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Published ahead of print on October 26, 2006, doi:10.1164/rccm.200606-851OC
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American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 345-354, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200606-851OC

Original Article

Endoscopic Ultrasound As a First Test for Diagnosis and Staging of Lung Cancer

A Prospective Study

Pankaj Singh1,6, Brian Camazine2, Yashodeep Jadhav3, Rahul Gupta3, Phalguni Mukhopadhyay4, Ahmed Khan1, Rama Reddy5, Qi Zheng6, David D. Smith7, Renu Khode1, Bankim Bhatt1, Sanjay Bhat3, Yasir Yaqub1, Rajnikant S. Shah3, Ashish Sharma8, Pawan Sikka9 and Richard A. Erickson10

1 Division of Gastroenterology, Central Texas Veterans Health Care System, Temple, Texas; 2 Department of Surgery, Henderson Memorial Hospital, Henderson, Texas; 3 Department of Radiology, Central Texas Veterans Health Care System, Temple, Texas; 4 Division of Oncology, Central Texas Veterans Health Care System, Temple, Texas; 5 Department of Internal Medicine, Central Texas Veterans Health Care System, Temple, Texas; 6 Department of Biostatistics & Epidemiology, School of Rural & Public Health, Texas A&M University, College Station, Texas; 7 Department of Biostatistics, City of Hope National Medical Center, Duarte, California; 8 Division of Gastroenterology, VA Boston Healthcare System, Boston, Massachusetts; 9 Division of Pulmonary & Critical Care, Central Texas Veterans Health Care System, Temple, Texas; and 10 Division of Gastroenterology & Hepatology, Scott & White Memorial Hospital, Temple, Texas

Correspondence and requests for reprints should be addressed to Pankaj Singh, M.D., M.S., Central Texas Veterans Health Care System, 1901 South 1st Street, Temple, TX 76504. E-mail: pankaj1110{at}hotmail.com


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Multiple tests are required for the management of lung cancer.

Objectives: Endoscopic ultrasound–guided fine needle aspiration (EUS-FNA) was evaluated as a single test for the diagnosis and staging (thoracic and extrathoracic) of lung cancer.

Methods: Consecutive subjects with computed tomography (CT) findings of a lung mass were enrolled for EUS and results were compared with those from CT and positron emission tomography scans.

Results: Of 113 subjects with lung cancer, EUS was performed as a first test (after CT scan) for diagnosis in 93 (82%) of them. EUS-FNA established tissue diagnosis in 70% of cases. EUS-FNA, CT, and positron emission tomography detected metastases to the mediastinal lymph nodes with accuracies of 93, 81, and 83%, respectively. EUS-FNA was significantly better than CT at detecting distant metastases (accuracies of 97 and 89%, respectively; p = 0.02). Metastases to lymph nodes at the celiac axis (CLNs) were observed in 11% of cases. The diagnostic yields of EUS-FNA and CT for detection of metastases to the CLNs were 100 and 50%, respectively (p < 0.05). EUS was able to detect small metastases (less than 1 cm) often missed by CT. Metastasis to the CLNs was a predictor of poor survival of subjects with non–small cell lung cancer, irrespective of the size of the CLNs. Of 44 cases with resectable tumor on CT scan, EUS-FNA avoided thoracotomy in 14% of cases.

Conclusions: EUS-FNA as a first test (after CT) has high diagnostic yield and accuracy for detecting lung cancer metastases to the mediastinum and distant sites. Metastasis to the CLNs is associated with poor prognosis. EUS-FNA is able to detect occult metastasis to the CLNs and thus avoids thoracotomy.

Key Words: lung cancer • non–small cell lung cancer • celiac lymph nodes • endoscopic ultrasound–guided fine needle aspiration • survival



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
Endoscopic ultrasound has emerged as an alternative test for mediastinal staging of non–small cell lung cancer in selected patient populations.

What This Study Adds to the Field
Endoscopic ultrasound–guided fine needle aspiration has high diagnostic yield and is an accurate test for detection of extrathoracic metastases. Endoscopic ultrasound–guided fine needle aspiration established lymph nodes at the celiac axis as a common site for occult metastases, which was associated with poor survival.

 
Lung cancer is the leading cause of cancer death in the United States, with an annual incidence of 170,000 cases (1). A variety of methods are available for cytologic or histologic diagnosis and preoperative staging. An ideal test would achieve the cytologic diagnosis, stage the tumor with high accuracy, and have low procedure-related morbidity.

Bronchoscopy is commonly used for the cytologic or histologic diagnosis of lung cancer; however, it fails to establish tissue diagnosis in 20–30% of cases (2). Also, bronchoscopy and the related procedure, transbronchial needle aspiration, play a limited role in staging (3). Mediastinoscopy has a high level of accuracy for the detection of metastases to mediastinal lymph nodes (MLNs). However, it is more invasive, has a complication rate of 1.7%, requires general anesthesia, and plays no role in evaluation of distant sites (4).

