Anatomic staging is a critical step in evaluation of patients with lung cancer. Accurate identification of stage based on features of primary tumor (T), regional nodes (N), and metastatic disease (M) is fundamental to determining appropriate care. In this article, the TNM components of the anatomic staging system and a framework for description of lung cancer with multiple pulmonary sites of involvement are discussed. TNM combinations are grouped according to prognosis, with patient-level, tumor-level, and environment-level factors also influencing survival outcomes. Although the staging system does not include molecular and immunologic information, anatomic staging remains the common language for communicating extent of disease.
Staging provides a universal language to communicate the extent of malignant disease.
Accurate staging is important to achieving best care for every patient with lung cancer. Better staging leads to better outcomes.
A thorough understanding of the 3 components of anatomic staging—tumor (T), node (N), and metastasis (M)—is essential to accurate staging.
Stages are separated by prognosis, but survival also is influenced by individual patient features, tumor-specific molecular and immunologic characteristics, and external environmental factors.
Lung cancer with multiple pulmonary sites of disease can be challenging to define. The current international staging effort offers a framework for 4 different subtypes.
Staging is a critical step in the evaluation of every patient with lung cancer. Although breakthroughs in understanding of lung cancer molecular and immunologic variability have dramatically changed the landscape of treatment of advanced disease, staging remains fundamental to informing best care for every patient. Staging provides a standardized nomenclature for defining the anatomic extent of disease, informs choice of best treatment of individual patients, allows identification of patients with similar outcomes for the important purpose of performing clinical trials, and establishes a common language for consistent communication. Accurate staging is foundational to providing optimal personalized care for individual lung cancer patients.
The TNM framework for anatomic staging of solid tumors was pioneered by Dr Pierre Denoix in the 1940s–1950s and initially applied to laryngeal and breast cancers. The original TNM staging for lung cancer was a seminal work published in 1974 by Mountain and colleagues, based on 2155 proved lung cancer cases. The simplicity and universal applicability of the TNM system have been remarkably robust over many decades. Revisions and newer editions of the staging system for lung and other cancers have added depth and detail, with advances in imaging technology and availability of larger patient databases facilitating expansion and refinement of TNM over time. The overall approach remains reliable, cost-efficient, and objective albeit dependent to an important extent on the rigor of evaluation by users.
The current eighth edition of the TNM classification for lung cancer is endorsed by the Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC) and serves as the single lung cancer staging system worldwide. This edition was informed by an extensive patient database supported by the International Association for the Study of Lung Cancer (IASLC). The IASLC global database included 94,708 patients from 16 countries who were diagnosed with lung cancer between 1999 and 2010. Geographic diversity was demonstrated with case distribution from Europe (49%), Asia (44%), North America (5%), and Australia (2%). Although more population diversity is aspirational, the database was robust and detailed and allowed extensive evaluation and validation of stage descriptors and groupings.
Fundamentally, the staging system is based on patient survival outcome. Revisions of the TNM descriptors as well as the TNM stage groupings were determined based on separation of groups with distinct survival outcomes. Tumors with different combinations of T, N, and M are grouped together in a single stage if they share similar survival. Although the staging system should not be used to forecast an individual patient’s survival and should not serve as a menu directing treatment, staging provides patients and their physicians valuable information about prognosis and is a critical factor in decisions relating to treatment.
The context of staging
Before describing details relating to the T, N, and M components of staging, it is important that the context of staging be defined, because this information is crucial in understanding when in a patient’s clinical course the staging was performed and how it should be interpreted ( Table 1 ). Context is assigned by a lower-case prefix preceding T, N, and M.
Clinical stage is identified by the prefix, “c.” In a patient newly diagnosed with lung cancer, the clinical stage is an important determinant of treatment. Other factors also contribute significantly to the choice of best treatment of an individual patient. Patient-level factors, such as the presence of medical comorbidities and patient preference, and tumor-level factors, such as targetable molecular mutations or PD-L1 expression, all influence treatment choice. Clinical stage is determined by all information obtained prior to definitive treatment and short of a complete surgical resection. This includes all available clinical information, both noninvasive (history and physical examination, laboratory evaluation, and imaging studies) and invasive (biopsies from any site). Because clinical stage typically is the key driver of treatment, close attention should be paid to achieving as much information as is necessary to be confident that the clinical stage is correct.
