Lung Cancer Workup and Staging

Transcription

1 CHAPTER 16 Lung Cancer Workup and Staging Bernard J. Park and Valerie W. Rusch The Staging System Diagnosis and Staging History and Physical Examination Noninvasive Modalities Chest Radiography Sputum Cytology High-Resolution Computed Tomography Positron Emission Tomography Bone Scan Magnetic Resonance Imaging Invasive Modalities Bronchoscopy Endobronchial Ultrasound Autofluorescence Bronchoscopy Percutaneous Transthoracic Needle Biopsy Cervical Mediastinoscopy Left Anterior Mediastinotomy and Extended Cervical Mediastinoscopy Scalene Node Biopsy Video-Assisted Thoracic Surgery Thoracotomy Metastatic Workup Summary It was estimated that in 2008 there were approximately 215,020 new cases of lung cancer in the United States, 1 and with 161,840 deaths projected for 2008, lung cancer remains the leading cause of cancer-related deaths in both men and women. Of newly diagnosed cases, approximately 80% will be non small cell lung cancer (NSCLC), and of these, 80% will involve disseminated or locally advanced disease. Unfortunately, only 20% will be in potentially surgically curable patients with early stage disease, where complete resection yields a 5-year survival rate approaching 70%. 2 Thorough workup and staging of the lung cancer patient are critical for a number of reasons. First, determining a patient s clinical TNM (tumor, node, metastasis) stage allows appropriate therapeutic decisions to be made on the basis of the specific stage of disease. This is particularly important for locally advanced disease in which multimodality therapy (induction or adjuvant) is now the standard of care, as well as for metastatic disease when unnecessary surgery should be avoided. Second, accurate staging allows the clinician to give the patient valuable prognostic information. Third, staging allows evaluation of new therapeutic interventions, and comparison of results of treatments between studies and institutions. There are differences and controversies regarding the extent of workup and staging that should be performed, as well as about the appropriate modalities employed. Newer modalities, such as positron emission tomography (PET) and endobronchial ultrasound (EBUS), and their roles in the characterization of lung cancer will be reviewed. THE STAGING SYSTEM Staging is a process through which the extent of lung cancer in a patient is measured by a combination of techniques that includes history, physical examination, imaging studies, and invasive procedures where appropriate. Before initiation of treatment, a clinical stage (ctnm) is generated. If surgical resection occurs, the operative findings and pathologic features determine the final pathologic stage (ptnm). In 1974, the American Joint Committee for Cancer (AJCC) Staging developed a lung cancer staging system based on TNM descriptors. 3 Naruke and coauthors 4 devised the original lymph node mapping schema that placed nodes into stations on the basis of clearly defined anatomic boundaries. Used to define the N (nodal) descriptors, it was modified for North America by the American Thoracic Society 5 and by Mountain and Dresler. 6 The current form of the map is seen in Figure In 1986, the AJCC, Union Internationale Contre le Cancer (UICC), and representatives from Japan and Germany proposed an International Staging System (ISS) for lung cancer that grouped patients with similar survival outcomes using anatomic and morphologic criteria. 7 This system was originally applied to a database of over 3000 patients from the M. D. Anderson Cancer Center and the Lung Cancer Study Group and verified significant survival differences between stages. The applicability of the ISS was subsequently confirmed by studies from Naruke and colleagues 8 and Watanabe and coworkers. 9 The version of the ISS adopted in 1997 attempted to further minimize heterogeneity within stages and refine prognostic groupings after reviewing the survival data of 5319 patients. 10 The significant changes included dividing stages I and II into A and B subsets and incorporating T3N0M0 tumors into stage IIB. In addition, satellite nodules in the same lobe of the lung as the primary lesion were designated as T4 disease, whereas all other ipsilateral synchronous lesions were designated as M1. The current sixth edition of TNM Classification of Malignant Tumours introduced in 2002 made no alterations to the previous edition with respect to lung cancer. 11 In 1996, the International Association for the Study of Lung Cancer (IASLC) initiated an international staging project to form the basis of the seventh edition of the TNM staging system. 12 The goals of the project were to validate the individual T, N, and M descriptors using a larger database made up of medical and surgical patients from a wide geographic distribution. 13 Data on 100,869 patients, including 67,725 cases of NSCLC, were submitted to the database, and several changes were proposed. 14 The existing N descriptors were validated 241