Computed tomography (CT) scan and CT-guided transthoracic needle aspiration are routinely used for the initial assessment of thoracic/extrathoracic sites and cytologic diagnosis, respectively. The limitations are as follows: patients require two visits; there is a high risk of pneumothorax (30%), with 15% requiring chest tube placement (5); and there is poor sensitivity and specificity for detection of nodal and distant metastases (6, 7). Node positivity on CT is based on the size of the lymph node, which has a poor correlation with the presence of malignancy (8–12). CT also has a high false-positive rate for detection of distant metastases, particularly in asymptomatic patients (13, 14).

Fluorodeoxyglucose positron emission tomography (FDG-PET), which is based on tumor physiology rather than anatomy, has a higher sensitivity than CT for the detection of mediastinal node disease and distant metastases (15–17). However, the false positivity of the PET scan may be as high as 25% (18–21). Because surgery is the only chance of cure for NSCLC, positive PET findings that would preclude surgical resection need to be verified.

Endoscopic ultrasound with fine needle aspiration (EUS-FNA) has emerged as an alternative test for the evaluation of lung cancer. Studies have shown EUS-FNA to be highly accurate in detecting metastases to MLNs (22–34). Because FNA can be performed simultaneously, confirmation of malignancy can usually be accomplished in a single procedure (35–38). Previous studies of the efficacy of EUS-FNA in diagnosing lung cancer have been conducted on selected populations in which the majority of patients already had the diagnosis of NSCLC established before having the EUS procedure. The utility of EUS-FNA for establishing the primary diagnosis of suspicious lung masses and simultaneous thoracic as well as extrathoracic staging remains unknown.

In this prospective study we determined the accuracy of EUS-FNA for the staging (thoracic and extrathoracic) and the diagnostic yield in unselected consecutive subjects with CT findings of a newly detected lung mass. Some of the results of these studies have been previously reported in the form of abstracts (39–44).


   METHODS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The institutional review board of the Central Texas Veterans Health Care System (Temple, TX) approved this study in March 2004. All the subjects provided written, informed consent for both the EUS procedure and participation in the study protocol.

Design
Consecutive patients with a newly detected lung mass suspicious of lung cancer or with a recent tissue diagnosis of non–small cell lung cancer (NSCLC) were enrolled in the study. Subjects were excluded if they met any of the following criteria: (1) advanced heart or lung disease that precludes moderate sedation, (2) patient undergoing chemotherapy or radiotherapy for lung cancer, and (3) established tissue diagnosis of small cell lung carcinoma (SCLC).

Physicians from primary care, thoracic surgery, and subspecialty clinics (oncology and Pulmonary clinics) referred patients to the gastroenterology clinic for EUS evaluation. Subjects who met the eligibility criteria were enrolled in the study and were offered EUS-FNA. Other tests for diagnosis (bronchoscopy and transthoracic needle aspiration) and staging (mediastinoscopy/mediastinotomy and PET scan) were performed when clinically indicated. The combination of tests and invasive procedures leading to clinical classification according to the tumor–node–metastasis (TNM) staging system of the American Joint Committee on Cancer (45) was considered traditional staging. A two-stage system was used to stage small cell lung cancer patients (37). Tumor confined to the lung from which it originated with involvement of the lymph nodes on the same side was categorized as limited stage, whereas cancer that had spread to the other lung, to lymph nodes on the other side of the chest, or to distant organs was defined as extensive stage (46).

Outcome
The primary outcome of the study was the determination of the accuracy of EUS-FNA for detecting metastasis to MLNs and distant regions in patients with lung cancer. Because undiagnosed lung mass was an eligibility criterion, the diagnostic yield of EUS-FNA was also obtained. Diagnosis of lung cancer and metastasis to the MLNs was established cytologically by FNA or by surgically resected sample that showed malignant cells. Surgical exploration and/or mediastinoscopy were performed when the tumor was considered resectable. Metastases to distant sites were defined either by the presence of cytologically positive malignant cells or by radiologic progression of the disease on follow-up imaging studies.

EUS Procedure
EUS was done by a single endoscopist. The endoscopist was not blinded to the studies or procedures done up to that point in the evaluation of the patient at the time of referral for the study. The curved linear-array echoendoscope (GF-UCT/P 1140; Olympus America Inc., Melville, NY) was used for endosonographic examination and FNA. EUS examination was done systematically in all patients and included the celiac axis, left adrenal gland, liver (visualized through the stomach and duodenum), and MLNs, examined in that order. If a celiac lymph node (CLN) was visualized, FNA was performed irrespective of the endosonographic features and size of the lymph node. The thoracic lymph node stations examined in detail included the paraesophageal, subcarinal, aortopulmonary window (station 5), and paratracheal regions.

EUS-FNA was performed with a 22-gauge needle (Olympus FNA needle; Olympus America Inc.). More distant sites of possible metastasis (e.g., CLNs, liver, or left adrenal) were always sampled before sampling the mediastinal lymph nodes. A pathologist and cytotechnologist were present in the room to provide immediate interpretation as to whether adequate material was obtained for diagnosis.

