This retrospective study collected patients from the Department of Hepatobiliary Surgery at Hunan Provincial People’s Hospital (the First Affiliated Hospital of Hunan Normal University) between January 2015 and December 2021. The patients included in the study had been pathologically diagnosed with ICC and had undergone radical surgery. A total of 525 patients with ICC were screened for inclusion in the study. The research was conducted in compliance with the protocol approved by the Ethics Committee of Hunan Provincial People’s Hospital (Approval No.: [2024]-121), following the principles outlined in the Declaration of Helsinki.

All the patients encompassed in the current study fulfilled the subsequent criteria: (1) underwent R0 resection, with postoperative pathology confirming ICC; comprehensive clinical case data and follow-up data were accessible; (2) did not undergo tumor-targeted treatments such as transcatheter arterial chemoembolization (TACE), chemotherapy, radiotherapy, targeted therapy, or immunotherapy, etc.; (3) preoperative Child-Pugh score of A/B; (4) had no history of previous malignant tumors. Patients with the following attributes were excluded: (1) R1/2 excision or distant metastasis (M1); (2) postoperative pathology indicating primary liver cancer such as hepatocellular carcinoma, mixed hepatocellular carcinoma, or other types of biliary malignancy; (3) patients with infectious diseases prior to operation; (4) taking hormones, aspirin, clopidogrel, and other drugs influencing peripheral blood cell indicators before surgery; (5) combined with blood diseases or immune system disorders; (6) postoperative perioperative mortality; (7) incomplete clinical data. After screening based on the inclusion and exclusion criteria, a total of 165 patients were excluded as they did not meet the inclusion criteria, and 360 patients with ICC were selected for inclusion in this study.

The preoperative NLR (ratio of neutrophils to lymphocytes), LMP (ratio of lymphocytes to monocytes), and SII (platelet * NLR) were all derived from the preoperative case data of patients. The cut-off values of LMR, SII and NLR were, respectively, 3.71, 730.14 and 2.36, employing the maximum Youden index method. As depicted in Figure 1, ROC curves were constructed to assess the correlation between three preoperative serum inflammatory indicators (LMR, SII, NLR) and the postoperative survival of patients, and the AUC values were 0.557, 0.567, and 0.786, respectively. The AUCs of both LMR and SII were less than 0.6, indicating that there was no significant correlation between them and the prognosis of ICC patients. Hence, they are not important indices in this study. The AUC of NLR is 0.786, and the cut-off value is 2.36, which is included in the significant indices of this study. The preoperative maximum tumor diameter (MTD), hepatolithiasis, vascular invasion, local invasion, and nerve invasion were all obtained from the preoperative CT/MR Imaging data. The TNM staging was in accordance with the AJCC eighth edition installment (22). Postoperative complications were graded in accordance with the Clavien-Dindo complication criteria (23).

In this study, outpatient review and telephone contact were employed to carry out follow-up and follow-up investigation. The follow-up period extended to June 2024. The principal contents of follow-up observation encompassed follow-up treatment, recurrence time, and survival time of patients. Regular postoperative follow-up should be conducted, specifically every 3 to 6 months. Postoperative follow-up should incorporate: imaging examinations, such as CT, MRI, etc., to assess the local control of the tumor after surgery and detect possible recurrence or metastasis; Tumor markers, such as AFP, CEA, CA19-9, etc., to evaluate tumor activity status and potential risk of recurrence. Overall survival (OS) was defined as from the day of surgery until the time of death or the time of the last follow-up, and patients who remained alive at the last follow-up were recorded as censored data.

