As an important part of TNM staging of lung cancer, the eighth edition of the International Association for the Study of Lung Cancer (IASLC) lymph node N-staging for lung cancer has not been adjusted compared with the seventh edition, and is still based on a single anatomical location of metastatic lymph nodes, and there is a non-negligible prognostic heterogeneity in the same N-stage, which urgently needs a more accessible and refined N-staging system to describe the tumor load of the lymph nodes. However, evidence-based evidence for the prognostic significance of the number of metastatic lymph nodes in N staging is currently insufficient.

Recently, Prof. Chang Chen's team from the Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, published an article entitled "The Number of Metastatic Lymph Nodes is More Predictive of Prognosis" in the International Journal of Surgery (IF: 15.3), a renowned surgical journal. The Number of Metastatic Lymph Nodes is More Predictive of Prognosis than Location-based N stage for Non-small Cell Lung Cancer: A retrospective cohort study". The study demonstrated that the number of metastatic lymph nodes is more predictive of prognosis than location-based N stage for Non-small Cell Lung Cancer: A retrospective cohort study. The study demonstrated that the number of metastatic lymph nodes is more predictive of prognosis than location-based N stage for Non-small Cell Lung Cancer: A retrospective cohort study.

Study Design

From January 2009 to December 2013, 4432 patients with NSCLC who underwent radical surgical resection and lymph node dissection that met the TNM staging criteria were retrospectively collected from Shanghai Pulmonary Hospital, Tongji University. The patients' clinical baseline data, imaging information, operative information, lymph node information, recurrence information with clinical regression and prognosis information were collected. External validation was also established by a cohort of 28,022 radical surgical resected NSCLC from SEER data, and the ability of nN staging to differentiate prognosis was assessed by multivariate Cox regression analysis, NRI reclassification improvement analysis, ROC staging and DCA analysis.

Findings

The nN staging cutoffs 1 ~ 3 (N1-3), 4 ~ 6 (N4-6), and >6 (N> 6) (with a maximum c2 value of 73.3 for prognostic discriminatory ability) identified in this study based on the Chinese cohort had the same superior prognostic discriminatory ability in the external validation cohort. In the Chinese cohort, the 5-year RFS of the N0, N1-3, N4-6, and N> 6 subgroups were 75.4%, 36.6%, 21.5%, and 15.6%, respectively, and the 5-year overall survival rates were 80.8%, 50.4%, 36.3%, and 24.5%, respectively, which showed a significant prognostic discriminatory ability; and the multivariate C2 values were corrected for the following factors: baseline clinical condition, surgical modality, pleural infiltration, pathologic T stage, and the presence of adjuvant therapy. After correction for factors, multivariate Cox regression analysis showed that nN staging independently predicted prognosis (all p-values <0.001). Similarly, neighboring nN subgroups in the N1 and N2 populations were also able to better differentiate prognosis, and the differences were statistically significant.

Figure 1: Prognostic differentiation ability of nN staging in China and SEER cohort

In order to compare the prognostic differentiation ability of nN staging with the existing 8th edition N staging, the researchers found that nN staging correctly reclassified more than 10% of the patients in the Chinese cohort compared with the existing 8th edition N staging by NRI analysis using several statistical analysis methods; based on the comparison of the area under the ROC curve in a time-dependent manner, it was found that the nN staging had a significantly better prognostic event prediction ability (5 years), and that nN staging had a better prognostic predictive ability (5 years). RFS and OS, both p-values <0.001). dCA analysis similarly found that nN staging provided higher standardized net benefit. All of these results were validated for stability outside of the SEER cohort, suggesting that the number of metastatic lymph nodes has universal prognostic value in large intercontinental populations.

Figure 2: DCA analysis exploring the standardized net benefit of nN staging compared to 8th edition N staging in the Chinese cohort and SEER cohort

Significance of the Study

This study confirms the prognostic significance and application of nN staging based on the number of metastatic lymph nodes in a large multi-population pan-ethnic cohort. The validation of existing N staging divisions is limited to Asian populations, and the anatomical divisions of lymph nodes per station are not exactly the same in different atlases, leading to prognostic overlap between different subgroups of existing N staging based on anatomical location, which makes it difficult to obtain a better differentiation. The prognostic analysis and validation of a large-sample intercontinental population demonstrated that the prognostic differentiation efficacy of nN staging was significantly better than that of the existing N staging, and suggested that the inclusion of the number of metastatic lymph nodes should be considered in the subsequent update of the TNM, and that its feasibility should be investigated through large-scale validation. It provides important theoretical evidence for the application of nN staging cutoff value setting and subsequent adjustment and refinement of the N staging system.

Link to original article：https://journals.lww.com/international-journal-of-surgery/abstract/9900/the_number_of_metastatic_lymph_nodes_is_more.673.aspx