Development and validation of prognostic nomograms for intrahepatic cholangiocarcinoma with concomitant hepatolithiasis after radical resection

Introduction

Intrahepatic cholangiocarcinoma (ICC), a malignancy arising from the intrahepatic biliary epithelium, is the second most common primary liver cancer after hepatocellular carcinoma (1,2). Its global incidence has risen steadily over recent decades (3,4). Despite ongoing advances in treatment strategies, radical resection remains the primary therapeutic option for ICC. The overall prognosis for ICC patients, however, remains poor, characterized by high postoperative recurrence rates and limited long-term survival (5,6). Prior research has established ICC as a highly heterogeneous disease, with substantial interpatient variability in tumor biology, recurrence risk, and survival outcomes. Consequently, achieving more accurate individualized postoperative prognostic assessment is a major clinical priority (7,8).

Hepatolithiasis is a chronic biliary disorder characterized by bile stasis, biliary stricture, and recurrent cholangitis, and is particularly prevalent in Asian populations (9). The persistent stasis and chronic inflammation drive cycles of biliary epithelial injury and repair, which promote epithelial dysplasia and cholangiocarcinogenesis. Consequently, hepatolithiasis is a well-established risk factor for ICC (10,11). Emerging evidence indicates that hepatolithiasis-associated ICC (HICC) bears greater etiological and pathobiological resemblance to large-duct type ICC, a subtype frequently associated with chronic biliary inflammation, and may follow a distinct evolutionary trajectory with unique clinical behavior compared to conventional ICC (12,13). The pathology of HICC is characterized by the frequent presence of large casts. Due to the high proportion of large casts in the tumor, the imaging manifestations show that the lesion is relatively small or even not obvious, and regional lymph node enlargement is relatively rare. Therefore, it is easily masked by biliary stones, liver atrophy or liver abscess, resulting in missed diagnosis. The preoperative missed diagnosis of HICC results in a lower R0 resection rate or the omission of necessary lymph node dissection. After the operation, patients are highly prone to recurrence, with a poorer prognosis and worse long-term outcomes compared to ordinary ICC (14). This distinction highlights the clinical necessity for dedicated prognostic assessment in this patient subgroup.

Against this background, biomarkers related to fibrosis and extracellular matrix remodeling may be of particular interest in HICC. Microfibrillar-associated protein 4 (MFAP4), an extracellular matrix-related glycoprotein, participates in tissue remodeling and cell-matrix interactions. Emerging evidence indicates that MFAP4 is closely associated with fibrotic processes in multiple organs and may contribute to the development of inflammatory and fibrotic microenvironments via integrin-mediated signaling (15,16). MFAP4 has also demonstrated potential as a biomarker in liver fibrosis and chronic liver disease (17,18). We conducted immunohistochemical assays on the postoperative tissue samples of HICC patients and ordinary ICC patients to detect the expression level of MFAP4. We found that compared to ordinary ICC, MFAP4 was abnormally highly expressed in the samples of HICC patients. However, its clinical significance in HICC remains unclear.

Several prognostic models have been developed for patients with ICC following surgery, but most were established in general ICC cohorts and rarely focus specifically on the distinct subgroup with HICC (19,20). In this retrospective study, we therefore analyzed the clinicopathological characteristics of patients with HICC, identified independent prognostic factors for overall survival (OS) and recurrence-free survival (RFS), and developed and validated nomogram models for individualized survival prediction. Our aim was to provide a practical tool for postoperative risk stratification, surveillance, and personalized treatment decision-making in this population. We present this article in accordance with the TRIPOD reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0541/rc).

Methods

Patients

This study enrolled patients with ICC and concomitant hepatolithiasis who underwent radical resection at Nanfang Hospital of Southern Medical University, Hunan Provincial People’s Hospital and Hunan Cancer Hospital from January 2019 to December 2024. Inclusion criteria required: (I) age between 18 and 80 years; (II) pathological confirmation of ICC; (III) ICC as the sole primary malignancy with no prior history of other cancers; (IV) concomitant hepatolithiasis; (V) radical resection with a margin ≥2 cm; (VI) no distant metastasis; and (VII) complete clinicopathological data with adequate follow-up. Exclusion criteria comprised: (I) extrahepatic metastases; (II) incomplete clinical data; (III) loss to follow-up; or (IV) a history of other malignancies. A total of 230 eligible patients from Nanfang Hospital of Southern Medical University (NFHSMU) were enrolled and randomly allocated to a training cohort (n=161) and an internal validation cohort (n=69). An additional 105 patients from Hunan Provincial People’s Hospital (HPPH), Hunan Cancer Hospital (HCH) and The First People’s Hospital of Zixing City (FPHZ) constituted an external validation cohort. These cohorts facilitated the development and validation of nomograms for predicting postoperative recurrence and OS in this patient population. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Medical Ethics Committee of Hunan Provincial People’s Hospital (No. [2026]-141). All participating hospitals were informed of and agreed to the study. As this is a retrospective study, the requirement for written informed consent was waived.

