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Endoscopic Ultrasound in Non–Small Cell Lung Cancer and Negative Mediastinum on Computed Tomography

Department of Medicine, Division of Gastroenterology, Pulmonology, and Oncology; Department of Surgery, Thoracic Division; Department of Pathology; Department of Radiology; Roudebush VA Medical Center; and The Regenstrief Institute, Inc., Indiana University Medical Center, Indianapolis, Indiana

Correspondence and requests for reprints should be addressed to Julia Kim LeBlanc, M.D., M.P.H., Indiana University Medical Center, 550 North University Boulevard, UH 4100, Indianapolis, IN 46202. E-mail: juleblan{at}iupui.edu

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Despite technical advances in staging non–small cell lung cancer (NSCLC), accurate staging remains a challenge. Endoscopic ultrasound is useful in staging NSCLC when lymphadenopathy is present on a computed tomography (CT), but its role in the absence of lymphadenopathy on CT has not been well defined. Therefore, we sought to determine the clinical impact of endoscopic ultrasound (EUS) in staging NSCLC in absence of mediastinal lymphadenopathy on CT. Seventy-six patients with NSCLC with absence of mediastinal lymphadenopathy on CT were enrolled and followed prospectively. EUS-guided fine-needle aspiration was performed on sites that were suspicious for metastases. Surgical pathology after thoracotomy was used as the reference standard for assessing accuracy. Sixty-two (86%) patients underwent surgery, and 10 (13%) did not. EUS precluded surgery in 9 patients (12%) and influenced management in 18 (25%) of all patients in this study. EUS detected malignant mediastinal lymphadenopathy more frequently in patients with lower lobe and hilar cancers combined compared with upper lobe cancers (p = 0.004). EUS played a significant role in identifying patients with unresectable (N3) NSCLC when adenopathy was not present on CT imaging and appears to be more sensitive in detecting lymph node metastases in lower lobe and hilar NSCLC compared with upper lobe NSCLC.

Key Words: endoscopic ultrasound • fine-needle aspiration • mediastinal lymphadenopathy • thoracotomy • non–small cell lung cancer

Lung cancer is our nation's leading cancer killer of men and women (1–2). An unpublished report from the Society of Cardiothoracic Surgeons of Great Britain and Ireland (1985) revealed that approximately one in five thoracotomies performed for lung cancer were "open and close." Certainly, thoracotomy for unresectable non–small cell lung cancer (NSCLC) is not only costly but would be expected to impact negatively on the patient's quality of life.

The accuracy of computed tomography (CT) staging of lung cancer varies widely (3–10). Because of the lack of contrast within the mediastinum and signal averaging, CT detects abnormal lymph nodes that are greater than 1 cm. However, lymph nodes that are undetected by CT may harbor metastases, and benign lymph nodes are often greater than 1 cm (5–19). Based on CT findings, approximately 23% of NSCLC patients are overstaged, and 19% are understaged (20). Although many studies have shown the benefit of positron emission tomography (PET) in staging NSCLC (21–32), Fritscher-Ravens and colleagues demonstrated an advantage of endoscopic ultrasound (EUS)–guided fine-needle aspiration (EUS-FNA) compared with CT and PET in detecting small mediastinal metastases (33, 34). EUS-FNA combined with polymerase chain reaction analysis of mediastinal lymph nodes is also useful in detecting cancer-specific mRNA (35). In addition, new technologies such as endobronchial ultrasonography have shown some promise in staging centrally located early squamous cell lung cancers (36).

