Staging

Cancer Staging System

Once the imaging and biopsy data has been obtained, the cancer can be staged. The most widely used cancer staging system worldwide is the TNM system, developed by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC). It describes the stage of a cancer based on three key factors: the size and extent of the primary tumor (T), the involvement of lymph nodes (N) and the presence of metastasis (M). The T, N and M classes are combined to categorize the cancer into one of four stages (I through IV), with subdivisions (e.g., Stage III is divided into IIIA, IIIB and IIIC). A reference chart for the 8^th (current) edition of the TNM system is shown in Figure 2-3. A new (9^th) edition of Lung Cancer TNM Staging is expected in early 2025.

The size and extent of primary tumor is classified into 7 main categories – Tx, T0, Tis, T1, T2, T3 and T4. Tx is used when the primary tumor cannot be assessed or confirmed (radiologically or bronchoscopically), T0 indicates that no primary tumor is found, and Tis refers to carcinoma in situ (squamous cell carcinoma or adenocarcinoma) – the lesion is cancerous, but has not spread to neighboring tissue. Categories T1-T4 describe the size and/or extent of the main tumor, with higher T numbers indicating progressively larger tumors and more ingrowth into nearby tissues. T1 refers to tumors up to 3 cm in size that remain within the lung. This category is further divided into T1mi (minimally invasive adenocarcinoma), T1a (tumors ≤1cm), T1b (tumors ≤2cm), and T1c (tumors ≤3cm). The T2 category defines tumors larger than 3 cm but smaller than 5 cm that invade the main airways and can cause atelectasis or obstructive pneumonitis. Additionally, local invasion can involve the visceral pleura, categorized as PL1 or PL2, depending on the depth of invasion. There are 2 subdivisions within this category – T2a (tumors >3 cm but ≤4 cm, or tumors that cannot be determined) and T2b (tumors >4 cm but ≤5 cm). Tumors in the T3 category range from 5 to 7 cm and directly invade the chest wall, parietal pleura (PL3), phrenic nerve, or parietal pericardium. Finally, T4 tumors are larger than 7 cm and can invade the carina, trachea, diaphragm, mediastinum, heart, great vessels, recurrent laryngeal nerve, esophagus and the vertebral body.

The involvement of lymph nodes is classified into 5 categories – Nx, which indicates that regional lymph nodes cannot be evaluated; N0, which indicates that there is no regional lymph node involvement; N1, which indicates the involvement of ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and includes direct extension to intrapulmonary nodes; N2, which indicates the involvement of the ipsilateral mediastinal and/or subcarinal lymph nodes; and N3, which indicates the involvement of mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular nodes.

The presence of metastasis is defined by M0 or M1. M0 signifies that no distant metastasis is detected, while M1 indicates that the cancer has spread to a distant site. The M1 category is further broken down into M1a, which indicates separate tumor nodules in the opposite lung from the primary tumor, tumors that involve nodules in the pleura or pericardium, or the presence of fluid buildup caused by cancer; M1b, which indicates single extrathoracic metastasis; and M1c, which indicates multiple extrathoracic metastases to one or more organs.

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Genetic and Biomarker Assessment

As discussed in the Overview, non-small cell lung cancer (NSCLC) typically has a high tumor mutational burden (TMB) and certain subtypes (e.g., adenocarcinoma) are often “addicted” to specific oncogenes; in Western populations, mutations in Kirsten Rat Sarcoma Viral Oncogene (KRAs) and Epidermal Growth Factor Receptor (EGFR) and fusion rearrangements in ALK are the most common. Therapies that target the alterations in these oncogenes have revolutionized the treatment of NSCLC; specific targeted agents are discussed in Treatment Options. Detection of genetic alterations can be performed using several methods (Table 2-2). For single nucleotide changes and small indels, PCR-based methods (for specific target mutations) or next-generation sequencing (for multiple mutations in different genes) are the most commonly used methods. For large structural changes, fluorescence in situ hybridization (FISH) is generally used.

Immunohistochemistry (IHC; staining with target-specific antibodies conjugated to a fluorophore or another signal molecule) is the standard method of protein biomarker detection in tissue samples. In the context of NSCLC, IHC is used to determine the cancer type by detecting the presence of characteristic markers (see the Diagnosis) and to determine how effective immunotherapy that targets the PD-1/PD-L1 pathway (see Treatment Options) is expected to be. There is a good correlation between PD-L1 expression in the tumor and the efficacy of immunotherapeutic agents that target this pathway. While PD-L1 expression within a tumor is heterogeneous and dynamic, it can be semi-quantitatively assessed, which is usually done by estimating the proportion of cells that are positive for PD-L1 signal.

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