Data collection

All patients underwent routine preoperative evaluation, which comprised a medical history review, serological testing, and imaging studies such as abdominal computed tomography and chest radiography. Table 1 summarizes the baseline demographic and clinicopathological characteristics of the cohort, including age, gender, history of hepatitis, cirrhosis, history of biliary disease, prothrombin time (PT, seconds), total bilirubin (TBIL, µmol/L), albumin (ALB, g/L), alanine aminotransferase (ALT, U/L), platelet count (PLT, ×10⁹/L), γ-glutamyl transferase (GGT, U/L), alpha-fetoprotein (AFP, µg/L), carcinoembryonic antigen (CEA, µg/L), carbohydrate antigen 19-9 (CA19-9, U/mL), tumor diameter (cm), tumor number, blood transfusion, lymph node metastasis, vascular invasion, tumor capsule, albumin-bilirubin (ALBI) grade, and liver segmental invasion. Tumor-related variables were derived from imaging examinations. Lymph node metastasis, vascular invasion, and tumor capsule status were determined through preoperative imaging, intraoperative exploration, and postoperative pathological assessment.

Establishment and validation of nomogram

A total of 230 patients from our center were randomly assigned to the training cohort and the internal validation cohort. We developed the nomogram using the training cohort and validated it in both the internal and external validation cohorts. Calibration curves and the area under the curve (AUC) were generated to assess the nomogram’s calibration and clinical applicability.

Follow-up

The follow-up period for this study was terminated on December, 30, 2025. All patients with HICC were first evaluated for recurrence 4 weeks after radical resection by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and measurement of the serum CA19-9 and CEA levels. The patients were then reevaluated every 3 months by measurement of their serum CA19-9 and CEA levels, and by contrast-enhanced CT or MRI until death or dropout from the follow-up program.

Statistical analysis

The data included in this study were all completely recorded and there were no missing data. Statistical analyses were conducted with SPSS Statistics version 25.0. Continuous variables are presented as medians and were compared via the Mann-Whitney U test. Categorical variables, expressed as frequencies and percentages, were analyzed using the chi-square test. Independent prognostic factors for RFS and OS were identified through multivariable Cox proportional hazards regression with the forward likelihood ratio method. Nomograms were constructed using R version 4.0.2. Their predictive performance was validated in the internal and external cohorts using calibration curves and the AUC. A two-sided P value <0.05 was considered statistically significant.

Results

Patient characteristics

This study enrolled 335 patients with ICC and concomitant hepatolithiasis who underwent radical resection at three institutions (Figure 1). The median follow-up time was 28.2 months. The 5-year RFS rates were 28.1%, 27.9% and 27.5% and the 5-year OS rates were 40.9%, 36.6% and 36.8% in the training cohort, internal validation cohort and external validation cohort, respectively. Table 1 summarizes the clinicopathological characteristics of the patients in the training and validation cohorts. The training cohort consisted of 140 men and 21 women, with a median age of 51.0 years and a median tumor diameter of 5.2 cm; most patients (72.0%) had a solitary tumor. Baseline characteristics were generally comparable across the three cohorts, with no statistically significant differences.

Figure 1 The patient flowchart. ICC, intrahepatic cholangiocarcinoma; FPHZ, The First People’s Hospital of Zixing City; HCH, Hunan Cancer Hospital; HPPH, Hunan Provincial People’s Hospital; NFHSMU, Nanfang Hospital of Southern Medical University.

Multivariate Cox regression analyses

The results of the multivariable Cox regression analyses for RFS and OS are presented in Figures 2,3. Multivariable analysis identified vascular invasion, tumor number, lymph node metastasis, tumor size, CEA, MFAP4, and ALBI grade as independent predictors of RFS. Specifically, vascular invasion [hazard ratio (HR) =1.98, 95% confidence interval (CI): 1.54–2.55, P<0.001], multiple tumors (HR =1.96, 95% CI: 1.21–2.85, P<0.001), lymph node metastasis (HR =1.68, 95% CI: 1.29–2.19, P<0.001), elevated CEA (HR =1.84, 95% CI: 1.43–2.36, P<0.001), positive MFAP4 expression (HR =2.11, 95% CI: 1.25–3.62, P<0.001), ALBI grade 2 (HR =1.50, 95% CI: 1.18–1.92, P=0.001), and ALBI grade 3 (HR =4.48, 95% CI: 1.71–9.56, P<0.001) were all significantly associated with worse RFS. Furthermore, compared with tumors <5 cm, tumors measuring 5–10 cm (HR =1.49, 95% CI: 1.01–2.22, P=0.048) and >10 cm (HR = 2.21, 95% CI: 1.39–3.50, P=0.001) were associated with a higher risk of recurrence.

