70: Techniques for Staging and Restaging of Lung Cancer

Lung cancer is the leading cause of cancer death in the United States in both men and women. In 2011, there were an estimated 221,000 new cases of lung cancer and 156,900 estimated deaths owing to the disease.¹ When indicated, surgery is the most effective curative therapy for lung cancer. For patients with limited non–small-cell lung cancer (NSCLC), lung resection remains the therapy of choice, offering the greatest potential for cure and long-term survival. Surgery also may play a limited role in small-cell lung cancer. However, of patients who present initially with lung cancer, 55% have distant metastatic disease, 30% have disease spread to regional lymph nodes, and only 15% have disease confined to the lung.² Thus, accurate staging in lung cancer is an essential component of management and prognosis.

After primary tumor diagnosis, in addition to evaluating for distant spread and assessing lung reserve and comorbidities, evaluation of the mediastinum and mediastinal lymph nodes is vital to defining tumor stage and subsequent surgical planning. Despite advances in technology, mediastinoscopy remains an important tool for the thoracic surgeon in the staging of bronchogenic carcinoma, as well as in the diagnosis of disease in the mediastinum, as described in Chapter 156.

Originally described by Carlens in 1959,³ mediastinoscopy has been the subject of a number of studies. It has been shown to be a safe procedure, with morbidity rates between 0.6% and 3.7% and mortality rates ranging from 0% to 3% in several large series.⁴ In comparison with noninvasive diagnostic procedures, such as CT scanning and MRI, studies have shown a sensitivity for cervical mediastinoscopy ranging from 0.44 to 0.92.⁵ Specificities and positive predictive values of 1.00 have been described, but this is often secondary to the study design, with reference made to findings during mediastinoscopy, rather than actual disease at various lymph node stations. Although mediastinoscopy is currently the “gold standard” for assessing lymph node status (its negative predictive value is >90%), this chapter also addresses other existing and emerging imaging modalities that can be used to augment staging accuracy. The indications and contraindications to cervical mediastinoscopy are outlined in Table 70-1.

Chest x-ray, chest CT scan, pulmonary function tests, and appropriate medical optimization are performed before mediastinoscopy and major lung resection. Although most surgeons prefer to delay the definitive pulmonary resection until final pathology is available from the mediastinoscopy, some perform mediastinoscopy in the setting of definitive resection if the frozen-section results are negative for metastatic tumor.

Although mediastinoscopy/otomy has the distinct advantage of providing direct visualization of suspicious mediastinal nodal disease, as well as a tissue diagnosis of such nodes, other studies are available in the preoperative staging repertoire. A noninvasive imaging modality currently in clinical use to evaluate for hilar, mediastinal, and extrathoracic metastases is positron-emission tomography (PET). By using the radioisotope [¹⁸F]fluorodeoxyglucose (FDG) to detect metabolically overactive cellular growth, one can more accurately describe a patient's clinical stage and appropriate therapeutic maneuvers.

There is currently no absolute indication for the use of PET scanning, although some guidelines do exist in the literature. It seems clear that for patients who display clear evidence of extrathoracic disease, PET scanning is a costly and unnecessary test that will not change clinical management. Generally, a PET scan is indicated for patients with a question of extrathoracic metastases, those with questionable clinical stage III (cIII) disease (and even cI and cII disease), because surgical management may be altered in at least 8% to 18% of these patients.^6,7

The data to support these clinical recommendations are substantial. PET scans, when compared with CT scans of the chest, abdomen, and pelvic anatomy, have an increased sensitivity for detecting disease, ranging from 79% to 95% versus 50% to 86% for CT.^8–10 The significance of this is most noticeable in light of evidence that 7.5%, 18%, and 24% of patients with cI, cII, and cIII disease, respectively, will have extrathoracic disease by PET scanning and hence may avoid an unnecessary nontherapeutic resection.¹¹ The strengths of PET scanning lie in its superior sensitivity and accuracy (>90%).¹² This has led many to provide recommendations about continued operative staging (i.e., mediastinoscopy) depending on PET and CT scanning. Surgical staging may not be necessary in patients with negative CT and PET,¹³ negative PET and mediastinal nodes less than 1.5 cm,¹⁴ or if the primary lesion has a PET standardized uptake value (SUV) of less than 2.5 and a negative mediastinum.¹⁵

Although it has excellent sensitivity, the specificity of PET scanning is unacceptably low. A number of inflammatory and infectious conditions can produce a positive PET scan in the absence of malignancy, thus leading to either unnecessary operative diagnostic procedures or, worse yet, a decision to forego definitive treatment because of a false assumption of metastatic disease (overstaging). This is critical because there are data to suggest that even minimal N2 disease (e.g., ipsilateral mediastinal nodal metastases) can be resected with a primary tumor for a 5-year survival rate of 40% compared with 8% for bulky N2 disease.¹¹ In addition, since several studies have demonstrated high false-negative and false-positive rates (11%–33% and 15%–52%, respectively, with PET), surgical staging continues to be an important part of the preoperative workup.

