- Email: [email protected]
Electromagnetic Navigation Bronchoscopy-Guided Dye Marking for Thoracoscopic Resection of Pulmonary Nodules
Electromagnetic Navigation Bronchoscopy-Guided Dye Marking for Thoracoscopic Resection of Pulmonary Nodules Omar Awais, DO, Michael R. Reidy, MD, Kunal Mehta, BSE, Valentino Bianco, DO, MPH, William E. Gooding, MS, Matthew J. Schuchert, MD, James D. Luketich, MD, and Arjun Pennathur, MD Division of Thoracic and Foregut Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh; and The University of Pittsburgh Cancer Institute Biostatistics Facility, Pittsburgh, Pennsylvania
Background. Computed tomography scans are increasingly used not only for lung cancer screening but also for staging and evaluation of other cancers. As a result, more patients with pulmonary nodules, many with subcentimeter lesions, are being referred to thoracic surgeons, some with concern for primary lung neoplasm and others with possible metastatic lung lesions. Obtaining a definitive diagnosis of these lesions is difficult. Electromagnetic navigational bronchoscopy (ENB)-guided pleural dye marking followed by thoracoscopic resection is a novel alternative technique for definitive diagnosis. The main objective of this study was to evaluate the feasibility and our initial experience with ENB-guided dye localization and minimally invasive resection for diagnosis of lung lesions. Methods. Selected patients with lung lesions underwent ENB-guided dye marking and minimally invasive resection. The primary end points were the rate of nodule localization and definitive diagnosis of the nodule.
Results. We performed ENB-guided localization and minimally invasive resection in 29 patients. The median lesion size was 10 mm, with a median distance from pleural surface of 13 mm. The operative mortality was 0%. The median hospital stay was 3 days. The nodule was localized and resected, and a definitive diagnosis was obtained in all patients (29 of 29; 100%). The nodule was neoplastic in 19 patients. All malignant lesions were completely resected with negative microscopic margins. Conclusions. Our initial experience with ENB-guided dye localization and minimally invasive resection found that the technique was feasible, safe, and successful in the diagnosis of small lung lesions. Thoracic surgeons should further investigate this method and incorporate it into their armamentarium.
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treatment of other malignancies. This, along with an increase in targeted therapies and the need for molecular testing, has led to the referral of many patients with possible metastatic disease to the lung (many with small lung lesions) to thoracic surgeons for biopsies. During video-assisted thoracoscopic surgery (VATS), subcentimeter lesions or ground glass opacities (GGOs) may be difficult to localize, and sometimes lesions larger than a centimeter are difficult to find because of the location or character of the lesion (eg, GGO versus solid). Small lesions that may be difficult to localize by VATS or roboticassisted surgery could potentially be resected more expeditiously and with higher accuracy if thoracic surgeons can apply an easy, reliable way of localizing the lesions before resection. Several groups have reported percutaneous techniques to localize lung nodules before minimally invasive resection [5–11]. The current techniques include CT-guided radiotracer injection, CT-guided wire localization, CT-guided fiducial placement and fluoroscopic localization, CT-guided contrast injection into the nodule and fluoroscopic localization, and ultrasonography and percutaneous staining with methylene blue [6–11]. These techniques require careful coordination among multiple
ung cancer is the most common cause of cancerrelated deaths in the United States with an annual mortality exceeding breast, colon, and prostate cancers combined [1, 2]. Advanced stage of lung cancer at the time of diagnosis is one of the contributing factors to decreased survival in patients with lung cancer. Developing methods for detecting and accurately diagnosing early-stage lung cancer is of paramount importance. The National Lung Screening Trial showed a 20% relative risk reduction in lung cancer mortality for participants who underwent computed tomography (CT) lung cancer screening instead of radiographic screening [3, 4]. As a result of lung cancer screening programs, thoracic surgeons are being referred an increased number of patients with small pulmonary nodules. In addition, CT is routinely used for staging, for evaluation of response, and detection of recurrence after
Accepted for publication Feb 11, 2016. Presented at the Sixty-first Annual Meeting of the Southern Thoracic Surgical Association, Tucson, AZ, Nov 5–8, 2014. Address correspondence to Dr Pennathur, Department of Cardiothoracic Surgery, University of Pittsburgh, 200 Lothrop St, C-800, Pittsburgh, PA 15213; email: [email protected].
Ó 2016 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2016;-:-–-) Ó 2016 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2016.02.040
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AWAIS ET AL ENB-GUIDED LOCALIZATION AND RESECTION
disciplines, including interventional radiologists, anesthesiologists, and thoracic surgeons. In addition, the risks of CT-guided transthoracic localization procedures include pneumothorax and hemothorax. Because localization techniques often occur in departments other than the operating room (OR), operations may have to be timed appropriately from the time the radiologic procedure was done. The ideal method for nodule localization before resection would be one that is accurate and can be achieved with minimal risk to the patient in the same operative setting as the thoracoscopic resection procedure. Pleural dye marking guided by electromagnetic navigation bronchoscopy (ENB) allows nodule localization and minimally invasive resection to be completed in one setting in the OR [5]. The main objective of this study was to evaluate the feasibility and our initial experience with the ENB-guided dye localization and minimally invasive resection for the definitive diagnosis of lung lesions.
Material and Methods We retrospectively reviewed our experience with ENB-guided dye localization, followed by minimally
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invasive resection (VATS or robotic-assisted surgery) for definitive diagnosis of lung lesions at the University of Pittsburgh Medical Center Mercy from March 2013 to April 2014. This retrospective review included patients who had undergone ENB-guided localization before VATS resection of lung nodules. The patients were referred to the thoracic surgeon for biopsy and underwent ENB-localization because the surgeon felt this would assist with thoracoscopic localization and resection and would decrease the possibility of conversion to thoracotomy. This retrospective study was approved by our institutional review board. Because this was a retrospective study, individual patient consent was waived.
