Key words: CT scan; endobronchial ultrasound; integrated PET; lung cancer; staging

Transcription

1 CHEST Original Research INTERVENTIONAL PULMONOLOGY Application of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Following Integrated PET/CT in Mediastinal Staging of Potentially Operable Non-small Cell Lung Cancer* Bin Hwangbo, MD; Seok Ki Kim, MD, PhD; Hee-Seok Lee, MD; Hyun Sung Lee, MD, PhD; Moon Soo Kim, MD; Jong Mog Lee, MD; Hyae-Young Kim, MD, PhD; Geon-Kook Lee, MD, PhD; Byung-Ho Nam, PhD; and Jae Ill Zo, MD, PhD Background: The role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) following integrated PET/CT scanning in mediastinal staging of non-small cell lung cancer (NSCLC) has not been assessed. Methods: We prospectively evaluated the diagnostic values of PET/CT scanning and EBUS-TBNA for mediastinal staging in 117 patients with potentially operable NSCLC with accessible mediastinal lymph nodes (diameter range, 5 to 20 mm) by EBUS-TBNA. Subgroup analysis according to histologic type was performed. Results: Of 30 cases of mediastinal metastasis, 27 were confirmed by EBUS-TBNA and 3 were confirmed by surgery. EBUS-TBNA results confirmed all cases with true-positive PET/CT scan findings and six of nine cases with false-negative PET/CT scan findings. The sensitivity, specificity, positive predictive value, negative predictive value (NPV), and accuracy of EBUS-TBNA in the detection of mediastinal metastasis were 90.0%, 100%, 100%, 96.7%, and 97.4%, respectively. For PET/CT scans, the values were 70.0%, 59.8%, 37.5%, 85.2%, and 62.4%, respectively (p 0.052; p < 0.001; p < 0.001; p 0.011; p < 0.001, respectively). In adenocarcinoma (n 55), EBUS-TBNA detected four of six cases with false-negative PET/CT scan findings, and the NPV was higher for EBUS-TBNA than for PET/CT scans (94.6% vs 77.8%, respectively; p 0.044). In squamous cell carcinoma (n 53), the NPV of EBUS-TBNA and PET/CT scans were similarly high (97.9% vs 96.3%, respectively; p 0.689). Conclusions: EBUS-TBNA was an effective invasive method following PET/CT scanning in the mediastinal staging of potentially operable NSCLC. In mediastinal PET/CT scan-positive cases, EBUS-TBNA was an excellent tool for detecting mediastinal metastasis. Even in mediastinal PET/CT scan-negative cases, EBUS-TBNA can be useful for confirming mediastinal metastases, especially in adenocarcinoma. (CHEST 2009; 135: ) Key words: CT scan; endobronchial ultrasound; integrated PET; lung cancer; staging Abbreviations: EBUS-TBNA endobronchial ultrasound-guided transbronchial needle aspiration; FDG 18 F- deoxyglucose; NPV negative predictive value; NSCLC non-small cell lung cancer; PPV positive predictive value; SUV standardized uptake value Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a promising method for the mediastinal staging of lung cancer. A comparison study 1 of EBUS-TBNA with chest CT scanning and PET scanning has demonstrated a higher accuracy of EBUS-TBNA than of noninvasive methods. Studies 2 5 have shown high diagnostic yields of EBUS-TBNA in mediastinal staging in various lung cancer patient groups, such as patients with enlarged mediastinal nodes by chest CT scan, 1280 Original Research

2 *From the Center for Lung Cancer (Drs. Hwangbo, H.-S. Lee, H.S. Lee, M.S. Kim, J.M. Lee, H.-Y. Kim, G.-K. Lee, and Zo), the Department of Nuclear Medicine (Dr. S.K. Kim), Research Institute and Hospital, and the Cancer Biostatistics Branch (Dr. Nam), Research Institute for National Cancer Control & Evaluation, National Cancer Center, Goyang, Gyeonggi, Korea. This work was supported by National Cancer Center grant The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received August 19, 2008; revision accepted November 28, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/site/misc/reprints.xhtml). Correspondence to: Jae Ill Zo, MD, PhD, Center for Lung Cancer, National Cancer Center, 809 Madu-dong, Ilsan-gu, Goyang, Gyeonggi, , Korea; DOI: /chest patients with a normal mediastinum by chest CT scan, patients with a positive mediastinum by PET scan, or even patients with a normal mediastinum by PET scan. Integrated PET/CT scanning has more anatomic advantages than PET scanning and has been reported 6 9 to be more accurate than PET scanning or a visual correlation of PET scanning with CT scanning in the staging of lung cancer. The use of PET/CT scanning in lung cancer staging is increasing. 