The TNM classification of lung cancer—a historic perspective

Introduction

More than half a century has passed since the Union for International Cancer Control (UICC) published a brochure introducing the first tumour, node, and metastases (TNM) classification of lung cancer. That happened in 1966, 6 years after the UICC had accepted the classification of anatomic extent of malignant tumours proposed by Pierre F. Denoix [1912–1990] in a series of articles that he had published between 1943 and 1954 (1). The first brochure that the UICC published, prior to the lung cancer edition, was for breast cancer in 1960 (2). Subsequent brochures on cancers of the bladder, mouth and upper-air passages followed. By 1964, new proposals were being prepared for cancers of the thyroid gland, lung, oesophagus, stomach and colon, rectum and cervix and corpus uteri (3). Finally, in 1968, the UICC published a pocket-size book entitled TNM Classification of Malignant Tumours in the format we know today (1). This article will review the main highlights of the history of the TNM classification of lung cancer with emphasis on those characters that made its development possible and on the most recent innovations.

The beginning: Pierre F. Denoix

Pierre F. Denoix was a French surgical oncologist and director of the Institute Gustave Roussy from 1956 to 1982. He also served as a Professor of Oncology in the Medical School of Paris University. During World War II, Denoix participated in the resistance in Paris and was briefly arrested by the Gestapo, earning the Croix de Guerre for his efforts. After becoming a surgeon at Paris Hospitals, he dedicated his career to the development of surgical oncology, especially in breast cancer surgery. One of his key contributions was developing the classification system for the anatomic tumour extent, a milestone in cancer staging. He chaired the Special Committee on Clinical Stage Classification of the UICC and served as its president from 1973 to 1978, while also holding the position of General Director of Health. Denoix was also honoured with the title of Commandeur de la Légion d’Honneur (4-6).

In 1943, the Cancer Section of the Institute National d’Hygiène began registering patients with cancer treated in the French Anticancer Centres. In 1949, the Services of Public Assistance of Paris, Lyon, Montpelier and Toulouse joined the cancer registration project. When the registration began, the definitions of tumour extent varied by cancer type, which complicated the system. To address this, a unified classification for all cancers was proposed in 1947. According to Denoix, this classification should be based on clinical findings, be universally accessible to all clinicians, independent of treatment and should allow for comparisons across patient groups from different institutions or countries. This classification had to be simple, but at the same time, detailed enough to distinguish meaningful patient groups, with a unique system for each cancer. It should be based exclusively on clinical findings, but founded on common rules applicable for all cancer sites. The classification of tumour extent was one of five components in the tumour nomenclature (7):

• An Arabic number of three digits (e.g., 162 for lung cancer defined as “malignant tumour of the trachea and malignant tumour of the bronchi and lung, specified as primary”) to code the cancers based on the International Nomenclature of Tumours;
• A capital letter to indicate the precise location of the cancer (for example, A: trachea; B: bronchi in the vicinity of the tracheal bifurcation; C: more distant bronchi, but accessible directly or indirectly to endoscopy; D: broncho-pulmonary tumour not accessible to endoscopy; E: alveolar; F: pleura);
• A Roman number (I, II, III, IV or V) that coded the stage of the tumour, i.e., the degree of tumour invasion;
• A lower-case letter to indicate the involvement of regional lymph nodes;
• A final number indicates the number of involved lymph nodes and the number of those examined histologically.

The original definitions of the degree of tumour invasion and the designations of adenopathies are shown in Figure 1 (7). In this early classification of tumour extent, no distinct metastatic component was identified, as the generalized cancers were categorized as stage V.