CT Scans
All CT examinations were performed on site with the use of a helical CT scanner (model PQ-5000; Picker International/Philips Medical Systems, Cleveland, OH). Images were acquired by the use of 10-mm collimation, a table speed of 6.25 mm/s at 175 mA and 120 kV, and a pitch of 1.50. Images were obtained during a single breath-holding session when possible. Omnipaque 300 (100 cm3; GE Healthcare, Piscataway, NJ) was administered intravenously to each patient. An injection rate of 3 cm3/s and a scan delay of 60–70 s were used. Lymph nodes were considered enlarged if the short-axis diameter was greater than 1 cm in all mediastinal stations.

Whole-body PET
PET was performed as part of routine clinical care with a PET scanner (Siemens, Knoxville, TN). After intravenous injection of [18F]fluorodeoxyglucose, transmission and emission scans were performed from the skull base through the inguinal regions. A positive PET scan had at least one hot spot. In selected cases PET was not performed when the tumor was advanced and patients had multiple comorbid illnesses.

Surgery and Mediastinoscopy/Mediastinotomy
Surgery was performed by a single surgeon experienced in thoracic oncology. With the exception of stages IIIB and IV, surgery was offered to patients who did not have comorbid illnesses precluding operation. Mediastinoscopy was also performed as part of the preoperative staging to evaluate lymph node levels 1, 2, 3, 4, and 7. Mediastinotomy was also performed for left upper lobe tumors to evaluate lymph node levels 5 and 6. These levels were also explored at the time of thoracotomy with the addition of mediastinal lymph node levels 8 and 9, as well as hilar lymph nodes.

Follow-up Visits: Description and Schedule
Follow-up consisted of a patient interview by a nurse or personal visit by a physician, communication with the primary physician, collection of additional radiologic test results, and review of cytopathologic findings. Follow-up data were gathered 24–72 h after the procedure and from subsequent clinic visits. Patients in whom the diagnosis of lung malignancy could not be made were monitored in the pulmonary or thoracic surgery clinic for repeat CT scans at 3- to 6-mo intervals. Patients were monitored to the time of death or to the time of their last visit to their physicians.

Statistics
Sample size assumptions and estimates.
The study was designed to detect with a power of 0.80 and a two-sided {alpha} level of 0.05, a difference of 20% between the sensitivity of EUS and CT (the sensitivity of which was assumed to be 50%) for the detection of metastases to the mediastinum. Assuming metastases to the mediastinum in 60% of the participants, the calculated sample size was 150.

Statistical analysis.
Continuous variables are reported as range, mean, and standard deviation. The diagnostic yield of EUS-FNA to establish the tissue diagnosis of lung malignancy was calculated. The primary analysis was based on patients in whom EUS was performed as a first test. The overall analysis was made up of all the cases, irrespective of whether EUS was performed as a first test. Subgroup analysis was performed to determine the diagnostic yield of EUS-FNA in subjects with CT evidence of a normal mediastinum, mediastinal invasion, enlarged mediastinal lymph nodes, and/or distant metastases. Sensitivity, specificity, and accuracy of EUS-FNA, CT scan, and PET scan for the detection of metastases to the mediastinum and distant sites (celiac axis, liver, and adrenal gland) were calculated and compared. McNemar's test for correlated proportions with the exact test was used to compare the findings of EUS, CT, and PET. p < 0.05 was considered statistically significant. Survival was measured from the original date of mass detection to the date of death. Data on living subjects were censored at the time of the last clinical follow-up. Log-rank tests were used to calculate the median survival time and for comparison of survival times between selected groups. Age, histologic type, metastases to distant regions (liver, adrenal gland, and celiac axis), surgical treatment, and chemotherapy and radiotherapy were used as covariates in the analysis. The Cox proportional hazards model was used to assess independent predictors of survival. All computations were performed with SAS (version 9.00; SAS Institute, Inc., Cary, NC). Survival analysis was done with proc lifetest (for log-rank tests) and proc phreg (for proportional hazard models). All other computations were performed with SAS proc freq.


   RESULTS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients
Between March 2004 and July 2005, 157 patients were enrolled in the study. CT scan, EUS, and PET scan were performed in 157, 157, and 106 cases, respectively. Of 157 cases, 113 were ultimately diagnosed with lung carcinoma (95 NSCLC and 18 SCLC) and included in the analysis. Forty-four cases were excluded, 21 of them for the following reasons: prior diagnosis of SCLC (2 cases); solitary metastases from melanoma, esophageal carcinoma, renal cell carcinoma, or colon carcinoma (5 cases); surgical confirmation of the benign nature of the lesion (3 cases), stable lesion on follow-up imaging (11 cases). In 12 of the remaining 23 cases, follow-up imaging showed evidence of increased size of the lung mass. Malignancy was suspected; however, a definitive diagnosis of malignancy could not be established by the time of study termination and therefore those patients were excluded from the analysis (Figure 1).


