Negative Lymph Node Count Is Associated With Survival of Colorectal Cancer Patients, Independent of Tumoral Molecular Alterations and Lymphocytic Reaction

OBJECTIVES: The number of recovered lymph nodes is associated with good prognosis among colon cancer patients undergoing surgical resection. However, little has been known on prognostic significance of lymph node count after adjusting for host immune response to tumor and tumoral molecular alterations, both of which are associated with the lymph node count and patient survival. METHODS: Among 716 colorectal cancers (stages 1-4) in two independent prospective cohorts, we examined patient survival in relation to the negative lymph node count and lymph node ratio (LNR; positive to total lymph node counts). Cox proportional hazard models were used to compute hazard ratio of deaths, adjusted for patient, specimen, and tumoral characteristics, including lymphocytic reactions, KRAS and BRAF mutations, p53 expression, microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), and LINE-1 methylation. RESULTS: Compared with patients with 0-3 negative lymph nodes, patients with 7-12 and >= 13 negative nodes experienced a significant reduction in cancer-specific and overall mortality in Kaplan-Meier analysis (log-rank P < 0.0001), univariate Cox regression (P trend < 0.0001), and multivariate analysis (P trend < 0.0003), independent of potential confounders examined. The benefit associated with the negative node count was apparent across all stages, although the effect was significantly greater in stages 1-2 than stages 3-4 (P(interaction) = 0.002). In both stage 3 and stage 4, smaller LNR was associated with improved survival (log-rank P < 0.0001). CONCLUSIONS: The negative lymph node count is associated with improved survival of colorectal cancer patients, independent of lymphocytic reactions to tumor and tumoral molecular features including MSI, CIMP, LINE-1 hypomethylation and BRAF mutation.