Figure 1 Classification of anatomic extent of primary tumour and of the lymph nodes according to Denoix and Viollet (7). Stage I: tumour strictly limited to the organ and of relatively small size. Stage II: tumour adherent to the organ or to the nearest tissue and still mobile, or limited to the organ but of a relative important size. Stage III: fixed tumour. Stage IV: tumour with considerable invasion or expanded to neighbouring organs. Stage V: tumour with generalization of the disease. a) Absence of clinically perceptible lymph nodes or non-invaded lymph nodes found after resection and histological examination. b) Lymph nodes removed by a large regional excision, with invasion verified histologically in all or in part of them (indicate, if possible, by a quotient the number of invaded lymph nodes in relation to the total number of examined lymph nodes). c) Lymph nodes the tumour invasion of which is clinically plausible, with or without histologic confirmation by simple biopsy of one of them. d) Lymph nodes the nature of which cannot be pronounced. Translated from the original French into English by the author.

Two years later, Denoix published another article presenting the results of the cancer registry over an 8-year period (8). In September 1951, the Expert Committee of the World Health Organization (WHO) convened at the Institute National d’Hygiène in Paris. The experts, as noted by Denoix, were greatly inspired by the work of the Cancer Section and discussed the classification of clinical tumour extent, which aligned with the WHO’s established terminology. They recommended the study of supplementary classifications for lymph nodes and metastases. The classification of tumour extent published in 1952 included: slight changes in its original wording, the deletion of stage V and the addition of a new classification for metastases based on organ location and the number of metastatic implants (Figure 2) (8).

Figure 2 Classification of anatomic tumour extent based on distant tumour spread according to Denoix (8). 0) No metastasis clinically perceptible. 1) Distant lymph node metastasis. 2) This number is reserved for a particular metastasis in the studied site. 3) Lung metastasis. 4) Liver metastasis. 5) Bone metastasis. 6) Skin metastasis. 7) Brain metastasis. 8) Metastasis in an organ not mentioned above. 9) Multiple metastases. Translated from the original French into English by the author.

In his comprehensive 1954 article, Denoix designated tumour classification into what he labelled as three domains: local, regional and distant (metastatic) extent (9). The local extent is determined by factors such as the relative volume of the cancer within the organ, its extension beyond the limits of the organ, its mobility and its spread to adjacent organs. The regional extent was defined by the involvement of the lymph nodes directly related to the tumour. Finally, the distant extent was defined by distant metastases in non-regional lymph nodes or in any other organ. Denoix cautioned against including the nodal and metastatic extents in this clinical classification because they can rarely be assessed by clinical methods and often needed surgical explorations for accurate definition. Instead, he proposed that involved lymph nodes and metastases would constitute what he called complementary classifications supplementary to the four stages of tumour extent already adopted by the WHO in 1952 (Table 1) (9). In his 1959 book Les cancers humains, Denoix elaborates on these three domains of cancer extent; however, curiously enough, he omits a detailed description of the clinical classification with the different stages (Figure 3) (10).

Figure 3 Les cancers humains, by Pierre Denoix. Hachette, Paris; 1959. The last part of chapter 7, Evolution of Cancer, is devoted to the local tumour extent, the lymph node involvement and the distant metastatic spread, but the clinical classification of tumour extent itself is not described.

When the first TNM classification, specifically for breast cancer, was published, the three domains had evolved into the components identified by the acronyms we use today: T for the primary tumour (the T component), N for the loco-regional lymph nodes (the N component), and M for distant metastases (the M component). Each component was assigned a series of numbers to better define the degree of extension or involvement, i.e., the present categories defined by descriptors (2).

