The IASLC Mesothelioma Staging Project: Proposals for the ‘N’ descriptors in the forthcoming 9th edition of the TNM classification for Pleural Mesothelioma

Abstract

Introduction:

The International Association for the Study of Lung Cancer developed an international database to inform potential revisions in the 9th edition of the Tumor, Node, Metastasis classification of diffuse pleural mesothelioma (PM). This study analyzed the clinical and pathological N categories to determine whether revisions were indicated relative to the 8th edition staging system.

Methods:

Of 7,338 PM cases diagnosed 2013 to 2022, 3,598 met all inclusion criteria for planned analyses. Data on 2,836 patients without metastases were included in this study. Overall survival (OS) was measured from date of diagnosis. Patients were included regardless of whether they received neoadjuvant treatment. For the pathological N analysis, patients who underwent resection (extrapleural pneumonectomy or pleurectomy/decortication) were included. N subgroups were analyzed and overall survival (OS) assessed by the Kaplan Meier method.

Results:

The existing 8th edition N categories performed adequately in the 9th edition dataset. A median OS advantage was noted for clinical and pathological N0 versus N1 patients: 23.2 versus 18.5 and 33.8 vs. 25.0 months, respectively. Patients with resected pN0 had a 3-year OS of 48%. No difference in OS was noted for single versus multiple station nodal metastases. The number of nodal stations sampled at the time of resection was not associated with a difference in OS.

Conclusions:

Data regarding clinical and pathological N categories corroborate those used in the 8th edition. No changes in the N categories are recommended in the 9th edition of PM staging system.

Introduction

Diffuse pleural mesothelioma (PM) is an aggressive cancer with a poor prognosis. Median overall survival (OS) from diagnosis is usually less than 1 year.(1) For patients treated with systemic therapy alone, OS ranges from 12 – 18 months.(2, 3) In the recent CheckMate 743 trial comparing platinum-based chemotherapy to dual immune checkpoint inhibitor (ICI) therapy in unresectable PM, the 3-year OS was 23% for ICI and 15% for chemotherapy.(4, 5) In retrospective analyses, longer survival is observed in patients treated with bi- or trimodality therapy that includes surgical resection with median OS in select patient subsets of over 30 months.(6–8) Other treatment combinations have been explored including photodynamic therapy or IMRT or new drugs combination with preliminary promising results (9–11). In these series, surgical resections have permitted pathological evaluation of the extent of the primary tumor and presence of lymph node metastases, and have enabled the assessment of prognostic factors.(12–16) In addition to the extent of the local tumor (T category), tumor histological subtype (epithelioid versus non-epithelioid) and lymph node involvement are consistently reported as important prognostic factors.(17–21).

The tumor, node, metastasis (TNM) staging system for PM was first developed in 1994 and remained unchanged for two decades.(22, 23) Because of a lack of data at that time regarding patterns of lymphatic spread in PM, the lung cancer lymph node categories were initially used in PM, with N1 designating ipsilateral peribronchial and hilar lymph node metastases, N2 ipsilateral mediastinal /subcarinal lymph nodes, and N3 contralateral mediastinal, hilar or supraclavicular lymph node involvement. Subsequently, data from retrospective series suggested that PM exhibited a different pattern of lymphatic spread than lung cancer with mediastinal lymph nodes being involved most frequently, often in the absence of hilar or peribronchial nodal disease, and sometimes in unusual mediastinal locations (e.g. internal mammary, pericardial fat pad or posterior intercostal lymph nodes).(11) Analyses of data submitted to the IASLC PM database for the 8th edition of the staging system showed no OS difference between involvement of intrapulmonary/hilar lymph nodes and mediastinal lymph nodes. Therefore the N1 and N2 categories used in the 7th edition of the PM staging system were combined and reclassified as N1. In the 8th edition of the PM staging system N1 includes ipsilateral intrapulmonary, hilar and mediastinal lymph nodes. The N2 category in the 8th edition describes metastases in contralateral intrathoracic, contralateral mediastinal, and/or supraclavicular lymph nodes, and the N3 category was deleted. (23) In preparation for the 9th edition of the PM TNM classification, key objectives of work by the Mesothelioma Domain of the IASLC Staging and Prognostic Factors Committee were to determine whether the nodal subgroupings in the 8th edition required further revision.

Methods

As described previously, the study cohort included patients with histologically proven PM, most of whom were diagnosed between July 2013 and September 2022.(24) Data were submitted from 38 centres across the world including Europe, South America, North America, Asia and Australia.