Figure 1
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  		Figure 1. Screening and enrollment of subjects for participation in the study. CT = computed tomography; EUS = endoscopic ultrasound; SCLC = small cell lung cancer.

 
Of the 113 cases with lung cancer, EUS was performed as a first test (after CT scan) for diagnosis in 93 (82%) of the cases. In 17 cases (15%) a diagnosis of lung cancer had already been made, and so those patients underwent EUS primarily for staging. However, because 93 (82%) of the 113 patients did not have a prior diagnosis of lung cancer, EUS was the first diagnostic test in the majority of cases. The clinical characteristics of the 113 patients who were evaluated are shown in Table 1.


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  		TABLE 1. DEMOGRAPHICS AND TUMOR CHARACTERISTICS OF 113 PATIENTS WITH LUNG CARCINOMA

 
Diagnosis of Lung Cancer
The overall diagnostic yield of EUS-FNA as a first test was 70% (95% confidence interval [CI], 60–79%). The diagnostic yields in the various subgroups are detailed in Table 2.


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  		TABLE 2. SENSITIVITY OF ENDOSCOPIC ULTRASOUND–GUIDED FINE NEEDLE ASPIRATION AS DIAGNOSTIC TEST IN VARIOUS SUBGROUPS

 
Detection of Metastases to the Mediastinum
Metastases to the MLNs were established in 49 cases. EUS, CT scan, and PET scan detected metastases to the mediastinum with accuracies of 93, 81, and 83%, respectively.

Detection of Distant Metastases to the Celiac Axis, Liver, and Adrenal Gland
Celiac axis.
CLNs were visualized and EUS-FNA was performed in 19 (17%) cases. Final diagnoses were as follows: metastatic NSCLC (10), metastatic small cell carcinoma (2), and negative for malignancy (7). Characteristics of the 10 patients with NSCLC metastases are shown in Table 3. The short-axis diameter of the CLNs was less than 1 cm in four of the cases. The median number of needle passes was 2.5 (range, 1–4). The diagnostic yield of EUS-FNA for the detection of metastases to the CLNs was significantly higher than that of the CT scan (100 vs. 50%; p < 0.05) (Table 4). CT scan missed NSCLC metastases to the CLNs in 5 of the 10 cases cytologically proven to be malignant on the basis of tissue obtained by EUS-FNA. The celiac nodes were less than 1 cm in size in four of the five cases that were missed by CT scan (Table 3, Figure 2A). See Video E1 of the online supplement for metastases to CLN missed by the CT scan.


Figure 2
Figure 2
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  		Figure 2. Celiac axis. (A) Celiac axis (CA) region was normal on CT and positron emission tomograhy scans. EUS showed a subcentimeter hypoechoic lymph node (arrow) measuring 5.7 x 10.3 mm. EUS- guided fine needle aspiration (FNA) confirmed the lymph node to be malignant. (B) Malignant lymph node, measuring 16 x 11 mm, at the origin of the celiac trunk from the aorta.

 

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  		TABLE 3. RADIOLOGIC AND ENDOSONOGRAPHIC FINDINGS OF NON–SMALL CELL LUNG CANCER METASTASES TO LYMPH NODES AT CELIAC AXIS

 

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  		TABLE 4. COMPARISON OF DIAGNOSTIC YIELD, SENSITIVITY, SPECIFICITY, AND ACCURACY OF ENDOSCOPIC ULTRASOUND–FINE NEEDLE ASPIRATION, COMPUTED TOMOGRAPHY SCAN, AND POSITRON EMISSION TOMOGRAPHY SCAN FOR DETECTION OF METASTASES TO CELIAC AXIS, LIVER, ADRENAL GLAND, AND DISTANT METASTASES*

 
An example of a metastasis to the celiac axis identified by EUS-FNA but missed by both CT and PET scans is shown in Figure 2A.

Univariate analysis of all radiologic and endosonographic variables showed that the endosonographic features of large and hypoechoic CLNs were significantly associated with metastases to the CLNs (p < 0.0001). The same variables were used to fit a multivariate model, and again hypoechoic and large-size (greater than 1 cm) lymph nodes were found to be independent predictors of metastasis to the CLNs (Tables 5–7). These features both had accuracies of 69% for the diagnosis of malignancy.


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  		TABLE 5. UNIVARIABLE LOGISTIC REGRESSION: PREDICTORS OF METASTASES TO LYMPH NODES AT CELIAC AXIS

 

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  		TABLE 6. MULTIVARIABLE LOGISTIC REGRESSION: INDEPENDENT PREDICTORS OF METASTASES TO LYMPH NODES AT CELIAC AXIS

 

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  		TABLE 7. ACCURACY OF ENDOSONOGRAPHIC FEATURES OF LYMPH NODES AT CELIAC AXIS FOR DETECTION OF METASTASES

 
Liver.
Metastases to the liver were detected in 13 cases (EUS-FNA cytologic confirmation in 11 cases; increase in the size of the lesion on the follow-up CT scan in 2 cases). CT scan detected lesions in the liver in 21 of the 113 cases with lung cancer. Thirteen of the 21 cases were ultimately determined to be true metastatic lesions. Of the remaining eight cases, six had a stable lesion on the follow-up CT scans and two patients died within 1 mo and therefore the definite nature of the lesions could not be ascertained. The specificity of EUS-FNA for detection of metastases to the liver was significantly higher than that of the CT scan (p = 0.007). There was no significant difference in the overall accuracy of EUS-FNA versus CT (p = 0.10). A comparison of the accuracy of EUS-FNA versus PET showed a trend in favor of EUS-FNA (p = 0.06) (Table 4).

