The IASLC Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming 9th 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 non-metastatic non-small cell lung cancer. We sought to determine whether the current N descriptors should be maintained or revised for the upcoming 9^th edition of the international Tumor Node Metastasis (TNM) lung cancer staging system.

Methods:

Data was assembled by the International Association for the Study of Lung Cancer on patients with non-small cell lung cancer, detailing both clinical and pathologic N status, with information about anatomic 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 demonstrated prognostically distinct groups. Furthermore, single station N2 involvement (N2a) demonstrated 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 sub-descriptors to N2 for single station involvement (N2a) and multiple station involvement (N2b).

INTRODUCTION

Cancer staging provides a standardized classification system with which to describe the anatomic extent of a malignancy and can serve as a common language for discussing treatment and prognosis. Staging is composed of three components: tumor (T), nodal involvement (N), and metastasis to distant sites (M). The TNM classification has been adopted by both the Union for International Cancer Control and the American Joint Committee on Cancer with periodic revision to account for new data.

Since the 7^th edition of the TNM staging system for lung cancer, revisions have been supported by data assembled by the International Association for the Study of Lung Cancer (IASLC). The IASLC’s Staging and Prognostic Factors Committee (SPFC) developed a large, independent, high-quality, international, multi-institutional database of lung cancer cases from which, in partnership with Cancer Research And Biostatistics (CRAB) in Seattle, rigorous statistical analysis is used to inform proposals for revising the staging classification for lung cancer.¹

The N component in lung cancer has historically been categorized on the basis of anatomic location and does not include the quantification of involved lymph nodes. Since the 4^th edition of the staging system, in 1987, the N component has been categorized as N0 (no nodes involved), N1 (ipsilateral peribronchial, hilar, interlobar, and/or intrapulmonary lymph node involvement), N2 (ipsilateral mediastinal and/or subcarinal node involvement), or N3 (contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular node involvement).² Exploratory analyses performed for the 7^th and 8^th editions suggested that the burden of nodal metastases at the hilar and mediastinal levels is associated with prognosis.^{3, 4} However, data and sample size limitations precluded validation of these findings, and no changes to the N categories were made. Further study was recommended to investigate the potential of introducing a subclassification that integrates single- versus multiple-station involvement: N1a (single), N1b (multiple), N2a1 (single N2 without N1 involvement, or “skip” metastasis), N2a2 (single N2 with N1 involvement), and N2b (multiple ipsilateral mediastinal nodal involvement).³

In preparation for the 9^th edition analysis, the SPFC proposed principles to guide the revision of the TNM classification, which the N-Descriptors Sub-committee tailored for the purpose of revising the nodal classification.^{5, 6} Prior data limitations prompted a call to redouble efforts to collect data with greater detail.⁷ In this study for the 9^th edition of the staging system, we sought to validate the current N classification, and determine whether alternative classifications, including revisions of the categories to include a measure of the burden of nodal metastasis, were warranted.

METHODS

Study design

The target population for the overarching staging project included patients with histologically proven lung cancer diagnosed between 2011 and 2019, with extent of disease classified according to the AJCC/UICC 8^th edition TNM system. The analysis of the N categories was limited to patients with stage 0-IIIC non-small cell lung cancer, based on either clinical or pathological findings.

Patients were enrolled retrospectively. Each participating institution was required to obtain institutional review board (IRB) approval and sign a Data Use Agreement in order to share limited or de-identified data. Generally, individual informed consent was waived due to the retrospective nature of the project. Data entry via the Electronic Data Capture (EDC) system designed by CRAB was the preferred method of data submission; alternatively, the transfer of external institutional data, termed “batch” data, was permitted. Full details about the database were recently published.⁸

Data screening

Successful data submission via the EDC system required a perfect match between the N category and the presence and location of positive stations, as well as a complete record of sampling results from resection, if attempted. For the batch data sets, patients with reported N2 disease were excluded if no individual N2 stations were identified as positive to allow confirmation of their nodal status. In analyses examining the number of positive stations in patients with reported N1 disease, patients were excluded if the specific positive stations were not identified. A least one sampling result was required for pathologic N category analysis.

Definitions

Clinical N descriptors were defined by nodal status on the basis of radiographic imaging or histologically via invasive sampling. Pathologic N descriptors were defined by nodal status based on pathologic review of surgical specimens in patients who had surgical treatment for their lung cancer. Lymph node stations were designated according to the IASLC lymph node map.⁹ Patients who received neoadjuvant therapy were excluded from the primary analysis of pathologic stage (but were included in the clinical stage analysis), and were analysed in a separate post-treatment pathologic (yp) stage analysis.

Statistical analysis

The primary endpoint was overall survival, measured from the date of diagnosis for clinical staging and the date of surgery for pathological staging. After screening for eligibility and data completeness, survival between N categories was explored graphically by the Kaplan-Meier method. Reproducibility of findings was assessed further in subgroup analyses including resection status, histologic type, T category, geographic region, and receipt of neoadjuvant therapy. Findings were further validated by replication of the analysis in the 8^th edition dataset.

Generally, differences of less than 5% between five-year survival estimates were not considered clinically meaningful. Initially, pairwise differences in survival between adjacent N categories were tested for statistical significance using the log rank test within the SAS System for Windows Version 9.4 LIFETEST procedure. Contrasts between proposed N categories were further assessed after adjusting for sex, age, history of prior malignancy, geographic region, completeness of resection (for pathologically staged tumors), and histologic type in multivariable Cox proportional hazard models of survival, using the SAS System for Windows Version 9.4 PHREG procedure.

RESULTS

Of 87,043 patients meeting the project’s eligibility criteria, 51,670 patients with 8^th edition clinical or pathologic stage 0-IIIC non-small cell lung cancer met the inclusion criteria for the analysis of the N categories. Patient selection is demonstrated in the CONSORT diagram in Figure 1. Most patients were treated in Asia, North America, and Europe, with smaller cohorts from Australia, South America, and Africa (grouped collectively as Rest of World). Patients were almost evenly split between male and female, with a median age of 66 years. Tumor resection was attempted in the majority (92%) of the patients studied (Table 1a). Other details of the full 9^th edition database have been previously reported.⁸

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

Table 1a.

Patient characteristics, all staged tumors

	Total (N=51,670)
Region, n (%)
Asia	34219 (66.2%)
North America	8344 (16.1%)
Europe	7855 (15.2%)
Rest of World	1252 (2.4%)
Sex, n (%)
Female	25840 (50.0%)
Male	25828 (50.0%)
No data	2
Age at diagnosis
N	51594
Mean (SD)	65.5 (10.29)
Median	66
Range	18, 100
Histopathologic type, n (%)
Adenocarcinoma in situ	1082 (2.1%)
Adenocarcinoma	36493 (70.6%)
Adenosquamous	850 (1.6%)
Large cell	683 (1.3%)
Squamous	11894 (23.0%)
NSCLC not otherwise specified	668 (1.3%)
History of Prior Malignancy, n (%)
No (includes no data)	45079 (87.2%)
Yes	6591 (12.8%)
Resection attempted, n (%)
No	4072 (8.0%)
Yes	46986 (92.0%)
No data	612

For the 45,032 patients with clinically staged tumors (Table 1b), five-year survival according to the 8^th edition N categories were 76% (N0), 52% (N1), 38% (N2), and 25% (N3) by clinical N (Figure 2a). Five percent of the 36,889 patients with pathologically staged tumors had neoadjuvant therapy. For the remaining 35,009 patients who had primary surgical resection (Table 1c), five-year survival by pathologic N was 83% (N0), 58% (N1), 47% (N2), and 28% (N3) (Figure 2b). All differences in survival between 8^th edition cN and pN categories were highly statistically significant (p<0.0001) (Table 2a).