The primary endpoints of this study encompassed the overall survival (OS) and recurrence rates at 1, 3, and 5 years subsequent to surgery. The postoperative survival time pertains to the duration from the date of surgery to the patient’s decease or the last follow-up, while the postoperative recurrence time refers to the period from the date of surgery to the emergence of distant metastases in other bodily regions or the last follow-up. All measurement data were presented as mean ± standard deviation, and the disparities of measurement data were compared by means of independent sample t test or Mann–Whitney U test. The count data were expressed as n (%), and the count data were compared via Chi-square test or Fisher exact test. The difference in tumor survival and recurrence was compared through log-rank test. All binary variables were classified by referring to international authoritative literature classification, clinical normal limit and cut-off values based on the best Youden index. The survival and recurrence curves were delineated by the Kaplan–Meier curve method. A single factor logistic regression model was utilized to estimate the probability ratio and 95% confidence interval for various variables, and variables with statistical differences in the single factor logistic regression model were incorporated into multivariate analysis. Multivariate analysis was used to get the prediction model, and Hosmer-Lemeshow test was used to check the fit degree of the model. SPSS 25.0 statistical software was employed for analysis, and p value less than 0.05 was regarded as statistically significant.

The flowchart of the manuscript design is presented in Figure 2. In this study, a total of 360 ICC patients were recruited. Based on the best Youden index of NLR, all ICC patients were categorized into the NLR < 2.36 group and the NLR ≥ 2.36 group, and subsequently, the prognostic analysis of the two groups was compared. Then, all ICC patients were divided into the HICC group and the NHICC group depending on whether they combined with hepatolithiasis. According to the value of NLR = 2.36, the two groups were further classified into the low-NLR group and the high-NLR group, and the prognosis in each group was compared. Subsequently, the prognosis prediction model based on NLR in each group was constructed.

The clinical characteristics of ICC patients in the NLR < 2.36 group and the NLR ≥ 2.36 group are presented in Table 1. Among the two cohorts, factors such as age, ALB, A/G, ALT, AST, ALP, GGT, PT, AFP, CA199, CA125, MTD, gender, hepatolithiasis, HBV carrier, Child-Pugh (A/B), vascular invasion, local invasion, poorly differentiation (PD), TNM staging, and complications grade between the two groups demonstrated no significant difference (p > 0.05), while factors including TBIL, CEA, LMR, SII, NLR, nerve invasion, and blood transfusion between the two groups showed a statistically significant difference (p < 0.05).

The comparison of overall survival and recurrence in all ICC patients between the NLR < 2.36 group and the NLR ≥ 2.36 group is presented in Figure 3. The median overall survival time of 360 ICC patients was 27 months, and the 1-year, 3-year, and 5-year overall survival rates were 74.0, 41.3, and 27.4%, respectively. Among ICC patients with NLR < 2.36, the 1-year, 3-year, and 5-year survival rates were 92.9, 70.7, and 48.2%, respectively; while among ICC patients with NLR ≥ 2.36, the 1-year, 3-year, and 5-year survival rates were 65.1, 27.7, and 18.0%, respectively, showing a statistically significant difference (p < 0.001). The median overall recurrence time was 24 months, and the overall recurrence rates at 1, 3, and 5 years were 24.8, 68.8, and 72.5%, respectively. Among ICC patients with NLR < 2.36, the recurrence rates at 1, 3, and 5 years were 11.1, 45.6, and 59.4%, respectively; while among ICC patients with NLR ≥ 2.36, the recurrence rates at 1, 3, and 5 years were 30.6, 73.3, and 79.1%, respectively, also showing a statistically significant difference (p < 0.001).

The univariable and multivariate regression analyses of the risk factors for mortality within 5 years after surgery in all ICC patients are presented in Table 2. Univariate analysis indicated that the variables related to the overall survival (OS) of ICC patients are as follows: TBIL >17.1 μmol/L, PT > 13 s, CEA > 10 ng/mL, LMR > 3.71, NLR ≥ 2.36, combined with hepatolithiasis, vascular invasion, local invasion, nerve invasion, blood transfusion, PD, and TNM stage-III. Multivariate analysis suggested that the variables associated with the OS of ICC patients are as follows: CEA > 10 ng/mL, NLR ≥ 2.36, local invasion, PD, and TNM stage-III.