Adrenal gland.
Metastases to the adrenal gland were detected in 15 cases (EUS-FNA cytologic confirmation in 14 cases; increase in size of the lesion on the follow-up CT scan in 1 case). CT reported findings suspicious for metastases in the adrenal gland in 19 cases. EUS-FNA confirmed malignancy in 12 of the 19 cases. Of the remaining seven cases, one patient died within 1 mo, and follow-up imaging of six patients revealed five with stable lesions and one with a progressive enlargement. EUS-FNA was performed in 25 patients with lung cancer who had normal-appearing adrenal glands on CT scan: 2 showed malignant cytology. Comparison of the accuracy of EUS versus CT showed a trend in favor of EUS (p = 0.07) (Table 4). An example of a metastasis to the adrenal gland that was identified by EUS-FNA but missed by both CT and PET scans is shown in Figure 3.


Figure 3
Figure 3
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  		Figure 3. Left adrenal gland. No abnormalities of the adrenal gland were observed on CT scan and PET scan. EUS showed a normal-sized adrenal gland in one plane (A) and a distinct bulge (arrow in B) in another plane. EUS-FNA of the bulged region of the adrenal gland was positive for malignant cells.

 
Distant metastases were detected in a total of 32 of the 113 cases. There was no significant difference in the sensitivity of EUS-FNA, CT scan, and PET scan for the overall detection of distant metastases. The specificity and accuracy of EUS-FNA for the detection of distant metastases were significantly higher than those of the CT scan (Table 4). Overall, 40 metastatic lesions were detected in the liver, adrenal gland, and celiac axis in 32 patients with distant metastases. EUS-FNA, CT, and PET had sensitivities of 93, 80, and 50%, respectively, for detection of distant metastatic lesions. Celiac metastases were not correlated with the presence of adrenal (p = 0.57) or liver metastases (p = 0.24).

Survival Analysis and EUS as a Prognosticator
The Cox proportional hazards model showed metastases to the celiac axis and liver to be independent predictors of poor survival (p = 0.02) (Tables 8 and 9; Figure 4).


Figure 4
Figure 4
Figure 4
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  		Figure 4. Kaplan-Meier curve showing the impact of metastases to the celiac axis lymph nodes (CLNs) on survival. (A) Survival of subjects with and without metastases to lymph nodes at the celiac axis. The median survival time for subjects with and without EUS evidence of metastases to the CLNs was 142.5 and 330 d, respectively. The difference was statistically significant (p = 0.0024). (B) Modified risk score–adjusted estimated survivor function showing survival of subjects with and without metastases to lymph nodes at the celiac axis after controlling for age and metastases to the liver and adrenal glands. Estimated median survival time was 183 d for those with metastases to the CLNs and 330 d for those without metastases to the CLNs. The difference was statistically significant (p = 0.02). (C) Comparison of survival of patients with non–small cell lung cancer metastases to lymph nodes at the celiac axis (small vs. large lymph nodes) versus patients without non–small cell lung cancer metastases to lymph nodes at the celiac axis.

 

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  		TABLE 8. LOG-RANK TESTS SHOWING IMPACT OF DIFFERENT VARIABLES ON SURVIVAL

 

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  		TABLE 9. COX PROPORTIONAL HAZARDS ANALYSIS SHOWING INDEPENDENT PREDICTORS OF SURVIVAL

 
The median survival time for subjects with and without EUS evidence of metastasis to the CLNs was 142.5 d (95% CI: 94–263 d) and 330 d (95% CI: 283–421 d). The difference was statistically significant (p = 0.002).

A log-rank test showed NSCLC metastases to the CLNs, liver, and adrenal gland to be associated with poor survival. The median survival of patients with NSCLC metastasis to the CLNs was significantly shorter than that of patients without metastasis to the CLNs (5 vs. 10.8 mo; p < 0.0001). The overall 1-yr survival of patients with and without metastasis to the CLNs was 0 and 42%, respectively. The median survival of patients with and without metastasis to the liver was 7.8 and 10.8 mo, respectively (p = 0.002), and to the adrenal gland it was 4.4 and 11 mo, respectively (p = 0.0002).

A stratified analysis on the basis of size of the CLNs (less than or more than 1 cm) showed that subjects with metastases to the CLNs with either large or small lymph nodes had significantly poorer survival than did patients without metastases to the CLNs (p < 0.01). There was no significant difference between the survival of patients with enlarged lymph nodes versus small lymph nodes at the celiac axis (p = 0.68) (Figure 4).