Pathologic stage is identified by the prefix, “p,” and is determined only in patients undergoing surgical resection with intent to remove the entire primary tumor. The surgical specimen yields the most precise information relating to T and N, with the M component determined by the information available for clinical staging. Patients who undergo surgery with intent to cure have both clinical and pathologic staging performed, with pathologic staging achieving more accuracy. Resected tumors are further classified by the extent of resection reflected by the designation, “R,” with R0 identifying a complete resection with negative margins, R1 identifying the presence of microscopically positive margins without visible residual tumor, and R2 identifying situations where there is gross (visible or palpable) evidence of residual tumor in the surgical bed.
The prefix, “y,” is used to identify patients who have been treated with nonsurgical neoadjuvant treatment prior to anticipated surgery. A typical situation for this designation is a patient with clinical stage IIIA lung cancer (for example, cT2N2M0 at initial presentation) treated with neoadjuvant chemotherapy anticipating eventual surgical resection. If the surgical specimen demonstrates that the lymph nodes are all free of disease involvement, the pathologic stage is ypT2N0M0.
The prefix “r” identifies patients with cancer recurrence. This designation is useful for communicating the assessment that a new tumor site is felt to be a recurrence of a previous primary as opposed to being a new, distinct primary.
The prefix “a” identifies staging performed in the context of an autopsy.
|T||Size and extent of the primary tumor|
|N||Presence/absence of tumor in lymph nodes in the region of the primary tumor|
|M||Presence/absence of tumor in sites distant to the primary tumor and regional lymph nodes|
|TNM groupings||Stage (I–IV)|
|Modifiers (use with stage)|
|c||Clinical stage, determined before treatment using all available clinical information, including imaging and biopsies|
|p||Pathologic stage, determined after intent-to-cure surgery, based on entirety of resection|
|y||Stage assessed after treatment, usually after neoadjuvant therapy and before surgery|
|r||Stage assessed after recurrence, assuming there was a period of time during which the tumor had been in complete remission|
|a||Stage determined by an autopsy|
|Residual tumor after treatment (use after surgical resection to indicate presence/absence of tumor)|
|R0||No residual tumor (gross or microscopic), negative margins|
|R1||Residual microscopic tumor; positive margins on microscopy without visual or palpable residual tumor|
|R2||Gross residual tumor; visible or palpable tumor remaining|
Residual Tumor After Resection
Patients who have undergone definitive surgical resection should be assigned an “R” designation that reflects the completeness of the resection. Although this indicator is not included as part of usual TNM staging, it is an important piece of information for every patient who has had surgical treatment of the primary site.
R0 identifies a tumor that has been completely resected, with no microscopic or gross (visual or palpable) evidence of residual tumor, and implies that the surgical margins were negative.
R1 identifies a resection with residual microscopic disease; in this case, residual disease typically is confined to microscopic involvement of surgical margins, without gross evidence of disease.
R2 identifies the situation in which there is visible or palpable tumor left unresected. It is unusual for a lung cancer surgery to be initiated if a surgeon did not anticipate doing a curative procedure; R2 resection may occur when anatomic factors encountered during the operation preclude complete resection or in the unusual situation of palliative resection.
The T component describes the extent of the primary tumor and includes 5 categories, T0–T4. The IASLC database for revision of the T descriptor included 10,230 clinical staged and 22,257 pathologically staged cases. This wealth of information allowed further splitting and refining of the T categories, based on identification of significant differences in survival. As seen in Table 2 , the factors defining the T component include size of the primary site, presence/absence of satellite sites within the lung parenchyma, and extension of tumor into adjacent thoracic structures. General comments regarding the T component:
Size is a major factor in defining the T component. Significant differences in survival were observed between groups with 1-cm increments in size within the T1 (≤3 cm) and T2 (>3 and ≤5 cm) designations. Survival differences also were seen with larger primary tumors within the T3 (>5 and ≤7 cm) and T4 (>7 cm) designations.
Satellite lesions, specifically pulmonary nodules in the ipsilateral lung separate from the primary tumor, have significant impact on assigning the T component. Because small pulmonary nodules are common findings, particularly in patients who have smoked, these situations arise frequently and require careful clinical consideration. For example, the decision of whether a satellite lesion in the right upper lobe is related or unrelated to a 1.0 cm solid tumor nodule in the right lower lobe determines whether the T designation is T4 versus T1a. In the absence of adenopathy or metastatic disease, this translates into the difference between and stage IIIA versus stage IA. The consequences of this decision are sufficiently significant that histologic confirmation of the relationship between the 2 sites may be warranted.
Invasion of the airway distal to the carina is classified as T2a, whereas involvement of the carina or the trachea is classified as T4. This approach to tumor airway involvement is simpler and more practical than prior iterations of the staging system, which require measurement of the distance of the tumor from the carina.