Table 1b.

Patient characteristics, clinically staged tumors

	Total (N=45,032)
Clinical Stage, n (%)
0	1,168 (2.6%)
I	3,156 (7.0%)
IA	19,936 (44.3%)
IB	5,624 (12.5%)
IIA	2,554 (5.7%)
IIB	4,749 (10.5%)
III	914 (2.0%)
IIIA	4,215 (9.4%)
IIIB	1,776 (3.9%)
IIIC	735 (1.6%)
Occult	205 (0.5%)
cT, n (%)
Tis/T0	1,169 (2.6%)
T1mi	984 (2.2%)
T1	23,852 (53.0%)
T2	10,522 (23.4%)
T3	4,344 (9.6%)
T4	3,043 (6.8%)
TX/No data	1,118 (2.5%)

Figure 2.

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

Table 1c.

Patient characteristics, pathologically staged tumors

	Total (N=36,889)
Pathological Stage, n (%)
0	159 (0.4%)
I	7,228 (19.6%)
IA	8,572 (23.2%)
IB	7,011 (19.0%)
IIA	1,405 (3.8%)
IIB	5,249 (14.2%)
III	4 (0.0%)
IIIA	5,745 (15.6%)
IIIB	1,381 (3.7%)
IIIC	65 (0.2%)
Occult	70 (0.2%)
pT, n (%)
Tis/T0	159 (0.4%)
T1mi	334 (0.9%)
T1	17,989 (48.8%)
T2	13,218 (35.8%)
T3	3,426 (9.3%)
T4	1,689 (4.6%)
TX/No data	74 (0.2%)
Neoadjuvant therapy, n (%)
No	35,009 (94.9%)
Yes	1,880 (5.1%)
Completeness of Resection, n (%)
R0	35,280 (95.6%)
R1	960 (2.6%)
R2	138 (0.4%)
No data	511 (1.4%)

Table 2.

Comparisons of overall survival between N Categories as defined (a) In the 8th edition, (b) as proposed by Asamura et al³, and (c) as proposed for the 9th edition N component

a)

comparison	cN	pN
	pvalue	pvalue
N1 vs N0	<0.0001	<0.0001
N2 vs N1	<0.0001	<0.0001
N3 vs N2	<0.0001	<0.0001

b)

comparison	cN	pN
	pvalue	pvalue
N1a vs N0	<0.0001	<0.0001
N1b vs N1a	0.8443	0.0088
N2a1 vs N1b	0.0508	0.4437
N2a2 vs N2a1	0.0036	0.0092
N2b vs N2a2	0.0064	<0.0001
N3 vs N2b	<0.0001	0.0042

c)

comparison	cN	pN
	pvalue	pvalue
N1 vs N0	<0.0001	<0.0001
N2a vs N1	<0.0001	<0.0001
N2b vs N2a	<0.0001	<0.0001
N3 vs N2b	<0.0001	0.0042

Exploratory analysis of the subclassification incorporating the number of positive lymph node stations as previously proposed [N1a (single), N1b (multiple), N2a1 (single N2 without N1 involvement, or “skip” metastasis), N2a2 (single N2 with N1 involvement), and N2b (multiple ipsilateral mediastinal nodal involvement)³ did not show a clear separation between each of the individual subcategories consistently across clinical and pathologic stage (Figure 3). In contrast to the 8^th edition analysis (Table 2a), the differences between the proposed N subcategories did not all meet statistical significance (Table 2b). In particular, the differences between the individual N1 subcategories and between the N1 subcategories and N2a1 (“skip metastases”) were small, statistically non-significant, and inconsistent across both clinical and pathologic staging. The differences between N2 subcategories however, were more pronounced, and were statistically significant (Table 2b).

Figure 3.

Exploratory analysis of overall survival incorporating the number of positive lymph node stations as suggested by Asamura et al³, by (a) clinical N categories and (b) pathologic N categories

Limiting the proposed changes to only subdividing N2 into single versus multiple station involvement resulted in a much cleaner separation of all subgroups. This definition is a simplified version of the 2015 exploratory proposal, removing the dichotomization of N1 into N1a vs N1b and N2a into N2a1 vs N2a2, but preserving N2b as distinct from N2a. In particular, there was a clear separation between single station N2 (N2a) and multiple station N2 (N2b) (Figure 4). The separation was consistent across both clinical and pathologic staging, and the differences between each of the subcategories in this modified proposal were statistically significant at every level (Table 2c).

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

This proposed change to the N category for the 9^th edition of the TNM staging system for lung cancer is summarized in Table 3 and is compared against the 8^th edition classification in Figure 5. Analysis of this modified proposal by Cox proportional hazards modeling demonstrated highly significant differences between the proposed subcategories with hazard ratios ranging between 1.27–2.40, after adjusting for age, sex, histologic type, history of prior malignancy, geographic region, and completeness of resection (in pathologic staging). These findings were consistent across both clinical and pathologic staging (Table 4).

Table 3.

Proposed N categories and descriptor

8th	9th
NX		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N1		Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
N2		Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
	N2a	Single N2 station involvement
	N2b	Multiple N2 station involvement
N3		Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph node(s)

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

Table 4.

Adjusted hazard ratios comparing overall survival between proposed 9th edition N categories, based on a Cox proportional hazards model with covariates of proposed 9th edition N category, sex, age, histologic type, history of prior malignancy, geographical region, and completeness of resection (for pathologically staged tumors)

	cN (44,309 patients)		pN (34,342 patients)
	HR (95% CI)	P-value	HR (95% CI)	P-value
N1 vs N0	1.96 (1.84, 2.08)	<0.0001	2.40 (2.26, 2.55)	<0.0001
N2a vs N1	1.42 (1.28, 1.56)	<0.0001	1.45 (1.31, 1.60)	<0.0001
N2b vs N2a	1.27 (1.13, 1.43)	<0.0001	1.46 (1.32, 1.62)	<0.0001
N3 vs N2b	1.51 (1.35, 1.70)	<0.0001	1.62 (1.29, 2.03)	<0.0001

HR- Hazard Ratio, 95% CI- 95% Confidence Interval, P-value from Score chi-quare test in Cox regression model

We performed additional sensitivity analyses to further test the robustness of this proposed classification across different subgroups. Comparisons between the proposed 9^th edition N categories and the 8^th edition categories are shown for completeness of resection (Figure 6), histologic type (Figure 7), T category (Figure 8), and geographic region (Figure 9). The differences between N2a and N2b were consistently observed across each of those subgroups. The ordering of survival outcomes (i.e. survival of N2a > N2b) was also consistent across each of those subgroups. Furthermore, the findings were consistent in the 8^th edition dataset (Figure 10).

