Should the TNM Staging of NSCLC Evolve Beyond Anatomical Descriptors?
Authors: Gavitt A. Woodard, Sanja Dacic
Journal: Journal of Thoracic Oncology (2024)

Since the first attempts at TNM staging for NSCLC, the TNM system has sought to group similar patients based on the anatomical extent of a tumor disease burden to offer standardized treatment algorithms, normalize research studies, and prognosticate outcomes. The first lung cancer TNM classification was published by the Union Internationale Contre le Cancer in 1968 in "TNM Classification of Malignant Tumors." The TNM descriptors simply conveyed the anatomical tumor extent: T1 tumor in one lung segment, T2 tumor confined to one lobe, T3 tumor involving the main bronchus or more than one lobe, T4 tumors extending beyond the lung, and N1 indicating intrathoracic lymph nodes.1Union for International Cancer ControlTNM Classification of Malignant Tumours. 1st. Union for International Cancer Control, Geneva. Switzerland1968Google Scholar Then in 1973, what is now the American Joint Committee on Cancer Task Force on Lung Cancer proposed new data-driven TNM definitions based on Dr. Clifton Mountain's database of 2155 surgical lung cancer specimens from MD Anderson Cancer Center. This system outlined most of the T descriptors still in use today, including a size cutoff of 3 cm, visceral and parietal pleural invasion, and involvement of the chest wall, diaphragm, and mediastinum. Stage groupings were also proposed for the first time.2Mountain C.F. Carr D.T. Anderson W.A. A system for the clinical staging of lung cancer.Am J Roentgenol Radium Ther Nucl Med. 1974; 120: 130-138Crossref PubMed Google Scholar Multiple updates followed, supported by a growing number of database cases and medical advances including the routine use of computed tomography scanning. In 1996, the International Association for the Study of Lung Cancer (IASLC) established its Lung Cancer Staging Project designed to combine large databases from around the world for the upcoming seventh edition staging system which included additional T-descriptor size measurement cutoffs.3Goldstraw P. Crowley J. Chansky K. et al.The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours.J Thorac Oncol. 2007; 2: 706-714Abstract Full Text Full Text PDF PubMed Scopus (3019) Google Scholar In the eighth edition, published in 2015, 1 cm size increment cutoffs were added up to 5 cm in size. In addition to tumors 3 to 5 cm in size, T2 also included visceral pleural invasion, involvement of the main bronchus, any atelectasis T3 included tumors 5 to 7 cm or those with chest wall invasion, and T4 included tumors more than 7 cm or those with invasion of the diaphragm.4Rami-Porta R. Bolejack V. Crowley J. et al.The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer.J Thorac Oncol. 2015; 10: 990-1003Abstract Full Text Full Text PDF PubMed Scopus (584) Google Scholar Since these earlier editions of the staging system, there has been dramatic improvements in our understanding of lung tumors. In this issue of the Journal of Thoracic Oncology, Van Schil et al.5Van Schil P.E. Asamura H. Nishimura K.K. et al.The International Association for the Study of Lung cancer lung cancer staging project: proposals for the revisions of the T-descriptors in the forthcoming ninth edition of the TNM classification for lung cancer.J Thorac Oncol. 2024; 19: 749-765Abstract Full Text Full Text PDF Google Scholar summarize the ninth edition TNM T-descriptor based on data from 33,982 patients from the IASLC database collected between 2011 and 2019. After applying the eighth edition T-descriptors to the ninth edition data set, the authors propose no T-descriptor changes. We congratulate the authors and all those who have contributed to the current and past staging systems on achieving a robust eighth edition T-descriptor system that now is strongly validated with a large cohort of ninth edition cases. This most recent staging update reveals that we have optimized what can be described with size and anatomical considerations. But should we be content to stop here with anatomical T-descriptors or should we aspire to ongoing improvements and more granularity in our tumor classification? There are biological differences between NSCLC tumors not captured by size alone. Historically, tumor size has served as a practical, easily attained variable to define a tumor's invasive potential. Obviously, nodal involvement, separate tumor nodules, direct invasion of pleura other structures, or distant spread are reasons for upstaging and are important parts of the TNM system. Nevertheless, in the absence of these features, is tumor size all that should be considered? In our current understanding of NSCLC, there are many other factors that affect an assessment of a higher risk tumor than size alone. Even within the ninth edition data set, there are several examples of outcome differences significantly driven by other variables. Squamous versus nonsquamous histology and the global region that cases came from (Asian versus non-Asian countries) are both highly significant on multivariate analysis.5Van Schil P.E. Asamura H. Nishimura K.K. et al.The International Association for the Study of Lung cancer lung cancer staging project: proposals for the revisions of the T-descriptors in the forthcoming ninth edition of the TNM classification for lung cancer.J Thorac Oncol. 