Endobronchial Ultrasound and Endoscopic Esophageal Ultrasound in Mediastinal Staging

The introduction of endobronchial ultrasound (EBUS) and endoscopic esophageal ultrasound (EUS) has aided clinicians in determining appropriate candidates for surgical versus nonoperative therapy for lung cancer in a less invasive manner. Endobronchial ultrasound with transbronchial FNA (EBUS-TBNA) can be used to biopsy lymph nodes in stations 1 to 4, 7, and 10 to 12. Accuracy rates of over 90% have been reported by the combined use of EBUS and EUS-FNA biopsy to stage the mediastinum in NSCLC.¹⁶

To describe the technique of EUS briefly, an endoscope is inserted into the esophagus with sonographic examination of nodal tissue distributed around the esophagus. By passing the endoscope distally, one can assess adrenal lesions and, more frequently, posterior mediastinal lymph nodes, most notably stations 7, 8, and 9. Level 5 nodes in the aortopulmonary window can be accessed, as well as occasionally the levels 2 and 4 paratracheal nodes. In contrast with PET, nodes as small as 3 mm can be visualized, and those 5 mm or larger may be biopsied.¹⁷ The only inaccessible mediastinal nodes are those anterior to the tracheobronchial tree (levels 2, 3, and 4) because air within the proximal airway distorts ultrasound findings.

EUS with FNA has gained considerable acceptance as an adjunct to mediastinoscopy, particularly in evaluating posterior mediastinal nodes at levels 5, 7, 8, and 9. Recent data suggest that EUS with FNA is superior to any other technique in investigating the posterior mediastinum, with sensitivity of 84% to 94%, specificity of 100%, and accuracy of 94% to 98% in determining regional disease.^18–21

Some have advocated the use of EBUS-TBNA and EUS-FNA as a primary method of staging the mediastinum. This method can be supported by its minimally invasive approach and relatively low risk, coupled with its ability to provide accurate, thorough information about locoregional and distant disease. A randomized controlled multicenter trial assigned 241 patients to either surgical staging alone or combined EBUS-TBNA and EUS-FNA followed by surgical staging if no nodal metastases were found. For patients without evidence of mediastinal metastases following surgical staging in either group, a thoracotomy with complete lymph node dissection was done. This study found that EBUS-TBNA and EUS-FNA improved the detection of nodal metastases and reduced the number of unnecessary thoracotomies by more than half compared with surgical staging alone.²² In a recent prospective trial, EBUS-TBNA and mediastinoscopy were performed in the same setting in 153 patients, and thoracotomy with pulmonary resection and mediastinal lymphadenectomy were performed on those patients for whom no evidence of N2 or N3 disease was found on EBUS-TBNA or mediastinoscopy.²³ EBUS-TBNA was found to have no statistical difference in sensitivity, negative predictive value, and diagnostic accuracy compared to mediastinoscopy.²⁴ In fact, such data are so encouraging that some centers have suggested replacing mediastinoscopy with EBUS-TBNA and EUS-FNA as the “gold standard” for staging the mediastinum.

Enthusiasm for EBUS/EUS used either alone or in conjunction with currently accepted surgical staging techniques must be tempered by a number of factors. Much of the current data supporting EBUS/EUS has been compiled at advanced tertiary care centers with significant experience in the technique. The assessment of tissue (mediastinoscopy) versus cytology (EBUS/EUS) also may factor into the accuracy of detecting micrometastases, as well as the ability to provide adequate tissue for tumor marker and mutation analysis.

Preparation

General anesthesia is induced with a single-lumen endotracheal tube. The patient is positioned supine on the OR table with the occiput of the head at the top of the table. The neck is maximally extended with the aid of an interscapular roll. The back is elevated to 20 to 30 degrees in a reverse Trendelenburg position. The headboard can be lowered to aid in extension, permitting direct access to the suprasternal notch. The endotracheal tube is positioned laterally, away from the operating hand of the surgeon and the mediastinoscope. The table generally is rotated 90 degrees away from the anesthetist. The anterior chest and neck are fully prepped and draped in the event that emergent sternotomy is necessary. Placing a right radial arterial line can be helpful for monitoring, especially dampening of the arterial waveform, which may indicate innominate artery compression.