Impact on Treatment
Of 44 patients with resectable tumor on CT scan, EUS-FNA changed the management in 18% (8) patients by upgrading the tumor to stage IV (7%), stage IIIA or IIIB (7%), and stage II to III A (4%) (Table 10). By using EUS-FNA, thoracotomy was avoided in 13.6% (95% CI: 5–27%) of patients with CT findings of a resectable tumor.


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  		TABLE 10. IMPACT OF ENDOSCOPIC ULTRASOUND–FINE NEEDLE ASPIRATION ON MANAGEMENT OF NON–SMALL CELL LUNG CARCINOMA AND SMALL CELL LUNG CARCINOMA BY UPGRADING TUMOR STAGE

 
Complications
One patient developed chest pain after EUS-guided FNA of the pleural effusion. There were no other immediate or late complications due to EUS-FNA.


   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study showed EUS-FNA to have both a high diagnostic yield and a high level of accuracy as a primary test for the staging of lung cancer (thoracic and extrathoracic) in consecutive subjects with CT findings of a lung mass. EUS-FNA established the primary diagnosis in 70% of the cases with lung tumor. The diagnostic yield was greater than 90% when there was also CT evidence of enlarged mediastinal lymph nodes or distant metastases. EUS-FNA was as accurate as the CT or PET scan for detection of metastases to the mediastinum. The accuracy of EUS-FNA was similar to PET scan and superior to CT scan for detection of metastases to distant regions (celiac nodes, liver, and adrenal glands). Importantly, the celiac axis was identified as a common site for distant metastasis, with an incidence of 11%. Patients with metastases to the CLNs had a significantly shorter survival, similar to that seen with metastatic disease at other distant sites. EUS-FNA detected occult metastases to the CLNs, which were missed in 50% of cases by CT scan. Occult metastasis to the CLNs had the same clinical significance as that of overt metastasis. By using EUS-FNA, thoracotomy was avoided in 14% of cases with CT findings of a resectable tumor.

This study found the diagnostic yield of EUS-FNA to be 70%, which is substantially lower than the 90% reported in other studies (33–35). One possible explanation for this difference is that in the previous studies the patients had tumors or enlarged MLNs that were located adjacent to the esophagus, whereas in this study we included consecutive patients with a lung mass. Of these lung masses, more than 80% were intraparenchymal (not adjacent to the esophagus) and more than 40% of our patients did not have CT evidence of enlarged lymph nodes. A number of studies have shown that PET is more accurate than CT for the detection of lung cancers and therefore can be used for diagnosis. However, PET lacks diagnostic specificity for primary and metastatic lesions (18–21). EUS-FNA offers the distinct advantage of being able to establish both the tissue diagnosis and histologic type of the malignancy. Unlike transthoracic needle aspiration, which is associated with a high complication rate of 30–45% (5), we did not observe any immediate or late complications as a result of EUS-FNA. The safety profile of EUS-FNA makes it a preferable diagnostic test, particularly because its diagnostic yield is in the same range as those reported for other tests.

The accuracy of EUS-FNA for the detection of metastases to MLNs has been reported previously (22–32). The results of this study are in agreement with previous studies. Stratification into large-sized (greater than 1 cm) mediastinal lymph nodes and normal mediastinum revealed that EUS-FNA detected metastases in 60 and 19%, respectively, comparable to previous reports. A 25% false-positive rate for PET scanning for metastases to the mediastinum has been reported previously (18–21). This fact mandates tissue confirmation of metastatic disease before denying a patient attempted surgical cure on the basis of a positive PET scan.

The high incidence (11%) of metastases to the celiac axis was an unexpected and important finding because patients with metastases to the CLNs had significantly shorter survival than patients without CLN involvement. LeBlanc and coworkers and Kramer and coworkers also reported metastases to the CLNs in patients with NSCLC (27, 32). However, we found a higher incidence of metastasis because we enrolled both operable and inoperable subjects with advanced stage lung cancers, and EUS-FNA was performed whenever a lymph node could be visualized at the celiac axis, regardless of its size or endosonographic features.

This study showed that the diagnostic yield of EUS-FNA is significantly superior to both CT scan and PET scan for the detection of metastases to the CLNs. A similar finding was reported in subjects with esophageal carcinoma (47–53). The CT scan requires malignant lymph nodes to be greater than 1 cm in size, and therefore CT will miss micrometastases that do not result in node enlargement. In this study, in 34% of cases the malignant celiac nodes were smaller than 1 cm. Although PET uses altered cell metabolic activity rather than anatomic size for detection of malignant cells, it is limited to a spatial resolution of about 6 mm. In addition, the scatter effects and motion artifacts secondary to esophageal and stomach peristalsis lower the sensitivity of PET for the detection of microscopic metastases to the upper abdominal lymph nodes (52, 53). Comparative studies have shown a higher diagnostic yield for laparoscopy and surgery than for EUS-FNA for metastases to the CLNs in esophageal cancer (54). In our study, because patients with negative celiac nodes did not undergo laparoscopic or surgical resection of the CLNs, the incidence may actually be higher than 11%.

