Tumor, node, metastasis (TNM) staging system for lung cancer

INTRODUCTION — The tumor, node, metastasis (TNM) staging system for lung cancer is an internationally accepted system used to characterize the extent of disease. The TNM system combines features of the tumor into stage groups that correlate with prognosis and are linked to treatment recommendations. The design criteria for stage classifications balance individual tumor characteristics as well as external priorities for applicability and implementation across international health systems. Specifically, criteria for stage classification include applicability across a broad spectrum of patients and geographic regions as well as simplicity and clarity [1].

This topic discusses the TNM staging system for lung cancer. The purpose of TNM staging is to provide a description of the anatomic extent of cancer that can be communicated to others, assist in treatment decisions, and indicate prognosis. Consistent application of staging criteria permits valid comparisons of patient cohorts, particularly in regards to the outcomes associated with different therapeutic options. In clinical practice, the links between stage, treatment, and prognosis are complex. For any individual patient, TNM stage should be combined with the unique clinical and socioeconomic characteristics of the patient, the molecular features of the tumor and treatment selections to guide the most accurate prognostic assessments.

The eighth edition of the TNM staging system and the evidence supporting it are described in this topic (table 1 and table 2) [2,3]. The eighth edition was effective internationally as of January 1, 2018. The clinical manifestations, diagnosis, pathology, and management of lung cancer are discussed in other topics.

●(See "Clinical manifestations of lung cancer".)

●(See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer".)

●(See "Overview of the initial treatment and prognosis of lung cancer".)

●(See "Management of stage I and stage II non-small cell lung cancer".)

●(See "Systemic therapy in resectable non-small cell lung cancer".)

●(See "Management of stage III non-small cell lung cancer".)

●(See "Overview of the initial treatment of advanced non-small cell lung cancer".)

●(See "Limited-stage small cell lung cancer: Initial management".)

●(See "Extensive-stage small cell lung cancer: Initial management".)

●(See "Treatment of refractory and relapsed small cell lung cancer".)

●(See "Large cell neuroendocrine carcinoma of the lung".)

●(See "Pathology of lung malignancies".)

PATHOLOGIC, CLINICAL AND OTHER STAGING DISTINCTIONS — Different staging systems are used prior to and after surgical resection, as described below.

●Clinical-diagnostic staging – Clinical-diagnostic staging (cTNM) is based primarily on imaging findings with or without additional information from minimally invasive biopsy procedures, such as endobronchial ultrasound-guided biopsy.

●Surgical-pathologic staging – TNM staging is described as surgical pathologic (pTNM) when it is based on findings combined from surgical resection or exploration of the primary tumor and lymph nodes with additional information from clinical imaging studies.

The individual definitions of the T, N and M categories are the same whether assessed clinically or pathologically (table 1). The same TNM groupings are used to determine the clinical-diagnostic stage and surgical-pathologic stage, as well as retreatment stage and autopsy stage (table 2). The suffix "X" is attached (ie, TX, NX) if the extent of disease cannot be assessed for any of these features.

NSCLC VERSUS SCLC AND OTHER NEUROENDOCRINE CANCERS — Lung cancer is clinically subclassified into two major categories based on a combination of clinical and pathologic features: non-small cell lung cancer (NSCLC) and small cell lung carcinoma (SCLC). NSCLC including the subtypes adenocarcinoma and squamous cell carcinoma is the most common tumor group by incidence rates. In practice, TNM staging is routinely applied to NSCLC without modification or clinical reclassifications.

SCLC comprises approximately 15 percent of all lung cancers. SCLC is a neuroendocrine carcinoma that has overlapping pathologic features with other rare tumors including large cell neuroendocrine carcinoma of the lung, as well as typical and atypical carcinoid tumors. Neuroendocrine tumors have distinctly different molecular, pathologic, and clinical features as well as treatment approaches when compared with NSCLC types. The utility of the staging system for SCLC and neuroendocrine tumors is complemented by additional classification in clinical treatment groups.

SCLC has been routinely approached using a two-stage classification system of clinical-limited or clinical-extensive disease. The origin of this approach is a historical classification scheme developed in part by the Veterans Administration Lung Study Group (VALSG) decades ago, which has been updated and internationally adopted [4]. The utility of this two-stage system is the simplicity of stage groupings by whether or not the tumor and regional nodes can be adequately covered in an effective radiation field. The eighth TNM staging system external validation data sets did include robust cohorts of 157,910 patients from the National Cancer Database and an additional 5002 patients from the International Association for the Study of Lung Cancer Database [5]. Although the TNM system derivation and validation cohorts included relatively few early stage SCLC cases, the TNM system is highly applicable to SCLC and provides more precision in classifying the disease than the two-stage system. To facilitate ongoing practical clinical care and to support ongoing development of registries and standardized clinical trials, a combined approach for staging SCLC using both the TNM staging system and the VALSG categories is recommended [3]. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Staging'.)