Data entry via the Electronic Data Capture (EDC) system, designed by Cancer Research And Biostatistics (CRAB in Seattle, WA), was the preferred method of data submission. Additionally, the transfer of external institutional data, termed “batch” data, was permitted. The EDC system required perfect matching between the recorded N category and the presence and location of positive lymph node stations, as well as a complete record of sampling results from resection, if attempted. For the batch data sets, patients were excluded from the clinical N descriptor analysis if the documented T or N descriptors suggested a higher T or N category than that assigned. Additionally, patients included in the pN descriptor analysis were required to have sampling results from at least one nodal station. Data management and analysis were provided by coinvestigators at CRAB.

Patients with clinical stages I-IIIB PM were eligible for the clinical N descriptor analyses. Clinical N descriptors were defined by nodal status based on radiographic imaging using computed tomography (CT) and/or positron emission tomography (PET), or by histological/cytological results obtained from pretreatment invasive sampling (endobronchial ultrasound [EBUS] or mediastinoscopy).

Pathologic N descriptors were defined based on pathological review of surgical resection specimens. The primary pathologic N analyses were restricted to patients with stage I-IIIB PM who underwent cytoreductive operations with extrapleural pneumonectomy (EPP) or pleurectomy/decortication (PD). The PD group included patients who underwent pleurectomy/decortication or extended pleurectomy decortication (EPD). Patients who underwent exploratory thoracotomy only were excluded because typically patients found to have unresectable tumor intraoperatively due to advanced T-stage do not undergo any form of systematic nodal sampling. Lymph node stations were designated according to the IASLC lymph node map.(25) Nodal classification was based on the 8th edition N categories, as noted above.

Patients who did or did not receive neoadjuvant treatment were included. To avoid lead time bias secondary to receipt of neoadjuvant treatment, which has been more frequent in the recent years, OS was calculated from the date of histologic diagnosis for analysis of both clinical and pathologic N descriptors (Figure 1).

Figure 1.

Consort diagram of patients included in the analysis

Statistical methods

The primary study endpoint was OS. After screening for eligibility and data completeness, survival differences between N categories were explored graphically using the Kaplan-Meier method. 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. Hazard ratios between N categories were estimated after adjusting for age, sex, geographic region, and histologic type in the multivariable Cox proportional hazard models of survival, using the SAS System for Windows Version 9.4 PHREG procedure (SAS Institute, Cary, NC). Distributions of the sum of maximum pleural thickness (Psum) measurements for each N and pN category were explored graphically with box plots.(16) Differences in median Psum between N categories were assessed using the Kruskal-Wallis test and the Dwass, Steel, Critchlow-Fligner multiple comparison procedures.

Results

Patient enrollment for clinical and pathological N categories

Of 7,338 cases submitted to the project, 3,598 met the general inclusion criteria for date of diagnosis, histologic type, availability of follow-up, and clinical (c) or pathologic (p) stage defined according to the 8th edition. Of these, 2,836 and 880 met criteria for clinical and pathological N category analyses, respectively (Figure 1).

Overall Survival according to clinical N categories

For the 2,836 patients included in the clinical N analysis, the mean age was 70.4 years and 2,178 (76.8%) were male (Table 1). Among patients with clinically staged tumors, 1,395 were evaluated based on imaging only (CT or PET/CT), 918 patients had invasive nodal assessment performed via mediastinoscopy or endobronchial ultrasound (EBUS), and 523 had no data regarding method of clinical nodal assessment. The 2,836 patients with N0 tumors had a median OS of 23.2 months and 3-year OS of 35%. The 549 (19.4%) patients whose tumors were staged as N1, and the 153 (5.4%) patients with N2 tumors had median OS of 18.5 and 13.3 months, respectively. After adjusting for age, sex, region, and histologic subtype (epithelioid versus non-epithelioid), a significant difference in OS was noted between N0 vs. N1 (HR=1.31, p=0.0009) and between N1 vs. N2 (HR=1.41, p=0.0016) (Figure 2a).

Table 1.

