Clementsen, Paul F. MD, DSc*; Skov, Birgit G. MD, DSc†; Vilmann, Peter MD, DSc‡; Krasnik, Mark MD§
*Department of Pulmonary Medicine, Gentofte Hospital
Departments of †Pathology
§Thoracic Surgery, Rigshospitalet, University of Copenhagen, Denmark
‡Department of Surgery, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
Disclosure: P.V. receives consultancy fee from MEDI-GLOBE GmbH (EUS and EBUS needle company). The remaining authors declare that there is no conflict of interest or other disclosures.
Reprints: Paul F. Clementsen, MD, DSc, Department of Pulmonary Medicine, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Copenhagen, Denmark (e-mail: firstname.lastname@example.org).
Received July 2, 2013
Accepted November 12, 2013
Background: Mediastinoscopy is the gold standard for preoperative mediastinal staging of patients with suspected or proven lung cancer. Since the development of endoscopic ultrasound-guided biopsy via the trachea (EBUS-TBNA), this status has been challenged. The purpose of the study was to examine whether mediastinoscopy is necessary, when EBUS-TBNA is performed in a center with (1) a high level of expertise, (2) “bed side” microscopy by a pathologist, (3) general anesthesia, and (4) achievement of representative tissue from station 4R, 7 and 4L, that is, the same mediastinal stations that mediastinoscopy gives access to.
Methods: A total of 95 consecutive patients with known or suspected lung cancer were referred for staging by EBUS-TBNA, which was performed as described.
Results: Benign and malignant disease was found in the mediastinum of 6 and 13 patients, respectively. The remaining 76 patients were operated, resulting in 9 benign and 67 malignant diagnoses; spread was found to station 4R, 5, and 5 and 6 in 4 patients. The negative predictive value (NPV) was 63/67=0.94. However, if you exclude station 5 and 6, as they cannot be reached by neither EBUS nor mediastinoscopy, NPV was 66/67=0.99. The sensitivity was 0.76, and the specificity was 1.0.
Conclusions: When EBUS-TBNA is performed under optimal conditions including general anesthesia and “bed side” microscopy performed by a pathologist resulting in representative biopsies from station 4R, 7, and 4L, the NPV is so high that mediastinoscopy seems unnecessary.
Mediastinoscopy since 1959 has been the gold standard for mediastinal staging of non–small cell lung cancer.1 Since the development of endoscopic ultrasound-guided biopsy via the esophagus with fine-needle aspiration (EUS-FNA) and via the trachea and main stem bronchi (EBUS-TBNA), this status has been challenged.2–4 However, whether mediastinoscopy can be totally avoided is still being discussed. According to the guidelines, EUS-FNA and/or EBUS-TBNA are recognized in the staging algorithm of NSCLC, and the value of these methods has already been proven in several studies.5–9 A few studies have compared EUS-FNA and/or EBUS-TBNA with mediastinoscopy showing a comparable or even improved sensitivity of the 2 former methods. However, according to the guidelines, mediastinoscopy is still required in patients where endoscopic ultrasound does not reveal mediastinal tumor spread irrespective of the lymph node size.2,10 In the early publications with EBUS-TBNA, the selection of patients was based on enlarged lymph nodes seen on computed tomography (CT).8,11 Herth et al9 have shown that in patients without enlarged lymph nodes on CT, defined as lymph nodes <10 mm in greatest diameter, metastases are still diagnosed by EBUS-TBNA in 20%. The median size of the lymph nodes in this study was 8 mm demonstrating that even small lymph nodes can be targeted. According to the ESTS guidelines, staging by mediastinoscopy in patients with non–small cell lung cancer requires a minimum exploration of and biopsies taken from station 4R, 7, and 4L,10 whereas no similar recommendation is given for endoscopic ultrasound biopsy techniques.
We hypothesized that surgical staging could be avoided if EBUS-TBNA was performed in a center with (1) a high level of expertise, (2) access to “bedside” microscopy performed by a pathologist, (3) access to general anesthesia for all patients, and (4) achievement of representative tissue from station 4R, 7, and 4L in all patients, that is, the same mediastinal stations that mediastinoscopy gives access to.