Figure 2 Multivariable analysis of prognostic factors for recurrence-free survival in intrahepatic cholangiocarcinoma. ALBI, albumin-bilirubin; CEA, carcinoembryonic antigen; CI, confidence interval; MFAP4, microfibrillar-associated protein 4.

Figure 3 Multivariable analysis of prognostic factors for overall survival in intrahepatic cholangiocarcinoma. ALBI, albumin-bilirubin; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CI, confidence interval; MFAP4, microfibrillar-associated protein 4.

For OS, the independent adverse prognostic factors were vascular invasion (HR =1.73, 95% CI: 1.28–2.34, P<0.001), multiple tumors (HR =2.22, 95% CI: 1.58–3.14, P<0.001), lymph node metastasis (HR =1.58, 95% CI: 1.15–2.15, P=0.004), elevated CA19-9 (HR =1.76, 95% CI: 1.20–2.35, P=0.005), elevated CEA (HR =1.97, 95% CI: 1.45–2.69, P<0.001), positive MFAP4 expression (HR =1.98, 95% CI: 1.12–3.17, P<0.001), ALBI grade 2 (HR =1.51, 95% CI: 1.11–2.06, P=0.009), and ALBI grade 3 (HR =3.91, 95% CI: 1.51–8.09, P=0.005).

Prognostic nomogram for prediction of OS and RFS

Based on multivariable analysis, we developed nomograms to predict 2- and 5-year RFS and OS. The RFS nomogram incorporated seven variables: lymph node metastasis, CEA, vascular invasion, tumor number, MFAP4, tumor size, and ALBI grade (Figure 4A). The OS nomogram also included seven prognostic factors: CEA, lymph node metastasis, vascular invasion, MFAP4, tumor number, CA19-9, and ALBI grade (Figure 4B). For a given patient, the points for each variable are summed; this total score is then located on the scales for 2- and 5-year RFS or OS to estimate the corresponding probability. The calibration curves showed close agreement between the predicted and observed probabilities for both 2- and 5-year RFS and OS in the training cohort, internal validation cohort, and external validation cohort, confirming the models’ good calibration and stability (Figure 5).

Figure 4 Nomograms for predicting the 2- and 5-year recurrence-free survival (A) and overall survival (B) in patients with intrahepatic cholangiocarcinoma and concomitant hepatolithiasis. ALBI, albumin-bilirubin; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; MFAP4, microfibrillar-associated protein 4.

Figure 5 The calibration curves for predicting 2- and 5-year recurrence (A-C) and mortality (D-F) in the training cohort, internal validation cohort, and external validation cohort.

Efficacy of the nomogram

Time-dependent receiver operating characteristic (ROC) curve analysis assessed the predictive accuracy and discriminative ability of the nomograms for RFS and OS (Figure 6). For the training cohort, the nomograms achieved C-index of 0.840 (95% CI: 0.79–0.89) for RFS and 0.852 (95% CI: 0.80–0.90) for OS. In the internal validation cohort, the corresponding C-index were 0.823 (95% CI: 0.78–0.86) and 0.832 (95% CI: 0.79–0.87). The external validation cohort yielded C-index of 0.862 (95% CI: 0.81–0.91) for RFS and 0.870 (95% CI: 0.82–0.92) for OS. Collectively, these results demonstrate that the nomogram models provide robust predictions of postoperative RFS and OS in patients with ICC and concomitant hepatolithiasis.

Figure 6 Time-dependent ROC curves of the nomograms for predicting RFS (A-C) and OS (D-F) in the training, internal validation, and external validation cohorts, respectively. AUC, area under the curve; OS, overall survival; RFS, recurrence-free survival; ROC, receiver operating characteristic.

Discussion

Prognostic assessment following ICC resection has increasingly shifted from conventional staging systems toward more comprehensive predictive models. Existing studies, however, largely derive from unselected surgical cohorts and fail to adequately address the heterogeneity inherent to patients with specific etiologies (21). Here, we developed and validated nomogram models for postoperative prognosis in patients with ICC and concomitant hepatolithiasis. The models demonstrated good discrimination and calibration in ROC and calibration analyses, indicating improved clinical applicability for this distinct subgroup.

