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LUNG CANCER WORKUP AND STAGINGValerie W. Rusch

In 2010, the most recent year for which numbers are available, there were 201,144 new cases of lung cancer (107,164 men and 93,984 women) in the United States.1 With 158,248 deaths, 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 metastatic or locally advanced disease. Only 20% will be in potentially surgically curable patients with early-stage disease, where complete resection yields 5-year survivals of 40% to 75%.2

Careful staging of newly diagnosed lung cancer is critical for several reasons. First, determining the patient’s clinical TNM (tumor, nodes, metastasis) stage allows appropriate therapeutic decisions to be made on the basis of the specific stage of disease. This is particularly impor-tant for locally advanced disease in which multimodality therapy (induction or adjuvant) is standard care, as well as for metastatic disease when 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 controversies about the extent of workup, and the methods used for staging have evolved during the past decade.

THE STAGING SYSTEM

Staging is a process through which the extent of lung cancer in a patient is determined by a combination of techniques including history, physical examination, imaging studies, and invasive procedures where appropri-ate. 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 coauthors4 devised the original lymph node map that placed nodes into stations on the basis of defined anatomic boundaries. This was subsequently modified for North America by the American Thoracic Society5 and by Mountain and Dresler.6 In 1986, the AJCC, International Union Against Cancer (UICC), and representatives from Japan pro-posed an International Staging System (ISS) for lung cancer that grouped patients with similar survival out-comes using anatomic criteria.7 This system was derived from analyses of a 3000-patient database at the M. D. Anderson Cancer Center (MDACC). The accuracy of the ISS was further confirmed by studies from Naruke8 and Watanabe.9 In 1997, analyses of the updated MDACC database of 5319 patients10 led to revision of the ISS,

C H A P T E R 1 6

THE STAGING SYSTEM

DIAGNOSIS AND STAGINGHistory and Physical Examination

NONINVASIVE MODALITIESChest RadiographySputum CytologyLow-Dose Computed TomographyHigh-Resolution Computed TomographyPositron Emission TomographyBone ScanMagnetic Resonance Imaging

INVASIVE MODALITIES

CHAPTER OUTLINE

BronchoscopyEndobronchial UltrasoundAutofluorescence BronchoscopyPercutaneous Transthoracic Needle BiopsyCervical MediastinoscopyLeft Anterior Mediastinotomy and Extended

Cervical MediastinoscopyScalene Node BiopsyVideo-Assisted Thoracic SurgeryThoracotomy

METASTATIC WORKUP

SUMMARY

ISBN: 978-0-323-24126-7; PII: B978-0-323-24126-7.00016-8; Author: Sellke & del Nido & Swanson; 00016ISBN: 978-0-323-24126-7; PII: B978-0-323-24126-7.00016-8; Author: Sellke & del Nido & Swanson; 00016

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16-2 SECTION 1 THORACIC SURGERY

not changed (Fig. 16-1).14 For the T descriptors, size cutoffs were added to the T1 and T2 tumors, and tumors greater than 7 cm in greatest dimension were designated as T3, in light of the prognostic significance of increasing size of the primary tumor (Table 16-1).15 Additional tumor nodules in the same lobe as the primary, previously known as “satellite nodules,” were reclassified from T4 to T3, and additional nodules in the ipsilateral lung became T4. The M descriptor was divided into M1a (for pleural metastases, malignant effusion, or contralateral pulmonary disease) and M1b (for extrathoracic metasta-ses).16 After incorporating the suggested changes into

incorporated into the sixth edition of the AJCC and UICC staging manuals.

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.11 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.12 Data on 100,869 patients, including 67,725 cases of NSCLC, were sub-mitted to the database, and several changes were pro-posed.13 The existing N descriptors were validated and

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, et al: 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 4:568–577, 2009.)