Similarly, rare neuroendocrine tumors including typical and atypical carcinoid tumors may be staged using the TNM classification system for lung cancer. In a cohort of 205 carcinoid tumors, the TNM system was predictive of survival and maintained clinical utility. However, in addition to the TNM factors of tumor size and nodal stage, the histology of the tumor (typical versus atypical) was also found to be highly predictive of recurrence and this factor should be considered in the initial assessment of pulmonary carcinoid tumors [6]. Additional factors particularly relevant to the management of lung carcinoid tumors include the feasibility of surgical resection based primarily on whether they arise proximally and involve large airways or are peripheral and surrounded by normal lung parenchyma. (See "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis".)

EIGHTH EDITION OF THE TNM SYSTEM — The eighth edition was a planned revision of the previous edition to incorporate new survival data gained from advances in imaging techniques, clinical testing, and therapeutics [3].

To inform the eighth edition of the TNM staging system, the International Association for the Study of Lung Cancer developed a database of approximately 95,000 diverse patients with lung cancer who were treated in 16 countries between 1999 and 2010 (table 1 and table 2) [1,2,7]. Data from 70,967 patients with non-small cell lung cancer were used to retrospectively validate the prognostic value of the TNM descriptors [1].

As with previous editions, the current edition of the TNM staging system categorizes tumors on the basis of primary tumor characteristics (T), the presence or absence of regional lymph node involvement (N), and the presence or absence of distant metastases (M). Molecular tumor features of lung cancer are not included in the TNM system. The overall stage of the tumor (stage I through IV) is determined by the combination of T, N, and M descriptors (table 2).

Prognosis by stage — Under the eighth edition of the TNM staging system, the median survival correlates with both the clinical stage and surgical-pathologic stage. The survival according to clinical and pathologic staging for the eighth edition is shown in the figures (figure 1 and figure 2).

Primary tumor (T) classification — The primary distinction between T classification categories is tumor size. Other features, including invasion of proximal airways, mediastinal involvement, pleural involvement, and extension through the diaphragm or chest wall, also define distinct prognostic categories and correlate with surgical resectability. Combined, these features may be grouped into distinct prognostic categories (figure 3).

●Tx - Primary tumor cannot be assessed or tumor proven by presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.

●T0 – No evidence of primary tumor.

●Tis – Carcinoma in situ.

●T1 – Tumor ≤3 cm in greatest dimension surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar bronchus (ie, not in the main bronchus).

•T1a(mi) – Minimally invasive adenocarcinoma (solitary adenocarcinoma, ≤3 cm with a predominately lepidic pattern and ≤5 mm invasion in any one focus)

•T1a – Tumor ≤1 cm in greatest dimension

•T1b – Tumor >1 but ≤2 cm in greatest dimension

•T1c – Tumor >2 but ≤3 cm in greatest dimension

●T2 - Tumor >3 but ≤5 cm or tumor with any of the following features:

•Involves main bronchus regardless of distance from the carina but without involvement of the carina

•Invades visceral pleura but does not extend beyond visceral pleural surface

•Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung

-T2a – Tumor >3 but ≤4 cm in greatest dimension

-T2b – Tumor >4 but ≤5 cm in greatest dimension

●T3 - Tumor >5 but ≤7 cm in greatest dimension or associated with separate tumor nodule(s) in the same lobe as the primary tumor or directly invades any of the following structures: chest wall (including the parietal pleura and superior sulcus tumors), phrenic nerve, and parietal pericardium.

●T4 - Tumor >7 cm in greatest dimension or associated with separate tumor nodule(s) in a different ipsilateral lobe than that of the primary tumor or invades any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, and carina.

Regional lymph node (N) classification — The lymph node classification is determined by the location of the lymph node in relationship to the primary tumor and hilum, mediastinum, and contralateral hilar regions [8]. As with the tumor designations, this classification correlates with survival (figure 4).

●Nx – Regional lymph nodes cannot be assessed.

●N0 – No regional lymph node metastasis.

●N1 – Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph node(s) and intrapulmonary nodes, inducing involvement by direct extension.

●N2 – Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).