2024; 19: 749-765Abstract Full Text Full Text PDF Google Scholar In the aggregate T-descriptor data presented, the overall survival (OS) of a pathologic stage T1a NSCLC is 94% at 5 years. When tumor histology is considered, patients with pT1a squamous cell NSCLC have only a 70% 5-year OS compared with 95% among patients with pT1a nonsquamous histology. Size cutoffs discriminate well in adenocarcinoma; however, in squamous cell tumors under 2 cm, the T1a and T1b descriptors produce no meaningful differences in survival.5Van Schil P.E. Asamura H. Nishimura K.K. et al.The International Association for the Study of Lung cancer lung cancer staging project: proposals for the revisions of the T-descriptors in the forthcoming ninth edition of the TNM classification for lung cancer.J Thorac Oncol. 2024; 19: 749-765Abstract Full Text Full Text PDF Google Scholar With such disparate survival outcomes, should squamous and nonsquamous NSCLC be group together in the same stage, clinical trials, surgical trials, and treatment recommendations? Large differences in survival also exist between geographic regions, in part a reflection of underlying differences in tumor biology. From the ninth edition data, Asian patients experienced superior survival (pT1a 98% 5-y OS) compared with European patients (pT1a 74% 5-y OS) and North American patients (pT1a 83% 5-y OS), probably driven by a higher number of semisolid adenocarcinoma tumors, EGFR driver mutations with better outcomes among Asian patients. When interpreting the aggregate survival outcomes from the final ninth staging edition data, it is worth noting that 64% of all pathologic T-descriptor cases came from Asian patients. Among the pT1 tumors used, 86% of tumors were adenocarcinoma and 88% of the cT1 patients were N0. Therefore, the aggregate survival numbers in the T-descriptor data reveal much better OS outcomes than what would be expected in a patient from North America, Europe, or the rest of the world where outcomes significantly differ from Asia. A tumor's invasive and metastatic potential matters the most when considering the role of systemic treatment in early stage disease. Five-year recurrence-free survival in CALGB 140503 was surprisingly poor at 71.2% among less than or equal to 2 cm stage IA1 and IA2 tumors that underwent a comprehensive preoperative staging evaluation, methodical nodal sampling, and complete surgical resection with lobectomy.6Altorki N. Wang X. Kozono D. et al.Lobar or sublobar resection for peripheral stage IA non-small-cell lung cancer.N Engl J Med. 2023; 388: 489-498Crossref PubMed Scopus (236) Google Scholar How can we better identify the stage IA tumors at higher risk of recurrence and appropriately treat these patients more aggressively? Historically, platinum-based adjuvant chemotherapy has not been found to improve survival in patients with stage I disease,7Woodard G.A. Li A. Boffa D.J. Role of adjuvant therapy in T1-2N0 resected non-small cell lung cancer.J Thorac Cardiovasc Surg. 2022; 163: 1685-1692Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar but targeted therapies, more effective and better tolerated than platinum-based chemotherapy, are already moving into this space and immunotherapy will likely follow.8Tsuboi M. Herbst R.S. John T. et al.Overall survival with osimertinib in resected EGFR-mutated NSCLC.N Engl J Med. 2023; 389: 137-147Crossref PubMed Scopus (113) Google Scholar,9Tsutani Y. Goldman J.W. Dacic S. et al.Adjuvant osimertinib vs. placebo in completely resected stage IA2-IA3 EGFR-mutated NSCLC: ADAURA2.Clin Lung Cancer. 2023; 24: 376-380Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar The ADAURA2 trial is currently underway to evaluate the benefit of 3 years of adjuvant osimertinib in resected, nonsquamous, EGFR-mutant stage IA2 and IA3 NSCLC.9Tsutani Y. Goldman J.W. Dacic S. et al.Adjuvant osimertinib vs. placebo in completely resected stage IA2-IA3 EGFR-mutated NSCLC: ADAURA2.Clin Lung Cancer. 2023; 24: 376-380Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Nevertheless, most patients with stage IA disease are cured with surgical resection alone.6Altorki N. Wang X. Kozono D. et al.Lobar or sublobar resection for peripheral stage IA non-small-cell lung cancer.N Engl J Med. 2023; 388: 489-498Crossref PubMed Scopus (236) Google Scholar,10Saji H. Okada M. Tsuboi M. et al.Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial.Lancet. 2022; 399: 1607-1617Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar Excellent outcomes were found in the Japanese JCOG0802 trial, with 5-year recurrence-free survival rates of 88% after surgical resection of node-negative, less than or equal to 2 cm NSCLC.10Saji H. Okada M. Tsuboi M. et al.Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial.Lancet. 2022; 399: 1607-1617Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar On the basis of these outcomes, it would be overtreatment to recommend three years of adjuvant therapy to all patients with stage IA disease, even with a well-tolerated treatment. Distinguishing between high-risk and low-risk tumors is increasingly important as novel therapies are explored in the adjuvant setting for stage IA disease. The T-descriptors would be a logical place to represent a higher risk tumor's biology and upstage an aggressive but small tumor to more accurately reflect a patient's survival prognosis and recommend additional treatments. Driver and secondary mutations could be considered, but heterogeneity exists within the same mutations. EGFR mutations are associated with a worse prognosis in pure-solid stage I adenocarcinoma, but not in EGFR-mutant tumors with a radiographic ground-glass features.11Yang F, Sun K, Li F, et al. The prognostic impact of epidermal growth factor receptor mutation in clinical Stage I lung adenocarcinoma [e-pub ahead of print]. Ann Thorac Surg. https://doi.org/10.1016/j.athoracsur.2023.05.031. Accessed January 9, 2024.Google Scholar Addition of a tumor's risk based on a validated gene expression assay to TNM stage significantly improves the identification of high-risk patients compared with conventional TNM staging alone.12Kratz J.R. Haro G.J. Cook N.R. et al.Incorporation of a molecular prognostic classifier improves conventional non-small cell lung cancer staging.J Thorac Oncol. 