Technique

A 3-cm incision is made in the midline one fingerbreadth above the sternal notch (Fig. 70-1A). The incision is carried down through the platysma. The midline then is opened vertically between the two layers of strap muscles until the trachea is exposed. Occasionally, the thyroid isthmus needs to be retracted cephalad or even divided to aid in exposure. Rarely, the thyroid artery, internal mammary artery, or branch of the inferior thyroid artery needs to be ligated. The anterior trachea is exposed, and the pretracheal fascia is incised and elevated. A pretracheal tunnel is fashioned with blunt dissection with the index finger (Fig. 70-1B). During the dissection, the dorsal aspect of the finger remains on the trachea, whereas the volar aspect comes in contact with the innominate artery (Fig. 70-1C). A side-to-side sweeping motion is made with the finger to clear the pre- and paratracheal spaces. The mediastinoscope is introduced into the pretracheal tunnel with constant traction anteriorly and a slow rotating motion during the dissection (Fig. 70-2). Care is taken to avoid forcing the scope at any time. Further blunt dissection is performed with a blunt metal suction device.

The mediastinum is inspected by direct vision using the scope. The surgeon proceeds with dissection of the right and left paratracheal regions first, working inferiorly to the tracheobronchial angles and finishing in the subcarinal region. Identification of the azygos vein, tracheal bifurcation, proximal mainstem bronchi, and pulmonary artery aid in anatomic reference. The subcarinal nodes generally are sampled last because bronchial artery and perinodal bleeding can be more difficult to control. The nodes are partially dissected free before biopsy with the aid of blunt dissection using the suction device, thus minimizing bleeding. If there is any doubt that a structure is indeed a lymph node, aspiration with a long needle can be performed. When sufficiently separated, the node is grasped with the aid of a large-cupped laryngeal forceps or similar instrument, and traction is applied under direct vision. If simple pulling and twisting cannot deliver the specimen, further dissection is indicated. Using a suction/cautery device, coagulation of any bronchial or nodal hilar vessels can be accomplished.

Video cervical mediastinoscopy permits precise visualization of small feeding vessels and has improved the safety of teaching the technique to future thoracic surgeons. The video mediastinoscope permits both video screen-aided dissection and dissection by aid of direct visualization down the barrel of the scope.

Nodal Sampling

Determining the ideal number of lymph nodes to biopsy depends on the indication:

1. Single specimen: Sarcoidosis, lymphoma, or other mediastinal mass once an adequate sample has been sent or frozen-section confirmation is given.

2. Lung cancer: High right paratracheal node (2R), low right paratracheal node (4R), tracheobronchial angle (10R, 10L), subcarinal lymph node (7L), and left paratracheal node (4L). Sampling of all accessible lymph node stations is ideal for accurate staging.

3. If pathologically malignant nodal disease is evident on the contralateral side to the primary tumor, other nodes need not be accessed because staging would not be affected. Alternatively, it may be more expedient to sample all the above-mentioned nodes rather than wait for a frozen section if no evidence of gross disease is present.

Aortopulmonary Window/Periaortic Nodal Sampling (Levels 5 and 6)

Left anterior mediastinotomy (Chamberlain procedure) and a VATS approach are both acceptable methods of assessing levels 5 and 6 lymph nodes on the left.

Hemorrhage is by far the most critical potential complication of mediastinoscopy. Once the lymph nodes are sampled, careful attention is turned to hemostasis. A 0.5-in gauze packing strip is used to pack the mediastinum. If copious bleeding is encountered, the first maneuver should be to keep the mediastinoscope engaged in the mediastinum and attempt to pack the wound with the gauze. This almost always temporizes the situation and allows the surgeon to prepare for more extensive surgery and potential increased blood loss. The bleeding is almost always from the bronchial artery, not from the pulmonary artery. Torquing the scope to apply pressure on the actual bleeding site usually will stop the hemorrhage while allowing constant visual inspection. Additional IV access, blood products, and surgical support can be mobilized while the mediastinum is tamponaded with gauze packing with the mediastinoscope in place. Very often, patience and adequate packing can avoid further surgery. Placing epinephrine-soaked gauze in the mediastinum also may stem localized bleeding. On rare occasion, a median sternotomy is required to control the hemorrhage. However, before undertaking a sternotomy to control a pulmonary artery bleeder, consideration may be given to performing an ipsilateral thoracotomy or lobectomy. Rarely, injury to one of the major veins including the innominate and superior vena cava can cause severe bleeding. Likewise, an injury to the azygos vein while performing a biopsy of level 10R LN is possible. When dissection proceeds along the left paratracheal area, care must be taken to avoid left recurrent nerve injury. Hoarseness may occur in 5% to 10% of patients. Avoidance of cautery and traction on the nerve are most important.