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

Although previous staging analyses excluded patients who received neoadjuvant therapy, we evaluated the proposed change in this subset of patients. The proposed 9th edition N categories maintained its prognostic discriminatory capacity in patients who received neoadjuvant therapy, including a robust difference between single versus multiple station ypN2 (Figure 11). Finally, we compared patients in the dataset who received neoadjuvant therapy versus primary surgical resection (Figure 12). The outcomes of matched ypN vs. pN categories (e.g., ypN0 vs. pN0) differed considerably, despite ostensibly similar nodal status on pathologic examination.

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)

DISCUSSION

In this analysis for the 9^th edition of the staging system for non-small cell lung cancer, the major findings were 1) validation of the 8^th edition categories for the N component (N0, N1, N2, N3) in both clinical and pathologic classifications, and 2) the identification of clearly distinct and consistent discrimination of subgroups in patients with N2 disease- i.e., between single station involvement (N2a), and multiple station involvement (N2b).

In preparing for this analysis, this subcommittee laid out the key clinical questions and current gaps in knowledge and enumerated the process considerations and adoption criteria to provide a framework for the present analysis for the 9^th edition.⁶ The N-category descriptors have remained unchanged since 1987 with the 4^th edition, and their discriminatory ability was again validated in the 9^th edition dataset. However, there is a long-held belief that the nodal staging system for lung cancer insufficiently accounts for the burden of disease, which is prognostic in many other solid malignancies.¹⁰ For example, there is no distinction within the staging system currently between unexpected pathologic nodal metastasis in a single paratracheal node and enlarged involved nodes in multiple ipsilateral mediastinal stations. Both would fall under the same prognostic N category.

This concept of disease quantification was explored in the 7^th edition analysis, by examining the prognostic impact of the number of involved lymph node zones, single versus multiple, at the N1 and N2 levels. The concept of lymph node zones was an expediency to reconcile then-existing discrepancies between the Naruke lymph node map and the Mountain-Dresler modification of the American Thoracic Society map (MD-ATS).⁴ Despite hints of prognostic differences, sample size limitations precluded validation across each T category, therefore no change was recommended.

Quantifying nodal disease burden was re-examined in the 8^th edition analysis by stratifying according to the number of involved lymph node stations, single versus multiple, along with delineation of “skip” metastases- a single positive N2 nodal station in the absence of positive N1 nodes. Although prognostic in pathologic staging, this finding could not be validated in clinical staging. Furthermore, most cases with sufficient station-level detail came from only one country – Japan. Given these limitations, a proposal was made to re-examine the descriptors pN0, pN1a, pN1b, pN2a1 (skip metastasis), pN2a2, pN2b in a more robust dataset.⁸ In the new 9^th edition dataset, there was a fair amount of overlap between the survival curves, and a lack of clear separation between the subcategories, with the differences in 5-year survival generally less than the 5% threshold. The skip metastases group (pN2a1) increased the complexity of staging and reduced the sample size in each subgroup. That proposal did not result in clearly separate prognostic groups in either clinical or pathologic staging (Figure 3).

However, when consolidated into the simpler single versus multiple station metastasis (without a separate skip metastasis subgroup), there was much clearer separation at the N2 level in both clinical and pathologic staging (Figure 4). With minimal difference (<5%) in 5-year survival between N1a and N1b (Figure 3), retaining a single N1 level allowed for a much clearer prognostic separation between all subgroups, in both clinical and pathologic staging (Figure 4). Compared with the 8^th edition classification, this modification preserved distinct subgroups, while recognizing the impact of disease burden at the N2 level (Figure 5). The differences between single station N2 and multistation N2 were consistent across histologic type, resection status, geographic region, and T category (Figures 6–9). Finally, this difference was observed when the analysis was performed on the 8^th edition dataset (Figure 10). The proposed change meets our a priori defined criteria for robustness, consistency across different cohorts, validation in both clinical and pathologic staging, and statistical significance.^5,6

This analysis benefited greatly from experience with analyses of the prior editions, a uniform lymph node map, support from the global lung cancer community, adoption of the web-based EDC system which greatly improved the uniformity, accuracy and completeness of data collection, resulting in more than 8000 evaluable node-positive patients, compared to approximately 3000 patients in the 7^th and 8^th edition analyses. The proposed change to split N2 into subsets makes clinical sense and reflects the realities of contemporary clinical practice. Unlike N1 stations which are difficult to distinguish in clinical staging procedures, N2 nodes are readily distinguished in radiologic and invasive clinical staging procedures. Separating the N2 category into single versus multiple stations aligns with long-standing clinical perception that single station N2 disease has a better prognosis.

We elected to use lymph node stations, rather than lymph nodes, as the base unit for quantification because enumeration of lymph nodes is less reliable. Lymph nodes with metastasis cannot be precisely counted on radiologic studies, rendering it infeasible for use in clinical staging. The variability introduced by the extent of the nodal dissection, fragmentation of nodes, and specimen handling call into question the accuracy of any pathologic lymph node counts.¹¹ Other proposed variables, such as nodal size and extracapsular extension, were also not feasible at this time. Analyses by zones consistently demonstrated similar results to analysis according to stations (data not shown). As there were no clear differences between station-level and zone-level analyses, the unfamiliarity of clinicians with lymph node zones meant that adoption of a zone-based classification would have imposed a major shift in conceptualizing lymph node staging. We felt this would be unnecessarily disruptive and potentially confusing, which could impair adoption of the revisions.

Recipients of neoadjuvant therapy were historically excluded from the pathologic stage analysis because of fear of confounding by treatment effect. While this exclusion may provide a more homogeneous study population whose pathologic status is unaffected by prior treatment, the resultant gap in representativeness limits our ability to prognosticate for these patients, who typically have more locally advanced disease. Patients who underwent primary resection in the pathologic stage analyses may differ from those who were selected for neoadjuvant therapy. They may have had a lesser burden of disease or even occult nodal disease, or the disparities may arise from differing regional or institutional practice patterns.

Nevertheless, the proposed system of subdividing N2 into single versus multiple station involvement performed consistently well, even in the neoadjuvant setting (Figure 11). However, stage for stage, ypN category does not appear to match pN category in terms of prognosis (Figure 12). Patients who received neoadjuvant therapy and had negative nodes at resection (ypN0) do not appear to have similar survival to those who were pN0 at upfront resection. With the emergence of immunotherapy and the rapid evolution into neoadjuvant chemoimmunotherapy paradigms such as CheckMate 816¹² and others on the horizon, attention to patients receiving neoadjuvant therapy will become even more important.