Supraclavicular zone

Upper zone

Superior Mediastinal Nodes

Aortic Nodes

11

2R

2L

Ao

PA4L

7

8

8

6

5

3p

9

11R

11R

10R

12R

12R

12R

13R

14R

9

10L

11L

12L

13L

14L

4R

3a

2R

AP zone

Inferior Mediastinal Nodes

Subcarinal zone

Lower zone

N1 Nodes

Hilar/Interlobar zone

Peripheral zone

5

7

10

11

12

13

14

8

9

6

2L

3a

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Low cervical, supraclavicular, and sternal notch nodes

Upper Paratracheal (right)

Subaortic

Subcarinal

Hilar

Interlobar

Lobar

Segmental

Subsegmental

Paraesophageal(below carina)

Pulmonary ligament

Para-aortic (ascendingaorta or phrenic)

Upper Paratracheal (left)

Prevascular

Retrotracheal

Lower Paratracheal (right)

Lower Paratracheal (left)

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16 LUNG CANCER WORKUP AND STAGING 16-3

From Goldstraw P, Crowley J, Chansky K, 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 2(8):709, 2007.

TABLE 16-1 Definitions for T, N, and M Descriptors in the Seventh Edition of the AJCC and UICC Staging Manuals

T (Primary Tumor)TX Primary tumor cannot be assessed, or tumor is proven by the presence of malignant cells in sputum or bronchial

washings but not visualized by imaging or bronchoscopyT0 No evidence of primary tumorTis Carcinoma in situT1 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)* T1a Tumor ≤ 2 cm in greatest dimension T1b Tumor > 2 cm but ≤3 cm in greatest dimensionT2 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 carinaInvades visceral pleura (PL1 or PL2)Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the

entire lung T2a Tumor > 3 cm but ≤5 cm in greatest dimension T2b Tumor > 5 cm but ≤7 cm in greatest dimensionT3 Tumor > 7 cm or one that directly invades any of the following: parietal pleural (PL3) 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 Regional lymph nodes cannot be assessedN0 No regional lymph node metastasesN1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including

involvement by direct extensionN2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular

lymph node(s)

M (Distant Metastasis)MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasisM1a 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 T1a.

†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 M0.

AJCC, American Joint Committee for Cancer; UICC, International Union Against Cancer.

TNM subsets, new stage groupings were identified that yield even distributions of overall survival among stages, particularly between stages IIA and IIB (Table 16-2).17,18

DIAGNOSIS AND STAGING

Diagnosis and clinical staging begin with the initial history and physical examination. A single study may serve 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 diag-nosis 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.

History and Physical ExaminationPatients often come to the surgeon for evaluation with some studies already performed. However, the history and physical examination remain important in the initial evaluation. A detailed history focusing on risk factors—such as duration of cigarette smoking, exposure to asbes-tos and other industrial hazards, a prior history of lung cancer, and the presence of symptoms—allows the clini-cian to assess the likelihood of a 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 risk of developing lung cancer.19


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difficult to identify, unless there is substantial enlargement.

Sputum CytologyCytologic analysis of sputum for malignant cells is a simple diagnostic technique but is rarely used in North America because of the epidemiologic shift from cen-trally located squamous cell to more peripherally located adenocarcinomas. However, sputum cytology is still a potentially relevant test in other parts of the world where squamous cell cancers are more common. Samples may be induced by saline nebulization or collected as a 3-day pool of sputum produced from spontaneous coughing in the morning. 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%). 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%.21

Low-Dose Computed TomographyAn increasing number of patients, particularly in devel-oped countries, now have lung cancers identified by low-dose computed tomography (CT) because of the results of a large prospective U.S. randomized clinical trial. The National Lung Screening Trial (NLST) enrolled 53,454 persons at high risk (participants between ages 55 and 74 years with at least 30 pack years of smoking) for lung cancer at 33 medical centers and randomized them to undergo three annual screenings with either low-dose CT or posteroanterior chest radiography. Patients in the low-dose CT group had a significantly lower risk of death from lung cancer (20% relative risk reduction) and from any cause. The majority (63%) of lung cancers detected by low-dose CT were stage I tumors.22,23 The use of low-dose CT will likely increase in the future, largely sup-planting chest radiography.