6 However, the role of EBUS-TBNA after PET/CT scanning is performed has not been assessed until now. PET scan or integrated PET/CT scan findings of the mediastinum can guide further invasive staging in lung cancer Guidelines recommend that positive PET scan findings on the mediastinum should be confirmed by invasive methods in the preoperative staging of lung cancer. In patients with a PET scan-negative mediastinum, invasive staging still is beneficial to patients, such as those with central tumors, N1 disease by CT or PET scan, positive mediastinal nodes by CT scan, or low 18 F-deoxyglucose (FDG) uptake of primary tumors. 11,12 It has been suggested that patients with adenocarcinoma may benefit from invasive staging. According to current guidelines, 11,12 EBUS-TBNA is recommended as one of the options for invasive mediastinal staging following PET scan or integrated PET/CT scan. However, the diagnostic yield of EBUS- TBNA for patients with a PET/CT scan-positive or a PET/CT scan-negative mediastinum has not been evaluated. Moreover, in PET/CT scan-negative cases, the patient groups that could benefit from EBUS-TBNA also have not been well evaluated. The purpose of this study is to evaluate the role of EBUS-TBNA after integrated PET/CT scanning is performed. We compared the diagnostic values of EBUS-TBNA and integrated PET/CT scans in the mediastinal staging of potentially operable nonsmall cell lung cancer (NSCLC). To evaluate the role of EBUS-TBNA, especially for PET/CT scannegative cases, we performed a subgroup analysis that focuses on histologic types. Patients Materials and Methods In this prospective study, consecutive patients with histologically confirmed or strongly suspected potentially operable NSCLC were enrolled from October 2006 to October Patients were required to have at least one mediastinal lymph node in an accessible location by EBUS-TBNA, with a short diameter of 5 to 20 mm on chest CT scan axial image. Surgical tumor resectability was evaluated after staging workup for NSCLC, including CT scan of the chest and upper abdomen, integrated PET/CT scan, and brain MRI (and/or bone scan). We excluded patients who had M1 disease and inoperable T4 disease based on the international system for staging lung cancer. 18 We also excluded patients who had a bulky mediastinal lymph node (short diameter 2 cm on chest CT scan axial image) or extranodal invasion of the mediastinal lymph node visible on chest CT scan. When we detected an abnormal supraclavicular lymph node by chest CT scan or integrated PET/CT scan in otherwise eligible patients, we performed fine-needle aspiration and excluded patients with supraclavicular lymph node metastasis. Patients with unresectable tumors detected by white light bronchoscopy and patients with Pancoast tumors were excluded. Medical operability was assessed by physical examination, blood tests, pulmonary function tests, and lung perfusion scans, and patients who were judged not physically fit for surgery were excluded from the study. The ethical committee of our institute approved this study, and informed consent was obtained from all study participants. Integrated PET/CT Scanning Whole-body integrated FDG-PET/CT scanning was performed before EBUS-TBNA. PET/CT scan images were obtained by using either one of the following two combined PET/CT scanners: a Biograph LSO (Siemens Medical Solutions; Hoffman Estates, IL) or a Discovery LS (General Electric Medical Systems; Milwaukee, WI). Patients fasted for 8 h and then received an IV injection of FDG (10 to 15 mci). Scanning was performed 60 min later. On each PET/CT scan, a spiral CT scan was performed and integrated with PET scan images. 