2 242 Section 1 / Thoracic Surgery 1 Supraclavicular zone 1 Low cervical, supraclavicular, and sternal notch nodes 13R 2R 2L 4R Ao 4L 12R 10R 10L PA 11R 7 12R 11R 8 12R R 11L 12L 13L 14L SUPERIOR MEDIASTINAL NODES Upper zone 2R Upper paratracheal (right) 2L Upper paratracheal (left) 3A Pre-vascular 3P Retrotracheal 4R Lower paratracheal (right) 4L Lower paratracheal (left) AORTIC NODES AP zone 5 Subaortic 6 Para-aortic (ascending aorta or phrenic) INFERIOR MEDIASTINAL NODES Subcarinal zone 7 Subcarinal Lower zone 8 Paraesophageal (below carina) 9 Pulmonary ligament 3A 6 N1 NODES Hilar/Interlobar zone 10 Hilar 11 Interlobar 3P 5 12 Lobar 13 Segmental 14 Subsegmental Peripheral zone Figure 16 1 Regional lymph node stations for the staging of non small cell lung cancer. Ao, aorta; PA, pulmonary artery. (From Rusch VW, Asamura H, Watanabe H, Giroux DJ, Rami-Porta R, Goldstraw P. The IASLC Lung Cancer Staging Project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2009;4:568.) and not changed. 15 For the T descriptors, suggestions were made to make additional size cutoffs to the T1 and T2 tumors and to designate tumors greater than 7 cm in greatest dimension as T3, recognizing the poor prognostic significance of increasing size of the primary tumor (Table 16-1). 16 Furthermore, additional tumor nodules in the same lobe as the primary are proposed to be T3, whereas other nodules in the ipsilateral lobes become T4. It was recommended that the M descriptor be divided into M1a (for pleural metastases, malignant effusion, or contralateral pulmonary disease) and M1b (for extrathoracic metastases). 17 After incorporating the suggested changes into the data and reanalyzing the TNM subsets, new stage groupings were identified that yield even distributions between stages, particularly between stages IIA and IIB (Table 16-2). DIAGNOSIS AND STAGING Diagnosis and clinical staging take place concurrently, beginning with the initial history and physical examination. A variety of noninvasive and invasive tests are available to evaluate a patient suspected of having lung cancer, and often a single study serves the dual purpose of securing a diagnosis and staging the patient. If a patient s treatment is nonsurgical or involves multimodality therapy, obtaining a tissue diagnosis prior to treatment is mandatory. If it appears that the patient s clinical stage will be most appropriately managed by surgical resection alone, tissue confirmation of malignancy can be secured either preoperatively or at the time of exploration, depending on the preference of the operating surgeon.

3 Chapter 16 Lung Cancer Workup and Staging 243 Table 16 1 Proposed Definitions for T, N, and M Descriptors T (Primary Tumor) TX T0 Tis T1 T1a T1b T2 T2a T2b T3 Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy No evidence of primary tumor Carcinoma in situ Tumor 3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus) * Tumor 2 cm in greatest dimension Tumor > 2 cm but 3 cm in greatest dimension Tumor > 3 cm but 7 cm or tumor with any of the following features (T2 tumors with these features are classified T2a if 5 cm) Involves main bronchus, 2 cm distal to the carina Invades visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung Tumor > 3 cm but 5 cm in greatest dimension Tumor > 5 cm but 7 cm in greatest dimension Tumor > 7 cm or one that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in the main bronchus < 2 cm distal to the carina * but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor nodule(s) in a different ipsilateral lobe N (Regional Lymph Nodes) NX N0 N1 N2 Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) N3 M (Distant Metastasis) Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) MX M0 M1 Distant metastasis cannot be assessed No distant metastasis Distant metastasis M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or pericardial) effusion M1b Distant metastasis * The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1. Most pleural (and pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be classified as T1, T2, T3, or T4. From Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007;2(8):709. History and Physical Examination Patients often present for evaluation with a number of studies already performed. However, for several reasons, the history and physical examination remain the most important initial steps in evaluating patients who are suspected of having lung cancer. A detailed history focusing on risk factors such as duration of cigarette smoking, exposure to asbestos and other industrial hazards, a prior history of lung cancer, and the presence of symptoms allow the clinician to assess the probability of the diagnosis of lung cancer. Bach and associates showed that the duration of tobacco smoking, more so than the amount of daily usage, increases an individual s

4 244 Section 1 / Thoracic Surgery Table 16 2 Descriptors, Proposed T and M Categories, and Proposed Stage Groupings Sixth Edition T/M Descriptor Proposed T/M N0 N1 N2 N3 T1 ( 2 cm) T1a IA IIA IIIA IIIB T1 (>2 3 cm) T1b IA IIA IIIA IIIB T2 ( 5 cm) T2a IB IIA IIIA IIIB T2 (> 5 7 cm) T2b IIA IIB IIIA IIIB T2 (> 7 cm) T3 IIB IIIA IIIA IIIB T3 invasion IIB IIIA IIIA IIIB T4 (same-lobe nodules) IIB IIIA IIIA IIIB T4 (extension) T4 IIIA IIIA IIIB IIIb M1 (ipsilateral lung) IIIA IIIA IIIB IIIB T4 (pleural effusion) M1a IV IV IV IV M1 (contralateral lung) IV IV IV IV M1 (distant) M1b IV IV IV IV Cells in bold indicate a change from the sixth edition for a particular TNM category. From Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007;2(8):709. risk of developing lung cancer. 18 Similarly, the risk associated with asbestos increases with the intensity and length of exposure, and together, tobacco use and asbestos exposure have a multiplicative effect. Certain symptoms, such as bone pain, hoarseness, weight loss, and neurologic changes, can indicate the presence of metastatic disease and mandate further investigation. A thorough physical examination is also critical. It provides an estimate of a patient s overall health status, which has significant implications for the types of treatments available to that individual. Certain physical findings, such as ptosis, miosis, and anhidrosis in patients with Horner s syndrome, or the presence of clubbing, can support the suspicion of lung cancer. Furthermore, the physical examination can often demonstrate advanced disease even before any radiographic or other studies are performed. For example, palpation of the supraclavicular fossae can reveal lymph node metastases, and auscultation of the lung fields can detect the presence of a malignant pleural effusion. NONINVASIVE MODALITIES Chest Radiography The standard posteroanterior and lateral chest radiographs are the most common initial study in which a suspected lung cancer is identified. Lesions are detected on a chest radiograph performed for symptoms or for unrelated reasons, such as part of a routine health assessment or preoperative clearance. Most lesions are not visible until they are at least 7 to 10 mm in diameter, 19 at which time they contain roughly 1 billion cells, representing 30 doublings. 