That first TNM classification of lung cancer was very simple, with the T component consisting of 5 categories described by the absence of tumour (T0) or by its segmental (T1), lobar (T2) or main bronchial (T3) location or by the invasion of anatomic structures beyond the lung (T4). There were three N categories to code the impossibility to assess nodal involvement (NX), the absence of nodal invasion (N0) or the presence of enlarged intrathoracic lymph nodes (N1). The M component included four categories, as those in the 8^th edition of the TNM classification of lung cancer. However, their descriptors were very different: M0 for absence of metastases, M1a for pleural effusion with malignant cells, M1b for palpable cervical nodes and M1c for other distant metastases (1). This classification was purely clinical and did not yet have a corresponding pathologic counterpart. Interestingly enough, in the initial proposal for the lung cancer classification, prior to publication of the brochure, there was the N2 category for palpable cervical nodes or paralysis of the diaphragm or the vocal cord. However, a note already indicated that these clinical findings could be more appropriately categorized under the M component (3). In fact, the first edition did not include the N2 category, and the palpable cervical nodes were classified as M1b. Harmer noted in his article that due to the challenges of evaluating the extent of lung cancer clinically, radiographic and bronchoscopic findings were essential. In cases lacking histologic or cytological confirmation of malignancy, these cancers should be reported separately (3), a caution that later became part of the general rule #1 of the TNM classification for all malignant tumours (11).

Development of the lung cancer classification: Clifton F. Mountain

By the time the first UICC edition of the TNM classification of lung cancer was published, Clifton F. Mountain [1924–2007] had already become the chair of the Department of Thoracic Surgery at the M. D. Anderson Cancer Centre in Houston, TX, USA. Educated in Harvard College and Harvard University Graduate School of Arts and Sciences and Boston University School of Medicine, he followed postgraduate training at the University of Chicago and the University of Texas M. D. Anderson Cancer Centre. However, before assuming the chair of the Department of Thoracic Surgery of this Texan institution, he served as first lieutenant and damage control officer in the submarine and destroyer escort service in the US Navy in World War II, where he earned six decorations for exemplary service in the Pacific theatre. Prior to joining M. D. Anderson Cancer Centre, he worked as a biostatistician and served as Chairman of the Office of Statistical Research and Director of the Computer Centre of Boston University. No doubt, his statistical expertise greatly contributed to his academic work in thoracic surgery and to the development of the TNM classification for lung cancer. In 1964, he began collaborating with David T. Carr from the Mayo Clinic in Rochester, MN, USA, to explore the TNM classification for lung cancer. In 1972, he co-founded the International Association for the Study of Lung Cancer (IASLC), and in 1978, he organized the 1^st IASLC World Conference on Lung Cancer, in Hilton Head, SC, USA (12,13).

In 1974, Mountain, Carr, and Anderson published a landmark article that would pave the way for the future development and improvement of the TNM classification for lung cancer (13). At that time, they had gathered data from 2,155 patients with histologically confirmed lung cancer. The information included 28 clinical factors obtained from physical examination, radiographic studies, endoscopies (including mediastinoscopy and thoracentesis), and any special examination to confirm extrathoracic metastatic spread. The data they collected would serve as the foundation for the descriptors of the TNM classification as they stand today, with only minor changes: size and location of the primary tumour, extrapulmonary extension, obstructive pneumonitis, atelectasis and pleural effusion, spread to hilar and mediastinal lymph nodes and distant metastases. The TNM classification allowed the incorporation of these relatively few data and the development of an index to universally define tumour extent. The survival graphs of the three T categories (T1, T2, and T3), of the three N categories (N0, N1, and N2) and of the two M categories (M0 and M1) separated clearly from the very beginning, describing, with no statistical analyses, the different prognosis of each category. In addition, the T component included the T0 (no evidence of tumour) and the TX categories (presence of malignant cells in bronchial secretion with no visible tumour on radiographic studies or bronchoscopy) defined identically to those in the 9^th edition TNM. Tumours with similar prognoses in the TNM classifications were grouped into stages I, II and III—an innovation, as no stages were present in the first edition of the lung cancer TNM. This new staging system provided a clear visual discrimination of prognosis, with worse survival as tumour stage increased (14).