Differentiating extent of mediastinal nodal disease remains a challenge in staging NSCLC. Mediastinoscopy remains the standard of care in staging the mediastinum, however, at our institution; the use of mediastinoscopy for staging lung cancer has decreased by 20%. Certainly, EUS is complimentary to mediastinoscopy and is not used in place of mediastinoscopy for lung cancer staging. However, EUS is useful in identifying patients with positive posterior mediastinal lymph nodes, particularly N2 and N3 disease, and positive lymph nodes as small as 3 mm in size can be detected (33, 37–60). Endoscopic ultrasound has also been demonstrated to influence subsequent rates of thoracic surgery (59). Patients with N2 (positive ipsilateral mediastinal lymph nodes stations 1 through 9) disease may benefit from surgery, whereas patients with N3 (contralateral mediastinal lymph nodes) disease do not (61, 62). In addition, identifying patients with N2 disease is significant as they may benefit from neoadjuvant chemotherapy (63, 64).

The role of EUS in staging NSCLC without lymphadenopathy on CT, however, remains unclear. Patients with enlarged mediastinal lymph nodes on CT often are further evaluated with mediastinoscopy, PET, or endoscopic ultrasound, whereas patients without evidence of mediastinal lymphadenopathy on CT do not undergo further interrogation of the mediastinum. Certainly, occult cancer may exist in both types of patients. The aim of this study was to evaluate the clinical impact of EUS in NSCLC patients without mediastinal lymphadenopathy on CT. The hypothesis for this investigation was that patients without mediastinal lymphadenopathy on CT might harbor occult metastases that may preclude unnecessary surgery if EUS identified occult malignancy in contralateral (N3) mediastinal lymph nodes or at distant sites. Findings related to this research have been presented in the form of an abstract (65).

	METHODS

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The institutional review board at Indiana University approved this protocol. Patients signed informed written consent. The funding agency played no role in the study or writing of this manuscript. NSCLC patients without mediastinal lymphadenopathy on CT were enrolled if they were operative candidates. Three patients with ipsilateral hilar lymphadenopathy (N1) on CT scan were included, as these lymph nodes are hilar and not mediastinal. All patients underwent a chest CT scan with intravenous contrast. However, not all patients underwent PET. Mediastinal lymph nodes on CT with a short axis diameter greater than 1 cm were considered abnormal, rendering a patient ineligible for enrollment.

Definitions
By EUS criteria, generally accepted echo characteristics for suspicious lymph nodes include more than 5 mm in short axis dimension, round, hypoechoic, and well demarcated. Lymph nodes were defined as positive by EUS if all four ultrasound features were present. EUS-FNA was performed if two or more ultrasound features were present. A change in patient management was defined as avoidance of unnecessary surgery or other deviation from the management plan that would have occurred as a result of the CT findings alone.

EUS Procedure
The EUS examination was performed on an outpatient basis using conscious sedation. A radial echoendoscope (GF-UM20 or GF-UM130; Olympus America Inc., Melville, NY) was introduced into the patient's stomach, where continuous sonographic imaging of the posterior mediastinum, left lobe of the liver, left adrenal gland, retroperitoneum, and celiac region were obtained. EUS-FNA was performed using a linear array echoendoscope (FG-32 UA or FG-36 UX; Pentax Precision Instruments Corp., Orangeburg, NY). FNA was performed on sonographically suspicious lymph nodes and lesions under direct real-time ultrasound imaging using a 22-gauge needle (Wilson-Cook, Winston-Salem, NC) that was passed through the echoendoscope through the esophageal wall or stomach. A cytotechnologist who was present during the procedure prepared the aspirate.

Patients were precluded from surgery if EUS-FNA histologically confirmed contralateral lymph node metastases (N3) or distant metastases. Thoracotomy and complete lymph node dissections were performed in accordance with American Thoracic Society guidelines and the American Joint Committee on Cancer. The surgeon was blinded to the results of the EUS examination to minimize bias unless findings were present that precluded the patient from surgery. Cytology and clinical follow-up were both used as reference standards in patients that did not undergo surgery.