Patient characteristics

	Clinically staged N cohort	Pathologically staged N cohort (resected)
	(N=2836)	(N=880)
Age (yr)
N	2,722	796
Mean	70.4	66.5
Range	18.4,99.0	21,86.0
Sex, n (%)
Female	657 (23%)	226 (26%)
Male	2,178 (77%)	654 (74%)
No data	1
Performance status, n (%)
0	1,304 (51%)	516 (66%)
1	1,050 (41%)	247 (32%)
2	172 (7%)	16 (2%)
3–4	46 (2%)	3 (0%)
No data	264	98
Histologic type/subtype, n (%)
Epithelioid mesothelioma	2,247 (79%)	727 (83%)
Biphasic mesothelioma	332 (12%)	126 (14%)
Sarcomatoid mesothelioma	225 (8%)	23 (3%)
Desmoplastic mesothelioma	32 (1%)	4 (0%)
Region, n (%)
Asia	587 (21%)	146 (17%)
Australia	65 (2%)	0 (0%)
Europe	1100 (39%)	283 (32%)
North America	1,043 (37%)	443 (50%)
South America	41 (37%)	8 (1%)
Treatment, n (%)
Not explored or resected	1,386 (49%)	0 (0%)
Neoadjuvant treatment followed by	653 (23%)	526 (60%)
exploration/resection
Exploration/resection, no	797 (28%)	354 (40%)
neoadjuvant treatment
Curative resection attempt, n (%)
Pleurectomy/decortication	417 (15%)	339 (39%)
Extended pleurectomy/decorticati on	364 (13%)	410 (47%)
Extrapleural pneumonectomy	198 (7%)	131 (15%)
None or no data	1,857 (65%)	0 (0%)

Figure 2.

Overall survival a) by clinical N category b) by pathological N category, patients with resected tumors.

Footnote Regarding comparisons of overall survival between groups after adjusting for age, sex, region, and histologic subtype (epithelioid versus non-epithelioid), significance values were 0.0009 for N1 vs N0, 0.0016 for N2 vs N1, and 0.0019 for pN1 vs pN0. Overall survival for pN2 is not shown due to insufficient numbers.

Based on the new proposed T categories showing that Psum is associated with OS, we investigated the potential relationship between Psum and lymph node metastases.(13) The analysis was restricted to 1,844 patients in whom pleural thickness data were available (Figure 1). Patients with N0 tumors had a median OS of 24.8 months with 3-year OS of 38% and differences in OS between N0, N1 and N2 were again observed (supplementary Figure S1). Summation of measurements of pleural thickness also correlated with nodal involvement, showing a higher Psum for N1 vs. N0 (p<.0001) and for N2 vs. N0 (p=.0002), (Figure 3). The cohort of patients with Psum measurements was comparable to the entire cohort in terms of differences in OS between clinical N categories; therefore, it was not necessary to limit the analysis of N categories to cases having pleural thickness data only.

Figure 3.

Distribution of sum of maximum pleural thickness by clinical N category Footnote Nobs, number of observations;Significance values from tests of no difference in median ranks of sum of pleural thickness were <0.0001 for N1 vs N0, 0.0002 for N2 vs N0, and 0.6328 for N2 vs N1 by the Kruskal-Wallace test, Dwass, Steel, Critchlow-Fligner multiple comparison procedure.

Among the 1,292 patients with tumors classifiable by proposed T, the proportion with lymph node metastasis generally increased as proposed T category increased, with nodal involvement in 2% of proposed T1, 19% of proposed T2, 47% of proposed T3, and 31% of proposed T4 (p=<0.0001) (supplementary Table S1).

Overall survival according to pathological N categories

A total of 1,602 patients who met the M0 criteria and underwent surgical resection (EPP, PD or EPD) were considered for the pathological N analysis. After excluding patients for whom nodal disease could not be assessed by pathologic findings or who lacked sampling results from individual stations to confirm the assigned pathologic nodal status, the analysis included 931 patients (Figure 1). Of these patients, 51 underwent an exploratory thoracotomy and were excluded and 880 underwent cytoreduction by EPP (n=131) or PD (PD=410, EPD=339). Of these 880 PM, 534 (61%) were classified pathological N0, 338 (38%) were classified N1, and 8 (1%) were classified N2. Most (79%) had epithelioid PM. Both clinical and pathological N data were available in 669 cases. Of these, 202 (36.1%) initially classified as clinical N0 PM and with matched pathological data were upstaged following resection to pathologic N1 (n=198) or N2 (n=4).

The median OS for patients with pathological N0 PM was 33.8 months with a 3-year OS of 48%. In contrast, the median OS was 25.0 months for patients with pN1 disease. After adjusting for age, sex, geographic region, and histologic subtype, a significant difference in OS was noted between pN1 vs. pN0 [HR=1.39, p=0.0019], (Figure 2b).

Subgroup analysis of patients with single (n=158) versus multiple (n=180) pN1 lymph node station involvement showed no difference in median or 3-year OS (25.1 vs 25.0 months and 40% and 41%, respectively [p=0.8780], (Figure 4).

Figure 4.

Overall survival by pN0 vs single vs multiple pN1, patients with resected tumors Footnote pN2 not shown due to insufficient cases.

