Introduction

This review covers recent developments in techniques for staging patients with lung cancer, focusing on the different modalities available for staging mediastinal adenopathy and highlighting the advantages and disadvantages of each method. The controversies regarding the sequence of tests required for nodal staging in the mediastinum are reviewed and evidence is provided for current best practice. The role of endoscopic ultrasonography (EUS) and the gastroenterologist in mediastinal nodal staging is explored. An algorithm is proposed that incorporates EUS as one of the staging modalities for patients with non–small cell lung cancer (NSCLC).

Epidemiology

Lung cancer is the second most common cancer and the most common cause of cancer-related death in both men and women in the United States and in the world. Most new cases of lung cancer (up to 80%) are NSCLC. Incidence and mortality for men have decreased in the past decade in the United States and in those countries in which smoking cessation efforts have been successful ; however, internationally, especially in Asia, this disease is becoming epidemic.

Epidemiology

Lung cancer is the second most common cancer and the most common cause of cancer-related death in both men and women in the United States and in the world. Most new cases of lung cancer (up to 80%) are NSCLC. Incidence and mortality for men have decreased in the past decade in the United States and in those countries in which smoking cessation efforts have been successful ; however, internationally, especially in Asia, this disease is becoming epidemic.

Diagnosis and staging

In cases in which small cell lung cancer is suspected, tissue diagnosis should be made by the easiest available method. Radiologic imaging is usually sufficient to distinguish limited from extensive disease.

In contrast, in patients who are suspected to have NSCLC, diagnosis and staging should occur concurrently. It is critical to stage the disease accurately, because the choice of therapy is dictated by the stage of the disease. Patients with mediastinal nodal metastases (ie, N2 or N3) are not likely to benefit from surgical resection. In some patients with limited ipsilateral lymph node involvement, surgery can still be advised. Incomplete or inaccurate staging can result in patients undergoing futile thoracotomies. Mediastinal metastases are missed in 7% to 17% of all patients NSCLC who undergo lung resection.

Lung cancer is staged by TNM classification. The current TNM staging system for NSCLC was last revised in 1997. The distribution and mapping of lymph nodes in the mediastinum was initially described by Mountain and colleagues, and its various revisions are used to describe the N factor in TNM staging. The American Thoracic Society regional lymph node station criteria are frequently used to divide the mediastinal lymph node stations ( Fig. 1 ).

Mediastinal lymph node stations based on the American Thoracic Society regional lymph node station criteria.

Noninvasive, minimally invasive, and invasive staging methods have been used for staging lung cancer.

Cross-sectional imaging studies of the chest, along with imaging of the liver and adrenal glands, are the first steps of assessment in patients with suspected NSCLC who may undergo treatment. Computed tomography (CT) and positron emission tomography (PET) scans, especially with their excellent safety profiles, are among the first noninvasive modalities that are used. They are widely available; however, their limited sensitivity and specificity undermine their usefulness.

The pooled sensitivity and specificity of CT for identifying mediastinal lymph node metastasis are 51% and 85%, respectively. PET has a sensitivity and specificity of 74% and 85%, respectively, for identifying mediastinal lymph node metastasis. Patients with negative CT for mediastinal adenopathy can have up to 35% prevalence of malignant mediastinal lymph nodes. Therefore, tissue sampling is often required.

Bronchoscopy is often necessary in every patient to confirm the diagnosis and to evaluate for synchronous occult contralateral lesions. Bronchoscopy is falsely negative in up to 30% of cases even if brushings, washings, and transbronchial biopsies are performed. To stage the cancer, confirm the diagnosis, and assess for respectability, patients usually need to undergo other investigations.

The American College of Chest Physicians (ACCP) guidelines for lung cancer staging recommend that patients with abnormal lymph nodes on CT or PET, or centrally located tumors without mediastinal adenopathy, should undergo invasive staging for tissue diagnosis and confirmation. Mediastinal tissue can be obtained by needle techniques or surgical biopsies.

Needle techniques

Needle techniques are generally less invasive, less expensive, and less associated with complications compared with surgical methods. Deep sedation is usually not necessary for needle techniques. The following techniques have been used for needle sampling of the mediastinal area.

Combined EUS-FNA and EBUS-TBNA

EBUS-TBNA assesses and samples the same nodal stations as cervical mediastinoscopy. However, the FN rate of EBUS-TBNA is 24%, whereas mediastinoscopy has an FN rate of approximately 10%. This rate has been partly attributed to the fact that EBUS-TBNA cannot access the posterior and inferior mediastinum, or stage 5 lymph nodes.

EUS has the highest yield in the posterior inferior mediastinum. The addition of EUS-FNA to EBUS-TBNA provides a safe way to sample the posterior inferior mediastinal lymph nodes. EUS and EBUS complement each other and provide access to most of the mediastinal lymph nodes in patients with NSCLC. In 1 study, it was shown that if mediastinoscopy had been performed only when results from EUS plus EBUS were negative, this surgical procedure would have been avoided in 28% of patients. Similarly, encouraging results using a combined approach have been reported by other investigators.

Herth and colleagues recently reported a sensitivity of 96% and NPV of 96% in 150 consecutive patients with suspected lung cancer and enlarged mediastinal lymph node (>1 cm) on CT who underwent combined endoscopic-endobronchial ultrasound-guided FNA using a single bronchoscope.

Two prospective studies looked at the feasibility, performance characteristics, and safety of combined EUS-EBUS for staging in patients with NSCLC.

Szlubowski and colleagues prospectively evaluated 120 patients with NSCLC with a radiologically normal mediastinum. PPV and NPV of combined EUS-EBUS was found to be 91%. Wallace and colleagues reported an NPV of 97% using a combined EUS-EBUS staging protocol in a prospective study that evaluated 138 patients with NSCLC. No complications were reported related to the combined EUS-EBUS procedure in any of these studies.

Surgical techniques

Traditionally, surgical techniques are considered the gold standard method for obtaining mediastinal lymph node biopsy samples (NPV, 89%; PPV, 100%). Mediastinoscopy is an underused procedure and its yield varies considerably based on the training and the experience of the surgeon.

In a US study of 11,668 patients who underwent thoracotomy for lung cancer, only 27% of these patients had preoperative mediastinoscopy. Lymphoid tissue samples were obtained in only 47% of these patients. Another study from the Netherlands showed that only 40% of the surgeons adhere to the examination of the 5 nodal stations that routinely should be examined during mediastinoscopy. Nevertheless, mediastinoscopy, if performed by experienced surgeons, will continue to have a role in the invasive staging of NSCLC.

Surgical techniques normally require deep sedation and general anesthesia after endotracheal intubation, and tend to be more expensive compared with the needle techniques. The risk of morbidity and serious complications, including stroke and aortic injury, is higher in surgical techniques. The following surgical techniques have been used for sampling of the mediastinal area.