Data Analysis
Using surgical pathology and EUS-FNA cytology results as the reference standards, the sensitivity of EUS imaging alone was calculated as the proportion of malignant mediastinal lymph nodes correctly identified by EUS. The specificity of EUS was calculated as the proportion of benign mediastinal lymph nodes correctly identified by EUS. Exact 95% confidence intervals for sensitivity and specificity of EUS were reported. Fisher's exact test was used to test the null hypothesis that the proportion of patients with mediastinal lymph node metastases correctly identified by EUS did not differ by location (upper or lower lobe). Malignant mediastinal lymph nodes were also stratified by location of the primary tumor.

	RESULTS

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There were 76 consecutive patients enrolled during a 3-year period (September 1997 to August 2000). Our cohort consisted of 48 men and 28 women between the ages of 33 and 89 (mean 61 years). Four patients were lost to follow-up or later refused to participate, leaving 72 patients in our study. Sixty-two (86%) patients underwent surgery, and 10 (14%) did not. Of the 10 patients that did not undergo surgery, 1 refused and 9 were precluded based on EUS-FNA findings: five patients were staged IIIb (N3 disease), three were staged IV, and one had a synchronous esophageal cancer (Table 1). EUS-FNA results altered management in 18 of 72 (25%) NSCLC patients (Table 2). There were no EUS- or CT-related complications.

Of 62 patients who underwent surgery, 39 had negative mediastinal lymph nodes (N0). Of the 39 patients with negative mediastinal lymph nodes at surgery, EUS imaging correctly staged 35 of these 39 patients. This resulted in a specificity of 90% (95% confidence interval, 76–97%). The remaining four patients had EUS-FNA caused by a suspicious-appearing mediastinal lymph node. When EUS-FNA was performed on the mediastinal lymph nodes of these four patients, it was correctly identified as negative. This resulted in an overall specificity of 100% (95% confidence interval, 91–100%) for N0 disease. EUS correctly identified 24 of 28 (86%) subcarinal lymph nodes as benign or malignant.

Of the 62 patients who underwent surgery, 23 (37%) patients had positive lymph nodes; 6 patients had peribronchial lymph node (N1) involvement, whereas the remaining 17 patients had ipsilateral or subcarinal lymph node (N2) involvement (Table 3). EUS imaging of hilar lymph nodes (N1) was not achieved because of air interference from the hilum; therefore, no EUS comment is made on these particular nodes. EUS imaging without FNA correctly identified positive ipsilateral nodes (N2) in 5 of 17 cases, resulting in a sensitivity of 29% (95% confidence interval, 10–56%) for N2 disease. EUS-FNA was performed on these five lymph nodes, confirming metastases in three (one paraesophageal and two subcarinal). In addition, there were 5 of 17 positive ipsilateral lymph nodes that were undetected by EUS in stations: 1 (highest mediastinal), 2 (upper paratracheal), 4 (lower paratracheal), and 6 (ascending paraortic) (Table 3). Therefore, 5 of 12 (42%) patients with positive ipsilateral mediastinal lymph nodes accessible to EUS imaging were correctly identified as malignant.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
EUS precluded unnecessary surgery in 12% or one of every eight patients with NSCLC without mediastinal lymphadenopathy on CT based on the presence of a stage IIIa and stage IIIb (malignant contralateral mediastinal lymph node) disease. EUS-FNA may be more useful in staging hilar and lower lobe NSCLC compared with upper lobe NSCLC. A potentially important role for EUS-FNA is in precluding patients from surgery by identifying patients with celiac lymph node and contralateral mediastinal lymph node metastases as well as occult metastases in the left lobe of the liver and left adrenal gland.

Currently, 30–64% of patients with NSCLC have mediastinal lymphadenopathy on CT (49, 57). Our study is the first prospective study that examines the potential role of EUS in patients with NSCLC without mediastinal lymphadenopathy on CT. Although this study was performed before the routine use of PET in staging NSCLC, our findings add to our current knowledge of NSCLC staging and the potential role for EUS.

