Predicting the Prognosis of Lung Cancer: The Evolution of Tumor, Node and Metastasis in the Molecular Age—Challenges and Opportunities

Ramón Rami-Porta; Hisao Asamura; Peter Goldstraw


Transl Lung Cancer Res. 2015;4(4):415-423. 

In This Article

The 7th Edition of the TNM Classification of Lung Cancer

By 2005, more than 100,000 patients had been registered and more than 80,000 met the established criteria for analysis, the largest database ever collected to revise the TNM classification of lung cancer. All these patients originated in 45 databases of different nature in 20 countries around the world, and had been diagnosed with lung cancer between 1990 and 2000.[11] From 2005 to 2009, the members of the subcommittees for the T, the N, and the M components, and those for stage grouping, validation, small-cell lung cancer, carcinoids, visceral pleura invasion, lymph node map, and non-anatomic prognostic factors analyzed, together with the biostatisticians of CRAB, the specific results, proposed recommendations for changes, and wrote their manuscripts that were eventually published in the Journal of Thoracic Oncology.[12–23] All recommendations were accepted by the UICC and the AJCC, and included in the lung cancer chapters of the 7th edition of their respective staging manuals.[1,2] In addition, the IASLC became the main provider of evidence to the UICC and the AJCC to revise future editions of the TNM classification of lung cancer and other thoracic malignancies, as pleural mesothelioma and thymic tumors had been incorporated into the IASLC Staging Project in 2008 and 2009, respectively. In 2009, the IASLC published its own staging manual and handbook.[3,24]

The most important innovations of the 7th edition were the increased relevance of tumor size; the reconciliation of separate tumor nodules in the same lobe, in another ipsilateral lobe and in the contralateral lung with their observed prognosis; the upstaging of malignant pleural and pericardial effusions and nodules to metastatic disease; the relocation of some TNM groups into a different stage; the separation of intrathoracic and extrathoracic metastases; the validation of the TNM classification for bronchopulmonary carcinoid tumors; the recommendation to use the TNM classification for small-cell lung cancer instead of the dichotomous limited and extensive disease classification; and the international and multidisciplinary agreement of a new pulmonary and mediastinal lymph node map. Visceral pleura invasion was defined by the involvement of its elastic layer, and elastic stains were recommended when visceral pleura invasion was not evident with standard stains. These changes were extensively reviewed from the general,[25–34] radiological,[35,36] clinical,[37–39] therapeutic[40–42] and pathological[43,44] points of view; and they were validated, in total or in part, with the series of many institutions.[45–63]

The classification of the 7th edition is very useful to indicate prognosis, which is one of the objectives of the classification. The 3-cm cut-point, that had been the only one to separate tumors according to size, was abandoned in favor of five tumor-size groups separated at 2, 3, 5 and 7 cm cut-points, defining groups of tumors with significantly different prognosis.[12] The downstaging of separate tumor nodules in the same lobe from T4 (6th edition) to T3 (7th edition), and in another ipsilateral lobe from M1 (6th edition) to T4 (7th edition), increased the awareness of these nodules, that are usually resected, in contradistinction with the contralateral nodules (M1a in 7th edition) that are rarely resected.[12] For the N component, the descriptors were unchanged, but the definition of nodal zones, grouping neighboring nodal stations, emphasized the concept of quantification of nodal disease, as it was evident that the more involved zones, the worse the prognosis. Although this information was not used to modify the present N descriptors because it could not be validated clinically, geographically or by T categories, it is practically useful as it helps refine the postoperative prognosis of patients with nodal disease.[13] For the M component, the separation of intrathoracic (M1a) from extrathoracic (M1b) metastasis also helps in assessing prognosis as both groups of metastases have different prognosis, but also reconciles common clinical practice as treatment of malignant pleural and pericardial effusions and nodules had been considered palliative, as with metastatic disease, even when these situations were in the T4 category in the previous editions of the TNM classification.[14]

The proposed nodal map was the result of a wide international and multidisciplinary consensus.[20] It reconciled the differences between the maps proposed by Mountain and Dresler[64] and the Naruke-Japan Lung Cancer Society,[65,66] and introduced important innovations: clear anatomical landmarks for each nodal station, recognizable by the radiologist, the endoscopist and the surgeon; the enlargement of the supraclavicular and subcarinal nodal stations; and the shift of the anatomic midline of the mediastinum to the left paratracheal margin (oncological midline) for the purpose of separating right and left superior and inferior paratracheal lymph nodes.[20]

In the new stage grouping, some aggregate TNM combinations moved from one stage to another. Large T2 tumors (T2b N0 M0) were upstaged from stage IB to IIA; T2a N1M0 tumors were downstaged from stage IIB to IIA; and T4 N0–1 M0 tumors were downstaged from stage IIIB to IIIA. The question of how to treat patients with these tumors arose. Were T2b N0 M0 tumors to be treated with adjuvant chemotherapy as the other tumors in stage IIA? The perception was that the changes in classification lead to a change in treatment,[41,42] but in principle the answer is that treatment recommendations should derive from properly conducted clinical trials and not from taxonomic changes. The mere change of stage does not provide any evidence on the best treatment. New trials will be necessary to answer this question. In the meantime, the multidisciplinary team will have to decide on the best therapeutic option based on all the available information on the patient, the tumor and the surgical resection.

The application of the TNM classification to small-cell lung cancer provides us with a clear example of its utility in refining prognosis. The traditional limited disease group includes tumors from stages IA to IIIB with a 29% absolute survival difference between them: 5-year postoperative survival rates of 38% and 9%, respectively, with the expected progressive degradation of survival as tumor stage increases.[18] This survival difference would be lost if the TNM were not applied to small-cell lung cancer and all tumors were put together in the same category of limited disease.