Surgical Procedure The ENB-guided dye marking was performed by the operating surgeon (OA or/and AP) in the OR at the time of resection. With the use of superDimension software (Covidien, Minneapolis, MN), the axial, coronal, and sagittal views of the patient’s CT scan were used to plan the procedure (Figs 1A, 2A). General endotracheal anesthesia was induced with a singlelumen endotracheal tube in the OR. Subsequently,
Fig 1. (A) Computed tomographic image of lung nodule visualized in axial, coronal, and sagittal views. (B) Focal pleural methylene blue dye visualization during video-assisted thoracoscopic surgery. (C) Lung nodule seen beneath the surface pleural dye. All images are from a single patient.
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Fig 2. (A) Computed tomographic image of lung nodule. (B) Electromagnetic navigational bronchoscopy-guided injection of methylene dye under fluoroscopic guidance. (C) Pleural dye visualized during video-assisted thoracoscopic surgery. (D) Resected specimen with blue dye adjacent to the lung nodule. All images are from a single patient.
ENB was performed with the platform’s software. Once the lesion was localized during navigation, fluoroscopy was used to visualize needle injection of 0.5 mL of methylene blue [12] (Fig 2B). A syringe with a 25-gauge needle was preloaded with 0.5 mL of methylene blue. Once the target lesion was in view with the use of navigational bronchoscopy, the locatable guide was removed from the extended working channel under fluoroscopy. The preloaded syringe with a 25-gauge needle was inserted into the extended working channel, and under fluoroscopic guidance approximately 0.5 mL of methylene blue was injected either into the lesion or midway between the lesion and the nearest pleural surface on the basis of the CT scan. As a general rule, lesions within 1 cm of the pleural surface were directly injected, and in those where the lesion was located more than 1 cm from the pleural surface the dye marking was performed midway between the lesion and the nearest pleural surface. After localization and injection of the lesion with methylene blue, the single-lumen endotracheal tube was changed to a double-lumen endotracheal tube. The patient was appropriately positioned for minimally invasive resection (VATS or robotic surgery) of the lung lesion. On inspection within the chest, the blue dye was visualized (Figs 1B, 2C). The lesion was resected with endoscopic staplers with the use of a sublobar resection (wedge in 28 patients and segmentectomy in 1 patient). Resection of the lesion was guided not only by the dye visualization but also by the CT assessment. It is important to use the CT scan to help guide for depth of resection. We found this essential to achieve an adequate margin. The biopsy
specimen was then evaluated by opening the specimen in the OR and with pathologic confirmation by frozen-section analysis (Figs. 1C, 2D).
Statistical Design and Analysis Information on patient demographic characteristics, history, comorbidities (Charlson comorbidity index), lesion characteristics, treatment, operative details, perioperative outcomes, and pathologic evaluation was collected [13]. The primary end points studied were the rate of localization of the lung nodule and the rate of definitive diagnosis of the lung nodule by the pathologist.
Results Patient Characteristics A total of 33 lesions were localized in 29 patients (16 men, 13 women; median age 66 years) with the use of methylene blue dye-marking guided by ENB (Table 1). Table 1. Patient Characteristics Characteristic Total patients/lesions, n/n Sex, n Male Female Age, median, y Smoking history, n (%) Smoking history, median pack-years Previous malignancy, n (%) Previous lung resection, n (%)
Value 29/33 16 13 66 25 (86.2) 25 19 (65.5) 7 (24.1)
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The median Charlson comorbidity index was 2. In addition, 86% (25 of 29) of the patients had a substantial smoking history with a median pack-year use of 25 (mean pack-year 36), and 66% (19 of 29) of patients had a history of malignancy. Of the 29 patients, 28 (97%) had either a history of smoking or a prior malignancy (Table 1).
Characteristics of the Lung Lesions The locations of the 33 pulmonary nodules were variable, with the right upper lobe (39.4%) being the most common site (Table 2). Six nodules (6 of 29 patients; 20.7 %) were GGOs. The median maximum diameter of localized lung lesions was 10 mm (range, 4 to 27 mm; interquartile range, 7.5 to 12 mm). The median maximum distance measured from the center of the lesion to the nearest parietal pleural surface was 13 mm (range, 3 to 44 mm; interquartile range, 8 to 23 mm; Table 2). The maximum depth from the pleural surface to the center of a lesion was 44 mm, and its location close to an interlobar fissure assisted in resection.
Operative Approach and Perioperative Outcomes ENB-guided dye marking was performed in the OR. There were no reported complications from the ENBguided dye localization. The mean navigation time (time from the onset of airway mapping to injection of methylene blue; available in a subset of patients) was 9.7 minutes. Seventeen patients (17 of 29; 59%) underwent VATS; the remaining 12 patients underwent a robotic resection. All lesions were resected in the same operative setting as the dye marking. The median hospital stay was 3 days. Major morbidity occurred in 1 patient (1 of 29; 3.4%) in whom postoperative pneumonia and respiratory failure developed. Another patient experienced a minor complication of atrial fibrillation (1 of 29; 3.4%). The operative mortality was 0%.
Localization and Resection of the Lung Nodule and Pathologic Evaluation In all patients, the index lung nodule was localized and resected with pathologic confirmation of the diagnosis. The lesions were inspected intraoperatively to correlate the nodule size and characteristics determined during the CT scan with the specimen before the lesion was sent to pathology. In most of the procedures, the dye Table 2. Characteristics of Lung Lesions Characteristics of Lesion (n¼33) Location, n (%) Right upper lobe Right middle lobe Right lower lobe Left upper lobe Left lower lobe Size, median (range), mm Size Distance from pleural surface
Value
13 2 5 6 7
(39.4) (6.1) (15.2) (18.2) (21.2)
10 (4–27) 13 (3–44)
was seen on the pleural surface closest to the tumor. After some injections, the blue dye was partially at the tumor site; this did not interfere with the pathologic assessment (Fig 2D). The resected specimen was evaluated by a pathologist, and on both gross and microscopic assessment the deep-stapled margin was negative (Fig 1C). A definitive diagnosis was obtained by pathologic evaluation in all patients (29 of 29; 100%). In 66% of patients (19 of 29), the final pathologic evaluation showed a neoplastic lesion (Table 3). This included 13 patients with primary lung cancer and 5 patients with metastatic lesions. In the patients with primary lung cancers, 11 had T1a lesions and 2 had T1b lesions. Every malignant lesion, both primary and metastatic, had negative gross and microscopic resection margins. The non-neoplastic nodules were mainly granulomatous or inflammatory nodules.