High-Resolution Computed TomographyOnce a suspect lesion has been detected on a chest radio-graph or a low-dose CT, the next step is a high-resolution CT of the chest and upper abdomen, preferably per-formed with intravenous contrast. This yields informa-tion about the size, characteristics (e.g., spiculation, ground-glass opacification, lack of calcification), and local extent of a potential lung cancer. Potential invasion of contiguous chest wall or mediastinal structures can be assessed.

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. The chest CT for a suspected lung cancer should include the upper abdomen, through 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.

The lung cancer risk associated with asbestos exposure also increases with the intensity and length of exposure, and together, tobacco use and asbestos exposure have a multiplicative effect. Symptoms, such as bone pain, hoarseness, weight loss, and neurologic changes, can indicate the presence of metastatic disease and direct further investigation.

A physical examination is also important. It provides an estimate of a patient’s overall health status, which influences treatment selection. Physical findings, such as Horner syndrome, or the presence of clubbing, may support the suspicion of lung cancer. Physical examina-tion may also demonstrate advanced disease. For example, palpation of the supraclavicular fossae can reveal lymph node metastases, and auscultation of the lung fields can identify the presence of a malignant pleural effusion.

NONINVASIVE MODALITIES

Chest RadiographyPosteroanterior and lateral chest radiographs, often done for unrelated reasons, are a common initial study in which a suspected lung cancer is identified. However, most lesions are not visible until they are at least 7 to 10 mm in diameter.20 A chest radiograph can localize the site of suspect lesions (central or peripheral) and the associated effects of disease, such as atelectasis, consolida-tion, or proximity to the pleural surface. The presence of a pleural effusion of chest wall invasion or of phrenic nerve involvement causing elevation of the hemidia-phragm may also be seen. Advanced disease may be iden-tified in the case of rib destruction from bone metastases or synchronous lesions in the pulmonary parenchyma. Hilar and mediastinal lymph node metastasis is more

From Goldstraw P, Crowley J, Chansky K, 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 2(8):709, 2007.

TABLE 16-2 Descriptors, Proposed T and M Categories, and Proposed Stage Groupings*

Sixth Edition T/M Descriptor

Seventh Edition T/M N0 N1 N2 N3

T1 (≤2 cm) T1a IA IIA IIIA IIIBT1 (>2-3 cm) T1b IA IIA IIIA IIIBT2 (≤5 cm) T2a IB IIA IIIA IIIBT2 (>5-7 cm) T2b IIA IIB IIIA IIIBT2 (>7 cm) T3 IIB IIIA IIIA IIIBT3 invasion IIB IIIA IIIA IIIBT4 (same lobe nodules) IIB IIIA IIIA IIIBT4 (extension) T4 IIIA IIIA IIIB IIIBM1 (ipsilateral lung) IIIA IIIA IIIB IIIBT4 (pleural effusion) M1a IV IV IV IVM1 (contralateral lung) IV IV IV IVM1 (distant) M1b IV IV IV IV

*These revisions were incorporated into the seventh edition of the AJCC and UICC staging manuals.


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Despite these limitations, PET has become an invaluable tool in lung cancer staging.

Several studies have shown that PET is superior to CT in staging the mediastinum in lung cancer patients. Piet-erman and colleagues26 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. A meta-analysis of 18 studies demonstrated an overall sensitivity of 84% and specificity of 89%.24,26 Toloza and associates24 also showed that combining CT and PET resulted in the highest diagnostic accuracy, with a sensitivity of 94% and a speci-ficity of 86%, supporting the use of both modalities for staging of the mediastinum. PET also 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 a higher stage of disease in 42 patients. PET was effective in identifying occult metastatic disease. In 11 patients (11%), PET demonstrated distant meta-static disease in bone, liver, and adrenal glands not detected by CT.