A system that has stood the test of time must not be blithely abandoned. Important questions to consider before implementing any changes include: How readily will the change be accepted? Will it be too confusing? Will it disrupt clinical practice? Are there problems with backwards compatibility with past staging systems? Will it confound eligibility criteria and treatment indications for patients who have been managed according to the 8^th edition classification? Most importantly does the proposed change provide a meaningful improvement? What implications will this have for clinicians in the routine care of patients? It will probably require greater precision from radiologists, practitioners of invasive staging procedures, surgeons and pathologists in providing sufficient information to distinguish between single station N2 metastasis and multi-station N2 metastasis. However, this practice change, which in itself is associated with better care delivery and improved patient outcomes, should be reasonably easy to adopt.

This proposal addresses the long-perceived shortcomings of a classification system for N staging purely based on anatomic location and provides a robust and clinically relevant mechanism for integrating a measure of disease burden into the location-alone based system. We propose two distinct N2 cohorts to better reflect the heterogeneity of N2 disease. The survival differences between these subgroups are robust and consistent across clinical and pathologic classifications, the change can be easily understood, is backwards compatible, and clinically relevant. The alternative would be to retain the 8^th edition N staging system. We deemed the strength of the data demonstrating a clear and consistent separation between single and multiple N2 nodal metastases too compelling to ignore. N2a and N2b clearly identify prognostically distinct groups of tumors.

In summary, regarding the N component for the 9^th edition of the TNM classification of lung cancer, the IASLC Staging and Prognostic Factors Committee recommends that the previous N0, N1, N2, N3 descriptors be carried forward, with the addition of new sub-descriptors to N2 for single station involvement (N2a), and multiple station involvement (N2b).

APPENDIX 1. IASLC Staging and Prognostic Factors Committee:

Hisao Asamura (chair), Keio University, Tokyo, Japan; Valerie Rusch (chair elect) Memorial Sloan Kettering Cancer Center, New York, New York, USA; Ramón Rami-Porta (past chair), Hospital Universitari Mutua Terrassa, Terrassa, Spain; Luiz Henrique Araujo, Brazilian National Cancer Institute, Rio de Janeiro, Brazil; David Beer, University of Michigan, Ann Arbor, Michigan, USA; Pietro Bertoglio, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy; Ricardo Beyruti, University of São Paulo Medical School, Sao Paolo, Brazil; Andrea Bille, Guy’s Hospital, London, United Kingdom; Souheil Boubia, Department of Thoracic surgery, University Hospital Ibn Rochd, Laboratoire de Pathologie Cellulaire et Moléculaire Hassan II University of Casablanca, Casablanca, Morocco; Elisabeth Brambilla, Centre Hospitalier Universitaire, Grenoble, France, University of Grenoble Alpes, Grenoble, France; A. K. Cangir, Ankara University Faculty of Medicine, Ankara, Turkey; David Carbone, The Ohio State University, Columbus, Ohio, USA; Vanessa Cilento, Cancer Research And Biostatistics, Seattle, Washington, USA; Casey Connolly, IASLC, Denver, Colorado, USA; Gail Darling, University of Toronto, Toronto, Canada; Frank Detterbeck, Yale University School of Medicine, New Haven, Connecticut, USA; Daniel Dibaba, Cancer Research And Biostatistics, Seattle, Washington, USA; Xavier Benoit D’Journo, Aix-Marseille University, Marseille, France; Jessica Donington, University of Chicago, Chicago, Illinois, USA; Wilfried Eberhardt, West German Cancer Centre, University Hospital Essen, Essen, Germany; John Edwards, Northern General Hospital, Sheffield, United Kingdom; Megan Eisele, Cancer Research And Biostatistics, Seattle, Washington, USA; Jeremy Erasmus, M. D. Anderson Cancer Center, Houston, Texas, USA; Wentao Fang, Department of Thoracic Surgery, Shanghai Chest Hospital, Jiaotong University Medical School, Shanghai, People’s Republic of China; Dean Fennell, Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester and University Hospital of Leicester National Health Service Trust, Leicester, United Kingdom; Kwun Fong, University of Queensland Thoracic Research Centre, Brisbane, Australia; Françoise Galateau-Salle, Centre Hospitalier Universitaire, Caen, France; Oliver Gautschi, Cancer Center, Cantonal Hospital Lucerne, Lucerne, Switzerland; Ritu R. Gill, Beth Israel Lahey Health, Boston, Massachussetts, USA; Dorothy Giroux, Cancer Research And Biostatistics, Seattle, Washington, USA; Meredith Giuliani, The Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada; Department of Otolaryngology - Head and Neck Surgery, The University of Toronto, Toronto, Ontario, Canada; Jin Mo Goo, Seoul National University, Seoul, Republic of Korea; Seiki Hasegawa, Hyogo College of Medicine, Nishinomiya, Japan; Emily Goren, Cancer Research And Biostatistics, Seattle, Washington, USA; Fred Hirsch, Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Health System, New York, New York, USA; Antje Hoering, Cancer Research And Biostatistics, Seattle, Washington, USA; Hans Hoffman, Technical University of Munich, Munich, Germany; Wayne Hofstetter, M. D. Anderson Cancer Center, Houston, Texas, USA; James Huang, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Philippe Joubert, Quebec Heart and Lung Institute, Quebec, Canada; Kemp H. Kernstine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA; Keith Kerr, University of Aberdeen, School of Medicine and Dentistry, Aberdeen, United Kingdom; Young Tae Kim, Seoul National University, Seoul, Republic of Korea; Hong Kwan Kim, Samsung Medical Center, Seoul, Republic of Korea; Hedy Kindler, The University of Chicago Medical Center, Chicago, Illinois, USA; Yolande Lievens, Radiation Oncology department, Ghent University Hospital and Ghent University, Ghent, Belgium; Hui Liu, Sun Yat-Sen University Cancer Center, Guangdong Sheng, People’s Republic of China; Donald E Low, Virginia Mason Medical Center, Seattle, Washington, USA; Gustavo Lyons, Buenos Aires British Hospital, Buenos Aires, Argentina; Heber MacMahon, University of Chicago, Chicago, Illinois, USA; Alyson Mahar, School of Nursing, Queen’s University, Ontario, Canada; Mirella Marino, IRCCS Regina Elena National Cancer Institute, Rome, Italy; Edith M. Marom, University of Tel Aviv, the Chaim Sheba Medical Center, Tel Aviv, Israel; José-María Matilla, Valladolid University Hospital, Valladolid, Spain; Jan van Meerbeeck, Antwerp University and Antwerp University Hospital, Antwerp, Belgium; Luis M. Montuenga, Center of Applied Medical Research, University of Navarra, Pamplona, Spain and Centro de Investigación Biomédica en Red de Cáncer, Spain; Andrew G.Nicholson, Royal Brompton and Harefield Hospitals, Guy’s and St Thomas’ NHS Foundation Trust and Imperial College, London, United Kingdom; Katie Nishimura, Cancer Research And Biostatistics, Seattle, Washington, USA; Anna Nowak, University of Western Australia, Perth, Australia; Isabelle Opitz, University Hospital Zurich, Zurich, Switzerland; Meinoshin Okumura, National Hospital Organization Osaka Toneyama Medical Center, Osaka, Japan; Raymond U. Osarogiagbon, Baptist Cancer Center, Memphis, Tennessee, USA; Harvey Pass, New York University, New York, New York, USA; Marc de Perrot, University of Toronto, Toronto, Canada; Helmut Prosch, Medical University of Vienna, Vienna, Austria; David Rice, M. D. Anderson Cancer Center, Houston, Texas, USA; Andreas Rimner, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Robert T. Ripley, Baylor College of Medicine, Michael E. DeBakey Department of Surgery, Houston, Texas, USA; Adam Rosenthal, Cancer Research And Biostatistics, Seattle, Washington, USA; Enrico Ruffini, University of Torino, Torino, Italy; Shuji Sakai, Tokyo Women’s Medical University, Tokyo, Japan; Paul Van Schil, Antwerp University and Antwerp University Hospital, (Edegem) Antwerp, Belgium; Navneet Singh, Postgraduate Institute of Medical Education and Research, Chandigarh, India; Francisco Suárez, Clínica Santa María, Santiago, Chile; Ricardo M. Terra, University of Sao Paulo, Sao Paulo, Brazil; William D Travis, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Ming S. Tsao, Princess Margaret Cancer Centre, Toronto, Canada; Paula Ugalde, Brigham & Women’s Hospital, Boston, Massachusetts, USA; Shun-ichi Watanabe, National Cancer Center Hospital, Tokyo, Japan; Ignacio Wistuba, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA; Murry Wynes, IASLC, Denver, Colorado, USA; Yasushi Yatabe, National Cancer Center Hospital, Tokyo, Japan.

