Prognostic impact of the lymph node yield on survival in patients with stage I lung adenocarcinoma receiving sublobar resection.

INTRODUCTION

It remains controversial regarding the prognostic impact and therapeutic implications for immunotherapy of lymph node yield (LNY) during sublobar resection (SR) on stage I lung adenocarcinoma (LUAD).

METHODS

We analyzed a retrospective cohort of 400 patients with stage I LUAD who underwent SR, with peripheral blood samples prospectively collected for detecting inflammatory cytokines (IFCs). The effect of different LNY (≥4 vs. <4 nodes) on survival and IFC change was evaluated. Consensus clustering analyses were performed using data from The Cancer Genome Atlas (TCGA) and our validation cohort to explore associations between IFCs and immune/cell death profiles. A Bayesian meta-analysis was further conducted to assess the impact of LNY in LUAD undergoing SR.

RESULTS

The survival analysis of our cohort demonstrated that increased LNY during SR did not prolong RFS (≥4 vs. <4 nodes: HR = 1.15; 95%CI: 0.76-1.74). A lower LNY during SR was associated with significantly better RFS in stage I LUAD receiving adjuvant immunochemotherapy (≥4 vs. <4 nodes: HR = 0.41; 95%CI: 0.17-0.94). In terms of IFCs, extensive lymph node dissection led to significantly increased levels of IL-6, IL-4, IL-10 and TNF-α after SR (p < 0.05). Consensus clustering based on the IFCs identified two subgroups (Cluster 1 and 2) in TCGA cohort with distinct immune and cell death profiles, including differences in immunogenic cell death and damage-associated molecular patterns. Cluster 2 exhibited a higher Tumor Immune Dysfunction and Exclusion (TIDE) and tumor mutation burden scores. Similar findings were observed in our validation cohort, where Cluster 2 displayed higher number of neoantigens. The Bayesian meta-analysis also corroborated that increased LNY did not improve RFS (HR = 0.98; 95%CI: 0.20-2.94) in pathological stage I LUAD.

DISCUSSION: Increased LNY during SR might confer no additional benefits to RFS for p-stage I LUAD. Excessive removal of LNs might exert adverse impact on physical sensitivity to immunochemotherapy. Personalized lymph node management should be adopted for selected node-negative disease.