Comment Our initial experience with ENB-guided methylene blue dye marking of small lesions followed by minimally invasive resection suggests that this technique is feasible, safe, and an effective method for biopsy of lesions that may be difficult to visualize or digitally palpate. For small pulmonary nodules (median maximum diameter 10 mm), we achieved a high rate of definitive diagnosis after minimally invasive sublobar resection. Dye marking was successful for identification even in lesions that were small and difficult to palpate, secondary to location or character (ie, GGOs). The pleural dye was visualized in every dye-marking procedure, and, after localization, the extent of resection was guided by careful evaluation of the CT scan in coronal, sagittal, and axial views. In addition, the lack of complications from the dye localization process and the mean navigation time of less than 10 minutes suggest that ENB-guided dye marking is safe and not cumbersome. Localization techniques for lung nodules are typically reserved for lesions that are small, that are deep in the lung parenchyma, or lesions that are GGOs. In some Table 3. Final Pathologic Finding in All Patients Pathologic Finding Neoplastic Primary lung Adenocarcinoma Carcinoid Neuroendocrine Large cell Metastatic Adenocarcinoma Squamous Renal cell Germ cell Other Inflammatory/granulomatous
n (%) 19 (66) 9 1 2 1
(31.0) (3.4) (6.9) (3.4)
2 1 1 1 1 10
(6.9) (3.4) (3.4) (3.4) (3.4) (34)
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instances, lesions may be deep; however, their proximity to an interlobar fissure may make dye marking favorable, especially if the fissures are well defined. The goal of ENB-guided dye marking is to enhance localization during the operation and to improve the chances of a successful VATS biopsy (without conversion to open thoracotomy). ENB-guided dye marking should not expand the indications for the operation. Recently, detection of pulmonary nodules with the use of intraoperative near-infrared imaging was described to locate nonpalpable, poorly visualized lung nodules [14, 15]. This technique is investigational and was performed with thoracotomy rather than a VATS procedure. Thoracic surgeons are referred patients with small lung lesions for consideration of biopsy. Our initial experience with ENB-guided dye marking followed by VATS resection indicated a high diagnostic yield, even though nearly 20% of the lung nodules were GGOs. Other options for biopsies include bronchoscopic or CT-guided biopsies. The diagnostic yield of bronchoscopic biopsy of a small peripheral lung lesion can be poor. In a series by Makris and colleagues [16], the overall diagnostic yield for navigational bronchoscopic biopsy was 62.5%, and only 43.7% of lesions smaller than 2 cm were successfully biopsied by navigation bronchoscopy alone. Other series have reported a diagnostic yield that ranged from 62.5% to 87.5% with the use of navigational bronchoscopic biopsy alone [14–17]. CT-guided transthoracic needle aspiration biopsy of small nodules may also have a low rate of definitive diagnosis and has the potential for pneumothorax. Ohno and colleagues [17] reported an accuracy of 52% with CT-guided fine-needle aspiration (FNA) in lesions smaller than 1 cm. Grogan and colleagues [6] performed radiotracerguided localization in 84 patients with small solitary lung lesions. Patients underwent CT-guided percutaneous placement of technetium solution within or in close proximity to the suspicious nodule. Seventy-seven nodules were localized and excised with a mean size of 9.8 mm and a mean distance from the nodule to the pleural surface of 11.7 mm. In that study, 50% of the nodules were benign, 39% were primary malignancies, and 11% were metastatic lesions or lymphoma. Complications occurred in 12 of 77 patients (16%) and included 8 pneumothoraces that required pigtail catheter insertion, 3 patients with atrial arrhythmias, and 1 with prolonged air leak. This radiotracer-guided technique appears to have excellent results for localization; however, localization and resection were performed in different settings. The mean nodule size of 9.8 mm reported by Grogan and colleagues [6] was comparable with the median nodule size of 10 mm seen in our experience, and the mean distance between the pleural surface and the nodule of 11.7 mm was also similar to our study (median distance, 13 mm). Approximately 66% of our patients had a neoplastic nodule, comparable with 50% in the report of Grogan and colleagues [6]. The rate of resection of benign lesions in our series was comparable with, yet slightly lower than, that reported by Grogan and
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colleagues [6], indicating we need to continue to improve our selection of patients. Although direct comparison between studies is problematic because of differing patient populations, these results suggest that both CTguided percutaneous placement of technetium and ENB-guided dye marking are satisfactory methods for localizing small lung nodules before resection; however, the ENB-guided pleural dye marking technique may be associated with less morbidity and may potentially entail less radiation exposure. Sancheti and colleagues [7] recently reported lung nodule localization with the use of CT-guided fiducial localization, followed by resection with fluoroscopy. This series included 65 small pulmonary nodules in 58 patients. All patients had gold fiducial markers placed preoperatively with a coaxial 17-gauge needle with CT guidance in a radiology suite. This series emphasized the importance of selection on the basis of size of the lesion and depth from the pleural surface as indicated by the mean size of 9.9 mm and mean distance from the pleural surface of 18.7 mm, similar to our study. Mean time to perform fluoroscopy was 10 21.8 minutes. Complications included 3 pneumothoraces, 1 fiducial embolization, 1 fiducial migration, and a parenchymal hematoma. Six of the 58 patients experienced localization technique-related complication, including fiducial embolization. CT-guided, hook-wire localization followed by resection is another technique for localizing small pulmonary nodules preoperatively. Although this is reported as a safe and effective technique, hook-wire localization has its limitations. Chen and colleagues [8] performed CT-guided hook-wire localization in 43 patients with solitary pulmonary nodules. Complications included 1 patient who had a major postoperative hemothorax and 3 patients had conversion to a thoracotomy. Two hook-wire localizations failed to locate the lesion of interest and 2 patients had dislodgement of the hook-wire. Similarly, Pittet and colleagues [9] performed CT-guided wire localization in 45 patients with small pulmonary nodules. Localization failed in 2 patients, conversion to thoracotomy occurred in 2 patients, pneumonia developed in 2 patients, and 1 patient had a hemothorax. Although hook-wire technique is successful in localizing most lung nodules, the reported morbidity may be similar to other percutaneous CT-guided localizing techniques. Furthermore, similar to other CT-guided localization techniques, patients who undergo wire localization typically have the localization performed in the radiology suite, which necessitates transfer to the OR for the surgical procedure. The technique of ENB-guided localization with methylene blue followed by minimally invasive robotic resection was also recently reported by Bolton and colleagues [5]. In their series, 19 patients underwent ENB-guided localization with methylene blue dye marking. The mean lesion size was 18 mm, and the median time for localization was 28 minutes, which included FNA of nodules for rapid onsite pathologic determination. In our series, after ENB-guided dye localization, we proceeded