Advisory Board to the Lung Cancer Domain:

Samuel Armato, The University of Chicago, Chicago, USA; Lawek Berzenji, University of Antwerp, Antwerp, Belgium; Alex Brunelli, St. James’s University Hospital, Leeds, UK; Giuseppe Cardillo, Azienda Ospedaliera San Camilo Forlanini, Rome, Italy; Jason Chang, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Keneng Chen, Peking University, Beijing Cancer Hospital, Beijing, China; Wendy Cooper, Royal Prince Alfred Hospital, NSW Health Pathology, Sydney, Australia; Pier Luigi Filosso, University of Torino, Torino, Italy; Liyan Jiang, Shanghai Chest Hospital, Shanghai, People’s Republic of China; Nagla Karim, Inova Cancer Institute-University of Virginia, Virginia, USA; Peter Kneuertz, The Ohio State University College of Medicine, Ohio, USA; Mark Krasnik, Gentofte University Hospital, Copenhagen, Denmark; Kaoru Kubota, Nippon Medical School Hospital, Tokyo, Japan; Catherine Labbe, Quebec Heart and Lung Institute, Quebec, Canada; Ho Yun Lee, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Eric Lim, Imperial College and the Royal Brompton Hospital, London, United Kingdom; Geoffrey Liu, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada; Hongxu Liu, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Liaoning, China; Philip Mack, Mount Sinai, New York, New York, USA; David Naidich, NYU-Langone Medical Center, New York, New York, USA; Mizuki Nishino, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Marcin Ostrowski, Medical University of Gdańsk, Gdańsk, Poland; Charles Powell, Mount Sinai School of Medicine, New York, New York, USA; Carolyn Presley, The Ohio State University, Ohio, USA; Paul Martin Putora, Kantonsspital St.Gallen, St. Gallen, Switzerland; Natasha Rekhtman, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Harry Ren, Shanghai Pulmonary Hospital, Shanghai, China; M Patricia Rivera, University of North Carolina, Dept of Medicine, Chapel Hill, North Carolina, USA; Gaetano Rocco, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Maria Teresa Ruiz Tzukazan, Pontifical Catholic University of Rio Grande do Sul, PUCRS, Porto Alegre, Brazil; Robert Samstein, Mount Sinai, New York, New York, USA; Yu Yang Soon, National University Hospital, Harvard University Hospital, Singapore; Kenichi Suda, Kindai University Faculty of Medicine, Osaka, Japan; Martin Tammemägi, Department of Community Health Sciences, Ontario, Canada; Lynn Tanoue,Yale University, Dept of Medicine, New Haven, Connecticut, USA; Akif Turna, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey; Benny Weksler, University of Tennesse Health Science Center, Tennessee, USA; Terence Williams, City of Hope comprehensive cancer center, California, USA; Dawei Yang Zhongshan Hospital Fudan University, Shanghai, China; Jeff Yang, Massachusetts General Hospital/Harvard Medical School, Massachusetts, USA; Masaya Yotsukura, Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.

Advisory Board to the Thymic Tumor Domain:

Usman Ahmad, Cleveland Clinic, Cleveland, Ohio, USA, Thoracic Surgery, Heart, Vascular and Thoracic Institute, Cleveland Clinic and Cleveland Clinic Abu Dhabi, United Arab Emirates; Sarit Appel, Sheba Medical Center, Ramat Gan, Israel; Cecilia Brambilla, Royal Brompton and Harefield hospital, Guy’s and St. Thomas NHS Foundation Trust, London, UK; Conrad B. Falkson, Queen’s University, Kingston, Ontario, Canada; Pier Luigi Filosso, University of Torino, Torino, Italy; Giuseppe Giaccone, Weill-Cornell Medicine, New York, New York, USA; Francesco Guerrera, University of Torino, Torino, Italy; Maurizio Infante, University and Hospital Trust Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Dong Kwan Kim, Asan Medical Center, Seoul, and University of Ulsan College of Medicine, Seoul, Republic of Korea; Marco Lucchi, Division of Thoracic Surgery, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; Anja Roden, Laboratory Medicine and Pathology, Mayo Clinic Rochester, Minnesota, USA; Charles B. Simone II, New York Proton Center and Memorial Sloan Kettering Cancer Center, New York, USA.

Advisory Board to the Esophageal Cancer Domain:

Mark Ferguson, The University of Chicago, Chicago, USA.

Advisory Board to the Mesothelioma Domain:

Jennifer Sauter, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Andrea Wolf, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

APPENDIX 2. Chairpersons and Members of the Subcommittees of the Lung Cancer, Thymic Epithelial Tumors, Pleural Mesothelioma and Esophageal Cancer Domains of the IASLC Staging and Prognostic Factors Committee

IASLC Staging and Prognostic Factors Committee Chair: Hisao Asamura.

Lung Cancer Domain

Lung Cancer Domain Chair: Paul Van Schil.

Lung Cancer Domain Vice Chair: Kemp H. Kernstine.

Lung Cancer Domain T Descriptors Subcommittee

Hisao Asamura (chair), Young Tae Kim (co-chair) Pietro Bertoglio, Ayten K. Cangir, Jessica Donington, Wentao Fang, Yolande Lievens, Hiu Liu, Gustavo Lyons, Shuji Sakai, William Travis, Paula Ugalde, Paul Van Schil, Jeff Yang, Masaya Yotsukura.