PATIENTS AND METHODS
A total of 95 consecutive patients with suspected or proven lung cancer were referred for final preoperative mediastinal staging from April 2008 to October 2008. The patients had all undergone evaluation with either/or bronchoscopy, percutaneous lung biopsy, CT scan or PET/CT, and/or EUS-FNA and were referred for EBUS before operation. Of the 95 patients, PET-CT was performed on 34 patients, 7 demonstrating fluorodeoxyglucose uptake in the mediastinum. The rest (61 patients) underwent CT without PET. In the 95 patients, the mean size of the lymph nodes in station 4R, 4L, and 7 was 9 mm (range, 2 to 35 mm). Twenty-one patients had undergone EUS-FNA without a finding of malignancy in the mediastinum and/or the left adrenal gland.
EBUS-TBNA was performed by a single examiner (M.K.) in all patients under general anesthesia. The procedures were performed with a flexible ultrasound bronchoscope (Olympus XBF-UC40P; Olympus Medical Systems Europe Ltd., Hamburg, Germany). A 22-G Olympus NA-200C needle was used for TBNA. The EBUS-TBNA was performed according to a standardized protocol taking biopsies from at least station 4R, 4L, and 7. At least 2 passes per lymph node were carried out. The biopsies were evaluated by a cytologist (B.G.S.) during the procedure. In cases of insufficient cytologic material from either of the lymph node stations, immediate rebiopsies were performed until sufficient material was obtained. All patients without malignancy in the mediastinum by EBUS-TBNA were referred to video-assisted thoracoscopic surgery or thoracotomy, excluding patients in whom a specific benign diagnosis was obtained. A long-term follow-up of all patients’ records was performed (Fig. 1).
The study was a retrospective observational study aimed to examine the quality of previously acquired biopsies in patients with proven or suspected lung cancer. There was no randomization or intervention in the treatment of the patients. In accordance with rules applicable, the local Research Ethics Committee does not want such a study reported.
The cytology obtained by the EBUS-TBNA was considered sufficient for diagnostic evaluation in all 95 consecutive patients, that is, in all aspirates, cells from lymph nodes were found. In 6 patients, no malignant disease was demonstrated. Four patients were diagnosed with granulomatous disease in the lymph nodes in the mediastinum and in 1 patient the lung infiltrate regressed, and these patients did not undergo operation. One patient was not operated because of comorbidity. In 13 patients, EBUS-TBNA demonstrated spread of malignant disease to lymph nodes in the mediastinum and they were submitted for radiotherapy and/or chemotherapy.
In the remaining 76 patients, no malignant cells were found in the cytologic material from EBUS, and these patients were all offered operation (48 male patients; mean age, 65 y). In 9 of the 76 operated patients, a specific benign diagnosis was established (2 bronchiolitis obliterans, 1 hamartoma, 4 inflammatory lesions, 1 infarction, and 1 fibrosis). In the remaining 67 patients, a malignant diagnosis was confirmed for the primary tumor, that is, 63 patients with non–small cell lung cancer, 1 with small cell lung cancer, 2 patients with sarcoma, and 1 with metastasis from a colon tumor. Thus, 80 of the 95 patients proved to suffer from malignant disease, 13 were found preoperatively by EBUS-TBNA and 67 were diagnosed with the primary tumor by operation.
In 4 of these 67 operated patients with benign preoperative EBUS, mediastinal lymph node metastases were found. One patient had metastasis in station 4R (adenocarcinoma), 2 patients in station 5 (squamous cell carcinoma), and 1 in station 6 (adenocarcinoma). In 63 patients, no mediastinal spread was found on operation. In a follow-up of these 63 patients after 48 months, there were no signs of mediastinal spread.
The negative predictive value (NPV) of EBUS-TBNA was 63/67=0.94. However, station 5 and 6 cannot be reached with either EBUS or mediastinoscopy, leaving only 1 patient with spread to station 4R as a “true” false-negative patient, when comparing EBUS-TBNAB with mediastinoscopy. In that case, it could be argued that the NPV was as high as 66/67=99%. The positive predictive value was 13/13=1.0, the sensitivity 13/13+4=0.76, and the specificity 63/63=1.0.
No complications to EBUS-FNA or the general anesthesia were observed.