The article by Mountain, Carr, and Anderson (14) informed the development of the second edition of the UICC TNM classification for lung cancer published in 1975, as well as the third UICC edition, published in 1978 and its 1982 revision (1,6). In the meantime, the American Joint Committee on Cancer Staging and End-Results Reporting (AJC), the forerunner of the current American Joint Committee on Cancer (AJCC), as it is known today, was created in 1959 as a multidisciplinary organization focused on cancer staging. That happened 3 years after the creation of the TNM Committee of the UICC, formerly known as the Committee on Clinical Stage Classification and Applied Statistics. The AJCC accepted the TNM classification with specific modifications to serve the needs of the physicians in the USA and Canada, and published its first staging manual in 1977 (1,15). The TNM classification for lung cancer in the first edition of the AJCC Manual for Staging of Cancer was also based on the 1974 article by Mountain, Carr, and Anderson (14). In addition to the clinical staging, it introduced the surgical-evaluative staging, the postsurgical treatment-pathologic staging—already alluded to in the Mountain, Carr, and Anderson article—as well as the retreatment staging and the autopsy staging. The manual also included postsurgical treatment residual tumour classification (R0: no residual tumour; R1: microscopic residual tumour; and R2: macroscopic residual tumour) along with the performance status of the host described by the H categories (H0: normal activity; H1: symptomatic but ambulatory, cares for self; H2: ambulatory more than 50% of time with occasional need for assistance; H3: ambulatory less than 50% of time, requiring nursing care; and H4: bedridden, possibly requiring hospitalization) (16).

The North American database managed by Mountain kept growing over time. In 1986, Mountain published an article revising the TNM classification of lung cancer based on data from 3,753 patients. This article was used to update the 4^th edition of the UICC Manual and the 3^rd and 4^th editions of the AJCC Staging Manual (17). Eleven years later, with a database of 5,319 patients, Mountain published another article that informed the simultaneous updates of the 5^th edition of both the UICC and AJCC classifications in 1997 (18). The 6^th edition of the classification was also based on Mountain’s latest article, but it did not include any innovation.

The internationalization of the data-driven revision process: Peter Goldstraw and the IASLC Lung Cancer Staging Project

The North American lung cancer databases, managed and analysed by Mountain, were the pillars on which five editions of the TNM classification of lung cancer stood. The innovations based on their analyses are summarized in Table 2. However, important as they were, those databases had some limitations that were thoroughly discussed during the International Workshop on Intrathoracic Staging. This Workshop, organized by Peter Goldstraw under the auspices of the IASLC, took place at the Royal Brompton Hospital, London, United Kingdom on 28^th and 29^th October 1996 (19). One key limitation was that the databases included only North American patients who had undergone surgical treatment, despite containing both clinical and pathologic classifications of lung cancer. Although the staging system was labelled “international”, it lacked global participation and did not represent other therapeutic modalities.

To address those limitations, Peter Goldstraw, a thoracic surgeon from the Royal Brompton Hospital and Professor of Thoracic Surgery at the National Heart and Lung Institute, Imperial College of London, summoned a group of renowned thoracic surgeons and other dedicated specialists to discuss how future editions of the TNM classification of lung cancer should be revised. The consensus was that an international database of patients with lung cancer, treated with all available therapeutic modalities and including data from as many countries as possible, was essential for revising the TNM classification. To achieve this objective, the IASLC approved the creation of the Staging Committee [later renamed the Staging and Prognostic Factors Committee (SPFC) in 2013], which would be responsible for the project. Additional objectives included defining systematic nodal dissection (19), designing an internationally accepted lymph node map (20), and proposing a definition of complete resection (21). All of these objectives were duly fulfilled (22).