The strap muscles are closed with simple interrupted or running absorbable suture, whereas the skin is closed with absorbable sutures applied in running subcuticular fashion. Steri-Strips are applied. A chest x-ray is taken by some surgeons after the procedure to rule out pneumothorax or unexpected hemothorax. Assessment for any hoarseness of voice is made. Patients usually are discharged home if only cervical mediastinoscopy was performed. Patients may shower the next day. The most frequent procedure-associated morbidity in our experience has been urinary retention in elderly males likely related to the general anesthetic (10% in men older than 70 years). Generally, anticoagulants and aspirin-containing products are avoided at least 7 days before the procedure and for 72 hours after the procedure.

Vats Staging

Thoracoscopy has become an integral part of thoracic surgery in both diagnostic and therapeutic resections. Most of our planned resections are accomplished with VATS, and a VATS exploration is useful for evaluating the primary tumor and pleura as well as ipsilateral and posterior mediastinal nodes.

VATS staging of the primary tumor and mediastinum has been investigated by a number of groups, with encouraging results reported in the literature. One such study revealed that in 17 patients undergoing VATS staging followed by definitive resection with open lymph node dissection, there was 100% correlation between VATS and open staging.²⁵ In 52 patients with biopsy-proved NSCLC and mediastinal lymphadenopathy by CT scan, there was a 0% false-negative rate. More important, patients with stage IIIa (44%) or stage IIIb (16%) disease were appropriately identified, thereby obviating the need for initial surgical therapy.²⁶ These early results would indicate that VATS is a valuable tool in surgical staging, helping to stratify newly diagnosed patients to initial surgical versus medical therapy.

Others have been more precise in applying VATS staging, specifically using a minimally invasive approach to discern stage IIIb disease. Some recent guidelines have suggested that VATS has greater than 90% accuracy in determining such locoregional disease, including diagnosing malignant pleural effusion and contralateral nodal (N3) disease.²⁷ These recommendations are based on two studies that showed the usefulness of this technique. VATS may upstage initially cytologically negative pleural effusions in 6% to 60% of patients, confirm M1 disease in up to 50%, and downstage disease in up to 30% of patients.^28,29 Most important, 6% to 14% of patients may be downstaged to a “resectable” status, highlighting the value of VATS and the hazard of initial overstaging by imaging studies only.

Despite these encouraging data, however, there remain some limitations to VATS. One study has shown that VATS staging may result in an open operation in up to 22% of patients undergoing the procedure³⁰ whereas another study has shown that VATS results were unreliable in 38% of patients studied.³¹ These data are less impressive than others and may be related to familiarity and skill with VATS. Nonetheless, they make the point that with all new technology and skill sets, education, practice, and a learning curve necessarily accompany any significant movement forward.

Of note, there is additional interest in using thoracoscopic techniques to stage other malignancies in the thorax. Krasna and Jiao, among others, have reported on a VATS and laparoscopic approach to stage esophageal cancer.³² While this technique is still investigational and not used widely for routine staging of nonpulmonary malignancies, the sophistication of this process may lend itself to more frequent application.

Restaging Stage III Disease

For patients who are diagnosed initially with stage III disease and undergo neoadjuvant chemotherapy with or without radiation therapy to downstage their disease, it may be important to pathologically restage the mediastinum.^33,34 There are at least theoretically increased risks with repeat mediastinoscopy. Safe mediastinoscopy is based on accurate identification of anatomic landmarks and the ability to dissect nodal tissue away from vasculature and vital structures. Obliterated planes and fibrosis from the first procedure and induction therapies can make the second dissection treacherous. Two studies have revealed that a second mediastinoscopy is both safe (no deaths in a series of 279 patients) and effective, with a sensitivity of 87% and an accuracy of 94%.^35,36 These studies aside, the second mediastinoscopy has the potential to be significantly more challenging from a technical standpoint. Concern has been raised that there may be decreased sensitivity with repeat mediastinoscopy, which is a valid issue to address. Patients with persistently positive mediastinal nodes after neoadjuvant therapy may have a significantly worse prognosis than those who respond to chemoradiotherapy, and a false-negative mediastinoscopy would lead to unnecessary surgery.