Lung Cancer Domain N Descriptors Subcommittee

James Huang (chair), Raymond U. Osarogiagbon (co-chair), Andrea Bille, Giuseppe Cardillo, Kemp H. Kernstine, Hong Kwan Kim, Kaoru Kubota, Yolande Lievens, Eric Lim, Edith M. Marom, Helmut Prosch, Paul Martin Putora, David Rice, Gaetano Rocco, Valerie Rusch, Paul Van Schil, Isabelle Opitz, Francisco Suárez, Jeff Yang, Shun-ichi Watanabe.

Lung Cancer Domain M Descriptors Subcommittee

Kwun Fong (chair), Wilfried Eberhardt (co-chair), Jeremy Erasmus, Yolande Lievens, Mirella Marino, Edith M. Marom, Paul Martin Putora, Navneet Singh, Francisco Suárez.

Lung Cancer Domain Lepidic & GGO Subcommittee

William Travis (chair), Philippe Joubert (co-chair), Hisao Asamura, Frank Detterbeck, Giuseppe Cardillo, Wendy Cooper, Ritu R. Gill, Jin Mo Goo, Young Tae Kim, Ho Yun Lee, Heber MacMahon, Edith M. Marom, David Naidich, Andrew G. Nicholson, Mizuki Nishino, Helmut Prosch, Ramon Rami-Porta, Valerie Rusch, Shuji Sakai, Yasushi Yatabe, Shun-ichi Watanabe.

Lung Cancer Domain Neuroendocrine Tumors Subcommittee

Ming Tsao (chair), Andrew G. Nicholson, (co-chair), Ricardo Beyruti, Frank Detterbeck, Wilfried Eberhardt, Pier Luigi Filosso, Yolande Lievens, Eric Lim, Geoffrey Liu, José-María Matilla, Natasha Rekhtman, William Travis, Jeff Yang, Yasushi Yatabe.

Lung Cancer Domain Stage Group Subcommittee

Hisao Asamura (chair), Giuseppe Cardillo, Frank Detterbeck, John Edwards, Kwun Fong, Meredith Giuliani, James Huang, Kemp H. Kernstine, Edith M. Marom, Andrew G. Nicholson, Ramón Rami-Porta, William Travis, Ming Tsao, Paul Van Schil, Shun-ichi Watanabe.

Lung Cancer Domain Lymph Node Chart Subcommittee

Shun-ichi Watanabe (chair), Jin Mo Goo (co-chair), Hisao Asamura, Hans Hoffman, James Huang, Kemp H. Kernstine, Yolanda Lievens, Raymond U. Osarogiagbon, Paul Martin Putora, Ramón Rami-Porta, Valerie Rusch, Paul Van Schil, Jeff Yang.

Lung Cancer Domain Validation and Methodology Subcommittee

Frank Detterbeck (chair), Alyson Mahar (co-chair), Hisao Asamura, Meredith Giuliani, Mirella Marino, Raymond U. Osarogiagbon, Valerie Rusch.

Lung Cancer Domain Prognostic Factors Subcommittee

Frank Detterbeck (chair), Raymond U. Osarogiagbon (co-chair), Alex Brunelli, Kwun Fong, Meredith Giuliani, James Huang, Young Tae Kim, Mark Krasnik, Hiu Liu, Jan van Meerbeeck, Luis M. Montuenga, Andrew G. Nicholson, Paul Martin Putora, Valerie Rusch, Robert Samstein, Navneet Singh, Martin Tammemägi, Ricardo Terra, Ming Tsao, Akif Turna, Terence Williams.

Lung Cancer Domain R Factor Subcommittee

John Edwards (chair), Marcin Ostrowski (co-chair), Souheil Boubia, Jessica Donnington, Hans Hoffman, Maurizio Infante, Mirella Marino, Edith M. Marom, Jun Nakajima, Andrew G. Nicholson, Paul Van Schil, William Travis, Ming Tsao, Yasushi Yatabe.

Lung Cancer Domain Imaging Subcomittee

Jim Mo Goo (chair), Ritu R. Gill (co-chair), Helmut Prosch (co-chair), Samuel Armato, Hui Liu, Heber MacMahon, Edith M. Marom, David Naidich, Charles Powell, Paul Van Schil, William Travis.

Lung Cancer Domain Multiple Pulmonary Nodules Subcommittee

Frank Detterbeck (chair), Edith Marom (co-chair), Sarit Appel, Jason Chang, Keneng Chen, Nicolas Girard, Jin Mo Goo, Young Tae Kim, Heber MacMahon, Andrew G. Nicholson, Paul Martin Putora, Natasha Rekhtman, M Patricia Rivera, Lynn Tanoue, Ricardo M. Terra, William Travis, Paula Ugalde, Yasushi Yatabe.

Lung Cancer Domain Molecular Subcommittee

David Carbone (co-chair), Fred Hirsch (co-chair), Luiz Henrique Araujo, Hisao Asamura, Elisabeth Brambilla, Jason Chang, Frank Detterbeck, Oliver Gautschi, Nagla Karim, Keith Kerr, Peter Kneuertz, Eric Lim, Philip Mack, José-María Matilla, Luis M. Montuenga, Andrew G. Nicholson, Raymond U. Osarogiagbon, Harvey Pass, Carolyn J Presley, Ramón Rami-Porta, Natasha Rekhtman, Harry Ren, Robert Samstein, Kenichi Suda, Ricardo M. Terra, William Travis, Ming Tsao, Terence Williams, Ignacio Wistuba, Dawei Yang, Yasushi Yatabe.

Lung Cancer Domain Database

Paula Ugalde (chair), Pietro Bertoglio (co-chair), Sarit Appel, Philippe Joubert, Catherine Labbe, Hongxu Liu, Gustavo Lyons, José-María Matilla, Robert Samstein, Ricardo Terra, Maria Teresa Ruiz Tzukazan, Benny Weksler.

Cancer Research And Biostatistics

Vanessa Cilento, Daniel Dibaba, Megan Eisele, Dorothy Giroux, Emily Goren, Antje Hoering, Katie Nishimura, Adam Rosenthal.

Thymic Epithelial Tumors Domain

Enrico Ruffini (chair), James Huang (co-chair), Usman Ahmad, Sarit Appel, Andrea Bille, Souheil Boubia, Cecilia Brambilla, Ayten K. Cangir, Frank Detterbeck, Conrad Falkson, Wentao Fang, Pier Luigi Filosso, Giuseppe Giaccone, Nicolas Girard, Francesco Guerrera, Maurizio Infante, Dong Kwan Kim, Marco Lucchi, Mirella Marino, Edith M. Marom, Andrew Nicholson, Meinoshin Okumura, Andreas Rimner, Anja Roden, Charles B. Simone II.

Thymic Domain T descriptor:

Andrew Nicholson (chair), Cecilia Brambilla, Ayten K. Cangir, Maurizio Infante, Mirella Marino, Edith M. Marom, Meinoshin Okumura.

Thymic Domain N descriptor:

Wentao Fang (chair), Frank Detterbeck, Pier Luigi Filosso, Marco Lucchi, Edith M. Marom, Charles B. Simone II.

