patients with cHCC-CCA undergoing either LLR or OLR, revealed that LLR was associated with superior short-term perioperative outcomes (e.g., amount of EBL and postoperative LOS) compared to OLR.

Although LLR was associated with superior short-term outcomes, long-term survival was comparable between the two surgical approaches. Although there was no statistically significant difference in long-term survival between the two groups, the OLR group showed better 5-year OS and median OS than the LLR group. Possible reasons for this trend include: (I) The statistical power of this study may still be insufficient to detect a small but real difference in survival outcomes, especially after PSM reduced the sample size. (II) cHCC-CCA is a highly heterogeneous tumor, and unmeasured or unrecorded confounding factors—such as specific molecular subtypes or related immunohistochemical expression profiles—may have persisted. This could have led to the inclusion of patients with a potentially better prognosis in the OLR group. (III) In clinical practice, surgeons tend to favor the open approach for patients with larger tumors, tumors located near major vessels, or suspected lymph node metastasis. This case-selection bias based on tumor aggressiveness and surgical complexity may have resulted in the OLR group containing more patients who achieved survival benefits through more extensive lymphadenectomy or more precise vascular control.

Results of related studies have shown an increasing trend in the incidence of cHCC-CCA, which increases the need for research on this rare tumor (3). In general, cHCC-CCA demonstrates an intermediate prognosis between HCC and ICC, typically exhibiting worse outcomes than HCC but better or equal to those of ICC (3,6,11,12).

Laparoscopic techniques are now widely used in liver surgery and are becoming increasingly sophisticated. Previous studies of HCC have shown that both LLR and OLR are safe and feasible with comparable short- and long-term survival outcomes (13-16). However, for cHCC-CCA patients, there is currently no standardized treatment protocol or globally accepted clinical guideline available. Surgical resection remains the primary treatment option for this disease, while the safety and efficacy of LLR for these patients remain unclear. In the present study, the perioperative and oncological outcomes of LLR and OLR were compared in patients with cHCC-CCA. After PSM, perioperative outcomes were similar between groups, but the LLR group had lower EBL and shorter postoperative LOS than the OLR group. The minimization of surgical blood loss correlates with improved perioperative outcomes. In particular, a reduction in blood loss was associated with a lower incidence of any complications and serious complications (17,18). Although the difference of 100 mL is modest, it is consistent with the established advantages of laparoscopic surgery, such as reduced intraoperative blood loss. Laparoscopic assistance provides enhanced visualization of the anatomical structures surrounding the surgical field, facilitating more precise dissection. More precise resection technique minimizes tissue trauma, thereby reducing intraoperative blood loss. In addition, previous studies have shown that the LLR and OLR postoperative LOS in patients with cHCC-CCA were 8.5 and 15 days (19), respectively. Compared with the OLR group, the LLR group demonstrated a significantly reduced postoperative LOS (10.0 vs. 15.0 days after PSM, P<0.001), which was consistent with the results of previous studies (20-23). Discharge criteria affecting LOS are influenced by a variety of factors, making the measure relatively subjective. Therefore, it is not accurate to judge the effectiveness of a procedure based on LOS alone. The study spanned over a decade, during which the widespread adoption of Enhanced Recovery After Surgery (ERAS) protocols, refinements in anesthesia management, and optimization of discharge criteria have undoubtedly contributed to improved short-term outcomes for all patients, constituting a potential confounding factor. Consequently, the long-term advancements in perioperative care and enhanced recovery pathways may partially explain the observed superior short-term outcomes associated with LLR.

In this study, the major component of the tumor was an independent prognostic factor for the cHCC-CCA patients. Zhou et al. found that cHCC-CCA patients with >70% HCC component had better OS than cHCC-CCA patients with ≤70% HCC component (24). Xiao et al. found that cHCC-CCA patients with >65% HCC component had a better prognosis (25). This finding may inform future investigations on whether elective lymph node dissection should be routinely performed in patients with cHCC-CCA, especially in those with ICC‑predominant histology. Furthermore, our results demonstrate that minimally invasive techniques can be safely applied even in the surgical management of this rare but more aggressive tumor subtype, which often requires extensive resection and is associated with poorer prognosis. Importantly, these observations underscore that clinical strategies and research conclusions derived from HCC should not be directly extrapolated to cHCC‑CCA, highlighting the necessity of developing evidence‑based guidelines specific to this distinct clinicopathological entity. Therefore, the prognosis of cHCC-CCA patients can be referred to the percentage of components in the postoperative pathological examination, according to which the postoperative treatment plan can be further guided.

This study has certain inherent limitations. First, as a retrospective study, this analysis is inherently subject to selection bias, which may not be fully eradicated despite the use of PSM to minimize baseline confounders. Second, our population was Chinese cHCC-CCA cases. The risk profile for cHCC-CCA exhibits significant geographic variation, influenced by regional differences in dietary patterns, environmental exposures, and prevalence of infectious pathogens. Regional variations in cHCC-CCA etiology are evident, with HBV infection endemic in Asian populations driving tumorigenesis, whereas Western populations demonstrate stronger associations with hepatitis C virus (HCV) and alcohol-related liver disease. These findings warrant verification in Western cohorts given the known regional variations in cHCC-CCA etiology and risk factors. Third, incomplete data on recurrence-free survival (RFS) and surgical resection margins were available for a subset of patients in this study. This limitation hindered an accurate assessment of the impact of radical surgical extent on prognosis in subgroup analyses and may have introduced bias into the survival analysis results. Finally, the statistical power of this study was limited by its single-center design and relatively small sample size, which may have been insufficient to detect small yet clinically meaningful differences in survival outcomes, particularly after PSM further reduced the cohort size. In the future, rigorously designed multicenter prospective studies are warranted to compare the efficacy of LLR versus OLR in patients with cHCC-CCA.

Conclusions

In conclusion, this study demonstrates that LLR is a safe and feasible approach for selected patients with cHCC-CCA, offering significant advantages in reducing EBL and shortening postoperative LOS compared to OLR. No statistically significant difference in long-term OS was observed between LLR and OLR.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-716/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-716/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-716/prf

Funding: The study was supported by Natural Science Foundation of Shandong Province (No. ZR2021MH332).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-716/coif). All authors report that the funding for this study was provided by Natural Science Foundation of Shandong Province (No. ZR2021MH332). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Medical Ethics Committee of Shandong Provincial Hospital (No. SWYX2024 − 695) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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