During the past decade, integrated PET-CT scanners have replaced PET alone, leading to improved diagnostic accuracy and anatomic localization of disease.27 Cerfolio and coauthors compared PET with and without inte-grated CT in 129 patients with biopsy-proved or sus-pected NSCLC who subsequently underwent surgical staging.28 PET-CT was a significantly better predictor of stages I and II disease and demonstrated superior accu-racy for both T status (70% versus 47%, P = 0.001) and N status (78% versus 56%, P = 0.008) compared with

Chest CT also allows assessment of mediastinal lymph nodes. The use of intravenous contrast is important in distinguishing nodes from vascular structures. The most widely used criterion to define abnormal lymph nodes is a short-axis diameter of 1 cm or greater. Although CT is the most accurate radiographic method of measuring lymph node enlargement, it does not reliably predict metastatic disease. Toloza and colleagues24 reported results of a meta-analysis of 20 studies with 3438 evalu-able patients that showed an overall sensitivity of 57% and specificity of 82%. Therefore, staging of the medi-astinum and subsequent therapeutic decisions should not be based solely on the results of the CT.

Positron Emission TomographyWhole-body positron emission tomography (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 (18F) is a D-glucose analog that is phosphorylated after cellular uptake and accumulates intracellularly, rather than being metabo-lized. 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).25 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. The lower limit of resolution of PET is approximately 1.0 to 1.2 cm and thus PET may not detect very small malignant lesions. Benign inflam-matory or infectious conditions (e.g., granulomas, sar-coidosis) can also produce false-positive PET findings.

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).

A B


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sulcus carcinoma (Pancoast tumor) to the subclavian vessels and brachial plexus more accurately than CT.

INVASIVE MODALITIES

BronchoscopyRigid 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 visual-ization of the remaining bronchial tree. Flexible video-assisted bronchoscopy has replaced rigid bronchoscopy for all but a few special circumstances. It is generally performed as an outpatient procedure on a spontaneously breathing patient through the nasal or oral route, follow-ing topical anesthesia and sedation. The tracheobron-chial 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. Using more than one 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%.36,37 Positive endobronchial findings are common in cases of squamous and small cell cancers because of their central location. In contrast, a bronchoscopic examination is likely to yield normal findings when there are 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 pres-ence of a bronchus sign (a bronchus leading to or con-tained in a lesion on CT) portend a higher diagnostic yield.37 The use of fluoroscopy to guide a transbronchial biopsy or TBNA and lavage can improve diagnostic accu-racy up to 80%.38 Electromagnetic navigation bronchos-copy (ENB) is a new technology that uses high-resolution CT to guide transbronchial biopsy in real time during bronchoscopy. The CT-based “navigation” of the bron-choscope allows accurate biopsy of small peripheral lung lesions, especially when coupled with rapid on-site cyto-logic evaluation.39

TBNA can also be used when there is bronchial distor-tion (thickening or blunting of the carina, extrinsic com-pression) secondary to the lesion or metastatic lymph nodes. Popularized by Wang and Terry, TBNA is per-formed with a 20- to 22-gauge, rigid needle through the channel of the fiberoptic bronchoscope to puncture the airway in the area of interest.40 It is a safe and inexpensive procedure with an overall sensitivity of 50% and a speci-ficity of 96%.36,37 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),

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 < 0.05). As in prior studies, PET-CT identified 19 (14.7%) patients with M1 disease.

PET-CT has proved to be more accurate than a bone scan, with a similar sensitivity and a higher specificity.29-32 In the largest study comparing PET with bone scan, Song and colleagues retrospectively analyzed 1000 newly diagnosed patients, 105 of whom were eventually diag-nosed with bone metastases and underwent PET-CT and bone scan.31 PET-CT was more accurate (98.3% versus 95.1%, P < 0.001), sensitive (94.3% versus 78.1%, P = 0.001), and specific (98.8% versus 97.4%, P = 0.006) 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 = 0.732. Based on its clear advantages in both intra- and extrathoracic staging, PET-CT is now a routine part of pretreatment staging.