Thymic Domain M descriptor:

Nicolas Girard (chair), Usman Ahmad, Sarit Appel, Conrad Falkson, Wentao Fang, Giuseppe Giaccone, Dong Kwan Kim, Edith M. Marom, Andreas Rimner.

Thymic Domain Database subcommittee:

Pier Luigi Filosso (chair), Usman Ahmad, Andrea Billè, Souheil Boubia, Frank Detterbeck, Wentao Fang, Nicolas Girard, Francesco Guerrera, James Huang, Dong Kwan Kim, Meinoshin Okumura, Enrico Ruffini.

Pleural Mesothelioma Domain

Valerie Rusch (chair), Anna Nowak (co-chair), Pietro Bertoglio, Andrea Billè, Ayten K. Cangir, Dean Fennell, Françoise Galateau, Ritu R. Gill, Seiki Hasegawa, Hong Kwan Kim, Hedy Kindler, Jan van Meerbeeck, Isabelle Opitz, Harvey Pass, Marc de Perrot, David Rice, Andreas Rimner, Robert T. Ripley, Jennifer Sauter, Ming Tsao, David Waller, Andrea Wolf.

Esophageal Cancer Domain

Wentao Fang (chair), Xavier D’Journo (co-chair), Gail Darling, Jeremy Erasmus, Mark Ferguson, Wayne Hofstetter, Hong Kwan Kim, Donald Low, Paula Ugalde.

APPENDIX 3. Participating Institutions in the third phase of the IASLC Lung Cancer Staging Project

Participating institutions ordered by number of eligible cases submitted

I. Yoshino, Japanese Joint Lung Cancer Registry, Chiba, Japan (23,663 cases); T. Muley, Thoraxklinik, University Hospital Heidelberg, Heidelberg, Germany (8887 cases); W. Li, CAALC: West China Hospital, Sichuan University, Chengdu, China (7345 cases); Y. Kim, Korean Association for Lung Cancer, Seoul, South Korea (4622 cases); H.K. Kim, Samsung Medical Center, Seoul, South Korea (4130 cases); F. Griesinger, CRISP, Berlin, Germany (5482 cases)*; J. Huang, Memorial Sloan Kettering Cancer Center, New York, USA (3146 cases); R. Osarogiagbon, Baptist Memorial Hospital, Memphis, USA (3021cases); S. Park, Seoul National University Hospital, Seoul, South Korea (2542 cases); G. Liu, Princess Margaret Cancer Center, Toronto, Canada (2280 cases); N. Singh, Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, India (2060 cases); P. Ugalde Figueroa, IUCPQ - Université Laval, Quebec, Canada (2018 cases); P. Kneuertz, The Ohio State University, Columbus, USA (1819 cases); J. Shih, Taiwan Society of Pulmonary and Critical Care Medicine, Taipei, Taiwan (1481 cases); S. Jordan, The Royal Brompton Hospital & E. Beddow, Harefield Hospital, part of Guy’s & St. Thomas’ NHS Foundation Trust, London, UK (1434 cases); B. McCaughan, University of Sydney, Newtown, Australia (1368 cases); H. Liu, Liaoning Cancer Hospital, Shenyang, China (1161 cases); A. K. Cangir, Ankara University School of Medicine, Ankara-Sihhiye, Turkey (887 cases); A. Billè, Guy’s Hospital, London, UK (882 cases); F. Leo, S Luigi Hospital, University of Turin, Orbassano, Torino, Italy (840 cases); H. Liu, Sun Yat-sen University Cancer Center, Guangzhou, China (825 cases); M. Redman, SWOG-0819, Seattle, USA (782 cases); H. Pass, NYU Langone Medical Center and Cancer Center, New York, USA (762 cases); J. Sun, CAALC: Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China (634 cases); K. Fong, The University of Queensland TPCH Thoracic Research Centre, Brisbane, Australia (577 cases); R. Terra, University of Sao Paulo Medical School, Sao Paulo, Brazil (555 cases); N. Wu, Second Department of Thoracic Surgery, Peking University Cancer, Beijing, China (455 cases); K. Chen, First Department of Thoracic Surgery, Peking University Cancer H, Beijing, China (451 cases); A. Mohan, All India Institute of Medical Sciences, New Delhi, India (448 cases); P. Van Schil, University Hospital Antwerp, Dept of Pneumology, Edegem, Belgium (304 cases); P. Bertoglio, IRCCS Sacro Cuore-Don Calabria Hospital, Negrar, Italy (298 cases); C. Yang, Massachusetts General Hospital, Boston, USA (295 cases); R. Moises, Hospital de Rehabilitación Respiratoria María Ferrer, Buenos Aires, Argentina (264 cases); A. Turna, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey (238 cases); A. Celik, Gazi University Faculty of Medicine, Ankara, Turkey (193 cases); M. Modesto Alapont, GCCB3: Consorcio Hospitalario Provincial de Castellón, Castellón, Spain (165 cases); L. Sánchez Moreno and M. Zabaleta Murguiondo, GCCB3: Hospital Universitario Marqués de Valdecilla, Santander, Spain (165 cases); C. Longo, Instituto COI, Rio de Janeiro, Brazil (150 cases); H. Zhou, Suining Central Hospital, Suining, China (147 cases); E. Pirondini, ASST San Gerardo, Monza, Italy (144 cases); G. Lyons, Hospital Británico de Buenos Aires, Buenos Aires, Argentina (143 cases); I. Gkiozos, Athens School of Medicine, Athens, Greece (133 cases); K. Kernstine, UT Southwestern Medical Center at Dallas, Dallas, USA (132 cases); M. Serra Mitjans and R. Costa, GCCB3: Hospital Mútua Terrassa. Barcelona (124 cases); M. Genovés Crespo and A. Nuñez Ares, GCCB3: Complejo Hospitalario Universitario of Albacete, Albacete, Spain (114 cases); C. Lee, Seoul National University Bundang Hospital, Seongnam, South Korea (104 cases); Y.K. Pang, Malaysian Thoracic Society, Kuala Lumpur, Malaysia (99 cases); N. Evans, Thomas Jefferson University Hospital, Philadelphia, USA (98 cases); F. Hirsch, Icahn School of Medicine at Mount Sinai, New York, USA (84 cases); M. Ridai, University Hospital of Casablanca, Casablanca, Morocco (83 cases); C. Martínez Barenys and J. Sanz Santos, GCCB3: Hospital Universitari Germans Trias i Pujol, Badalona, Spain (77 cases); J. Sauleda Roig, Hospital Universitari Son Espases, Palma de Mallorca, Spain (76 cases); H. Hoffmann, University of Munich - Division of Thoracic Surgery, Munich, Germany (75 cases); M.A. Iñiguez-García, National Institute of Respiratory Diseases, Mexico City, Mexico (74 cases); L.H. de Lima Araujo, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil (72 cases); C. Grohé, Evangelische Lungenklinik Berlin - NET Registry, Berlin, Germany (71 cases); D. Ball, Peter MacCallum Cancer Institute, Melbourne, Australia (70 cases); J.C. Peñalver Cuesta, GCCB3: Fundación Instituto Valenciano de Oncología, Valencia, Spain (65 cases); N. Tarek, Ain Shams University Hospitals, Cairo, Egypt (64 cases); D. Yang, CAALC: Zhongshan Hospital Fudan University, Shanghai, China (63 cases); D. Sánchez, GCCB3: Hospital Clínic, Barcelona, Spain (62 cases); J.A. Gullón Blanco, GCCB3: Hospital Universitario San Agustín, Avilés, Asturias, Spain (61 cases); L. Montuenga, CIMA/Clínica Universidad de Navarra, Pamplona, Spain (55 cases); G. Galán Gil and R. Guijarro Jorge, GCCB3: Hospital Clínico Universitario de Valencia, Valencia, Spain (52 cases); C. García Rico, J.M. Matilla and B. de Vega Sánchez, GCCB3: Hospital Clínico Universitario de Valladolid, Valladolid, Spain (50 cases); A. Rodríguez Fuster and V. Curall, GCCB3: Hospital del Mar, Barcelona, Spain (50 cases); L. Miravet, GCCB3: Hospital La Plana, Castellón, Spain (49 cases); J. Abal Arca and I. Parente Lamelas, GCCB3: Complexo Hospitalario Universitario Ourense, Ourense, Spain (48 cases); E. Melis, IRCCS Regina Elena National Cancer Institute, Rome, Italy (41 cases); S. García Fuika, GCCB3: Hospital UA Txagorritxu, Vitoria-Gasteiz, Spain (34 cases); K. Tournoy, University Hospital Ghent, Ghent, Belgium (33 cases); M. Zuil Martín, GCCB3: Hospital Royo Villanova, Zaragoza, Spain (31 cases); L. García Aranguena, GCCB3: Hospital Sierrallana, Torrelavega, Cantabria, Spain (28 cases); O. Arrieta, Instituto Nacional de Cancerología, Mexico City, Mexico (28 cases); M. G. Blum, Penrose Cancer Center, Colorado Springs, USA (28 cases); D. Mishra, BP Koirala Institute of Health Sciences, Dharan, Nepal (25 cases); J.M. García Prim, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain (25 cases); M. Mariñán Gorospe, Hospital San Pedro de Logroño, Logroño, Spain (24 cases); R. Stirling, The Alfred Hospital, Melbourne, Australia (23 cases); B. Steen, GCCB3: Hospital de Alcorcón, Madrid, Spain (23 cases); D. Chimondeguy, Hospital Universitario Austral, Buenos Aires, Argentina (22 cases); F.J. Montoro Zulueta, GCCB3: Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Spain (22 cases); M. Paradela de la Morena and A. Souto Alonso, GCCB3: Complejo Hospitalario Universitario de A Coruña, La Coruña, Spain (21 cases); R. Cordovilla and T. Gómez Hernández, GCCB3: Hospital Universitario de Salamanca, Salamanca, Spain (21 cases); C. Thomas, Mayo Clinic Rochester, Rochester, Minessota, USA (20 cases); J. Hernández Hernández, and I. Lobato Astiárraga, GCCB3: Complejo Asistencial de Ávila, Ávila, Spain (19 cases); I. Macía Vidueira and S.Padrones, GCCB3: Hospital de Bellvitge, Barcelona, Spain (16 cases); J.R. Jarabo Salcedo and B. Morales Chacón, GCCB3: Hospital Clínico San Carlos, Madrid, Spain (16 cases); Y. L. Wu, Guangdong General Hospital, Guangzhou, China (15 cases); E. Martínez Tellez, J.C. Trujillo and V. Pajares Ruiz, GCCB3: Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (14 cases); L. Bai, CAALC: Xinqiao Hospital, No. 3 Army Medical University, Chongqing, China (14 cases); R. Magaroles and L. de Esteban Júlvez, Hospital Universitari Joan XXIII, Tarragona, Spain (14 cases); R. Melchor Íñiguez, Fundación Jiménez Díaz, Madrid, Spain (14 cases); I.R. Embun Flor and P.Teller Justes, GCCB3: Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain (13 cases); C.M. Ariza Prota, GCCB3: Hospital Universitario Asturias, Oviedo, Spain (13 cases); M. J. Pavón Fernández, Hospital Severo Ochoa, Leganés, Spain (13 cases); J. Menéndez, Hospital General de Agudos José M. Penna, Buenos Aires, Argentina (11 cases); S. Defranchi, Hospital Universitario-Fundación Favaloro, Buenos Aires, Argentina (11 cases); E. Martínez Tellez, Hospital de Terrassa, Terrassa, Spain (11 cases).