20 A high-quality chest radiograph can impart a large amount of information and should be reviewed carefully. It localizes the site of suspect lesions (central or peripheral) and the local extent and effects of disease, showing areas of atelectasis, consolidation, or proximity to the pleural surface. The presence of a pleural effusion indicative of a T4 tumor can be seen, as well as elevation of the hemidiaphragm in the event of phrenic nerve involvement. Advanced disease may be identified in the case of rib destruction from bone metastases or synchronous lesions in the pulmonary parenchyma. Hilar and mediastinal lymph node metastasis is more difficult to identify, unless there is substantial enlargement. Sputum Cytology Cytologic analysis of sputum for malignant cells is a simple diagnostic technique, although it is being used less often in North America than in the past because bronchoscopy and percutaneous needle biopsy are used more now, and because of the decrease in the proportion of squamous cell cancers. Samples obtained may be induced by saline nebulization or collected as a 3-day pool of sputum produced from spontaneous coughing in the morning. Induced specimens should be immediately fixed and stained. Pooled samples are preserved in Saccomanno s solution (50% ethanol and 2% polyethylene glycol), or 70% ethanol until fixation and staining can be performed. Schreiber and McCrory 21 performed a meta-analysis of the published data on the diagnostic accuracy of sputum cytology in lung cancer. Most studies included a variety of indications for testing with only a few evaluating the sensitivity and specificity of sputum cytology in patients suspected of having lung cancer. Based on 16 published studies of at least 50 patients each, the overall sensitivity is 66% (range, 42% to 97%) and the overall specificity is 99% (range, 68% to 100%). The false-positive and false-negative rates are 9% and 6%, respectively. When sputum cytology is used for patients suspected of having lung cancer on clinical grounds, the diagnostic yield is higher, with a sensitivity of 87% and a specificity of 90%, as demonstrated by Jay and colleagues. 22 A number of authors have shown that the sensitivity of sputum cytology for detecting lung cancer depends on the number of specimens collected per patient. Pilotti and coworkers, 23 Liang, 24 and Böcking and coworkers 25 confirmed that the optimal diagnostic sensitivity requires three specimens per patient. Other factors that influence the diagnostic sensitivity of sputum cytology include tumor location, size, and histologic type. Schreiber and McCrory 21 reviewed 17 studies that compared the sensitivity of sputum cytology in central versus peripheral lung lesions. Meta-analysis showed that the overall sensitivity was 71% for central lesions and 49% for peripheral lesions. The most likely explanation is that central tumors have a higher likelihood of shedding tumor cells into expectorated sputum because of their proximal bronchial location. Kato and associates 26 found that large tumors (greater than 3 cm), tumors associated with atelectasis or consolidation, and lower lobe location had higher diagnostic yields. In their study, the lowest sensitivity (20%) for sputum cytology occurred with peripheral tumors less than 3 cm in diameter. Histology of the tumor generally has less influence on the diagnostic accuracy of sputum cytology than the other

5 Chapter 16 Lung Cancer Workup and Staging 245 A B Figure 16 2 Positron emission tomography computed tomography (PET-CT) showing a right superior sulcus tumor (A) and the presence of an asymptomatic retroperitoneal metastasis (B). factors mentioned. Squamous carcinomas are, however, more frequently diagnosed by sputum analysis than adenocarcinomas or large cell carcinomas. This is probably related to the fact that squamous tumors are more commonly central in location. High-Resolution Computed Tomography Once a suspect lesion is detected on a chest radiograph or a low-dose computed tomography (CT) scan, the standard next step in the evaluation is a high-resolution CT of the chest and upper abdomen. This will yield information about the features and local extent of a potential lung cancer, giving precise size measurements and demonstrating signs of malignancy within a given lesion (spiculation, ground-glass opacification, lack of calcification). Evidence of invasion of contiguous structures, such as chest wall or mediastinal structures, can be assessed. This is especially critical when planning operative intervention, although unresectable involvement of surrounding structures may require surgical exploration for verification. CT also provides details about the remaining lung parenchyma and pleural spaces. Satellite or additional nodules, bullous or emphysematous changes, pleural thickening, masses, or effusion may be identified. Typically, the chest CT for a suspected lung cancer includes the upper abdomen, specifically the liver and adrenal glands. Although most asymptomatic, incidental lesions in the upper abdomen are benign (adrenal adenoma, hepatic cysts), unsuspected metastases are identified in a