The SPFC organized the IASLC Lung Cancer Staging Project, which remains active nearly three decades after its creation. The project expanded to include thymic epithelial tumours and pleural mesothelioma in the 8^th edition of the TNM classification. Three lung cancer databases, duly managed and analysed by the statisticians at Cancer Research And Biostatistics (CRAB), were used to inform the 7^th, the 8^th, and the 9^th editions of the TNM classification. The relevant features of these three lung cancer databases are shown in Table 3 (23-25). Data were provided voluntarily from contributing institutions around the world. For the 7^th edition, retrospective data of 81,495 evaluable patients were submitted to CRAB from 45 sources in 20 countries. For the 8^th edition, CRAB created an electronic data capture (EDC) system that enabled the online submission of patients’ data. Thirty-five institutions in 16 countries submitted 77,156 evaluable patients: 3,905 were submitted using the EDC system and 73,251 were submitted as batch data. Batch data are institutional databases that may have not been designed with the objective to study lung cancer classification and, therefore, may lack essential elements needed for the revision of the classifications. These batch data have to be revised and cleaned to harmonize them with the EDC data elements. For the 9^th edition, 75 institutions in 25 countries submitted a total of 87,043 evaluable patients: 21,503 through the EDC system and 65,540 as batch data (23-25).

The novelty for the 9^th edition was the registration of molecular data to enhance prognostic capabilities beyond those provided by the TNM classification alone. Tables 4-6 outline the innovations in the T, the N and the M components as derived from the analyses of the three IASLC lung cancer databases that informed the 7^th (26), the 8^th (27), and the 9^th (28) editions in comparison to the 6^th edition of the TNM classification of lung cancer. The 6^th edition, the last to rely on the North American database, introduced no changes from the 5^th (29).

Lessons learnt

Changes in the T, the N, and the M components

In general, along these nearly six decades of lung cancer TNM, we have learnt that the amount of tumour extent is prognostic. Although this is now evident in the three components of the classification, the T component is the one that has undergone the most revisions. In the first six editions of the classification, the only relevant size measurement was the 3 cm landmark that divided T1 from T2 tumours. With larger and more granular datasets, we now know that tumour size plays a much more significant role than previously recognized. Tumour size is broken down now from centimetre to centimetre, and each centimetre from 1 to 5 defines a different T category. Since the 8^th edition, tumour size has been a descriptor across all T categories (Table 4) (30,31). There were no changes in the T categories of the 9^th edition as the distinctions introduced in the 8^th edition were found to clearly differentiate tumours of different prognosis (32).

Since the introduction of the N3 category in the 4^th edition TNM in 1987, there have been no changes to the N component. However, the analyses of the 7^th and the 8^th edition databases showed that the extent of nodal disease had prognostic implications, whether quantified by the number of involved nodal zones (33) or by the number of involved nodal stations (34). A proposed subclassification of nodal categories, differentiating single vs. multiple involvement of hilar/intrapulmonary and ipsilateral mediastinal/subcarinal nodal stations, worked well for pathologic staging but not for clinical staging, and thus was not adopted to modify the N categories. It was only with the 9^th edition database that the quantification of nodal disease based on the number of involved ipsilateral mediastinal/subcarinal nodal stations could be validated in the clinical and pathologic classifications. This validation allowed for the subclassification of N2 into N2a and N2b (Table 5) (35).

The M component has also undergone several innovations in the three latest editions of the classification. For the first six editions, M1 remained unchanged. However, in the 7^th edition, it was found that intra and extrathoracic metastases had statistically significant different prognosis. As a result, M1 was subdivided into M1a (intrathoracic) and M1b (extrathoracic) to differentiate their anatomic location and prognosis (36). In the 8^th edition, it was further found that single and multiple extrathoracic metastases carried different prognosis, as well. Thus, the 7^th edition M1b was redefined to classify single extrathoracic metastasis, while a new category, M1c, was created to include multiple extrathoracic metastases (37). Yet, in the 9^th edition, the availability of a larger and more granular database enabled the subclassification of M1c into two categories: M1c1 (multiple extrathoracic metastases in a single organ system) and M1c2 (multiple extrathoracic metastases in multiple organ systems) (Table 6) (38).