At 48-month follow-up of the 95 patients included in the study, no malignancy was reported in patients diagnosed with benign disease. Of the 80 patients with malignant disease, 14 patients had local recurrence of lung cancer, 8 patients had brain metastases, 2 had lung metastases, 1 had liver metastasis, 1 had retroperitoneal metastasis, 1 had bone metastasis, and 1 not stated. Twenty-one patients had died, 9 directly related to recurrent lung cancer and the other 12 patients because of causes not related to their lung cancer disease (Tables 1 and 2).
Mediastinoscopy is still the gold standard for staging of the mediastinum in patients with lung cancer. As in any other surgical diagnostic procedure, false-negative results are also present with this method.11 According to the literature, the sensitivity for mediastinoscopy ranges from 67% to 92% (median 81%), with a NPV of 91% (range, 82% to 92%).
Whenever a new method is introduced in clinical practise, several considerations should be made including among others its diagnostic values, invasiveness of the method, cost-effectiveness, and patient tolerance. To replace a diagnostic method that is considered the gold standard, well-conducted controlled trails should have demonstrated at least equal or superior diagnostic values compared with the old standard. Both EUS-FNA and EBUS-TBNA have been introduced recently in the staging algorithm of lung cancer. Each of these methods seem to have comparable and high diagnostic values with a sensitivity of around 90%.12–17 When the 2 methods are used in combination, several studies have demonstrated superiority compared with either of the methods used alone.3,7,16 Earlier publications of EBUS-TBNA have shown a high diagnostic yield from 80% to 94% and a specificity of 100%.5 Recently, Annema et al7 in a multicenter randomized study have shown that the combination of EUS-FNA and EBUS-TBNA is superior to surgical staging and results in fewer complications. When mediastinoscopy followed a negative endosonography procedure, 11 patients needed to undergo mediastinoscopy to identify one single patient with mediastinal node metastasis.7
In several studies it has been demonstrated that EBUS-TBNA has an NPV in analyzing mediastinal lymph nodes between 60% and 97%.3 However, it must be remembered that most studies were performed in patients under conscious sedation, bedside microscopy18 was seldom performed, and, in none, a systematic examination with collection of tissue from lymph node stations 4R, 7, and 4L was described. We therefore decided to examine if EBUS-TBNA performed in an optimal setting could further decrease the risk of a superfluous surgical staging. We hypothesized that surgical staging could be avoided if EBUS-TBNA was routinely performed given the same conditions and using the same strict criteria as required during mediastinoscopy. The patients in our study were selected patients, but patients who would otherwise have undergone mediastinoscopy for final evaluation before surgery according to guidelines. The patients underwent a standardised mediastinal evaluation of each lymph node station by EBUS during which lymph nodes in station 4R, 4L, and station 7 were targeted with fine-needle aspiration. In all patients, cells from lymph nodes were demonstrated in station 4R, 7, and 4L by a pathologist. In only 4 of the 67 operated patients with benign preoperative EBUS-TBNA, mediastinal lymph node metastases were found by surgery, 1 in station 4R, 2 in station 5, and 1 in station 6. When considering the limitations of the alternative method, it is very unlikely that the two station 5 lymph nodes and one station 6 node would have been diagnosed, leaving only 1 possible patient of 67 patients to be excluded from surgery by mediastinoscopy, thus an NPV of 0.99.
There are several limitations: this is only a nonrandomized retrospective single center study with EBUS performed by a single operator under conditions that not all centers have access to. The results cannot be considered generalizable, and they cannot serve as a proof that “our” EBUS concept is superior to others. Larger prospective randomized studies are required. Secondly, the enrolled patients represent a quite heterogenous group, but this reflects the daily life in our and other departments examining patients with proven or suspected lung cancer.
In conclusion, we find that EBUS-TBNA performed under general anesthesia is a safe and effective method for evaluation of the mediastinum in patients with lung cancer scheduled for final mediastinal staging before surgery. The results of the present study seem to challenge mediastinoscopy as the gold standard for mediastinal staging of lung cancer. When EBUS-TBNA is performed under the same standardised conditions as described by the ESTS guidelines for mediastinoscopy with demonstration of cells from lymph nodes from relevant lymph node stations, our study shows that very little, if anything, is gained by an additional mediastinoscopy and consequently can be avoided. Our suggestion is that the guidelines takes into account under what circumstances EBUS-TBNA is performed, when deciding if a negative EBUS-TBNA shall be followed by mediastinoscopy.
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