The univariable and multivariate regression analyses of the risk factors for neoplasm recurrence within 5 years after surgery in all ICC patients are shown in Table 3. Univariate analysis indicated that the variables related to the recurrence of ICC patients are as follows: ALP > 135 U/L, PT > 13 s, CEA > 10 ng/mL, CA199 > 37 U/mL, LMR > 3.71, NLR ≥ 2.36, MTD > 5 cm, combined with hepatolithiasis, vascular invasion, nerve infiltration, blood transfusion, and TNM stage-III. Multivariate analysis suggested that the variables associated with the recurrence of ICC patients are as follows: ALP > 135 U/L, PT > 13 s, CEA > 10 ng/mL, LMR > 3.71, NLR ≥ 2.36, MTD > 5 cm, vascular invasion, blood transfusion, and TNM stage-III.

The comparison of clinical characteristics in the NHICC group and the HICC group is presented in Supplementary Table S1 in the Supporting Information. Among the two cohorts, factors such as ALB, A/G, ALP, GGT, PT, CA199, NLR, MTD, gender, vascular invasion, local invasion, nerve invasion, and blood transfusion between the two groups exhibited a statistically significant difference (p < 0.05). Similarly, the ICC patients in the NHICC group and the HICC group were classified into the H-NLR group and the L-NLR group based on the NLR cut-off value of 2.36 for further comparative analysis.

The comparison of overall survival and recurrence in the HICC and NHICC groups between the L-NLR group and the H-NLR group is presented in Figure 4. In the HICC group, the median survival time of 151 HICC patients was 27 months, and the 1-, 3-, and 5-year survival rates were 75.6, 37.9, and 29.4%, respectively. The patients in the L-NLR group had a lower 5-year survival rate than those in the H-NLR group (49.3% vs. 12.9%, P<0.001). The median recurrence time was 25 months, and the recurrence rates at 1, 3, and 5 years were 28.1, 65.4, and 71.9%, respectively. The patients in the L-NLR group had a higher 5-year recurrence rate than those in the H-NLR group (46.8% vs. 86.3%, p < 0.001). In the NHICC group, the median survival time of 209 NHICC patients was 26 months, and the 1-, 3-, and 5-year survival rates were 74.0, 32.5, and 25.3%, respectively. The patients in the L-NLR group had a lower 5-year survival rate than those in the H-NLR group (40.8% vs. 21.4%, p < 0.001). The median recurrence time was 24.5 months, and the recurrence rates at 1, 3, and 5 years were 24.8, 68.8, and 72.5%, respectively. There was no significant difference between the two groups (65.8% vs. 67.6%, p = 0.071).

The univariable and multivariate regression analyses of the risk factors for OS and recurrence within 5 years after surgery in HICC patients are presented in Tables 4, 5. Univariate and multivariate analyses indicated that the variables associated with the OS of HICC patients are as follows: PT > 13 s, CEA > 10 ng/mL, LMR > 3.71, NLR ≥ 2.36, blood transfusion, and PD; and the variables related to the recurrence of HICC patients are as follows: PT > 13 s, LMR > 3.71, NLR ≥ 2.36, blood transfusion, and PD.

The univariable and multivariate regression analyses of the risk factors for OS and recurrence within 5 years after surgery in NHICC patients are presented in Tables 6, 7. Univariate and multivariate analyses suggested that the variables associated with the OS of HICC patients are as follows: CEA > 10 ng/mL, NLR ≥ 2.36, PD, and TNM stage-III; and the variables related to the recurrence of NHICC patients are as follows: CEA > 10 ng/mL, vascular invasion, and TNM stage-III.