19 We analyzed the data using dedicated workstations loaded with e.soft (Siemens Medical Solutions) and entegra (General Electric Medical Systems) software. The standardized uptake value (SUV) was calculated as follows: SUV (decay-corrected activity [in kilobecquerels] per milliliter of tissue volume) / (injected-fdg activity [in kilobecquerels] / body mass [in grams]). The SUV was obtained by locating a region of interest on a lesion, and the maximum SUV within a region of interest was used. A maximum SUV 2.5 on a lymph node was interpreted as positive. 1,20 We performed mediastinal staging by integrated PET/CT scan irrespective of the accessibility of mediastinal nodes by EBUS- TBNA. A nuclear physician (S.K.K.) with 11 years of experience, including 5 years of integrated PET/CT scan experience, and blinded to the patient details read the PET/CT scan. EBUS-TBNA EBUS-TBNA was performed using a flexible ultrasonic puncture bronchoscope with a linear scanning transducer (convex probe-ebus, BF-UC260F-OL8; Olympus; Tokyo, Japan). The same bronchoscopist (B.H.) performed all the EBUS-TBNA procedures. Local anesthesia (lidocaine) was applied, and the CHEST / 135 / 5/ MAY,

3 Figure 1. Clinical course of 129 patients enrolled in the study. chemotx chemotherapy; LN lymph node; Pn pneumonia; RT radiation therapy; SCLC small cell lung cancer. # due to unexpected pleural metastases found during surgery. procedure was performed with the patient under conscious sedation (midazolam). After inspecting the mediastinal lymph nodes accessible by EBUS-TBNA, each target nodal station was aspirated one to four times (median 3) with a dedicated 22-gauge needle (NA-201SX-4022; Olympus). A different needle was used for each station to avoid contamination. N3 nodes were sampled first, and then N2 nodes were punctured. We calculated the procedure time from the insertion of the bronchoscope through the mouth to the retrieval after the procedure. Lymph node location was classified according to the international staging system. 21 The aspirate was expelled onto glass slides, smeared, fixed immediately with 95% alcohol, and stained using hematoxylineosin and Papanicolaou. Tissue cores obtained by EBUS-TBNA were fixed with 10% neutral-buffered formalin and stained using hematoxylin-eosin. A pathologist (G.K.L.) blinded to patient details performed the cytopathological examinations. Rapid onsite cytopathologic examination was not performed. Treatment We recommended open thoracotomy or video-assisted thoracic surgery with systematic lymph node dissection to operable patients whose EBUS-TBNA results did not show mediastinal metastases. We recommended chemotherapy (with or without radiotherapy) to patients with mediastinal metastases, with curative or neoadjuvant intent. Statistical Analysis The diagnostic consistency of the two diagnostic modalities was compared using the McNemar test. We measured the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of integrated PET/CT scan and EBUS-TBNA in the detection of mediastinal metastases. We used the z-test to evaluate differences in the diagnostic values of the two modalities. We considered a p value 0.05 as significant. All statistical analyses were performed using statistical software (STATA9; StataCorp; College Station, TX). Results Patients We enrolled 129 patients in the study (Fig 1) and safely performed EBUS-TBNA on all without complications. Two patients ultimately were given a diagnosis of small cell lung cancer and one with organizing pneumonia. Of the 126 remaining patients, 9 could not be evaluated (ie, 7 refused Table 1 Characteristics of Patients and Lymph Nodes* Characteristics Data Patients, No. 117 Men 92 Women 25 Median age, yr (range) 66 (41 84) Histologic type of lung cancer Adenocarcinoma 55 (47.0) Squamous cell carcinoma 53 (45.3) Large cell carcinoma 7 (6.0) Sarcomatoid carcinoma 1 (0.9) NSCLC, unspecified 1 (0.9) Location of PET/CT scan-positive 99 mediastinal LNs 2R 3 (3.0) 4R 29 (29.3) 4L 21 (21.2) 5 11 (11.1) 6 2 (2.0) 7 25 (25.3) 8 5 (5.1) 9 3 (3.0) Location of LNs sampled by EBUS-TBNA 223 2R 5 (2.2) 4R 75 (33.6) 4L 50 (22.4) 7 90 (40.4) 8* 3 (1.3) Median size of LNs sampled by EBUS-TBNA, mm (range) Short axis 7.9 ( ) Long axis 14.4 ( ) *Values are given as No. (%), unless otherwise indicated. Three paraesophageal nodal stations were accessible by EBUS-TBNA through the left mainstem bronchus. LN lymph node. Size of the largest node in each lymph node station on axial CT scan image Original Research