Bone ScanAlthough PET-CT has essentially replaced bone scans for evaluation of potential skeletal metastases, when used in the setting of a positive clinical assessment (e.g., bone pain or tenderness), a technetium-99m methylene diphos-phate (99mTc MDP) whole-body bone scan is relatively sensitive but not specific. In their meta-analysis of seven studies and 633 patients, Toloza and colleagues24 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 with magnetic resonance imaging 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.33

Magnetic Resonance ImagingMagnetic resonance imaging (MRI) of the chest offers few advantages over CT in the diagnosis or staging of lung cancer. Heelan and coworkers34 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 a recent study, whole-body MRI with diffusion-weighted imaging was compared with FDG-PET-CT in 33 patients before surgery for lung cancer. Whole-body MRI had compa-rable sensitivity, specificity, and accuracy for tumor detec-tion and staging but showed no superiority to PET-CT.35 However, MRI can be useful in some situations. When tumors are adjacent to the spine, MRI provides superior visualization of the spinal canal and can more accurately detect subtle changes in the marrow suggestive of inva-sion. It also delineates the relationship of a superior


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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. In a subsequent prospective con-trolled trial, Yasufuku and colleagues performed EBUS-TBNA followed immediately by cervical mediastinoscopy, in 153 patients with known or suspected lung cancer. No significant differences were found between EBUS-TBNA and mediastinoscopy with respect to sensitivity, negative predictive value, diagnostic accuracy, and determination of true pathologic N stage.47 The same group of investi-gators has also reported that EBUS-TBNA can accu-rately access hilar and interlobar lymph nodes.48 The accuracy of EBUS-TBNA is enhanced by rapid on-site evaluation (ROSE) of cytology specimens during the pro-cedure, which also optimizes specimen submission for tumor molecular profiling.49 A recent meta-analysis of 1066 patients from nine studies confirms the excellent accuracy of EBUS-TBNA.50 In many centers, EBUS-TBNA has largely replaced mediastinoscopy in the staging of resectable NSCLC.

Autofluorescence BronchoscopyDetection and treatment of dysplastic or early invasive centrally located neoplastic lesions whose presence is suggested by positive sputum cytology remain a chal-lenge. Approximately one third of patients with positive sputum cytology, but radiographically occult lung cancers, require more than one bronchoscopy for localization.51 In an effort to improve identification of superficial bron-chial mucosal malignancy, Hung and associates52 were able to demonstrate that normal and malignant bronchial mucosa have different autofluorescence intensities under blue light (wavelength, 442 nm). This led to the develop-ment 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.53 Subsequent prospective trials comparing white-light bronchoscopy alone with white-light bronchoscopy

peripheral lesions and inaccessibility of certain lymph node stations, including anterior, aortopulmonary, para-esophageal, and pulmonary ligament nodes. This tech-nique has now been largely supplanted by the more recent development of endobronchial ultrasound.

Endobronchial UltrasoundIn an effort to improve on the diagnostic accuracy of TBNA, endobronchial ultrasound (EBUS) was devel-oped and commercially introduced in the early 1990s.41 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.42,43 Subsequently, an ultra-sonic 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 saline-filled balloon at the tip. The ultrasound image is processed by a dedicated scanner (EU-C2000) that allows for image freezing, size mea-surement, and Doppler mode. A special 22-gauge needle is passed under direct visualization through the instru-ment 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 generally not approachable.

Several studies have shown the accuracy of EBUS-TBNA for mediastinal and hilar nodal staging in NSCLC.44-46 In one of the earliest series, Yasufuku and colleagues45 successfully performed EBUS-TBNA in 105 patients with proved or suspected lung cancer and ade-nopathy by CT criteria alone. They sampled 163 lymph

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.