Overall survival according to the extent of lymph node sampling

The extent of nodal sampling and the per station frequency of involvement with metastatic disease are shown in Table 2. A median of 3 lymph node stations were sampled in patients who underwent resection with slightly more nodal stations harvested in EPP vs. PD (median 4 vs. 3, respectively, p<=0.0001). In a subgroup analysis, we evaluated the association between the number of resected lymph node stations and OS. In patients with 1–3 lymph node stations sampled, patients who were pN0 and pN1 had median OS of 36.3 and 26.5 months, respectively (p=0.08). Sampling of a greater number of lymph node stations was not associated with significant differences in OS. Patients with 4–10 lymph node stations removed had median OS of 31.4 months vs 23.9 months for pN0 and pN1, respectively [p=0.08] (Supplementary figure S2).

Table 2.

Frequency of lymph node station sampling and percent positivity by pathologic N category

	Total (N=869)		pN0 (N=526)	pN+ (N=343)
	Sampled (n)	Positive (n (%))	Sampled	Sampled (n)	Positive (n (%))
Station 1	4	0 (0%)	3	1	0 (0%)
Station 2	98	12 (12%)	72	26	12 (46%)
Station 3	47	9 (19%)	30	17	9 (53%)
Station 4	399	78 (20%)	242	157	78 (50%)
Station 5	238	49 (21%)	135	103	49 (48%)
Station 6	99	15 (15%)	53	46	15 (33%)
Station 7	662	163 (25%)	391	271	163 (60%)
Station 8	273	60 (22%)	153	120	60 (50%)
Station 9	303	64 (21%)	175	128	64 (50%)
Station 10	415	113 (27%)	222	193	113 (59%)
Station 11	134	43 (32%)	67	67	43 (64%)
Station 12	76	24 (32%)	34	42	24 (57%)
Station 13	9	1 (11%)	7	2	1 (50%)
Station 14	11	1 (9%)	9	2	1 (50%)
Intercostal	60	22 (37%)	26	34	22 (65%)
Internal Mammary	96	27 (28%)	48	48	27 (56%)
Pericardial	45	19 (42%)	19	26	19 (73%)
Peridiaphragmatic	39	11 (28%)	18	21	11 (52%)
Retrocrural	7	3 (43%)	1	6	3 (50%)

Discussion

Despite certain therapeutic advances and reductions in operative mortality in recent decades, PM remains a highly lethal malignancy. Selected patients may be candidates for a multimodality approach which, in retrospective series and some clinical trials, has been associated with prolonged OS.(12–14) Lymph node involvement, identified in at least half of patients who undergo cytoreductive operations, is consistently reported as a negative prognostic factor, although the optimal approach to classifying lymph node metastases has been controversial.(14;26) Optimally categorizing lymph node involvement in relationship to OS is important in selecting PM patients for treatment and stratifying them in clinical trials.

The current report is compiled from the largest multicenter and international PM database assembled to date. Importantly, it includes data for both clinical and pathological N descriptors, obtained both from patients managed surgically and those treated non-surgically. The clinical N group also included patients with and without sum of pleural thickness measurements. The inclusion of both groups maximized the number of cases available for analysis and provides information relevant to the majority of patients with PM who are managed without surgical resection.

In this report, pleural thickness is shown to predict nodal involvement and may therefore inform a decision of whether more invasive staging is needed pre-treatment. This is the first report exploring this correlation and represents a relevant tool in the algorithm to improve staging at diagnosis

The analyses in this study corroborate the N categories established for the 8th edition of the PM staging system. For both clinical and pathological N stage, N0 showed significantly better survival compared to N1 and N2 disease. The greater robustness of the current database and the requirement for station-specific sampling results strengthen the findings from the previous iteration which informed the 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control PM staging system.

In subgroup analyses, we observed no difference in OS between single- and multi-station lymph node involvement, or relative to the number of lymph node stations resected. These findings warrant further investigation in work planned for the 10th edition of the PM staging system. As noted in analyses for the 8th edition, among patients with nodes assessed both clinically and pathologically, 16.0% had clinically identified nodal metastases, while 40.6% had pathologically positive nodal disease. In the current study 36.1% were upstaged from clinical N0 to pathological N1, showing the need to improve the clinical nodal staging. This discrepancy reflects the difficulty in accurately identifying nodal metastases using current imaging techniques. Invasive mediastinal staging by EBUS or mediastinoscopy, routinely practiced pre-treatment in some institutions, is known to improve the detection of mediastinal nodal metastases relative to imaging alone but does not diagnose disease in some of the intrathoracic locations uniquely involved in PM, such as internal mammary, peridiaphragmatic or posterior intercostal stations.(26, 27) The optimal clinical staging paradigm in patients with PM being managed non-surgically merits further study but our data suggest that the presence of any lymph node disease is a principal determinant of poorer OS.