small percentage of patients. In addition to providing information about the primary tumor and the possibility of distant metastases, CT of the chest allows assessment of mediastinal lymph nodes. If not contraindicated, intravenous contrast is useful in distinguishing nodes from vascular structures. The most widely used criterion to define metastatic involvement is a short-axis diameter of 1 cm or greater. Although it is the most effective radiographic method of measuring lymph node enlargement, CT alone is inadequate to reliably predict metastatic nodal disease. In a prospective study of 143 patients with bronchogenic carcinoma in which CT findings were correlated with surgical pathologic staging, McLoud and coauthors 27 reported that the sensitivity of CT in predicting mediastinal nodal status was 64%, with a specificity of 62%. Toloza and colleagues 28,29 reported results of a meta-analysis of 20 studies with 3438 evaluable patients that showed an overall sensitivity of 57% and specificity of 82%. Therefore, staging of the mediastinum and subsequent therapeutic decisions should not be based solely on the results of the CT in most cases. Positron Emission Tomography Whole-body PET is a physiologic imaging technique based on the detection of positrons emitted by low-atomic-weight isotopes (carbon, fluorine, oxygen, nitrogen). Fluorodeoxyglucose (FDG) labeled with radioactive fluoride ( 18 F) is a d-glucose analog that is phosphorylated after cellular uptake and accumulates intracellularly, rather than being metabolized. Because lung cancer cells have an increased rate of glycolysis and overexpress the glucose transporter, there is preferential accumulation and visualization of FDG in the primary tumor and in potentially metastatic sites (Fig. 16-2). 30 The criterion for an abnormal PET scan is either a standardized uptake value (SUV) of greater than 2.5 or uptake in the lesion that is greater than the background activity of the mediastinum. Currently, the lower limit of resolution of PET is approximately 1.0 to 1.2 cm. In addition, certain non-neoplastic processes (such as inflammatory conditions and infections) can produce false-positive PET findings. Despite these limitations, PET has become an invaluable tool in lung cancer staging.

6 246 Section 1 / Thoracic Surgery Several recent studies have shown that PET is superior to CT in staging the mediastinum in lung cancer patients. Pieterman and colleagues 31 prospectively compared standard staging approaches to PET for detection of mediastinal lymph node and distant metastases in 102 patients with resectable NSCLC who underwent histologic staging of the mediastinum. The sensitivity and specificity of PET for detection of mediastinal nodal metastases were 91% and 86%, respectively, compared with a sensitivity of 75% and a specificity of 66% for CT. Similarly, meta-analysis of 18 studies by Toloza and coworkers 28,29 demonstrated an overall sensitivity of 84% and specificity of 89%. Pieterman and associates 31 also showed that combining CT and PET resulted in the highest diagnostic accuracy, with a sensitivity of 94% and a specificity of 86%, supporting the use of both modalities for staging of the mediastinum. Another significant result in the study by Pieterman and coauthors 31 was the observation that PET resulted in a stage different from the one arrived at by the standard methods in 62 of 102 patients, correctly indicating a lower stage in 20 patients and higher-stage disease in 42 patients. More importantly, PET was effective in identifying occult metastatic disease. In 11 patients (11%), PET demonstrated distant metastatic disease that was not detected by the usual staging tests. The sites of metastasis included bone, liver, and adrenal gland. Within the past 10 years, integrated PET-CT scanners have replaced dedicated PET alone because of improved diagnostic accuracy and anatomic localization of disease. 32 Lardinois and colleagues 33 compared the diagnostic accuracy of integrated PET-CT with CT alone, PET alone, and visually correlated PET and CT in 50 patients with proved or suspected NSCLC. In 40 patients who underwent histologic confirmation, tumor staging was significantly more accurate with integrated PET- CT than with CT alone (P =.001), PET alone (P <.001), or visual correlation of PET and CT (P =.013). In 37 patients with histologic confirmation of nodal status, integrated PET- CT was more accurate in assessing the mediastinum than PET alone (P =.013). Moreover, unsuspected extrathoracic metastases were discovered in 16% (8 of 49 patients). Similarly, Cerfolio and coauthors compared PET with and without integrated CT in 129 patients with biopsy-proved or suspected NSCLC who subsequently underwent surgical staging. 34 PET-CT was a significantly better predictor of stages I and II disease and demonstrated superior accuracy for both T status (70% versus 47%, P =.001) and N status (78% versus 56%, P =.008) compared with PET alone. Moreover, PET-CT was more sensitive and more specific and had a higher positive predictive value for the status of N1 and N2 disease (P <.05). As in prior studies, PET-CT identified 19 (14.7%) patients with M1 disease. With respect to the evaluation for the presence of bone metastases, PET-CT has proved to be more accurate than a bone scan, with a similar sensitivity and a higher specificity In the largest study comparing PET with bone scan, Song and colleagues retrospectively analyzed 1000 newly diagnosed patients, 105 of whom were eventually diagnosed with bone metastases and underwent PET-CT and bone scan. 37 PET-CT was more accurate (98.3% versus 95.1%, P <.001), sensitive (94.3% versus 78.1%, P =.001) and specific (98.8% versus 97.4%, P =.006) than bone scan. PET-CT also showed a lower incidence