The overall low sensitivity (29%) of EUS in detecting malignant mediastinal lymph nodes may be explained by the location of positive mediastinal lymph nodes and EUS criteria used to define a malignant lymph node. Anterior, hilar, and paratracheal lymph nodes are not reliably imaged with EUS because of air interference from the air-filled trachea. Lymph nodes that are readily imaged and biopsied by EUS-FNA are located in the aortopulmonary window (station 5), subcarina (station 7), paraesophageal region (station 8), inferior pulmonary ligament (station 9) and tracheobronchial angle (station 10) (11, 12, 33–37, 43–48, 51–59, 66–68). In our study, 12 of 17 (71%) patients with positive ipsilateral nodes at surgery were located in regions that were accessible to EUS-FNA, and 5 (29%) were not (Table 2). Hence, the sensitivity was 42% (5 of 12) for positive mediastinal lymph nodes that are accessible to EUS imaging. In addition, we found that 7 of 12 (58%) patients with positive ipsilateral lymph nodes that were accessible to EUS imaging were undetected because of lack of echo characteristics that are predictive of malignancy. This finding emphasizes the importance of histologic confirmation by EUS-FNA, as echo characteristics alone are not adequately sensitive to predict malignancy (50, 55).

We also learned that the location of the tumor might influence EUS detection of malignant lymph nodes. This has not been previously described. Patients with hilar and lower lobe NSCLC had positive mediastinal lymph nodes that were accessible to EUS more often than patients with upper lobe NSCLC. This finding is likely due to the lymphatic drainage patterns of the lower lung lobes, which pass through the subcarinal lymph nodes. Likewise, lymphatics of the upper lobes pass through the anterior and paratracheal lymph nodes. EUS access to the subcarina explains why the accuracy in diagnosing subcarinal lymph nodes was high. These findings are of interest because CT is less reliable in predicting malignant subcarinal lymph nodes (69–72). Although the sample size in this group is small, these findings suggest that EUS may be more useful in staging lower and hilar NSCLC when the CT is negative for lymphadenopathy.

Surprisingly, 17 of 62 (27%) of the patients in our study had evidence of mediastinal lymph node metastases at surgery. This finding is notable because patients without mediastinal adenopathy on CT may not undergo further evaluation to preclude surgery. Extensive and complete mediastinal lymph node dissections performed in this study may explain the high prevalence of occult mediastinal lymph node metastases and low sensitivity of EUS. Previous reports of EUS-FNA in lung cancer staging may have inflated the true sensitivity and specificity if a complete lymph node dissection was not performed. In addition, the mean of 32 days elapsed between CT and EUS may explain a relatively high prevalence of advanced disease.

A potentially critical role of EUS is the detection of metastases to celiac lymph nodes in addition to the adrenal glands and left lobe of the liver. Although celiac lymph nodes are not routinely biopsied at surgery, they are of interest as left-sided lung cancers may spread to the celiac lymph nodes via lymphatics. Two patients were found to have celiac lymph node metastases and were precluded from surgery; however, one patient with celiac lymph node metastases had a right-sided NSCLC. This suggests that EUS evaluation of the celiac region may be important regardless of tumor location.

The findings of our study compliment the findings of Gress and colleagues that EUS is useful in precluding lung cancer patients from surgery. In Gress's prospective study 58% (14 of 24) of patients with NSCLC with lymphadenopathy on CT were precluded from surgery based on EUS findings (46). Although we found that EUS precluded 12% of patients with NSCLC compared with 58%, one major difference of our study is the study population. Patients in our study were not enrolled if mediastinal adenopathy was present on CT.

Our study also supports the role of EUS in staging lung cancer as described by Wallace and colleagues in their retrospective study of 121 patients with NSCLC and small cell lung cancer. In their study, EUS confirmed mediastinal metastases in over two-thirds of patients with lymphadenopathy on CT. In a subgroup analysis of patients without mediastinal lymphadenopathy CT, their study demonstrated that EUS detected stage III or stage IV disease in 10 of 24 (42%) patients (37). This is similar to our finding of 39% with stage III and stage IV disease. One major difference between our study and Wallace's study, however, is that our study was performed prospectively in efforts to minimize selection bias. Another difference is that patients with small cell lung cancer were not enrolled in our study. Despite these differences, EUS proved useful in precluding surgery retrospectively and prospectively.