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Cervical MediastinoscopyAccurate assessment of the mediastinum is paramount as mediastinal lymph node involvement by metastatic carci-noma strongly influences treatment decisions. Until the development of EBUS, cervical mediastinoscopy was the most accurate pre-resection method of staging the medi-astinum in lung cancer. Described by Carlens in 1959, mediastinoscopy is performed with 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 speci-ficity of 100% in a recent meta-analysis of 5687 patients.65a A negative mediastinoscopy also predicts a high rate of complete resection at thoracotomy. Luke and colleagues66 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 coworkers67 reported overall morbidity and mortality rates of 0.6% and 0.05%, respectively.

In the pre-EBUS era, the indications for mediastinos-copy were often debated and routine mediastinoscopy was controversial. Most thoracic surgeons agreed 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 included the presence of T2 or T3 tumor or poor prognostic tumor histologies such as large cell carcinoma.68 Those who supported the practice of routine mediastinoscopy emphasized its low complica-tion rate and high level of 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. During the past decade, the combination of PET-CT and EBUS-TBNA has gradually replaced mediastinoscopy in the staging of NSCLC. However, mediastinoscopy remains appropriate in situations where EBUS-TBNA samples are inadequate for diagnosis or for tumor molecular profiling.

Left Anterior Mediastinotomy and Extended Cervical MediastinoscopyOne 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

plus LIFE have shown enhanced sensitivity in detection of intraepithelial neoplasms and invasive carcinoma.53-56 Lam and coauthors56 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 in follow-up for recurrence or second primary tumors, and for moni-toring intraepithelial dysplasia in some chemoprevention trials, it is not currently in widespread use. This relates in part to the epidemiologic shift away from centrally located squamous cancers and in part to the lack of devel-opment of more advanced autofluorescence technology than can be used outside of the research setting.

Percutaneous Transthoracic Needle BiopsyPercutaneous transthoracic needle biopsy is a well-established procedure used to obtain 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 peripherally located pulmonary nodules by low-dose CT, transthoracic needle biopsy has become a critical tool in the detection of early-stage lung cancer. The accuracy of percutaneous needle biopsies has been enhanced by the development of fluoroscopy CT, which allows precise targeting of very small peripheral nodules for biopsy.57,58 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 obstruc-tive pulmonary disease (COPD).61 Hemoptysis occurs in 5% to 10% of cases and is usually self-limited. Massive hemoptysis is 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 diag-nosis is made.

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 al87 221 28 9 19 28Naruke88 714 33 18 15 30Asamura et al89 337 26 10 16 25Oda et al90 524 22 8 14 51Graham et al91 86 29 19 10 34


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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 decu-bitus position, the thoracoscope and endoscopic instru-ments are inserted through one or more operating ports placed via small intercostal incisions. The entire hemi-thorax can be explored, including the hilum, mediasti-num, visceral and parietal pleural surfaces, and chest wall. The principal use of VATS has been to perform the exci-sional biopsy of peripheral lung nodules for the diagnosis of primary lung cancer or to rule out synchronous or metastatic disease.73 It can be used to evaluate mediastinal lymph nodes—in particular, those inaccessible by cervical mediastinoscopy (anterior, aortopulmonary, para-aortic) or anterior mediastinotomy (hilar, inferior pulmonary ligament).74,75 Several studies have shown that the sensi-tivity and accuracy of VATS are almost 100% for diag-nosis and staging of lung cancer, with minimal morbidity and mortality.

ThoracotomyWith the myriad of accurate, less invasive diagnostic methods available, more than 95% of tumors can be characterized without thoracotomy. Exploratory thora-cotomy, however, still allows the most thorough assess-ment of the primary lesion, the pleural space, and the ipsilateral mediastinal lymph nodes. The tumor is typi-cally biopsied with a 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 a delay in 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 few prospective randomized trials of extrathoracic imaging for NSCLC. It is well accepted that patients who have certain symptoms, abnormal phys-ical 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 associated with a roughly 50% rate of abnormal scans.76 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 multior-gan imaging in patients without symptoms or signs is controversial. Several studies have shown that routine preoperative scanning in asymptomatic patients is

need to be sampled. In this situation, there are two options for surgical staging. Levels 5 and 6 mediastinal lymph nodes can be accessed from a left anterior or para-sternal approach, as described by McNeill and Chamber-lain.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 proce-dure include preservation of the internal mammary vessels, use of the mediastinoscope for better visualiza-tion, 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 rates in previously reported series are low—8% and 0%, respectively.