of false positives (1.2% versus 2.9%) and false-negative results (5.7% versus 21.9%) compared with a bone scan. Agreement between PET-CT and bone scan findings was good, with a calculated κ = Based on its clear advantages in noninvasive intrathoracic staging, and particularly in the identification of occult extrathoracic disease, PET- CT should be a routine part of pretreatment staging. Bone Scan Although PET-CT has essentially replaced it for evaluation of potential skeletal metastases, when utilized in the setting of a positive clinical assessment (e.g., bone pain or tenderness), a technetium-99m methylene diphosphate ( 99m Tc MDP) wholebody bone scan is relatively sensitive, but not specific. In their meta-analysis of seven studies and 633 patients, Toloza and colleagues 28,29 showed that bone scans have an overall sensitivity of 87% and specificity of 67%. False-positive abnormalities are more common when scans are done in asymptomatic patients and can be the result of degenerative or traumatic skeletal injury. Follow-up imaging with magnetic resonance imaging (MRI) may or may not aid in establishing a definitive diagnosis. False-negative results, although uncommon, do occur, and in one series 6% of patients with an initially negative bone scan developed confirmed skeletal metastases within 1 year. 38 Magnetic Resonance Imaging MRI of the chest for the evaluation and characterization of pulmonary lesions and the mediastinum offers few advantages over CT in the diagnosis or staging of lung cancer. Heelan and coworkers 39 evaluated both CT and MRI in otherwise operable patients with NSCLC and found that MRI was no more accurate than CT in identifying hilar or mediastinal lymph node metastases and actually had a higher false-positive rate. In some situations, however, MRI can be useful. When tumors are adjacent to the vertebral body or spinal canal, MRI provides superior visualization of the spinal canal and can more accurately detect subtle changes in the marrow suggestive of invasion. In addition, MRI can more accurately delineate a superior sulcus tumor s relationship to major vessels and the brachial plexus at the thoracic outlet. INVASIVE MODALITIES Bronchoscopy Rigid or flexible bronchoscopy with conventional white light allows visualization of the tracheobronchial tree and is a standard part of evaluating patients with known or suspected lung cancer. It serves several critical purposes: diagnosis, staging, assessment of resectability, and visualization of the remaining bronchial tree. Flexible video-assisted bronchoscopy has become a widely used technique, replacing rigid bronchoscopy for all but a few special circumstances. Flexible bronchoscopy is generally performed as an outpatient procedure on a spontaneously breathing patient through the nasal or oral route, following topical anesthesia and sedation. The tracheobronchial tree up to the second or third subsegmental bronchi is easily visualized. The options available to secure a diagnosis include direct biopsy, brushing, saline lavage for cytology, and transbronchial needle aspiration (TBNA) with or without fluoroscopic guidance. Employing more than one

7 Chapter 16 Lung Cancer Workup and Staging 247 A B Figure 16 3 A, CT scan of the chest revealing enlarged right paratracheal lymph node. B, Endobronchial ultrasound (EBUS) guided transbronchial needle aspirate of an enlarged right paratracheal lymph node. technique (e.g., biopsy, brushing, and cytologic lavage) generally improves the diagnostic yield. When bronchoscopy reveals an endobronchial tumor, biopsy is best accomplished with either a forceps or brush biopsy, with sensitivities in the range of 80% to 100%. 40,41 Positive endobronchial findings are more common with squamous and small cell cancers because of their central location. In contrast, a normal bronchoscopic examination is usually seen with peripheral lesions, and the diagnostic sensitivity of bronchoscopy varies widely from 37% to 98%, depending on the size and location of the target lesion. Increasing size and presence of a bronchus sign (a bronchus leading to or contained in a lesion on CT) portend a higher diagnostic yield. 41 The use of fluoroscopy to guide a transbronchial biopsy or TBNA and lavage can improve diagnostic accuracy up to 80%. 42 TBNA can also be used when there is bronchial distortion (thickening or blunting of the carina, extrinsic compression) secondary to the lesion or metastatic lymph nodes. Popularized by Wang and Terry, TBNA employs a 20- to 22-gauge, rigid needle through the channel of the fiberoptic bronchoscope to puncture the airway in the area of interest. 43 It is a safe and inexpensive procedure with an overall sensitivity of 50% and a specificity of 96%. 40,41 As previously mentioned, diagnostic yield is enhanced by the use of fluoroscopy, as well as the use of rapid, on-site cytopathology. A positive result, especially from a mediastinal lymph node station, can obviate further surgical staging, although a negative result should still be confirmed surgically. Limitations include a sensitivity of only 30% for small (<2 cm), peripheral lesions, and inaccessibility of certain lymph node stations, including anterior, aortopulmonary, paraesophageal, and pulmonary ligament nodes. Endobronchial Ultrasound In an effort to improve on the diagnostic accuracy of TBNA, EBUS was developed and commercially introduced in the early 1990s. 44 The original probe was radial, and radial EBUS guidance was shown to improve the yield of TBNA in the lymph node staging of lung cancer. 