When a single tumor has multiple T descriptors, the highest T designation should be used. For example, a 1.8-cm solid nodule is T1b, but if there is a satellite nodule in another ispsilateral lobe that is felt to be related tumor, the T designation should be T4.
Extension of tumor confined to the visceral pleura defines the T component as T2 for tumors up to 5 cm. Tumors larger than 5 cm with extension confined to the visceral pleura are staged as T3 or T4, depending on size. This is consistent with the rule that the highest T designation should be used when a single tumor has multiple T descriptors. Extension of tumor into any thoracic structure other than the visceral pleura and the main bronchi distal to the carina defines the T component as T3 or T4 (see Table 2 for specific sites of extension).
|T0||No primary tumor identified||T0|
|Tis||Carcinoma in situ||Tis|
|T1||Tumor ≤3 cm|
|Minimally invasive (adenocarcinoma only) a||T1a (mi)|
|Superficial spreading tumor in central airways, confined to tracheal or bronchial wall b||T1a (ss)|
|Tumor ≤1 cm||T1a ≤1|
|Tumor >1 and ≤2 cm||T1b >1–2|
|Tumor >2 and ≤3 cm||T1c >2–3|
|T2||Tumor >3 and ≤5 cm |
Tumor involving visceral pleura or main bronchus (excluding carina) with atelectasis to the hilum
|Tumor >3 and ≤4 cm||T2a >3–4|
|Tumor >4 and ≤5 cm||T2b >4–5|
|Tumor involving visceral pleura c||T2 Visc Pl|
|Tumor involving main bronchus (excluding carina) with atelectasis to the hilum c||T2 Centr|
|T3||Tumor >5 and ≤7 cm |
Tumor invading chest wall, pericardium, phrenic nerve
Separate tumor nodule(s) in the same lobe
|Tumor >5 and ≤7 cm||T3 >5–7|
|Tumor invading chest wall, pericardium, phrenic nerve||T3 Inv|
|Separate tumor nodule(s) in the same lobe||T3 Satell|
|T4||Tumor >7 cm |
Tumor invading mediastinum, diaphragm, heart, great vessels, recurrent laryngeal nerve, carina, trachea, esophagus, spine
Tumor nodule(s) in a different ipsilateral lobe
|Tumor >7 cm||T4 >7|
|Tumor invading mediastinum, diaphragm, heart, great vessels, recurrent laryngeal nerve, carina, trachea, esophagus, spine||T4 Inv|
|Tumor nodule(s) in a different ipsilateral lobe||T4 Ipsi Nod|
|TX||T status not able to be assessed|
T component: special situations
The eighth edition staging system clarifies the T descriptor for subsolid nodules. Radiographically, these nodules may be pure ground-glass, heterogeneous, or part-solid. For clinically staged tumors, the assignment of the T descriptor should be based on the size of the solid component on thin-cut chest computed tomography (CT) scan. For pathologically staged tumors, the T descriptor should be determined by the size of the invasive component. Pathologic measurement is relatively straightforward. Unfortunately, a standardized definition of how to identify and measure the solid component radiographically is lacking, with wide variation in practice. The 2013 Fleischner Society guidelines on the management of subsolid nodules recommended using the mediastinal window to measure the size of the solid component. This approach has been demonstrated in several studies to be helpful in the reproducibility of reporting. , In the absence of an accepted standard approach, however, measurements of the solid component are made using either lung or mediastinal windows. Because the size of the solid component may be an important determinant of decisions relating to resection, the approach to measurement of subsolid nodules within a given institution should be clarified.
Superior Sulcus (Pancoast) Tumors
The term, superior sulcus tumor or Pancoast tumor, typically is applied to cancers located in the apex of the lung. Adjacent structures include the brachial plexus (anterior rami of C5, C6, C7, C8, and T1), sympathetic trunk, vagus and phrenic nerves, first thoracic rib, and subclavian artery and vein. Extension of tumor into these structures results in the characteristic presentations of superior sulcus tumors with ipsilateral shoulder and arm pain, Horner syndrome (ptosis, miosis, and anhidrosis), and/or atrophy of the hand muscles. The T component for these tumors usually is determined by the degree of extension. Tumors that involve only the thoracic nerve roots are T3, whereas tumors that extend to the anterior cervical rami of the brachial plexus, other adjacent neural or vascular structures, or spine are T4.
The N component describes the extent of nodal involvement in the thorax and supraclavicular regions. The IASLC database for revision of the N descriptor included 38,910 clinically staged and 31,426 pathologically staged cases. Table 3 outlines the N component categories, which have been remarkably stable over recent iterations of the staging system. Fig. 1 provides the international lymph node map now consistently used around the world.