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directly with minimally invasive surgical procedures, VATS or robotic, with no difference in the diagnostic yield between these two approaches. We report a median lesion size of 10 mm, compared with 18-mm median lesion size in the Bolton study [5], indicating that the diagnostic yield with the use of ENB-guided dye localization and resection may be less dependent on size of the lesion than CT-guided or ENB-guided FNA. There are several potential advantages to the ENB-guided dye marking localization technique. It can be performed safely and effectively in a single setting in the OR, so a coordinated effort between multiple departments (specifically the OR staff and interventional radiology) does not need to occur. Given the previously documented pneumothorax rates with percutaneous techniques for nodule identification, the morbidity associated with ENB-guided localization appears to be lower than with some percutaneous techniques. We observed minimal morbidity associated with ENB-dye marking. Another advantage of the ENB-guided pleural dye marking is that there is minimal exposure to radiation during the localization. In addition to the characteristics of the lung nodule, the patient’s characteristics should be taken into account to assess the risk of malignancy when a lung nodule is detected, before obtaining a biopsy. In an interesting study of 629 patients with a solitary pulmonary nodule that ranged from 4 to 30 mm, 3 patient characteristics (age, smoking, history of cancer) and 3 lesion characteristics (diameter, spiculation, and upper lobe location) were independent predictors of malignancy [18]. In another analysis of 8 large trials of lung cancer screening, the prevalence of malignancy varied by nodule size (6% to 28% for nodules 5 to 10 mm in size and 64% to 82% for nodules >20 mm). Interestingly, nodules that were GGOs were more likely to be malignant (59% to 73%) than solid nodules (7% to 9%) [19]. Note that these studies on lung screening trials are not comparable with our current study in which more than one-half the patients had history of other cancers and were referred for biopsies. In our current series, a neoplastic lesion was diagnosed in approximately 66% of the patients. This higher rate of malignancy of small tumors likely reflects the patient population studied, because patients with either a screen-detected nodule or metastatic nodules detected during follow-up surveillance CT scans for other cancers were included. Notably, more than 95% of patients in our series had either a smoking history or a history of another malignancy. Nonetheless, further work is needed to optimally select patients for invasive biopsy and to decrease the rate of resection of benign nodules.
Strengths and Limitations One strength of this study is that it is the largest study to our knowledge to report the technique of ENB-guided dye marking followed by minimally invasive resection. In addition, our initial experience suggests a high diagnostic yield for small nodules, including GGOs. This study also has its limitations. The limitations of ENB-guided dye marking technique include dispersion of
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the blue dye into the pleural space if the injection needle has penetrated the visceral pleura. This occurred rarely and did not interfere with localization in this initial experience. However, if the dye is not visualized and the lesion is not localized by VATS, one would have to consider converting to a thoracotomy to palpate and resect the lesion. Our study is also limited by the constraints of the retrospective study design, including restraints that are common to retrospective studies such as selection bias. Patients who underwent the resection of lung nodules with the use of this technique are a small subset of the total patients who underwent lung resection during this time period at our institution. Further, patients in this study comprised a select group because of the history of other cancer or smoking history or both in more than 95% of the patients. Further studies are required to identify and define the patient population who will best be suited for localization and resection with the use of this technique. In addition, this report is our initial experience, and larger numbers of patients, with follow-up data, are required to fully evaluate the safety and efficacy of this technique.
Conclusions Our preliminary experience with ENB-guided dye localization and minimally invasive resection suggests that the technique is feasible and safe and appears to be successful in the diagnosis and resection of small lung lesions. This technique appears to be a viable option for diagnosing patients with suspicious pulmonary nodules and can be considered by thoracic surgeons attempting to localize a pulmonary lesion that may be difficult to find thoracoscopically. Further studies are required to identify and define the patient population who will best be suited for localization and resection with the use of this technique. Thoracic surgeons should further investigate this method and incorporate it into their armamentarium. This work was supported in part by in part by the National Institutes of Health (NIH) Specialized Program of Research Excellence (SPORE) in Lung Cancer (P50 CA090440). This project used the UPCI Biostatistics Facility that is supported in part by NIH award P30CA047904.
References 1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61: 212–36. 2. Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 2011;32:605–44. 3. National Lung Screening Trial Research T, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409. 4. National Lung Screening Trial Research Team, Church TR, Black WC, et al. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med 2013; 368:1980–91.
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5. Bolton WD, Howe H III, Stephenson JE. The utility of electromagnetic navigational bronchoscopy as a localization tool for robotic resection of small pulmonary nodules. Ann Thorac Surg 2014;98:471–5; discussion 475–6. 6. Grogan EL, Jones DR, Kozower BD, Simmons WD, Daniel TM. Identification of small lung nodules: technique of radiotracer-guided thoracoscopic biopsy. Ann Thorac Surg 2008;85:S772–7. 7. Sancheti MS, Lee R, Ahmed SU, et al. Percutaneous fiducial localization for thoracoscopic wedge resection of small pulmonary nodules. Ann Thorac Surg 2014;97:1914–8; discussion 1919. 8. Chen S, Zhou J, Zhang J, et al. Video-assisted thoracoscopic solitary pulmonary nodule resection after CT-guided hookwire localization: 43 cases report and literature review. Surg Endosc 2011;25:1723–9. 9. Pittet O, Christodoulou M, Pezzetta E, Schmidt S, Schnyder P, Ris HB. Video-assisted thoracoscopic resection of a small pulmonary nodule after computed tomography-guided localization with a hook-wire system. Experience in 45 consecutive patients. World J Surg 2007;31:575–8. 10. Matsumoto S, Hirata T, Ogawa E, et al. Ultrasonographic evaluation of small nodules in the peripheral lung during video-assisted thoracic surgery (VATS). Eur J Cardiothorac Surg 2004;26:469–73. 11. Wicky S, Mayor B, Cuttat JF, Schnyder P. CT-guided localizations of pulmonary nodules with methylene blue injections for thoracoscopic resections. Chest 1994;106:1326–8.