Multivariate analysis and risk score of postoperative survival and neoplasm recurrence in HICC patients 5 years after surgery are presented in Supplementary Tables S2, S3. Multivariate analysis indicated that the variables associated with the OS of HICC patients are as follows: NLR ≥ 2.36 (HR: 4.791, 95%CI: 3.452–10.002), CEA > 10 ng/mL (HR: 3.356, 95%CI: 2.352–9.683), and blood transfusion (HR: 1.332, 95%CI: 0.731–5.017). The prognosis prediction model based on NLR was obtained by adding the total number of points scored in each of the three independent risk factors. The model was: 5-year mortality risk of HICC = 2.120 * NLR + 2.123 * CEA + 3.305 * blood transfusion - 5.292. Multivariate analysis indicated that the variables associated with the neoplasm recurrence of HICC patients are as follows: NLR ≥ 2.36 (HR: 3.321, 95%CI: 1.343–5.174), PT > 13 s (HR: 1.103, 95%CI: 0.231–3.744), blood transfusion (HR: 1.842, 95%CI: 0.892–3.194), and PD (HR: 2.635, 95%CI: 0.877–7.922), and the model was: 5-year recurrence risk of HICC = 3.378 * NLR + 0.072 * PT + 2.472 * blood transfusion +0.969 *PD - 4.630.

An NLR-based survival/recurrence predictive nomogram is established for HICC patients following curative resection, and its area under the curve (AUC) in the HICC group is shown in Figure 5. It can be seen that NLR shows a higher score in predicting the incidence of 5-year mortality risk of HICC patients, followed by CEA and blood transfusion, and the AUC of the prediction model based on NLR in the HICC group was 0.764, H-L test indicated that p value was 0.359 > 0.05 (Figures 5A,B). The NLR also shows a higher score in predicting the incidence of year recurrence risk of HICC patients, followed by blood transfusion, PD, and PT, and the AUC of the prediction model based on NLR in the HICC group was 0.791, H-L test indicated that p value was 0.680 > 0.05 (Figures 5C,D).

Multivariate analysis and risk score of postoperative survival and neoplasm recurrence in NHICC patients 5 years after surgery are presented in Supplementary Tables S4, S5. Multivariate analysis indicated that the variables associated with the OS of NHICC patients are as follows: NLR ≥ 2.36 (HR: 0.339, 95%CI: 0.177–0.649), CEA > 10 ng/mL (HR: 3.170, 95%CI: 1.617–6.217), and PD (HR: 2.936, 95%CI: 1.063–5.378), and the model was: 5-year mortality risk of NHICC = 1.082*NLR + 1.154*CEA + 1.077*PD - 1.205. Multivariate analysis indicated that the variables associated with the neoplasm recurrence of HICC patients are as follows: NLR ≥ 2.36 (HR: 1.285, 95%CI: 0.665–2.481), CEA > 10 ng/mL (HR: 6.338, 95%CI: 3.151–12.748), vascular invasion (HR: 0.310, 95%CI: 0.155–0.619), and TNM stage-III (HR: 3.214, 95%CI: 1.633–6.326), and the model based on NLR was: 5-year recurrence risk of NHICC = 0.251*NLR + 1.847*CEA + 1.172* vascular invasion +1.168* TNM stage - 1.102.

An NLR-based survival/recurrence predictive nomogram is also established for NHICC patients following curative resection, and its area under the curve (AUC) in the NHICC group is shown in Figure 6. It can be seen that CEA shows a higher score in predicting the incidence of 5-year mortality risk of NHICC patients, followed by NLR and PD, and the AUC of the prediction model based on NLR in the NHICC group was 0.729, H-L test indicated that p value was 0.268 > 0.05 (Figures 6A,B). The CEA also shows a higher score in predicting the incidence of year recurrence risk of NHICC patients, followed by vascular invasion and TNM stage, while the NLR did not present a good score in predicting. The AUC of the prediction model based on NLR in the NHICC group was 0.649, H-L test indicated that p value was 0.01 < 0.05 (Figures 6C,D).