2019; 14: 1223-1232Abstract Full Text Full Text PDF PubMed Google Scholar Disparities in molecular testing of basic driver mutations in adenocarcinoma and programmed death ligand-1 testing persist even in advanced metastatic disease.13Burns L. Jani C. Radwan A. et al.Implementation challenges and disparities in molecular testing for patients with Stage IV NSCLC: perspectives from an urban safety-net hospital.Clin Lung Cancer. 2023; 24: e69-e77Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Until molecular profiling of all histologic subtypes is incorporated into clinical practice, there is a need to include more basic biological variables as a proxy for metastatic potential. Histologic grade for adenocarcinoma has been recently recommended by the 2021 WHO classification of lung tumors14Nicholson A.G. Tsao M.S. Beasley M.B. et al.The 2021 WHO classification of lung tumors: impact of advances since 2015.J Thorac Oncol. 2022; 17: 362-387Abstract Full Text Full Text PDF PubMed Google Scholar,15Moreira A.L. Ocampo P.S.S. Xia Y. et al.A grading system for invasive pulmonary adenocarcinoma: a proposal from the International Association for the Study of Lung Cancer pathology committee.J Thorac Oncol. 2020; 15: 1599-1610Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar and there remains an unmet need for a prognostically validated grading system for squamous cell carcinoma. Integration of more basic variables such as "radiographic presence of ground glass" and "histologic grade" is feasible. Semisolid adenocarcinomas are currently staged with measurements of the invasive, solid component above 5 mm to determine T-descriptor size.16Travis W.D. Asamura H. Bankier A.A. et al.The IASLC lung cancer staging project: proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer.J Thorac Oncol. 2016; 11: 1204-1223Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar Semisolid adenocarcinomas are a unique entity with increased prevalence in never smokers and women, frequent multifocality, and excellent survival outcomes. Should they be combined with the rest of pure-solid NSCLC? Differences in the prevalence of semisolid adenocarcinoma are partially responsible for the differences between Asian and non-Asian countries in the ninth edition T-descriptors5Van Schil P.E. Asamura H. Nishimura K.K. et al.The International Association for the Study of Lung cancer lung cancer staging project: proposals for the revisions of the T-descriptors in the forthcoming ninth edition of the TNM classification for lung cancer.J Thorac Oncol. 2024; 19: 749-765Abstract Full Text Full Text PDF Google Scholar and in the differences in survival outcomes between the Japanese JCOG080210Saji H. Okada M. Tsuboi M. et al.Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial.Lancet. 2022; 399: 1607-1617Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar and North American CALGB 140503.6Altorki N. Wang X. Kozono D. et al.Lobar or sublobar resection for peripheral stage IA non-small-cell lung cancer.N Engl J Med. 2023; 388: 489-498Crossref PubMed Scopus (236) Google Scholar Describing semisolid adenocarcinoma as a unique type of lung tumor would allow for more accurate survival estimates in the T-descriptors for pure-solid tumors. Attempting to stage all "non-small cell lung cancer" as a group may be too broad a category in the modern era. The important data generated by IASLC staging committee and Van Schil et al.5Van Schil P.E. Asamura H. Nishimura K.K. et al.The International Association for the Study of Lung cancer lung cancer staging project: proposals for the revisions of the T-descriptors in the forthcoming ninth edition of the TNM classification for lung cancer.J Thorac Oncol. 2024; 19: 749-765Abstract Full Text Full Text PDF Google Scholar are cited as current benchmarks and reference points for NSCLC survival outcomes. Particularly among smaller tumors without nodal involvement, biological differences are critical to consider and are associated with different risks of locoregional spread and recurrence. Without consideration for tumor biology, the TNM staging system will eventually fall behind our modern, nuanced, and evolving understanding of lung cancer and current personalized therapies, which have major impacts on treatment and survival for patients currently grouped within the same TNM stage. Gavitt A. Woodard: Original draft preparation, Editing. Sanja Dacic: Original draft preparation, Editing. Dr. Woodard reports having participation in advisory boards for AstraZeneca. Dr. Dacic declares no conflict of interest. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revisions of the T-Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung CancerJournal of Thoracic OncologyVol. 19Issue 5PreviewAn international database was created by the International Association for the Study of Lung Cancer to inform on the ninth edition of the TNM classification of lung cancer. The present analyses concern its T component. Full-Text PDF