Metastasis to the CLNs as an independent predictor of poor survival in NSCLC is an important finding of our study. This has not been reported previously. The median survival of patients with metastases to the CLNs was 5 mo, which is in the same range as that for metastases to the adrenal gland (4.4 mo) and liver (7.8 mo). The 1-yr overall survival of patients with and without metastases to the CLNs was 0 and 42%, respectively. Forty percent of the NSCLC metastases to CLN were less than 1 cm and were not detected on CT scan. Importantly, occult metastases to the CLNs that are not detected by CT scan, but are confirmed to be cytologically malignant by EUS-FNA, have the same clinical significance as large lymph nodes. The median survival of patients with metastases to lymph nodes was 5 mo for small nodes and 7 mo for large nodes. This highlights a critical role for EUS-FNA, because it is the only test that can both detect subcentimeter-sized lymph nodes at the celiac axis and cytologically confirm the malignant nature of the node.

At present, EUS is not considered the standard of care for the diagnosis and staging of lung cancer. The results of this study show the celiac axis as a common site for metastases. Therefore, it is important to determine which patients with a diagnosis of NSCLC should undergo EUS evaluation of the celiac axis for complete and accurate staging. Are there clinical or radiologic predictors that could define a high-risk group for metastases to the CLNs? Of multiple variables, including tumor size, tumor location, and evidence of metastases to the mediastinum and other distant sites, there was no significant radiologic predictor of metastases to the CLNs.

Endosonographic findings of hypoechoic lymph nodes and those of large size (greater than 1 cm) were independent predictors of metastases to the CLNs. However, using size as a criterion, EUS would miss metastases in 40% of cases, and using hypoechoic lymph nodes, EUS would overdiagnose metastases in 31% of cases. Different EUS criteria have been studied for the prediction of malignant lymph nodes. In particular, size (greater than 1 cm), echogenicity (hypoechoic), margins (sharp), and shape (round) are commonly used for determining metastases to the lymph nodes in the mediastinum as well as in the CLNs in patients with esophageal cancer (18). Both the clinical importance of metastatic microscopic foci at the CLNs and the superiority of EUS-guided FNA over endosonographic features, shown by other studies (19), suggest that EUS-FNA should be performed regardless of node size once the lymph nodes are visualized at the celiac axis. Absence of metastases to other organs should not deter evaluation of the celiac axis in patients with NSCLC, because celiac nodes may be the only site for distant metastases.

Current staging for lung cancer does not include lymph nodes at the celiac axis as a potential site for distant metastases. Instead, staging is based on imaging studies and mediastinoscopy/thoracotomy, which are either suboptimal or lack the ability to examine the celiac region. This study shows that evaluation of the CLN region is important for staging for three reasons: (1) metastases to other sites do not predict metastasis to the celiac axis; (2) metastasis to the CLNs is associated with poor prognosis independently of metastases to other distant sites; and (3) metastasis to the CLNs categorizes the tumor as nonoperable. In this study, 98% of the subjects were male and 35% had advanced metastatic disease. Additional studies in different groups of patients are required to determine the incidence and importance of the celiac axis as a site for distant metastases.

EUS-FNA had higher sensitivity than PET and both higher specificity and accuracy than CT for detection of metastases to the liver. The rationale for including a liver examination was based on studies that have shown the ability of EUS to detect occult metastases to the liver that are missed by CT scan (55–57). In this study, 21 cases had CT evidence of lesions in the liver that were suggestive of metastases. EUS-FNA confirmed the cytologic diagnosis in 12 of the 13 cases with malignancy. Of the eight cases with benign lesions, EUS correctly identified all of them as benign. Although CT-guided FNA is available for the same purpose, it requires a second visit and the yield is dependent on the size of the lesion. Because PET lacks the ability to determine anatomic relationships, it misdiagnosed a celiac axis lymph node and a lesion in the right rib as potential liver metastases.

The adrenal glands are a common site for metastases of lung cancer. CT scan of the thorax and upper part of the abdomen has been the standard for assessing the adrenal glands. Because adrenal adenomas are quite common, adrenal masses found in patients being staged for NSCLC are often benign lesions (13, 14). Studies have shown that although PET has a high sensitivity (16) for adrenal metastases, its specificity is low (13). Because surgery is the only curative option, patients with abnormal imaging results should not be exempted from surgery without tissue confirmation, except when the radiologic evidence is overwhelming. This study showed that EUS-FNA has both high specificity and high sensitivity for adrenal metastases, giving it a higher level of accuracy than either CT or PET scan. The utility of EUS-FNA for determining metastases to the left adrenal gland was reported earlier in a selected patient population (58, 59). However, our study differs from previous studies because consecutive cases underwent EUS examination of the left adrenal gland and FNA was performed whenever the adrenal gland appeared endosonographically deformed or large, regardless of the CT and PET findings. This approach detected metastases to the adrenal gland in two cases that were negative by CT scan and in one case that was negative by PET scan. The probable explanation of high diagnostic yield of FNA is that micrometastases to the adrenal gland do not lead to adrenal enlargement and therefore are missed in imaging studies.