Limitations of this study require comment. In patients that were precluded from surgery based on EUS-FNA results, it is not possible to estimate true-positive from false-positive results because of the possibility of overestimating the specificity of FNA. For the purposes of this study, we assumed that EUS-FNA had a positive predictive value of 100%. However, a false positive may occur if the cytology specimen is interpreted incorrectly.

Another study limitation is the small number of subjects with NSCLC in subgroup analysis of upper versus lower lung tumors. Although we observe a statistically significant difference in the mediastinal lymph nodes detected by EUS in lower lobe NSCLC, this observation requires confirmation in a larger study. A larger study may also address the frequency of positive mediastinal lymph nodes with respect to location of the primary tumor. A lack of radiographic and histologic correlation may also be a limiting factor in this study, particularly if more than one lymph node is present in a given location. If multiple mediastinal lymph nodes are present at a given station, it is difficult to correlate which lymph nodes underwent EUS-FNA at the time of surgery.

Variations in acquiring CT performed by other institutions may or may not be a study limitation. We attempted to reduce the variation of CT scan results by using an expert in chest CT radiology to interpret all scans and repeating suboptimal scans at our institution. Although performing all CT in our institution would have been optimal, this would not reflect community practice patterns and would limit generalizability of the study findings. Our study was also performed before the routine use of PET in staging NSCLC; therefore, we cannot comment on the advantages of PET in patients without mediastinal lymphadenopathy on CT. In our study, four patients had a PET scan, one of which was performed after the endoscopic ultrasound. The physician performing the endoscopic ultrasound was blinded to the PET scans. Brain metastases were present in two patients that had a PET scan, one of which was performed after endoscopic ultrasound. One patient had uptake in the mediastinum that was also positive on endoscopic ultrasound-guided fine needle aspiration for adenocarcinoma. The fourth patient did not have uptake in the mediastinum on PET and was found to have N0 disease by EUS and surgery. Because of the small number of patients with PET scan, however, any correlation between PET and endoscopic ultrasound cannot be made within the confines of our study.

When modeled with PET, mediastinoscopy, and transbronchial needle aspiration, EUS-FNA was demonstrated to be the least costly diagnostic test in patients with NSCLC with subcarinal lymphadenopathy (73). The cost savings of EUS in staging NSCLC can be appreciated by examining the number of patients that are precluded from unnecessary thoracotomy. In our study, one of every eight (13%) patients without mediastinal lymphadenopathy on CT was precluded from surgery. If half of all new cases of NSCLC in the United States have no evidence of mediastinal lymphadenopathy on CT, there is the potential for over 10,000 patients each year to be precluded from surgery if staging with EUS-FNA is performed. With an estimated direct cost of $30,000 per thoracotomy, the cost saving would approximate $300,000,000 per year.

In summary, the overall sensitivity and specificity of EUS in detecting occult mediastinal lymph node metastases in patients with NSCLC with absence of mediastinal lymphadenopathy on CT were 29% and 100%, respectively. EUS precluded surgery in 13% (9 of 72) patients with NSCLC and altered management in 25% (18 of 72) of patients with NSCLC without mediastinal lymphadenopathy on CT. There were no complications of EUS-FNA in the mediastinum despite the lack of prophylactic antibiotic use. The results of this study suggest that EUS-FNA is safe and should be performed on benign-appearing lymph nodes, as occult metastases can be missed. EUS appears to play a significant role in local staging of patients with NSCLC, particularly in patients with lower lobe and hilar NSCLC. Further comparisons of EUS, PET, and CT may help generate an improved algorithm for staging NSCLC.

	FOOTNOTES

 
Conflict of Interest Statement: J.K.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; B.M.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.F.I. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.M.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; O.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form May 3, 2004; accepted in final form October 18, 2004

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