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12. Krimsky WS, Minnich DJ, Cattaneo SM, et al. Thoracoscopic detection of occult indeterminate pulmonary nodules using bronchoscopic pleural dye marking. J Community Hosp Intern Med Perspect 2014;4. 13. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40: 373–83. 14. Okusanya OT, Holt D, Heitjan D, et al. Intraoperative nearinfrared imaging can identify pulmonary nodules. Ann Thorac Surg 2014;98:1223–30. 15. Holt D, Okusanya O, Judy R, et al. Intraoperative nearinfrared imaging can distinguish cancer from normal tissue but not inflammation. PLoS One 2014;9:e103342. 16. Makris D, Scherpereel A, Leroy S, et al. Electromagnetic navigation diagnostic bronchoscopy for small peripheral lung lesions. Eur Respir J 2007;29:1187–92. 17. Ohno Y, Hatabu H, Takenaka D, et al. CT-guided transthoracic needle aspiration biopsy of small (< or ¼ 20 mm) solitary pulmonary nodules. AJR Am J Roentgenol 2003;180: 1665–9. 18. Swensen SJ, Silverstein MD, Ilstrup DM, Schleck CD, Edell ES. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med 1997;157:849–55. 19. Wahidi MM, Govert JA, Goudar RK, et al. Evidence for the treatment of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132(3 Suppl):94S–107S.
Background. Computed tomography scans are increasingly used not only for lung cancer screening but also for staging and evaluation of other cancers. As a result, more patients with pulmonary nodules, many with subcentimeter lesions, are being referred to thoracic surgeons, some with concern for primary lung neoplasm and others with possible metastatic lung lesions. Obtaining a definitive diagnosis of these lesions is difficult. Electromagnetic navigational bronchoscopy (ENB)-guided pleural dye marking followed by thoracoscopic resection is a novel alternative technique for definitive diagnosis. The main objective of this study was to evaluate the feasibility and our initial experience with ENB-guided dye localization and minimally invasive resection for diagnosis of lung lesions. Methods. Selected patients with lung lesions underwent ENB-guided dye marking and minimally invasive resection. The primary end points were the rate of nodule localization and definitive diagnosis of the nodule.
Results. We performed ENB-guided localization and minimally invasive resection in 29 patients. The median lesion size was 10 mm, with a median distance from pleural surface of 13 mm. The operative mortality was 0%. The median hospital stay was 3 days. The nodule was localized and resected, and a definitive diagnosis was obtained in all patients (29 of 29; 100%). The nodule was neoplastic in 19 patients. All malignant lesions were completely resected with negative microscopic margins. Conclusions. Our initial experience with ENB-guided dye localization and minimally invasive resection found that the technique was feasible, safe, and successful in the diagnosis of small lung lesions. Thoracic surgeons should further investigate this method and incorporate it into their armamentarium.
L
treatment of other malignancies. This, along with an increase in targeted therapies and the need for molecular testing, has led to the referral of many patients with possible metastatic disease to the lung (many with small lung lesions) to thoracic surgeons for biopsies. During video-assisted thoracoscopic surgery (VATS), subcentimeter lesions or ground glass opacities (GGOs) may be difficult to localize, and sometimes lesions larger than a centimeter are difficult to find because of the location or character of the lesion (eg, GGO versus solid). Small lesions that may be difficult to localize by VATS or roboticassisted surgery could potentially be resected more expeditiously and with higher accuracy if thoracic surgeons can apply an easy, reliable way of localizing the lesions before resection. Several groups have reported percutaneous techniques to localize lung nodules before minimally invasive resection [5–11]. The current techniques include CT-guided radiotracer injection, CT-guided wire localization, CT-guided fiducial placement and fluoroscopic localization, CT-guided contrast injection into the nodule and fluoroscopic localization, and ultrasonography and percutaneous staining with methylene blue [6–11]. These techniques require careful coordination among multiple
ung cancer is the most common cause of cancerrelated deaths in the United States with an annual mortality exceeding breast, colon, and prostate cancers combined [1, 2]. Advanced stage of lung cancer at the time of diagnosis is one of the contributing factors to decreased survival in patients with lung cancer. Developing methods for detecting and accurately diagnosing early-stage lung cancer is of paramount importance. The National Lung Screening Trial showed a 20% relative risk reduction in lung cancer mortality for participants who underwent computed tomography (CT) lung cancer screening instead of radiographic screening [3, 4]. As a result of lung cancer screening programs, thoracic surgeons are being referred an increased number of patients with small pulmonary nodules. In addition, CT is routinely used for staging, for evaluation of response, and detection of recurrence after
Accepted for publication Feb 11, 2016. Presented at the Sixty-first Annual Meeting of the Southern Thoracic Surgical Association, Tucson, AZ, Nov 5–8, 2014. Address correspondence to Dr Pennathur, Department of Cardiothoracic Surgery, University of Pittsburgh, 200 Lothrop St, C-800, Pittsburgh, PA 15213; email: [email protected].