45,46 More recently, a new ultrasonic endoscope with a built-in linear-array, convex probe at the tip was developed by the Olympus Corporation (Tokyo) to enable real-time EBUS-guided TBNA. This EBUS is integrated with a convex transducer at 7.5 MHz at the tip of a flexible bronchoscope (XBF-UC260F-OL8, Olympus), whose angle of view is 90 degrees and direction of view is 30 degrees forward oblique. The ultrasound scans parallel to the insertion direction of the scope, and images are obtained by directly contacting the probe, with or without a salinefilled balloon at the tip. The ultrasound image is processed by a dedicated scanner (EU-C2000) that allows for image freezing, size measurement, and Doppler mode. A special 22- gauge needle is passed under direct visualization through the instrument channel to biopsy the target lesion through the bronchial wall (Fig. 16-3). The procedure can be done under monitored anesthesia care or general anesthesia. Indications for EBUS-TBNA include diagnosis of lung and mediastinal tumors and assessment of mediastinal and hilar lymph nodes. Accessible nodal stations include levels 2, 3, 4, 7, 10, and 11. Subaortic, paraesophageal, peribronchial, segmental, and subsegmental nodes are general not approachable. Several retrospective studies have demonstrated excellent accuracy of EBUS-TBNA for mediastinal and hilar nodal staging in NSCLC In one of the earliest and largest series of patients, Yasufuku and colleagues 48 successfully performed EBUS-TBNA in 105 patients with proved or suspected lung cancer and suspect adenopathy by CT criteria alone. They sampled 163 lymph nodes and reported an overall diagnostic accuracy rate of 96.3%, with a sensitivity of 94.6% and a specificity of 100%. Of note, patients who proved to have benign disease were excluded from analysis, and not all patients had confirmatory surgical biopsy of the nodal stations biopsied by EBUS. No studies to date have compared results of EBUS-TBNA with those of cervical mediastinoscopy. Despite the lack of studies with histologic confirmation of all nodal stations sampled by EBUS, this new technology is clearly emerging as a potential alternative to more invasive mediastinal and hilar staging. Autofluorescence Bronchoscopy Detection and treatment of subtle dysplastic or early invasive neoplastic lesions whose presence is suggested by positive sputum cytology remain a challenge. In one study,

8 248 Section 1 / Thoracic Surgery Woolner 50 reported that only 29% of the carcinoma in situ detected by sputum cytology could be localized by conventional bronchoscopy. Additional studies have shown that roughly one third of patients with positive sputum cytology, but radiographically occult lung cancers, require more than one bronchoscopy for localization. 51,52 In an effort to improve identification of superficial bronchial mucosal malignancy, Hung and associates 53 were able to demonstrate that normal and malignant bronchial mucosa have different autofluorescence intensities under blue light (wavelength, 442 nm). This led to the development of the LIFE (light imaging fluorescence endoscope) Lung system (Xillix Technologies, Richmond, BC, Canada). Whereas normal bronchial mucosa appears green, premalignant and malignant tissue appears brown-red. 54 Subsequent prospective trials comparing whitelight bronchoscopy alone with white-light bronchoscopy plus LIFE have shown enhanced sensitivity in detection of intraepithelial neoplasms and invasive carcinoma Lam and coauthors 57 reported the results of a multicenter North American trial of 173 patients that showed the relative sensitivity of white-light bronchoscopy plus LIFE versus white-light bronchoscopy alone to be 6.3 for intraepithelial lesions, and 2.71 if invasive cancers were included. The role of LIFE was in preoperative screening for synchronous squamous carcinomas, but follow-up for recurrence or second primary tumors, and for monitoring intraepithelial dysplasia in some chemoprevention trials, it is not currently in widespread use. Percutaneous Transthoracic Needle Biopsy Percutaneous transthoracic needle biopsy is a well-established procedure used in confirming a tissue diagnosis of lung cancer in patients who are not surgical candidates because of advanced disease or medical contraindications. However, with the identification of increasing numbers of noncalcified pulmonary nodules by low-dose CT, transthoracic needle biopsy is becoming a critical tool in the detection of early stage lung cancer. Although both fluoroscopic and CT guidance are employed, CT is the preferred modality for several reasons. CT allows planning precise trajectories that avoid aerated lung, blood vessels, bullae, and vital cardiovascular structures in the mediastinum. Smaller lesions can be biopsied, and CT can enable differentiation between necrotic and viable areas in a larger tumor, improving diagnostic yield. 58 The most common complications of the procedure are pneumothorax and mild hemoptysis. Although the reported incidence of pneumothorax varies greatly, the rate of postprocedure pneumothoraces requiring intervention ranges from 1.6% to 17%. 59,60 The most important risk factor is underlying chronic obstructive pulmonary disease (COPD). 61 Hemoptysis occurs in 5% to 10% of cases and is usually self-limited. Massive hemoptysis is extremely rare with the use of 20-gauge or smaller needles. 62,63 Relative contraindications to transthoracic biopsy, therefore, are the presence of severe COPD, a bleeding disorder, contralateral pneumonectomy, and severe pulmonary hypertension. When successful, the results of percutaneous transthoracic biopsy are positive in patients with lung cancer in roughly 90% of cases, with a low false-positive rate of less than 2%. 