In this study, in addition to making a primary diagnosis, EUS-FNA significantly changed patient management in 18% of the 44 patients with resectable NSCLC. In 14% of the cases, in which surgical resection was indicated by CT, thoracic surgery was avoided. This is consistent with findings of previous studies (25, 27, 31), one of which estimated the national cost saving of using EUS-FNA in lung cancer to be approximately $300,000,000 per year, considering a direct cost of $30,000 per thoracotomy and an assumption that 50% of patients with a diagnosis of lung cancer have a normal mediastinum on CT scan in the United States (27).

As a result of our study, we recommend that, after the initial assessment of a lung mass by CT scan, EUS-FNA may be considered the next test to establish the diagnosis and stage of lung cancer, particularly when there is CT evidence of metastases to the mediastinum and distant sites. The diagnostic yield of EUS-FNA is in the same range as that of bronchoscopy, with the distinct advantage that thoracic and extrathoracic staging can be performed simultaneously. Bronchoscopy may be reserved for cases with nondiagnostic EUS-FNA and for operable cases, which require accurate endobronchial T staging. The ability of EUS-FNA to acquire tissue and its high specificity and accuracy for thoracic and extrathoracic staging make it preferable to the PET scan. The main limitation of EUS in accessing the pretracheal lymph nodes remains a concern. However, studies with endobronchial ultrasound (E-BUS) show that E-BUS in combination with EUS should overcome this shortcoming (60, 61). The high frequency of occult metastases to the CLNs found in this study and the high sensitivity of EUS-FNA for their detection represents a distinct advantage of EUS-FNA over other tests. This finding alone argues for EUS-FNA being an integral part of the preoperative staging of NSCLC.

The limitations of this study were that surgical exploration for verification of EUS-FNA findings was not performed in all cases and a cytopathologic diagnosis of malignancy was the gold standard for the diagnosis of malignant lymph nodes and lesions in the distant sites. Because the false-positive rate of cytopathology is less than 1% (62), it would be unethical to use other invasive studies, such as surgery, just to confirm the cytopathologic diagnosis of malignancy. Another limitation of the study is that we did not include 44 cases with lung masses in the analysis because tissue diagnosis could not be established. It is possible that up to 12 of these patients ultimately could still prove to have lung cancer, which would decrease the overall diagnostic yield of EUS-FNA.

In this study, the definition of CLNs was not predetermined. During EUS examination the celiac axis was identified and the echoendoscope was rotated clockwise and counterclockwise. If a lymph node could be visualized, it was classified as a CLN. Other investigators have used distance criteria, such as within 2 cm of the origin of the celiac axis irrespective of whether the lymph node is along the celiac axis, gastric artery, or hepatic artery. We do not believe that these criteria will have an impact on prognosis and management as long as the nodal metastases have been established outside the thoracic region. In this study we have compared the accuracy of EUS-FNA with PET scans. Studies have shown that newer generation combined FDG-PET/CT scanners have a higher accuracy than PET alone because of better lesion characterization and accurate lesion localization (63). Another possible limitation of the study is that CT examinations were performed with 10-mm collimation, which may have lowered the detection rate in comparison with EUS. It seems logical that with multidetector CT imaging with thinner collimation, the sensitivity to detect smaller lesions may be higher; however, the downside of thinner collimation would be that a greater number of benign lesions would be detected, which would require additional follow-up diagnostic studies. The high resolution of EUS and ability to perform EUS-FNA in a single setting is an advantage to characterize such lesions.

In conclusion, EUS-FNA is an excellent test for the diagnosis and staging (thoracic and extrathoracic) of lung cancer. Importantly, metastasis to the CLNs in lung cancer is common and is associated with poor survival. In 50% of NSCLC cases, metastasis to the CLNs is not evident on CT scan. Occult metastasis to the CLNs detected by EUS-FNA has the same clinical significance as when metastasis is evident by CT. There are no radiologic predictors of metastases to the CLNs. Absence of metastases to other organs should not deter evaluation of the celiac axis because celiac lymph nodes may be the only region for distant metastases. EUS-FNA is superior to other tests for the detection of occult metastases to the celiac region, which would obviate thoracotomy in patients with otherwise resectable disease.


   Acknowledgments
 
The authors thank Kathleen Orlando and Shelley Schetat for invaluable assistance during endoscopic procedures.


   FOOTNOTES
 
Supported by a grant award from Veterans Affairs and by a grant from Scott & White Hospital and Texas A&M University.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200606-851OC on October 26, 2006

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form June 26, 2006; accepted in final form October 26, 2006


   REFERENCES
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
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