4 Table 2 Correlation of Mediastinal Staging by Integrated PET/CT Scan and EBUS-TBNA Patient Groups EBUS-TBNA PET/CT Scan N0 or N1 N2 N3 Total (n 117) N0 or N1 55 (3*) N N Adenocarcinoma (n 55) Squamous cell carcinoma (n 53) N0 or N1 23 (2*) 9 5 N N N0 or N1 27 (1*) 11 9 N N *Number of cases with false-negative findings confirmed by surgical lymph node dissection. surgery, and 2 did not undergo lymph node dissection because of unexpected pleural metastasis found during surgery). Table 1 shows the characteristics of the 117 evaluated patients and the lymph node findings. EBUS-TBNA and Surgical Lymph Node Dissection Mediastinal metastases were confirmed by EBUS-TBNA in 37 nodal stations of 27 patients (18 with single-station N2, 6 with multistation N2, and 3 with N3) Fig 1. Two patients with N2 disease did not agree to neoadjuvant treatment and underwent surgery, which confirmed singlestation N2 metastasis. Ninety with benign mediastinal nodes as detected by EBUS-TBNA underwent surgery and mediastinal lymph node dissection (55 by open thoracotomy and 35 by video-assisted thoracic surgery), which confirmed N2 disease in 3 patients. Of these three patients, one with double primary squamous cell carcinoma had a 5-mm metastasis on the subcarinal node that we diagnosed as benign by EBUS- TBNA. The second patient had a left upper lobe adenocarcinoma and a 3-mm metastasis on nodal station 5, which was not accessible by EBUS-TBNA. The third patient had a left lower lobe adenocarcinoma that we confirmed surgically to have a 5-mm metastasis on nodal station 5 and a 6.5-mm and two 1-mm metastases on nodal station 4L. Comparison of EBUS-TBNA With Integrated PET/CT Scan Table 2 shows the correlation of mediastinal staging by integrated PET/CT scan and EBUS-TBNA of the 117 evaluated patients as well as the cases of falsenegative EBUS-TBNA findings. The result of integrated PET/CT scan and EBUS-TBNA was statistically different (p [McNemar test]). Among 56 patients with PET/CT scan-positive nodes on the mediastinum (N2 or N3), 21 were found to have mediastinal metastasis. These 21 cases of true-positive PET/CT scan findings were pathologically confirmed by EBUS- TBNA. Among 61 patients with a normal mediastinum as detected by PET/CT scan, 9 were found to have mediastinal metastasis (6 adenocarcinoma, 1 squamous cell carcinoma, 1 sarcomatoid carcinoma, 1 NSCLC unspecified). Six of these nine cases of false-negative PET/CT scan findings were pathologically confirmed by EBUS-TBNA (adenocarcinoma, four cases; sarcomatoid carcinoma, one case; NSCLC unspecified, one case), and three were confirmed by surgery (adenocarcinoma, two; NSCLC unspecified, one). Table 3 shows the diagnostic values of integrated PET/CT scan and EBUS-TBNA in detecting mediastinal metastases (N2 or N3). The difference in sensitivity between PET/CT scan (70%) and EBUS-TBNA (90%) was of borderline significance (p 0.052). The specificity, PPV, NPV, and accuracy were higher for EBUS-TBNA than for PET/CT scan. Table 3 Diagnostic Values of Integrated PET/CT Scanning and EBUS-TBNA in the Detection of Mediastinal Metastases Patient Groups and Procedures Sensitivity, % Specificity, % PPV, % NPV, % Accuracy, % Total (n 117) PET/CT scan EBUS-TBNA p Value Adenocarcinoma (n 55) PET/CT scan EBUS-TBNA p Value Squamous cell carcinoma (n 53) PET/CT scan EBUS-TBNA p Value CHEST / 135 / 5/ MAY,