Ó 2016 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2016;-:-–-) Ó 2016 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2016.02.040
2
AWAIS ET AL ENB-GUIDED LOCALIZATION AND RESECTION
disciplines, including interventional radiologists, anesthesiologists, and thoracic surgeons. In addition, the risks of CT-guided transthoracic localization procedures include pneumothorax and hemothorax. Because localization techniques often occur in departments other than the operating room (OR), operations may have to be timed appropriately from the time the radiologic procedure was done. The ideal method for nodule localization before resection would be one that is accurate and can be achieved with minimal risk to the patient in the same operative setting as the thoracoscopic resection procedure. Pleural dye marking guided by electromagnetic navigation bronchoscopy (ENB) allows nodule localization and minimally invasive resection to be completed in one setting in the OR [5]. The main objective of this study was to evaluate the feasibility and our initial experience with the ENB-guided dye localization and minimally invasive resection for the definitive diagnosis of lung lesions.
Material and Methods We retrospectively reviewed our experience with ENB-guided dye localization, followed by minimally
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invasive resection (VATS or robotic-assisted surgery) for definitive diagnosis of lung lesions at the University of Pittsburgh Medical Center Mercy from March 2013 to April 2014. This retrospective review included patients who had undergone ENB-guided localization before VATS resection of lung nodules. The patients were referred to the thoracic surgeon for biopsy and underwent ENB-localization because the surgeon felt this would assist with thoracoscopic localization and resection and would decrease the possibility of conversion to thoracotomy. This retrospective study was approved by our institutional review board. Because this was a retrospective study, individual patient consent was waived.
Surgical Procedure The ENB-guided dye marking was performed by the operating surgeon (OA or/and AP) in the OR at the time of resection. With the use of superDimension software (Covidien, Minneapolis, MN), the axial, coronal, and sagittal views of the patient’s CT scan were used to plan the procedure (Figs 1A, 2A). General endotracheal anesthesia was induced with a singlelumen endotracheal tube in the OR. Subsequently,
Fig 1. (A) Computed tomographic image of lung nodule visualized in axial, coronal, and sagittal views. (B) Focal pleural methylene blue dye visualization during video-assisted thoracoscopic surgery. (C) Lung nodule seen beneath the surface pleural dye. All images are from a single patient.
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Fig 2. (A) Computed tomographic image of lung nodule. (B) Electromagnetic navigational bronchoscopy-guided injection of methylene dye under fluoroscopic guidance. (C) Pleural dye visualized during video-assisted thoracoscopic surgery. (D) Resected specimen with blue dye adjacent to the lung nodule. All images are from a single patient.
ENB was performed with the platform’s software. Once the lesion was localized during navigation, fluoroscopy was used to visualize needle injection of 0.5 mL of methylene blue [12] (Fig 2B). A syringe with a 25-gauge needle was preloaded with 0.5 mL of methylene blue. Once the target lesion was in view with the use of navigational bronchoscopy, the locatable guide was removed from the extended working channel under fluoroscopy. The preloaded syringe with a 25-gauge needle was inserted into the extended working channel, and under fluoroscopic guidance approximately 0.5 mL of methylene blue was injected either into the lesion or midway between the lesion and the nearest pleural surface on the basis of the CT scan. As a general rule, lesions within 1 cm of the pleural surface were directly injected, and in those where the lesion was located more than 1 cm from the pleural surface the dye marking was performed midway between the lesion and the nearest pleural surface. After localization and injection of the lesion with methylene blue, the single-lumen endotracheal tube was changed to a double-lumen endotracheal tube. The patient was appropriately positioned for minimally invasive resection (VATS or robotic surgery) of the lung lesion. On inspection within the chest, the blue dye was visualized (Figs 1B, 2C). The lesion was resected with endoscopic staplers with the use of a sublobar resection (wedge in 28 patients and segmentectomy in 1 patient). Resection of the lesion was guided not only by the dye visualization but also by the CT assessment. It is important to use the CT scan to help guide for depth of resection. We found this essential to achieve an adequate margin. The biopsy
specimen was then evaluated by opening the specimen in the OR and with pathologic confirmation by frozen-section analysis (Figs. 1C, 2D).
Statistical Design and Analysis Information on patient demographic characteristics, history, comorbidities (Charlson comorbidity index), lesion characteristics, treatment, operative details, perioperative outcomes, and pathologic evaluation was collected [13]. The primary end points studied were the rate of localization of the lung nodule and the rate of definitive diagnosis of the lung nodule by the pathologist.
Results Patient Characteristics A total of 33 lesions were localized in 29 patients (16 men, 13 women; median age 66 years) with the use of methylene blue dye-marking guided by ENB (Table 1). Table 1. Patient Characteristics Characteristic Total patients/lesions, n/n Sex, n Male Female Age, median, y Smoking history, n (%) Smoking history, median pack-years Previous malignancy, n (%) Previous lung resection, n (%)
Value 29/33 16 13 66 25 (86.2) 25 19 (65.5) 7 (24.1)
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The median Charlson comorbidity index was 2. In addition, 86% (25 of 29) of the patients had a substantial smoking history with a median pack-year use of 25 (mean pack-year 36), and 66% (19 of 29) of patients had a history of malignancy. Of the 29 patients, 28 (97%) had either a history of smoking or a prior malignancy (Table 1).
Characteristics of the Lung Lesions The locations of the 33 pulmonary nodules were variable, with the right upper lobe (39.4%) being the most common site (Table 2). Six nodules (6 of 29 patients; 20.7 %) were GGOs. The median maximum diameter of localized lung lesions was 10 mm (range, 4 to 27 mm; interquartile range, 7.5 to 12 mm). The median maximum distance measured from the center of the lesion to the nearest parietal pleural surface was 13 mm (range, 3 to 44 mm; interquartile range, 8 to 23 mm; Table 2). The maximum depth from the pleural surface to the center of a lesion was 44 mm, and its location close to an interlobar fissure assisted in resection.
Operative Approach and Perioperative Outcomes ENB-guided dye marking was performed in the OR. There were no reported complications from the ENBguided dye localization. The mean navigation time (time from the onset of airway mapping to injection of methylene blue; available in a subset of patients) was 9.7 minutes. Seventeen patients (17 of 29; 59%) underwent VATS; the remaining 12 patients underwent a robotic resection. All lesions were resected in the same operative setting as the dye marking. The median hospital stay was 3 days. Major morbidity occurred in 1 patient (1 of 29; 3.4%) in whom postoperative pneumonia and respiratory failure developed. Another patient experienced a minor complication of atrial fibrillation (1 of 29; 3.4%). The operative mortality was 0%.