The following institutions submitted ten eligible cases or less listed alphabetically.

M. Curado, A.C. Camargo Cancer Center, Sao Paulo, Brazil; A. Badawy, Alexandria University, Alexandria, Egypt; X. Zhang, CAALC: Henan Provincial People’s Hospital, Zhengzhou, China; Q. Wang, CAALC: The Second Hospital of Dalian Medical University, Dalian, China; S. Han, CAALC: Zhongda Hospital Affiliated to Southeast University, Nanjing, China; D. Levy Faber, Carmel Medical Center, Haifa, Israel; P. García Herreros, Clínica Cardiovid, Medellín, Antioquia, Colombia; F. Suárez, Clínica Santa María, Santiago, Chile; D. Subotic, Clinical Center of Serbia, Belgrade, Serbia; T. Horvath, Czech Republic-Urazova nemocnice Brno, BRNO, Czech Republic; M. Velásquez, Fundación Clínica Valle del Lili, Cali, Colombia; T. Ruiz Albi, GCCB3: Hospital Río Hortega, Valladolid, Spain; M. Serraj, Hassan II University Hospital, Fez, Morocco; V. Baysungur, Health Science University Sureyyapasa Thoracic and Chest Disease, Istambul, Turkey; M. Raíces, Hospital Italiano de Buenos Aires, Argentina; M.J. Pavón Fernández, GCCB3: Hospital Severo Ochoa, Leganés, Madrid, Spain; V. Cvijanovic, Military Medical Academy, Belgrade, Serbia; M. Zereu, Pavilhao Pereira Filho, Santa Casa de Porto Alegre, Brazil; W. Aguiar, SECITOR - Servico de Cirurgia Toracica de Recife, Recife, Brazil.

* CRISP is an AIO study (project no. AIO TRK-0315) under the medical leadership of the Executive Committee (Prof. F. Griesinger (Oldenburg), Prof. M. Thomas (Heidelberg), Dr. M. Sebastian (Frankfurt) and Dr. W. Eberhardt (Essen)). CRISP is conducted by AIO-Studien-gGmbH (sponsor) in cooperation with iOMEDICO (conception, project management, analysis). CRISP is supported by AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Celgene GmbH, Lilly Deutschland GmbH, MSD Sharp & Dohme GmbH, Novartis Pharma GmbH, Pfizer Pharma GmbH, Roche Pharma AG and Takeda Pharma Vertrieb GmbH & Co. KG. However, these companies have no input into or influence over data analysis, data interpretation, or writing of the manuscript.