5 Figure 2. A representative case of a false-negative mediastinal PET/CT scan finding, with mediastinal metastases detected by EBUS-TBNA. Top left, A, and top center, B: a 66-year-old female patient with adenocarcinoma on the right upper lobe (RUL) had lymph nodes on station 7 (8.3 mm) and 4R (7.1 mm). No positive N1 node ( 1 cm) was seen on the chest CT scan as well. Middle left, C, and middle center, D, and top right, E: PET/CT scan findings were negative for the mediastinum. Bottom left, F, and bottom center, G: EBUS-TBNA was performed on nodal stations 7 and 4R. Bottom right, H: aspirate from 7. Cytologic evaluation of aspirates by EBUS-TBNA confirmed metastatic cells on nodal stations 7 and 4R. Analysis of Diagnostic Values of Integrated PET/CT Scanning and EBUS-TBNA by Histologic Type Adenocarcinoma was the most frequent histologic type of case of false-negative mediastinal PET/CT scan findings. Among 55 adenocarcinoma cases, 4 of 6 cases of false-negative PET/CT scan findings were confirmed by EBUS-TBNA (Table 2, Fig 2). The sensitivity was greater for EBUS-TBNA than for PET/CT scan, but the difference was not statistically significant. The specificity, PPV, NPV, and accuracy were higher for EBUS-TBNA than for PET/CT scan (Table 3). Among 53 squamous cell carcinoma cases, one case of N2 disease missed by PET/CT scanning also was missed by EBUS-TBNA (Table 2). The sensitivity of the two methods was the same. The NPV was similarly high for both. The specificity, PPV, and accuracy were significantly higher for EBUS-TBNA than for PET/CT scanning (Table 3). Discussion In this study, EBUS-TBNA had high diagnostic values that were superior to integrated PET/CT scan in the mediastinal staging of potentially operable NSCLC. We found that EBUS-TBNA was more sensitive than PET/CT scan, although the difference was of borderline statistical significance. EBUS- TBNA had significantly higher specificity, PPV, NPV, and accuracy than PET/CT scan. These results show that EBUS-TBNA is an effective invasive method for mediastinal staging after PET/CT scan is performed. The results of our study are similar to a previous study 1 that showed a higher diagnostic accuracy for EBUS-TBNA than for PET scanning in the mediastinal staging of lung cancer. According to published guidelines, positive PET scan or integrated PET/CT scan findings on the mediastinum should be confirmed pathologically because of the high rate of false-positive findings. In 1284 Original Research

6 the present study, PPV of PET/CT scan for detecting mediastinal metastasis was very low, irrespective of histologic types of NSCLC. However, EBUS-TBNA detected mediastinal metastasis in all cases with true-positive PET/CT scan findings. Yasufuku et al 1 reported a high sensitivity of EBUS-TBNA (92.3%) and a low PPV for PET scanning (46.5%) in the mediastinal staging of surgical candidates with lung cancer. Bauwens et al 5 also reported a high sensitivity (95%) of EBUS-TBNA in the mediastinal staging of lung cancer patients who were PET scan-positive in the mediastinum. In agreement with these previous studies that used EBUS-TBNA following PET scanning, our data show that EBUS-TBNA is an excellent and highly recommended tool for detecting metastases in potentially operable mediastinal PET/CT scan-positive NSCLC. The diagnostic approach for potentially operable patients with NSCLC whose mediastinal PET scan result is negative is controversial. 17,22 25 Although high NPVs for PET scans have suggested that mediastinoscopy could be omitted for PET scannegative cases, 22,23 invasive staging is still recommended in some clinical situations. 11,12,17,24,25 In the present study, EBUS-TBNA confirmed mediastinal metastasis in six PET/CT scan-negative cases and had a considerably higher NPV (96.7%) than PET/CT scanning (85.2%). This finding suggests a role for EBUS-TBNA in detecting mediastinal metastases, even in mediastinal PET/CT scan-negative cases. Herth et al 4 also showed that EBUS-TBNA could detect mediastinal metastasis in PET scannegative and CT scan-negative cases, which supports our findings. If EBUS-TBNA can be beneficial in cases of negative PET/CT scans findings in the mediastinum, the next question is which patient groups would benefit more from an EBUS-TBNA in cases of negative PET/CT scan findings? We analyzed data according to the histologic type of NSCLC. EBUS- TBNA detected mediastinal metastasis in four of six cases of false-negative PET/CT scan findings for adenocarcinoma. We observed one case of falsenegative PET/CT scan findings for squamous cell carcinoma, which was not detected by EBUS-TBNA. Statistical analysis showed that the NPV of EBUS- TBNA (94.6%) was higher than that of PET/CT scanning (77.8%) in adenocarcinoma, whereas in squamous cell carcinoma, the NPV of PET/CT scan was very high (96.3%), and an additional diagnostic yield of EBUS-TBNA for mediastinal PET/CT scan-negative cases was not observed. It has been suggested that the histologic type of lung cancer can guide the decision to perform invasive staging A higher rate of occult mediastinal metastasis in adenocarcinoma compared to squamous cell carcinoma in the presence of a negative CT scan finding was reported. 