●N3 – Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).

Although these N descriptors from the prior edition consistently predicted prognosis and were carried forward unchanged in the eighth edition, an exploratory subclassification of pathologic (surgically staged) N1 and N2 disease based on the number of involved nodal stations and individual nodes has been proposed (figure 4) [3,9]. However, these subcategories of the N descriptors have not been formally incorporated into the staging system.

●pN1 – Involvement of ipsilateral intrapulmonary, peribronchial, or hilar lymph nodes.

•pN1a – Single-station metastasis.

•pN1b – Multiple-station metastasis.

●pN2 – Involvement of ipsilateral mediastinal or subcarinal lymph nodes.

•pN2a1 – Single N2 station without concurrent N1 station involvement (skip metastasis).

•pN2a2 – Single N2 station with concurrent N1 involvement.

•pN2b – Multiple N2 station metastasis.

Distant metastasis (M) classification — The primary determinants of prognosis in patients with metastatic disease are determined by the presence of metastasis within the thorax, extrathoracic metastasis, and the presence of malignant pericardial or pleural effusions (figure 5).

●M0 – No distant metastasis.

●M1 – Distant metastasis present.

•M1a – Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodule(s) or malignant pleural or pericardial effusion.

•M1b – Single extrathoracic metastasis.

•M1c – Multiple extrathoracic metastasis in one or more organs.

The eighth edition of the TNM staging created a new category, M1b, designating a single extrathoracic metastasis, which is distinguished from M1c, in which there are multiple metastatic lesions (in one or multiple organs (table 1)). These changes led to the designation of stage IVA disease, in which disease is limited to either intrathoracic metastatic involvement or a single extrathoracic metastasis, versus stage IVB disease, in which multiple extrathoracic metastases exist. It is intended that this degree of precision will ultimately help guide treatment options for oligometastatic disease. (See "Oligometastatic non-small cell lung cancer" and "Limited-stage small cell lung cancer: Initial management".)

Stage groupings — Stage groupings reflect prognosis groupings whether clinically or pathologically staged. The eighth edition TNM staging system has refined the stage groupings by increasing the number of stage subcategories (figure 1 and figure 2 and table 2). As an example, a new disease category stage IIIC was created for patients with N3 disease and either a T3 or T4 primary lesion [2]. This category reflects the poor prognosis of such cancers relative to stage IIIB cancers. Although the prognosis for stage IIIC disease is similar to stage IV disease, the distinction is made due to different treatment approaches available for locally advanced, nonmetastatic disease. Similarly, categories for stage IVA and IVB, as well as for IA1, IA2, and IA3 were developed as prognostic differences and became statistically significant. (See "Management of stage III non-small cell lung cancer", section on 'Clinical mediastinal (N2, N3) involvement' and "Overview of the initial treatment of advanced non-small cell lung cancer".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Lung cancer risks, symptoms, and diagnosis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Introduction

•The tumor, node, metastasis (TNM) staging system for lung cancer is an internationally accepted system used to characterize the extent of disease. The purpose of TNM staging is to provide a description of the extent of cancer that can be easily communicated to others, assist in treatment decisions, and serve as a prognostic indicator. (See 'Introduction' above.)

•The TNM staging system relies on anatomic, macroscopic groupings of disease with similar prognoses rather than on molecular characterization. (See 'Introduction' above.)

●Eighth edition of the TNM system

•The TNM staging system predicts survival, but should not be used alone to dictate treatment. Patient specific factors and health system resources must be considered. (See 'Eighth edition of the TNM system' above.)

•The most recent version of the TNM staging system is the eighth edition of the "TNM Classification of Malignant Tumors," effective internationally as of January 1, 2018. The eighth edition preserved the majority of features in the prior systems, but refined and subclassified tumor stage groupings, as well as T and M descriptors (table 1 and table 2).

-The eighth edition emphasizes size cutoffs, such that there are distinct categories for each centimeter increase in size from 1 to 5 cm. (See 'Primary tumor (T) classification' above.)

-For N descriptors the eighth edition makes the recommendation to quantify nodal disease by the number of involved nodal stations; however, it stops short of formally including this in the subsequent stage groupings. (See 'Regional lymph node (N) classification' above.)

-Metastatic disease is divided according to whether metastatic disease is limited to the chest, and if not, whether there are single or multiple extrathoracic sites of metastasis.

-Stage groupings reflect combinations of T, N, and M factors, which have similar prognosis and treatment approaches. Subcategories of stage reflect further refinements of prognosis based on specific T, N, or M features.