Changes in the stages

Stages based on anatomic tumour extent are a function of the T, the N, and the M components of the classification. These stages were introduced in the second edition of the classification and have experienced several modifications over time. Table 7 shows the changes in the stages along the history of the classification (14,17,18,26-28). The subdivision of N2 into N2a and N2b created new tumour groups that required stage reassignments. Survival analyses from the 9^th edition database revealed that T1N2a tumours had better survival than stage IIIA tumours and similar survival to stage IIB tumours, leading to the assignment of T1N2a tumours to stage IIB. This represented a drastic change as N2 had always been part of stage III. Additionally, T1N1 tumours, previously classified as stage IIB in the 8^th edition, were found to have similar survival to tumours in stage IIA, and were therefore downstaged to stage IIA. Conversely, T2N2b tumours had worse prognoses than those in stage IIIA, to which they had belonged in the 8^th edition, but similar survival to stage IIIB tumours, and were thus reassigned to stage IIIB. Finally, T3N2a tumours, which had been in stage IIIB in the 8^th edition, were found to have similar prognosis than those in stage IIIA and were downstaged accordingly (28). These changes are likely to raise discussions on how to treat patients whose tumours have moved from one stage to another. To this respect, it is important to have in mind that a mere change in classification does not automatically imply a change in therapy. Therapeutic decisions must be based on evidence from well-designed clinical trials, not merely on taxonomic adjustments (39,40).

Another novelty in the study of the 9^th edition stages was the inclusion of survival analyses for patients whose tumours had undergone induction treatment and were subsequently resected. In previous editions, these patients were excluded from analyses of pathologic stages but not from the analyses of clinical stages. However, in the 9^th edition, it was observed that the survival outcomes of patients who had undergone induction therapy and resection did not align with the survival outcomes of those who had not received induction therapy. This underscores the need for future revisions of the classification to include specific survival data and graphs for patients undergoing induction treatment, as their survival cannot be inferred from the survival of patients without induction (28).

Other innovations

Besides the changes in the T, the N, the M components and the stages other innovations have taken place in the last three editions of the classification. In the 7^th edition, visceral pleura invasion was defined as the involvement of its elastic layer, and the use of elastic stains was recommended if this involvement was not clearly seen with haematoxylin-eosin stains (41). Then, in the 8^th edition, significant differences in prognosis were found between the two categories of visceral pleura invasion: PL1 (involvement of the elastic layer but not the lung surface) had a better prognosis than PL2 (involvement of the lung surface) (31).

The analyses of the 7^th edition database showed that the TNM classification can be applied to both surgical and non-surgical small cell lung cancer and to bronchopulmonary carcinoids, despite their differing survival outcomes compared to non-small cell lung cancer (NSCLC). This difference reflects the distinct natural histories of both malignancies (42-44). Further analyses using the 8^th edition database confirmed the applicability of the TNM classification for small cell lung cancer. In fact, the TNM classification is favoured over the traditional dichotomy of limited vs. extended disease to classify small cell lung cancer as it provides better prognostic discrimination (45).

For the first time in the history of the TNM classification of lung cancer, the 8^th edition provided specific instructions on how to measure tumour size under three different circumstances (46):

• For part solid non-mucinous adenocarcinoma, only the size of the solid component on computed tomography for clinical classification, and the size of the invasive component at pathologic examination are considered when assigning a T category based on size;
• For solid tumours, the pulmonary window of the computed tomography in the projection that renders the largest dimension of the tumour is to be used to measure tumour size;
• For tumours that have received induction therapy, if only scattered tumour cells are identified, the tumour size is calculated by multiplying the percent of viable tumour cells by the total size of the residual mass.

Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma were introduced into the 8^th edition TNM classification and were coded as Tis (AIS) and T1mi, respectively (46).

For the 8^th edition, clear recommendations on how to classify lung cancers presenting with multiple lesions were reported in four different articles (47-50) (Table 8).

In the 9^th edition, cells spread through air spaces (STAS) will be recommended as an additional histopathologic descriptor, alongside vascular invasion (V), lymphatic invasion (L), and perineural invasion (Pn), as the presence of STAS is clearly associated with a worse prognosis (51).