As an adjunct or alternative to repeat mediastinoscopy, repeat PET scanning is often pursued. The benefits of PET scanning are clear in that using a noninvasive staging technique avoids the necessity of submitting the patient to repeat mediastinoscopy in an environment of adhesions and fibrosis while theoretically providing an equally reliable staging report. Data suggest that repeat PET scanning may accurately down- or upstage disease in up to 37% of patients, ultimately dictating operative versus nonoperative therapy.³⁷ However, one study has revealed that a repeat PET scan may be far less sensitive than initial staging PET scans.³⁸ Clearly, more research needs to be done before repeat PET scanning is viewed as a sole modality for restaging stage III lung cancer after the patient has undergone neoadjuvant therapy.⁵

The need for reliable restaging of stage III lung cancer is substantial because the response to chemoradiation has critical prognostic value. While a complete response with no evidence of residual disease is ideal, this is a rare event. Even a partial response may be beneficial, however, permitting the patient to be categorized as having a resectable and potentially curative operation. In numerous studies, patients who have had a partial response to chemoradiation and subsequently undergo definitive surgical resection have demonstrated 5-year survivals in the range of 30% to 50%, as well as a 50% improvement in locoregional control.^39–43 These results stand in sharp contrast to those of nonresponders, who have similar survival rates as patients who have surgery initially for their stage III tumor, in the range of 18% at 3 years and 9% at 5 years. Therefore, we generally suggest that patients undergo restaging following neoadjuvant chemoradiation to avoid unnecessary surgery in some patients who have had no mediastinal clearance or have documented progression.

Anterior mediastinotomy, or Chamberlain procedure, can also be used for restaging when the goal is to biopsy lymph nodes or masses in the aortopulmonary window on the left side of the chest or in the region of the hilus. Nodes in this region filter lymph from the left lung, in particular, the left upper lobe. The technique for anterior mediastinotomy is described in Chapter 156.

Since the introduction of cervical mediastinoscopy in 1959, many improvements in the diagnosis, staging, and treatment of lung cancer have been introduced. CT/PET scanning has shown promising results that may affect the use of routine mediastinoscopy in all patients with suspected lung cancer. EUS/FNA gives minimally invasive access to areas in the mediastinum inaccessible by mediastinoscopy (e.g., lower subcarinal and inferior mediastinal). That said, the importance of accurate pathologic assessment of lymph nodes remains. Thoracic surgeons need to remain facile in mediastinoscopy to ensure continued accurate pathologic nodal staging for the future.

Given the importance of pathologic staging, mediastinoscopy and thoracoscopy are crucial tools for lymph node staging. Although PET scanning has revolutionized our ability to predict the nature of pulmonary nodules and identify distant lesions that are suspicious for metastasis, tissue diagnosis is still mandatory, since a change in stage will result in a change in treatment. All patients with an identifiable lymph node by CT greater than 5 mm should be offered a noninvasive approach first if this technology and expertise are available. In addition, for those undergoing neoadjuvant treatment for stage III disease, repeat pathologic staging can predict prognosis and help avoid unnecessary resection in high-risk patients who have persistent mediastinal disease. We therefore currently try to obtain a tissue diagnosis by needle biopsy (EUS)/(EBUS) or transbronchial fine needle aspiration (TBNA)/percutaneous needle biopsy (PNB) and reserve mediastinoscopy for restaging. Alternatively, a repeat mediastinoscopy can be performed with relatively few complications. We do not accept a PET-negative mediastinum as evidence of N0 disease and likewise do not accept a PET-positive mediastinum as evidence of N2 disease. Rather, tissue, by cytology or mediastinoscopy biopsy, is routinely obtained.

The mediastinoscope used should have a rounded tip to avoid injury to vascular structures during insertion. I currently prefer to use the videomediastinoscope as it provides excellent visual acuity (for the surgeon older than 40 years old!) and a great opportunity for teaching this technically demanding procedure to residents and fellows. We routinely have a tray that includes a “box” with five compartments for the upper, lower paratracheal, and subcarinal lymph nodes. In addition, an attempt is made routinely to obtain the right level 10 tracheobronchial lymph node. I personally dissect down to level 7 first without taking any samples to avoid blood draining down and obscuring the view. Alternatively, for patients with a suspicion of lymphoma, for example, we sample “abnormal” lymph nodes as we go and send for frozen sections, stopping once any positive result is obtained.