Localization and Resection of the Lung Nodule and Pathologic Evaluation In all patients, the index lung nodule was localized and resected with pathologic confirmation of the diagnosis. The lesions were inspected intraoperatively to correlate the nodule size and characteristics determined during the CT scan with the specimen before the lesion was sent to pathology. In most of the procedures, the dye Table 2. Characteristics of Lung Lesions Characteristics of Lesion (n¼33) Location, n (%) Right upper lobe Right middle lobe Right lower lobe Left upper lobe Left lower lobe Size, median (range), mm Size Distance from pleural surface
Value
13 2 5 6 7
(39.4) (6.1) (15.2) (18.2) (21.2)
10 (4–27) 13 (3–44)
was seen on the pleural surface closest to the tumor. After some injections, the blue dye was partially at the tumor site; this did not interfere with the pathologic assessment (Fig 2D). The resected specimen was evaluated by a pathologist, and on both gross and microscopic assessment the deep-stapled margin was negative (Fig 1C). A definitive diagnosis was obtained by pathologic evaluation in all patients (29 of 29; 100%). In 66% of patients (19 of 29), the final pathologic evaluation showed a neoplastic lesion (Table 3). This included 13 patients with primary lung cancer and 5 patients with metastatic lesions. In the patients with primary lung cancers, 11 had T1a lesions and 2 had T1b lesions. Every malignant lesion, both primary and metastatic, had negative gross and microscopic resection margins. The non-neoplastic nodules were mainly granulomatous or inflammatory nodules.
Comment Our initial experience with ENB-guided methylene blue dye marking of small lesions followed by minimally invasive resection suggests that this technique is feasible, safe, and an effective method for biopsy of lesions that may be difficult to visualize or digitally palpate. For small pulmonary nodules (median maximum diameter 10 mm), we achieved a high rate of definitive diagnosis after minimally invasive sublobar resection. Dye marking was successful for identification even in lesions that were small and difficult to palpate, secondary to location or character (ie, GGOs). The pleural dye was visualized in every dye-marking procedure, and, after localization, the extent of resection was guided by careful evaluation of the CT scan in coronal, sagittal, and axial views. In addition, the lack of complications from the dye localization process and the mean navigation time of less than 10 minutes suggest that ENB-guided dye marking is safe and not cumbersome. Localization techniques for lung nodules are typically reserved for lesions that are small, that are deep in the lung parenchyma, or lesions that are GGOs. In some Table 3. Final Pathologic Finding in All Patients Pathologic Finding Neoplastic Primary lung Adenocarcinoma Carcinoid Neuroendocrine Large cell Metastatic Adenocarcinoma Squamous Renal cell Germ cell Other Inflammatory/granulomatous
n (%) 19 (66) 9 1 2 1
(31.0) (3.4) (6.9) (3.4)
2 1 1 1 1 10
(6.9) (3.4) (3.4) (3.4) (3.4) (34)
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instances, lesions may be deep; however, their proximity to an interlobar fissure may make dye marking favorable, especially if the fissures are well defined. The goal of ENB-guided dye marking is to enhance localization during the operation and to improve the chances of a successful VATS biopsy (without conversion to open thoracotomy). ENB-guided dye marking should not expand the indications for the operation. Recently, detection of pulmonary nodules with the use of intraoperative near-infrared imaging was described to locate nonpalpable, poorly visualized lung nodules [14, 15]. This technique is investigational and was performed with thoracotomy rather than a VATS procedure. Thoracic surgeons are referred patients with small lung lesions for consideration of biopsy. Our initial experience with ENB-guided dye marking followed by VATS resection indicated a high diagnostic yield, even though nearly 20% of the lung nodules were GGOs. Other options for biopsies include bronchoscopic or CT-guided biopsies. The diagnostic yield of bronchoscopic biopsy of a small peripheral lung lesion can be poor. In a series by Makris and colleagues [16], the overall diagnostic yield for navigational bronchoscopic biopsy was 62.5%, and only 43.7% of lesions smaller than 2 cm were successfully biopsied by navigation bronchoscopy alone. Other series have reported a diagnostic yield that ranged from 62.5% to 87.5% with the use of navigational bronchoscopic biopsy alone [14–17]. CT-guided transthoracic needle aspiration biopsy of small nodules may also have a low rate of definitive diagnosis and has the potential for pneumothorax. Ohno and colleagues [17] reported an accuracy of 52% with CT-guided fine-needle aspiration (FNA) in lesions smaller than 1 cm. Grogan and colleagues [6] performed radiotracerguided localization in 84 patients with small solitary lung lesions. Patients underwent CT-guided percutaneous placement of technetium solution within or in close proximity to the suspicious nodule. Seventy-seven nodules were localized and excised with a mean size of 9.8 mm and a mean distance from the nodule to the pleural surface of 11.7 mm. In that study, 50% of the nodules were benign, 39% were primary malignancies, and 11% were metastatic lesions or lymphoma. Complications occurred in 12 of 77 patients (16%) and included 8 pneumothoraces that required pigtail catheter insertion, 3 patients with atrial arrhythmias, and 1 with prolonged air leak. This radiotracer-guided technique appears to have excellent results for localization; however, localization and resection were performed in different settings. The mean nodule size of 9.8 mm reported by Grogan and colleagues [6] was comparable with the median nodule size of 10 mm seen in our experience, and the mean distance between the pleural surface and the nodule of 11.7 mm was also similar to our study (median distance, 13 mm). Approximately 66% of our patients had a neoplastic nodule, comparable with 50% in the report of Grogan and colleagues [6]. The rate of resection of benign lesions in our series was comparable with, yet slightly lower than, that reported by Grogan and