Finally, the residual tumour classification (R), which has been included in the TNM classification since the first AJCC edition in 1977, was thoroughly detailed in an article that compiled the best evidence to support an expanded definition of its categories (52).

Future perspectives beyond 2024

In the era of molecular biology, where tumour markers can be predictive of response to certain drugs and have prognostic value, the role of the TNM classification in managing lung cancer patients and guiding therapeutic decisions has been questioned (53). However, in the absence of a drug or a combination of drugs that can control any extent of the disease in all patients with lung cancer, the TNM classification remains relevant and offers some advantages over a molecular classification (54). It is universally accessible, applicable in all medical settings and does not require a minimum number of tests, although it can be qualified by the certainty factor (C) which reflects the thoroughness of tumour assessment (55). Additionally, the TNM classification can be streamlined by the Essential TNM, which prioritizes the evaluation of metastatic spread first, followed by nodal involvement and, finally, the primary tumour. The idea behind essential TNM is to assign a tumour stage—distant, regional or localized—while utilizing minimal resources (11).

The TNM classification is a good prognosticator, but prognosis is multifactorial depending not only on the anatomic extend of the tumour, but also on other tumour-related factors, patient-specific factors, and environmental influences (56). The combination of all these factors into prognostic groups will enhance our capacity to prognosticate for a given patient with a given tumour beyond the prognosis provided by the TNM classification alone. The development of these prognostic groups will be a focus of future TNM classification editions. In fact, at the time of this writing, the nearly 10,000 patients with NSCLC of the 9^th edition database that have molecular data information are being analysed. The first step of this analysis is to see how molecular characterization of lung cancer impacts prognosis in early, locally advanced and metastatic tumours. These preliminary analyses will set the methodology for the revision of the 9^th edition towards the 10^th. However, it is important to have in mind that molecular characterization of lung cancer may refine prognosis and guide therapy but it does not enhance the classification of anatomic tumour extent because molecular information tells us nothing about the anatomy of the tumour. Anatomic tumour extent, tumour profile and other prognostic factors can be combined in prognostic groups that predict prognosis more accurately than any prognostic factor individually (57).

The tumour extent can be further determined by analysing the presence of circulating tumour cells or their fragments, i.e., circulating tumour DNA and RNA. Their presence in the blood stream after treatment worsens prognosis (58). As such, these analyses, among other clinical applications (59), can improve the classification of anatomic tumour extent and contribute to refining the definition of complete lung cancer resection (60).

Conclusions

The TNM classification of lung cancer has stood the test of time. Originally a mere clinical classification, it has evolved to including a pathologic classification, determined after resection of the tumour, which provides a postoperative prognosis and guides further therapeutic decisions. The North American and the IASLC databases have supported the revision of the nine editions of the classification to date, each improving our understanding of the relevance of anatomic tumour extent in the management of patients with any type of lung cancer. Looking ahead, it is hoped that new IASLC databases, with sufficient data and granularity, will continue to support future revisions of the classification, ensuring the classification remains valuable in both clinical practice and research.

Acknowledgments

This article is liberally based on a lecture delivered at the meeting entitled “Experiences Learned from the Past! Improvement for the Future” that took place in Mons, Belgium, on 30^th and 31^st March 2023. The author thanks Ms. Patricia (Pat) Vigués-Frantzen, MA in English Philology, MPM, PMP, for her thorough revision of the English language and for her suggestions to improve the fluency and the readability of the text. Ms. Conxi Caro, MA, Librarian of the Hospital Universitari Mútua Terrassa, Terrassa, Barcelona, Spain, is to be acknowledged for her persistent and tireless search for historical references important to this article. The author also thanks Ms. Dolores Martínez, BA, Secretary to the Department of Thoracic Surgery, for her invaluable assistance in the preparation of this manuscript.

Funding: None.

Footnote

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