14,15 According to a study by Lee et al, 16 among 224 patients with NSCLC and a normal mediastinum as determined by CT and PET scan, all 16 patients found to have occult mediastinal metastasis also had adenocarcinoma. Herth et al 4 reported that 6 out of 100 patients with a normal mediastinum by CT scan and PET scan were confirmed to have mediastinal metastasis by EBUS-TBNA; all 6 patients also had adenocarcinoma. Occult metastasis was rarely observed in patients with a PET scan-negative mediastinum in squamous cell carcinoma. 4,16,17 This phenomenon can be related to the higher rate of mediastinal metastasis 17,26 and the lower FDG uptake in adenocarcinoma than in squamous cell carcinoma The rate of expression of the glucose transporter 1, the enzyme related to the uptake of FDG in cells, was reported to be lower in adenocarcinoma than in squamous cell carcinoma. 30,31 Corresponding to the previous studies, our data also showed that adenocarcinoma was a frequent histologic type of NSCLC that yielded a false-negative finding on PET/CT scans of the mediastinum, which suggests that adenocarcinoma should be carefully staged preoperatively even in cases of negative findings on mediastinal PET/CT scans. EBUS-TBNA can be helpful for these patients. However, a PET/CT scannegative finding on the mediastinum in squamous cell carcinoma was reliable, and EBUS-TBNA might not be beneficial for these patients. This study had several limitations. In the subgroup analysis, the patient number is relatively small, and we did not consider other factors that may influence the decision for invasive staging in mediastinal PET scan-negative cases, such as the size of mediastinal lymph nodes, whether positive N1 nodes are detected on chest CT scan or PET/CT scan, and tumor location. Analysis of various factors in a large group of patients will be needed to find patient groups who can benefit from EBUS-TBNA. In this study, we excluded potentially operable patients with lung cancer who did not have a mediastinal node of at least 5 mm in an accessible location by EBUS-TBNA because of technical difficulties and a presumed low rate of mediastinal metastasis. Therefore, we may have overestimated the diagnostic values of EBUS- TBNA by excluding patients with metastases in very small lymph nodes that are difficult to diagnose by EBUS-TBNA or by excluding some patients with mediastinal metastasis only on inaccessible lymph nodes by EBUS-TBNA. In this study, we used integrated PET/CT scanning instead of PET scanning. However, the advantage of PET/CT scanning over PET scanning prior to EBUS-TBNA was not addressed. Our results are CHEST / 135 / 5/ MAY,

7 generally similar to previous studies 1,4 that used PET scanning and EBUS-TBNA for mediastinal staging. However, we tried not to overlook PET/CT scanpositive lymph nodes or PET/CT scan-positive areas in a lymph node during the EBUS-TBNA procedure. This process might have affected the diagnostic yield of EBUS-TBNA, especially for mediastinal PET/CT scan-positive cases, although we do not know whether integrated PET/CT scanning provided better information than PET scan scanning during EBUS-TBNA. Conclusions EBUS-TBNA, which is more accurate than integrated PET/CT scanning, is an effective invasive method in the mediastinal staging of potentially operable NSCLC after PET/CT scanning is performed. EBUS-TBNA is an excellent tool for detecting mediastinal metastasis in mediastinal PET/CT scan-positive, potentially operable NSCLC and should be considered for patients with this condition. 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