The International Association for the Study of Lung Cancer Staging Project for Lung Cancer: Proposals for the Revision of the N Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer

Abstract

Introduction: The accurate assessment of nodal (N) status is crucial to the management and prognostication of nonmetastatic NSCLC. We sought to determine whether the current N descriptors should be maintained or revised for the upcoming ninth edition of the international TNM lung cancer staging system.

Methods: Data were assembled by the International Association for the Study of Lung Cancer on patients with NSCLC, detailing both clinical and pathologic N status, with information about anatomical location and individual station-level identification. Survival was calculated by the Kaplan-Meier method and prognostic groups were assessed by a Cox regression analysis.

Results: Data for clinical N and pathologic N status were available in 45,032 and 35,009 patients, respectively. The current N0 to N3 descriptors for both clinical N and pathologic N categories reflect prognostically distinct groups. Furthermore, single-station N2 involvement (N2a) exhibited a better prognosis than multistation N2 involvement (N2b) in both clinical and pathologic classifications, and the differences between all neighboring nodal subcategories were highly significant. The prognostic differences between N2a and N2b were robust and consistent across resection status, histologic type, T category, and geographic region.

Conclusions: The current N descriptors should be maintained, with the addition of new subdescriptors to N2 for single-station involvement (N2a) and multiple-station involvement (N2b).

Keywords: Lung cancer; Lung cancer staging; Lymph node metastasis; N component; N descriptors; TNM classification.

Figure 1.

CONSORT diagram of analyzed patients. a - 35,373 patients excluded due to M1 disease b - 5,388 patients excluded due to having documentation on pathological but not clinical stage c - 6,950 patients excluded due to having documentation on clinical but not pathological stage d - 1,250 patients excluded due to missing cN category; cNX; cN0 with positive stations; cN1 with positive N2 stations; cN2 with positive N3 stations or no positive N2 station identified; or bilateral disease e - 9,711 patients excluded due to neoadjuvant treatment; not having at least one sampling result; missing pN category; pNX; pN0 with positive stations; pN1 with positive N2 stations; pN2 with positive N3 stations or no positive pN2 station identified or bilateral primary or side not specified f - 42,480 patients excluded due to no neoadjuvant treatment; not having at least one sampling result; missing ypN category; ypNX; ypN0 with positive stations; ypN1 with positive N2 stations; ypN2 with positive N3 stations or no positive ypN2 station identified or bilateral primary or side not specified

Figure 2.

Overall survival by (a) clinical N categories, and (b) pathologic N categories (9th edition data, by current 8th edition N classification)

Figure 3.

Exploratory analysis of overall survival incorporating the number of positive lymph node stations as suggested by Asamura et al, by (a) clinical N categories and (b) pathologic N categories

Figure 4.

Proposed simplified classification incorporating only the number of ipsilateral mediastinal lymph node stations with metastasis (N2); overall survival by (a) clinical N categories, and (b) pathologic N categories

Figure 5.

Comparison of current (8th edition) to proposed 9th edition N categories; (a1 and a2) overall survival by clinical N categories, and (b1 and b2) pathologic N categories

Figure 6.

Validation analyses comparing 8th edition to proposed 9th edition N categories with respect to completeness of resection; overall survival by pathologic N categories (a) R0 resection, and (b) R-any

Figure 7.

Validation analyses comparing 8th edition to proposed 9th edition N categories with respect to histologic type; overall survival by clinical N categories (a) squamous, and (b) non-squamous

Figure 8.

Validation analysis of proposed 9th edition N categories stratified according to T categories; overall survival by clinical N categories

Figure 9.

Validation analysis of proposed 9th edition N categories by geographic region; overall survival by clinical N categories

Figure 10.

Validation analysis analyses comparing 8th edition to proposed 9th edition N categories using previous 8th edition dataset; overall survival by pathologic N categories

Figure 11.

Validation analysis comparing 8th edition to proposed 9th edition N categories in post-neoadjuvant therapy patients (ypN); overall survival by pathologic N categories.

Figure 12.

Overall survival by 8th edition pathologic N categories in (a) post-neoadjuvant therapy patients (ypN), and (b) upfront surgery patients (pN)