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. 2025 Jul;20(7):856-870.
doi: 10.1016/j.jtho.2025.01.013. Epub 2025 Jan 24.

The International Association for the Study of Lung Cancer Staging Project: The Database and Proposal for the Revision of the Staging of Pulmonary Neuroendocrine Carcinoma in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer

Ming Sound Tsao  1 , Adam Rosenthal  2 , Andrew G Nicholson  3 , Frank Detterbeck  4 , Wilfried E E Eberhardt  5 , Yolande Lievens  6 , Eric Lim  7 , Jose-Maria Matilla  8 , Yasushi Yatabe  9 , Pier Luigi Filosso  10 , Ricardo Beyruti  11 , Katherine K Nishimura  2 , William D Travis  12 , Raymond Uyiosa Osarogiagbon  13 , Ramon Rami-Porta  14 , Valerie Rusch  15 , Hisao Asamura  16 ; Members of the IASLC Staging and Prognostic Factors Committee, the Advisory Boards, and Participating Institutions
Affiliations

The International Association for the Study of Lung Cancer Staging Project: The Database and Proposal for the Revision of the Staging of Pulmonary Neuroendocrine Carcinoma in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer

Ming Sound Tsao et al. J Thorac Oncol. 2025 Jul.

Abstract

Introduction: Pulmonary high-grade neuroendocrine carcinoma (NEC) includes SCLC and large cell NEC (LCNEC). The seventh and eighth editions of the TNM classification for lung cancer confirmed the applicability of this staging system for SCLC. With the proposal of N2 and M1c subcategories for the ninth edition classification, we assessed the applicability to NECs.

Methods: The database included NEC cases diagnosed between January 2011 and December 2019. Eligible cases, with valid survival time and eighth edition TNM stage, were classified as pure SCLC, combined SCLC with NSCLC, and LCNEC. Survival was calculated using the Kaplan-Meier method, pairwise differences using a log-rank test, and prognostic groups using a Cox regression analysis.

Results: There were 6181 pure and combined SCLC and 697 LCNEC cases available. For SCLC, survival outcome analyses included 4453 cases with clinical stage and 583 with pathologic stage data. The corresponding numbers for LCNEC were 585 and 508. The SCLC data validated the ninth edition classification for lung cancer, including the proposed new subcategories, N2a, single-station ipsilateral mediastinal or subcarinal lymph node involvement, and N2b, involvement of multiple ipsilateral or subcarinal stations. The data also validated the subcategorization of M1c into M1c1 (multiple lesions in a single extrathoracic organ system) and M1c2 (involvement of multiple extrathoracic organ systems). The LCNEC data were insufficient for complete survival analysis, but the available data reported decreasing survival with increasing clinical and pathologic stages.

Conclusions: The ninth edition TNM classification applies to patients with NEC and is the appropriate standard for use in clinical practice.

Keywords: IASLC; LCNEC; Large cell neuroendocrine carcinoma; Neuroendocrine neoplasm; SCLC; Small cell lung carcinoma.

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Conflict of interest statement

Disclosure Dr. Tsao discloses research grants from AstraZeneca and Sanofi and serves on the Board of Directors for IASLC (International Association for the Study of Lung Cancer). Dr. Nicholson has received consultancy fees from Merck, Boehringer Ingelheim, Novartis, AstraZeneca, Bristol Myer Squib, Roche, AbbVie, Oncologica, Takeda UK, and Sanofi; grant and consultancy fees from Pfizer, and payment for educational materials from UpToDate, European Society for Oncology, and Liberum. Dr. Eberhardt has received research grants from AstraZeneca, consultancy fees from AstraZeneca, Daiichi Sankyo, Merck Sharp & Dohme, Roche, Amgen, Novartis, Pfizer, Sanofi-Aventis, Regeneron, Eli Lilly, Bohringer Ingelheim, and Pierre Fabre, and payment for educational lectures from AstraZeneca, Daiichi Sankyo, Merck Sharp & Dohme, Roche, Amgen, Novartis, Boehringer Ingelheim, Eli Lilly, Regeneron, Pfizer, Sanofi-Aventis, and onkowissen.de. Dr. Lievens serves as an unpaid member of the ESTRO Scientific Committee and the Belgian College of Oncology. Dr. Lim has received research grants from AstraZeneca, Boehringer Ingelheim, Medela, Johnson and Johnson/Ethicon, Covidien/Medtronic, Guardant Health, Takea, Eli Lilly Oncology, and Bayer. He discloses consultancy fees from BeiGene, Roche, and Bristol-Myers Squibb, and lecture honoraria payment from Medela. He discloses two patents for imperial innovations. He is a founder of My Cancer Companion, Healthcare Companion Ltd., and discloses three NIHR HTA financial interests. Dr. Yatabe discloses contracted research for Merk Biopharma, Chugai-pharma, Konica-Minolta REALM, and Optieum Biotechnologies, has received consultancy fees from AstraZeneca, Merck Sharp & Dohme, AbbVie, Novartis, Amgen, Daiichi-Sankyo, Janssen Pharma, Konica-Minolta REALM, and has received honoraria for lectures from Merck Sharp & Dohme, Chugai-pharma, AstraZeneca, Merck Biopharma, Novartis, Amgen, Daiichi-Sankyo, Thermo Fisher Science. Dr. Nishimura discloses research contract funding, consultancy fees, honoraria, and travel support from the IASLC. Dr. Travis reports an NCI research grant. Dr. Osarogiagbon discloses a research grant, consultancy fees from GE Healthcare and Median Technologies, honoraria from AstraZeneca, one patent, and stock in Eli Lilly, Immunocore, Pfizer, and BridgeBio. He serves on the Board of Scientific Advisors for NCI, the Chair of the ASCO Research Committee, and the Steering Committee for the National Lung Cancer Roundtable. Dr. Rusch discloses travel funding support from IASLC, MSKCC, and the American College of Surgeons. She serves as a part-time consultant at the American College of Surgeons Health Outreach Program for Equity in Global Surgery (ACS H.O.P.E.). Dr. Asamura reports lecture payments from Johnson and Johnson. The remaining authors declare no conflict of interest.

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