In summary, the current study confirms the N categories established for the 8th edition of the PM staging system. Thus, no changes in N categories are recommended for the 9th edition of the PM staging system. Capturing additional data about the potential impact of the number and locations of involved lymph node stations on OS is warranted in work planned for the 10th edition.

Supplementary Material

4

Figure S1. Overall survival by clinical N category for patients with pleural thickness measured

Figure S2. Overall survival by pN for patients with resected tumors with a) 1–3 stations removed vs b) 4–10 stations removed

5

Table S1: Proposed T category vs clinical N status (node-negative vs node-positive) for patients with M0 tumors classifiable by the 9^th edition T proposal*

Footnote: *All tumors require documentation of T-descriptors to be classifiable by the 9^th edition T proposal; additionally, T1-T3 tumors require measurements of maximum pleural thickness.

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 Medical University, 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 K. Nowak, The 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 Division 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:

J. Friedberg, Temple University, Philadelphia, Pennsylvania, USA; 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 D. 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 D. 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 S. 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 D. 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 D. Travis, Ming S. 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 S. 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 D. Travis, Ming S. 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 D.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 D. 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 D. Travis, Ming S. 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 K. Nowak (co-chair), Pietro Bertoglio, Andrea Billè, Ayten K. Cangir, Dean Fennell, Françoise Galateau, Ritu R. Gill, Seiki Hasegawa, Hong Kwan Kim, Hedy Kindler, Joseph Friedberg, Jan van Meerbeeck, Isabelle Opitz, Harvey Pass, Marc de Perrot, David Rice, Andreas Rimner, Robert T. Ripley, Jennifer Sauter, Ming S. 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 Mesothelioma Tumors Staging Project Participating institutions listed in alphabetical order according to the last names of the PIs

K. Ando, Yokosuka Kyosai Hospital, Yokosuka, Japan; C. Atinkaya, Health Science, Hamidiye Medicine Faculty, Istanbul, Turkey; H. Batirel, Marmara University Dep of Thoracic Surgery, Istanbul, Turkey; A. Billè, Guy’s Hospital, Thoracic Surgery Department, London, UK; A. Billè, ESTS Registry, Exeter, UK; K.G. Blyth, School of Cancer Sciences, University of Glasgow, Glasgow, Scotland; A.J Bograd, Swedish Cancer Institute, Seattle, Washington, USA; S. Call, Mutua Terrassa University Hospital, Terrassa, Barcelona, Spain; A.K. Cangir, Ankara University Faculty of Medicine, Ankara, Turkey; F.L. Cecere, IRCCS Regina Elena National Cancer Institute, Rome, Italy; S. Cedres, Vall d’Hebron University Hospital, Barcelona, Spain; H. Date, Japanese Joint Committee of Lung Cancer Registry, Tokyo, Japan; J. Friedberg, Temple University, Philadelphia, Pennsylvania, USA; M. de Perrot, UHN, Toronto General Hospital & Princess Margaret Hospital, Toronto, Canada; F. Galateau-Salle, MESOBANK, MESOPATH College Cancer Center Leon Berard Lyon, France; M. Ginsberg, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; S. Hasegawa, Hyogo Medical University, Hyogo, Japan; K. Kernstine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; H. Kindler, University of Chicago, Chicago, Illinois, USA; J. Luketich, University of Pittsburgh - Dept of Cardiothoracic Surgery, Pittsburgh, Pennsylvania, USA; P. Martín-Martorell, Hospital Clínico Universitario de Valencia, Valencia, Spain; B. McCaughan and C. Kennedy, University of Sydney (SPH Campus), Sydney, Australia; A.K. Nowak, Sir Charles Gairdner Hospital, Nedlands, Australia; I. Opitz, University Hospital Zurich, Zurich, Switzerland; H. Pass, NYU Langone Medical Center, New York, USA; D. Rice, The University of Texas MD Anderson Cancer Center, Texas, USA; R. T. Ripley, Baylor College of Medicine, Division of Thoracic Surgery, Houston, Texas, USA; K Syrigos, University of Athens Oncology Unit, Athens, Greece; R. Terra, University of Sao Paulo Medical School, Sao Paulo, Brazil; A. Turna, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey; D. Waller, Barts Thorax Center, St Bartholomew’s Hospital, London, UK; M. Zereu, Pavilhao Pereira Filho, ISCMPA, Porto Alegre, Brazil.