64 However, false-negative results can be frequent, so all results should be considered indeterminate unless a specific benign diagnosis is made. Cervical Mediastinoscopy Accurate assessment is paramount as mediastinal lymph node involvement by metastatic carcinoma strongly influences treatment decisions. Cervical mediastinoscopy is the most accurate pre-thoracotomy method of staging the mediastinum in bronchogenic carcinoma. Described by Carlens in 1959, mediastinoscopy employs a rigid, lighted scope placed in the avascular, pretracheal space to access the superior mediastinum. 65 Its efficacy is well established, with a pooled procedural sensitivity of 81% and a specificity of 100% in a recent meta-analysis of 5687 patients. 29 Moreover, a negative mediastinoscopy predicts a high rate of complete resection at thoracotomy. Luke and colleagues 66 demonstrated that of 590 patients with a negative mediastinoscopy, 93% had complete tumor resection. Cervical mediastinoscopy is an outpatient procedure that is extremely safe. In a review of 2137 patients, Hammoud and coworkers 67 reported overall morbidity and mortality rates of 0.6% and 0.05%, respectively. The indications for mediastinoscopy are often debated, and routine mediastinoscopy is controversial. Most thoracic surgeons would agree that mediastinoscopy should be performed for the following: (1) lymph node enlargement greater than 1 cm in the short axis on CT, (2) hypermetabolic uptake on PET, and (3) possible enrollment into induction therapy protocols. Relative indications include the presence of T2 or T3 tumor, adenocarcinoma, or large cell carcinoma. 68 Those who support the practice of routine mediastinoscopy emphasize its low complication rate and accuracy, the high rate of complete resection after a negative mediastinoscopy, the relatively low sensitivity of CT, the prevalence of nodal disease even in T1 tumors (Table 16-3), and the ability to select patients who might benefit from induction therapy. Left Anterior Mediastinotomy and Extended Cervical Mediastinoscopy One limitation of mediastinoscopy can be in the setting of a left upper lobe cancer, in which aortopulmonary window and para-aortic lymph nodes (levels 5 and 6) may need to be sampled. In this situation, there are two options for surgical staging. Most commonly, level-5 and level-6 mediastinal lymph nodes can be accessed from a left anterior or parasternal approach, as described by McNeill and Chamberlain. 69 A transverse incision is placed over the second rib, and the costal cartilage is removed. The retrosternal extrapleural space is entered by blunt dissection and the para-aortic space is explored. Modifications of the procedure include preservation of the internal mammary vessels, use of the mediastinoscope for better visualization, and preservation of the cartilaginous rib. In three reported series totaling 194 patients with left upper lobe cancers who underwent a Chamberlain procedure, 38% (73 of 194) had positive biopsy results, and resectability in those patients with a negative anterior mediastinotomy was 95%. 70 As with cervical mediastinoscopy, morbidity and mortality in previously reported series are low 8% and 0%, respectively. A second, less commonly employed surgical approach to the anterior mediastinum in left upper lobe cancers is extended mediastinoscopy, as described by Ginsberg and associates. 71 After a pathologically negative standard cervical mediastinoscopy, the mediastinoscope is withdrawn, and blunt digital

9 Chapter 16 Lung Cancer Workup and Staging 249 Table 16 3 Prevalence of Nodal Metastases in Clinical T1 Non Small Cell Lung Cancer Author (ref) Patients (N) Node + (%) N1 (%) N2 (%) Skip N (%) Ishida et al. (87) Naruke (88) Asamura et al. (89) Oda et al. (90) Graham et al. (91) dissection is used to create a window between the innominate and left carotid arteries posterior to the innominate vein. The mediastinoscope is reinserted and advanced along the anterolateral surface of the aortic arch into the node-containing fat pad. Extended mediastinoscopy should be avoided in patients with a dilated or calcified aortic arch or previous sternotomy. Because of the nature of the dissection and the emergence of other minimally invasive alternatives to accessing the aortopulmonary window, such as EUS and video-assisted thoracic surgery (VATS), extended mediastinoscopy is not widely performed. Scalene Node Biopsy Scalene node biopsy is used to assess suspect nodes in the supraclavicular fossa, identified by either palpation or imaging (specifically, PET). It has also been shown to be valuable to rule out N3 disease in patients with proven N2 disease. In the event that there are grossly palpable nodes in the supraclavicular fossa, a fine-needle aspiration (FNA) in the office is often sufficient. Should an FNA be nondiagnostic, or if metastatic disease is suspected on imaging alone, a formal excision of the fat pad may be performed. A 3- to 4-cm incision is placed over the insertion of the sternocleidomastoid muscle parallel to the clavicle. Dissection is performed between the clavicular and sternal heads, exposing the scalene fat pad on top of the scalenus anterior muscle. Care must be taken to preserve the phrenic nerve lying posterior on the scalenus anterior muscle. Alternatively, Lee and Ginsberg 72 reported a technique whereby scalene node biopsy can be done during a positive cervical mediastinoscopy employing a single incision. They showed that 15.4% of patients (6 of 39) with positive N2 disease had positive scalene nodes as well, indicating N3 disease. Video-Assisted Thoracic Surgery Video-assisted thoracic surgery, with a thoracoscope and enhanced video optics and instrumentation, provides another valuable tool for the diagnosis and staging of NSCLC. It requires general anesthesia and a patient who can tolerate single-lung ventilation. With the patient in a standard lateral decubitus position, the thoracoscope and endoscopic instruments are inserted through two or more operating ports placed via small incisions through the intercostal space. With this technique, the entire hemithorax can be explored, including the hilum, mediastinum, visceral and parietal pleural surfaces, and chest wall. The principal use of VATS has been to perform the excisional biopsy of peripheral lung nodules for the diagnosis of primary lung cancer or to rule out synchronous or metastatic disease. 