Another surgical approach to the anterior mediasti-num in left upper lobe cancers is extended mediastinos-copy, described by Ginsberg and associates.71 After a pathologically negative standard cervical mediastinos-copy, the mediastinoscope is withdrawn, and blunt digital dissection is used to create a window between the innom-inate 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 mediastinos-copy should be avoided in patients with a dilated or calci-fied aortic arch or previous sternotomy. Because of the challenging nature of the dissection required for extended mediastinoscopy and the development of other minimally invasive alternatives to accessing the aortopul-monary window, such as EUS and video-assisted thoracic surgery, extended mediastinoscopy is no longer widely performed.

Scalene Node BiopsyScalene node biopsy is used to assess suspect nodes in the supraclavicular fossa, identified by either palpation or imaging (specifically, PET-CT). If there are palpable nodes in the supraclavicular fossa, a fine-needle aspira-tion (FNA) in the office is often sufficient. If an FNA is nondiagnostic, or metastatic disease is suspected on imaging, 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. Dis-section 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. Scalene node biopsy can also be done during a mediastinoscopy using a single incision. Lee and Gins-berg reported that 15.4% of patients (6 of 39) with posi-tive N2 disease had positive scalene nodes as well, indicating N3 disease.72

Video-Assisted Thoracic SurgeryVideo-assisted thoracic surgery (VATS), now performed with a videothoracoscope, is a valuable tool for the


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(symptoms, signs, blood work), (2) patients with locally advanced disease (stage IIIA) being considered for mul-timodality 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 patient. The most important components of the workup are the initial history and the physical examination. Numerous nonin-vasive and invasive techniques can be used to establish an accurate and valid clinical estimate of tumor stage.

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TABLE 16-4 Clinical Evaluation for Metastatic Disease

Clinical Evaluation Finding

Symptoms Constitutional: weight loss > 5% of body weight, malaise

Musculoskeletal: focal skeletal painNeurologic: headache, seizure,

mental status or personality changes

Physical signs Focal neurologic deficitSupraclavicular lymphadenopathyHoarsenessSuperior vena cava syndromeBony tendernessSkin or soft tissue massHepatomegaly

Laboratory tests AnemiaElevated liver function testsHypercalcemia

associated with a low percentage (3% to 10%) of positive results, with silent metastases found in 2.7% to 15%.77 In their meta-analysis, Silvestri and colleagues76 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 pro-spective, randomized trial that compared routine multi-organ 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 recur-rence, or overall survival.78 Despite this, more recent data have shown whole-body PET and PET-CT to be invalu-able in disclosing non–central nervous system metastatic disease in up to 10% to 20% of cases missed by standard methods.26,79,80 On this basis, PET-CT should be consid-ered 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.81,82 Others have shown that adenocarcinomas have a higher rate of asymptomatic cerebral metastases than squamous carcinomas.77,83 However, the evidence to support routine brain imaging in the evaluation of potentially resectable NSCLC is scant and is based primarily on retrospective series. MRI with or without intravenous gadolinium is considered the optimal imaging study. A generally accepted approach is to add brain MRI to CT and PET-CT for evaluation of clinically higher stage tumors (stages II and III) but not for stage I tumors where the frequency of asymptomatic brain metastases is only about 5%.84-86

Based on available information, it is appropriate for all patients with established or suspected lung cancer to undergo high-resolution, contrast CT of the chest and whole-body PET-CT. Selected patients should undergo brain MRI. Multiorgan scanning should be considered for (1) any patient with a positive clinical evaluation


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