Unveiling the prognostic role of blood inflammatory indexes in a retrospective cohort of patients undergoing liver resection for intrahepatic cholangiocarcinoma

Abstract

Background: Systemic inflammation is relevant in intrahepatic cholangiocarcinoma (iCCA), but controversial results exist on the prognostic role of inflammatory indexes and their correlation with tumor microenvironment. The authors aimed to explore the biological and prognostic values of these indexes.

Materials and methods: A retrospective cohort study involving iCCA patients who underwent hepatic resection between 2010 and 2021 was conducted. The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and clinic-pathological factors were recorded. Immune-cell subpopulations, isolated from surgical specimens, were analyzed by flow cytometry. NLR and LMR cut-offs were calculated by X-Tile software. Linear regression, Kaplan-Meier, and Cox regression analyses were conducted.

Results: A total of 101 iCCA patients were considered. NLR ≥3.83 and LMR <2.28 correlated with worse survival. Patients were divided into groups: 67 (66.3%) in the low-risk and 34 (33.7%) in the high-risk (having at least one worse prognostic ratio). The 5-year overall survival was 49.8 and 18.9% for low- and high-risk groups, respectively ( P =0.003). An elevated CA19-9 in the high-risk group gives 2.148 HR (95% CI: 1.060-4.349) of mortality and 2.182 HR (95% CI: 1.206-3.948) of disease recurrence. Flow cytometry analysis of 20 surgical specimens highlighted that NLR was associated with tumor-derived NLR ( P =0.026) and LMR with tumor-infiltrating lymphocytes ( P =0.002). In a subset of five high-risk vs five low-risk patients, T-cell evaluation showed a higher prevalence of CD4+ compared to CD8+ cells in the high-risk group (78.5 vs. 21.5%, P <0.0001). Conversely, low-risk patients demonstrated a noteworthy infiltration of CD8+ cells compared to the high-risk group (21.5 vs. 48.7%, P =0.037).

Conclusions: The combination of blood inflammatory indexes determined two survival-risk profiles. The correlation between the blood scores and the iCCA microenvironment suggests a link between immune-cell infiltration and the risk group. These findings open the possibility of patient stratification with the chance to identify subgroups suitable for dedicated follow-up and targeted immuno-chemotherapy protocols.

Graphical abstract

Figure 1

Survival of the analyzed cohort according to the risk score. A) Overall survival and disease-free survival comparisons between the high-risk and the low-risk score populations. B) Overall survival and disease-free survival comparisons between high-risk and CA19-9pos versus reference group.

Figure 2

T cell subpopulation analysis of iCCA high-risk and low-risk patients. A) Immunohistochemistry (IHC) analysis and graphical representation of CD4+ and CD8+ cells in iCCA high-risk and low-risk patients. Scale bar 50 μm. B) Percentage of infiltrating T cell subpopulations in iCCA high-risk (n=5) and low-risk (n=5) patients. Two-way ANOVA (mean±SEM). *P<0.05; ****P<0.0001.