Neutrophil-lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment

Background & Aims: Although the Milan criteria (MC) have been used to select liver transplantation candidates among patients with hepatocellular carcinoma (HCC), many patients exceeding the MC have shown good prognosis. Preoperative neutrophil-lymphocyte ratio (NLR) is a predictor of patient prognosis, but its mechanism has never been clarified. Methods: We assessed outcomes in 158 patients who had undergone living-donor liver transplantation (LDLT) for HCC. Recurrence-free survival (RFS) was determined in patients with high (≥4) and low (<4) NLR. Levels of expression of vascular endothelial growth factor (VEGF), interleukin (IL)-8, IL-17, CD68, and CD163 were measured. Results: The 5-year RFS rate was significantly lower in patients with high (n = 26) than with low (n = 132) NLR (30.3% vs. 89.0%, p <0.0001), in patients with high (n = 15) than with low (n = 79) NLR who met the MC (73.6% vs. 100%, p = 0.0008) and in patients with high (n = 11) than with low (n = 53) NLR who exceeded the MC (0% vs. 76.1%, p = 0.0002). Tumor expression of VEGF, IL8, IL-17, CD68, and CD163 was similar in the high and low NLR groups, but serum and peritumoral IL-17 levels were significantly higher in the high-NLR group (p = 0.01 each). The density of peritumoral CD163 correlated with the density of peritumoral IL-17-producing cells (p = 0.04) and was significantly higher in the high-NLR group (p = 0.005). Conclusions: NLR predicts outcomes after LDLT for HCC via the inflammatory tumor microenvironment. Combined with the MC, NLR may be a new criterion for LDLT candidates with HCC.