Peripheral blood neutrophil-to-lymphocyte ratio in NK/T-cell lymphoma - prognostic significance and correlation with tumor transcriptomic profiles

Abstract

Background: Extranodal NK/T-cell lymphoma, nasal type (NKTCL) is an aggressive Epstein- Barr Virus-associated lymphoproliferative malignancy typified by local immune cell infiltration and variable states of systemic inflammation. This study aims to investigate the clinical relevance of peripheral blood neutrophil-lymphocyte ratio (NLR) in patients with NKTCL. Methods: Retrospective review of patients with histologically-proven NKTCL and available blood counts at diagnosis (1993-2016) from the National Cancer Centre Singapore and Samsung Medical Center, South Korea was completed. An optimal cutoff for high NLR (>3.5) in predicting overall survival (OS) was determined using receiver operating curve analysis. Survival analysis was performed using the Kaplan-Meier method and multivariate Cox proportional models. Gene expression profiling was performed for each subgroup (n = 4 per group). NLR-associated signaling pathways were explored with gene set enrichment analysis (GSEA) using the MSigDB Hallmark gene set. Results: The median age at diagnosis was 54 years (range, 17-86), with a male preponderance (70.8%). Median NLR was 2.6 (range, 0.7-24.5) and 59 patients (33.1%) possessed high NLR. High NLR was associated with advanced age ≥60 (p = 0.032), ECOG score ≥2 (p = 0.0025), elevation of lactate dehydrogenase (p = 0.02) and IPI score 3-4 (p = 0.014). Estimated 5-year OS was 53% in patients with low NLR and 25% in those with high NLR. In multivariate analysis, high NLR, in addition to B-symptoms and advanced stage, were independently associated with both worse overall survival (HR 2.08; 95% CI 1.36 to 3.18; p = 0.0008) and progression-free survival (HR 1.66; 95% CI 1.11 to 2.46; p = 0.0128). In subgroup analysis, the prognostic ability of NLR on OS was observed in both Singapore an (p = 0.0072) and Korean (p = 0.031) cohorts. GSEA suggests that high NLR is associated with tumors harboring upregulated DNA repair genes including POLD3 and ERCC2 (false discovery rate, 0.137; p < 0.001). Conclusions: High NLR is correlated with distinct tumor transcriptomic profiles in NKTCL and is an independent marker of poor survival outcomes.