73,74 However, VATS is less effective for lesions located in the posterior paravertebral space or situated deep in the lung parenchyma. It can be used to evaluate mediastinal lymph nodes in patients with lung cancer. In particular, VATS can be used to sample nodes inaccessible by cervical mediastinoscopy (anterior, aortopulmonary, paraaortic) or anterior mediastinotomy (hilar, inferior pulmonary ligament). 75,76 Several studies have shown that the sensitivity and accuracy of VATS approach 100% for diagnosis and staging of lung cancer, with minimal morbidity and mortality. Thoracotomy When other diagnostic and staging modalities have failed, thoracotomy is indicated for accurate diagnosis, staging, and subsequent curative treatment of potential lung cancers. With the myriad of accurate, less invasive diagnostic methods available, more than 95% of tumors can be characterized without thoracotomy. Exploratory thoracotomy, however, still allows the most thorough assessment of the primary lesion, the pleural space, and the ipsilateral mediastinal lymph nodes. The tumor is typically biopsied by Tru-Cut needle, and the local extent and status of the mediastinal lymph nodes are assessed while the pathologists analyze the specimen by frozen section. METASTATIC WORKUP Approximately 40% of patients with newly diagnosed lung cancer are found to have extrathoracic metastases. Identifying these patients is critical to avoid unnecessary thoracotomy and delaying appropriate systemic therapy. Currently, the standard multiorgan imaging techniques used to rule out the most common metastases in patients with NSCLC (adrenal, liver, brain, bone) are CT of the chest and upper abdomen, CT or MRI of the brain with contrast, and whole-body PET-CT. Who should undergo evaluation for distant metastatic disease? There are precious few prospective randomized trials of extrathoracic imaging for NSCLC. It is well accepted that patients who have certain symptoms, abnormal physical findings, or laboratory abnormalities are at increased risk of having metastatic disease. Silvestri and coauthors showed in a large meta-analysis that a positive clinical evaluation was

10 250 Section 1 / Thoracic Surgery Table 16 4 Clinical Evaluation for Metastatic Disease Clinical Evaluation Symptoms Physical signs Laboratory tests Finding Constitutional: weight loss > 5% of body weight, malaise Musculoskeletal: focal skeletal pain Neurologic: headache, seizure, mental status or personality changes Focal neurologic deficit Supraclavicular lymphadenopathy Hoarseness Superior vena cava syndrome Bony tenderness Skin or soft tissue mass Hepatomegaly Anemia Elevated liver function tests Hypercalcemia associated with a roughly 50% rate of abnormal scans. 77 These results underscore how critical the findings of the initial history, physical examination, and laboratory tests are in guiding subsequent workup. Patients with a positive clinical evaluation (Table 16-4) should undergo multiorgan scanning. What about asymptomatic patients? Routine multiorgan imaging in patients without symptoms or signs is controversial. Several studies have shown that routine preoperative scanning in asymptomatic patients is associated with a low percentage (3% to 10%) of positive results, with silent metastases found in 2.7% to 15%. 78,79 In their meta-analysis, Silvestri and colleagues 77 calculated the probability that a scan will be negative if the clinical evaluation is negative (i.e, the negative predictive value of the clinical evaluation). For CT of the abdomen or brain, and for bone scan, the negative predictive values were 94%, 95%, and 89%, respectively. The only prospective, randomized trial that compared routine multiorgan scanning with chest CT and mediastinoscopy in asymptomatic patients with clinically operable lung cancer showed no statistically significant difference in the rate of unnecessary thoracotomy, postoperative recurrence, or overall survival. 80 Despite this, more recent data have shown whole-body PET and PET-CT to be invaluable in disclosing non central nervous system metastatic disease in up to 10% to 20% of cases missed by standard methods. 31,81-83 On this basis, PET-CT should be considered a standard staging modality in all cases of biopsy-proved or suspected lung cancer, and it obviates the need for bone scan as well. In addition, some authors have reported that more locally advanced lesions (T3 or N2) have a higher rate of asymptomatic distant metastases. 84,85 Others have shown that adenocarcinomas have a higher rate of asymptomatic cerebral metastases than squamous carcinomas. 79,86 Based on the available information, we believe that all patients with established or suspected lung cancer should undergo high-resolution, contrast CT of the chest and whole-body PET-CT. Additional appropriate multiorgan scanning should be considered for (1) any patient with a positive clinical evaluation (symptoms, signs, blood work), (2) patients with locally advanced disease (stage IIIA) being considered for multimodality therapy, and (3) patients with earlier-stage disease (stages I, II) who are marginal operative candidates. Summary Lung cancer remains a challenging and deadly disease. Proper diagnosis and staging are critical for determining the best treatment strategy for each individual patient. 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