Multivariable Cox regression identified lymph node metastasis and vascular invasion as common determinants of both OS and RFS, underscoring that tumor invasiveness and metastatic potential remain central to postoperative outcome. Prior studies have similarly established a close association between lymph node metastasis and postoperative recurrence as well as long-term survival in ICC (22,23). Vascular invasion likewise signifies greater local aggressiveness and an elevated risk of postoperative recurrence. Furthermore, indicators of tumor burden, including tumor number and size, were significantly associated with recurrence risk. Kawashima et al. reported that lymph node metastasis, a tumor size >5 cm, multiple nodules, and vascular invasion were independent predictors of poor prognosis after curative hepatectomy for ICC (24). Yoon et al. also demonstrated that patients with multiple tumors experienced significantly worse postoperative survival than those with solitary tumors (25).

Our analysis further confirmed the stable prognostic value of CEA and CA19-9. Recent evidence suggests that the predictive utility of any single tumor marker is limited, whereas a combined biomarker assessment may better identify high-risk patients after surgery. Wang et al. stratified ICC patients based on preoperative serum CA19-9, CA125, and CEA levels, showing that this combined grading system offered superior prognostic value for OS and RFS compared to any single marker alone (26). Concurrently, ALBI grade emerged as an independent prognostic factor in our study. As patients with HICC experience chronic bile stasis, biliary stricture, and recurrent inflammatory injury, their baseline hepatic functional reserve may continuously influence postoperative outcomes. Recent studies indicate that a higher ALBI grade correlates with worse long-term survival, more perioperative adverse events, and a greater risk of recurrence (27,28). Impaired liver function may not only compromise postoperative recovery and tolerance to subsequent treatment but could also indirectly promote recurrence and mortality by affecting the tumor microenvironment and host immune status (29,30).

MFAP4, an extracellular matrix-related glycoprotein, is closely linked to extracellular matrix remodeling and liver fibrosis. It may exacerbate hepatic fibrosis by activating the integrin αvβ3-mediated FAK/PI3K/NF-κB signaling pathway, thereby promoting hepatic stellate cell activation, migration, and resistance to apoptosis (31). In cholestatic liver disease, elevated MFAP4 has also been associated with fibrosis severity and clinical outcome (18,32). The dysregulation of MFAP4 expression can participate in fibrosis, immune disorders and promote the progression of malignant tumors through integrin-dependent or -independent pathways (3). In lung adenocarcinoma, MFAP4 interacts with the epidermal growth factor receptor (EGFR) signaling pathway, inhibiting cell cycle progression and promoting the progression of lung cancer. Studies have shown that MFAP4, as a secreted protein, binds to the receptor of cytoskeletal-associated protein 4 (CKAP4) on the cell membrane of ICC cells, specifically activating the ERK signaling pathway, thereby upregulating the expression and secretion of matrix metalloproteinases matrix metalloproteinase-2 (MMP2) and -9 (MMP9), ultimately enhancing the invasion and metastasis ability of ICC cells, leading to poor prognosis (33,34). Given that patients with HICC are exposed to persistent biliary inflammation and fibrotic remodeling, MFAP4 positivity may reflect a more profoundly altered fibrotic milieu and tumor microenvironment, contributing to tumor progression and adverse postoperative outcomes.

Several limitations must be acknowledged. First, the retrospective design could not entirely avoid selection bias. Second, the training cohort of the nomogram was developed from a single-center cohort, the results may be influenced by institution-specific factors, including surgical indications, perioperative management, pathological assessment, postoperative surveillance protocols, and adjuvant treatment practices. The relatively limited sample size necessitates further validation of the model’s generalizability in larger multicenter cohorts. Finally, the specific biological role of MFAP4 in this distinct subgroup remains unclear, and its translational value warrants further investigation.

Conclusions

In summary, we developed two conveniently available models that could accurately and objectively predict mortality and recurrence for patients with HICC after radical resection. Our models are designed to serve as a supplementary prognostic tool for risk assessment, which can be used to guide postoperative monitoring for patients with a high risk of recurrence, thus may contribute to better survival for these patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0541/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0541/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0541/prf

Funding: This work was supported by Hunan Provincial Natural Science Foundation of China (Nos. 2023JJ60021, 2025JJ80749, and 2024JJ931).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0541/coif). The authors have no 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 Medical Ethics Committee of Hunan Provincial People’s Hospital (No. [2026]-141). All participating hospitals were informed of and agreed to the study. As this is a retrospective study, the requirement for written informed consent was waived.

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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