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colleagues [6], indicating we need to continue to improve our selection of patients. Although direct comparison between studies is problematic because of differing patient populations, these results suggest that both CTguided percutaneous placement of technetium and ENB-guided dye marking are satisfactory methods for localizing small lung nodules before resection; however, the ENB-guided pleural dye marking technique may be associated with less morbidity and may potentially entail less radiation exposure. Sancheti and colleagues [7] recently reported lung nodule localization with the use of CT-guided fiducial localization, followed by resection with fluoroscopy. This series included 65 small pulmonary nodules in 58 patients. All patients had gold fiducial markers placed preoperatively with a coaxial 17-gauge needle with CT guidance in a radiology suite. This series emphasized the importance of selection on the basis of size of the lesion and depth from the pleural surface as indicated by the mean size of 9.9 mm and mean distance from the pleural surface of 18.7 mm, similar to our study. Mean time to perform fluoroscopy was 10 21.8 minutes. Complications included 3 pneumothoraces, 1 fiducial embolization, 1 fiducial migration, and a parenchymal hematoma. Six of the 58 patients experienced localization technique-related complication, including fiducial embolization. CT-guided, hook-wire localization followed by resection is another technique for localizing small pulmonary nodules preoperatively. Although this is reported as a safe and effective technique, hook-wire localization has its limitations. Chen and colleagues [8] performed CT-guided hook-wire localization in 43 patients with solitary pulmonary nodules. Complications included 1 patient who had a major postoperative hemothorax and 3 patients had conversion to a thoracotomy. Two hook-wire localizations failed to locate the lesion of interest and 2 patients had dislodgement of the hook-wire. Similarly, Pittet and colleagues [9] performed CT-guided wire localization in 45 patients with small pulmonary nodules. Localization failed in 2 patients, conversion to thoracotomy occurred in 2 patients, pneumonia developed in 2 patients, and 1 patient had a hemothorax. Although hook-wire technique is successful in localizing most lung nodules, the reported morbidity may be similar to other percutaneous CT-guided localizing techniques. Furthermore, similar to other CT-guided localization techniques, patients who undergo wire localization typically have the localization performed in the radiology suite, which necessitates transfer to the OR for the surgical procedure. The technique of ENB-guided localization with methylene blue followed by minimally invasive robotic resection was also recently reported by Bolton and colleagues [5]. In their series, 19 patients underwent ENB-guided localization with methylene blue dye marking. The mean lesion size was 18 mm, and the median time for localization was 28 minutes, which included FNA of nodules for rapid onsite pathologic determination. In our series, after ENB-guided dye localization, we proceeded
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directly with minimally invasive surgical procedures, VATS or robotic, with no difference in the diagnostic yield between these two approaches. We report a median lesion size of 10 mm, compared with 18-mm median lesion size in the Bolton study [5], indicating that the diagnostic yield with the use of ENB-guided dye localization and resection may be less dependent on size of the lesion than CT-guided or ENB-guided FNA. There are several potential advantages to the ENB-guided dye marking localization technique. It can be performed safely and effectively in a single setting in the OR, so a coordinated effort between multiple departments (specifically the OR staff and interventional radiology) does not need to occur. Given the previously documented pneumothorax rates with percutaneous techniques for nodule identification, the morbidity associated with ENB-guided localization appears to be lower than with some percutaneous techniques. We observed minimal morbidity associated with ENB-dye marking. Another advantage of the ENB-guided pleural dye marking is that there is minimal exposure to radiation during the localization. In addition to the characteristics of the lung nodule, the patient’s characteristics should be taken into account to assess the risk of malignancy when a lung nodule is detected, before obtaining a biopsy. In an interesting study of 629 patients with a solitary pulmonary nodule that ranged from 4 to 30 mm, 3 patient characteristics (age, smoking, history of cancer) and 3 lesion characteristics (diameter, spiculation, and upper lobe location) were independent predictors of malignancy [18]. In another analysis of 8 large trials of lung cancer screening, the prevalence of malignancy varied by nodule size (6% to 28% for nodules 5 to 10 mm in size and 64% to 82% for nodules >20 mm). Interestingly, nodules that were GGOs were more likely to be malignant (59% to 73%) than solid nodules (7% to 9%) [19]. Note that these studies on lung screening trials are not comparable with our current study in which more than one-half the patients had history of other cancers and were referred for biopsies. In our current series, a neoplastic lesion was diagnosed in approximately 66% of the patients. This higher rate of malignancy of small tumors likely reflects the patient population studied, because patients with either a screen-detected nodule or metastatic nodules detected during follow-up surveillance CT scans for other cancers were included. Notably, more than 95% of patients in our series had either a smoking history or a history of another malignancy. Nonetheless, further work is needed to optimally select patients for invasive biopsy and to decrease the rate of resection of benign nodules.
Strengths and Limitations One strength of this study is that it is the largest study to our knowledge to report the technique of ENB-guided dye marking followed by minimally invasive resection. In addition, our initial experience suggests a high diagnostic yield for small nodules, including GGOs. This study also has its limitations. The limitations of ENB-guided dye marking technique include dispersion of
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the blue dye into the pleural space if the injection needle has penetrated the visceral pleura. This occurred rarely and did not interfere with localization in this initial experience. However, if the dye is not visualized and the lesion is not localized by VATS, one would have to consider converting to a thoracotomy to palpate and resect the lesion. Our study is also limited by the constraints of the retrospective study design, including restraints that are common to retrospective studies such as selection bias. Patients who underwent the resection of lung nodules with the use of this technique are a small subset of the total patients who underwent lung resection during this time period at our institution. Further, patients in this study comprised a select group because of the history of other cancer or smoking history or both in more than 95% of the patients. Further studies are required to identify and define the patient population who will best be suited for localization and resection with the use of this technique. In addition, this report is our initial experience, and larger numbers of patients, with follow-up data, are required to fully evaluate the safety and efficacy of this technique.
Conclusions Our preliminary experience with ENB-guided dye localization and minimally invasive resection suggests that the technique is feasible and safe and appears to be successful in the diagnosis and resection of small lung lesions. This technique appears to be a viable option for diagnosing patients with suspicious pulmonary nodules and can be considered by thoracic surgeons attempting to localize a pulmonary lesion that may be difficult to find thoracoscopically. Further studies are required to identify and define the patient population who will best be suited for localization and resection with the use of this technique. Thoracic surgeons should further investigate this method and incorporate it into their armamentarium. This work was supported in part by in part by the National Institutes of Health (NIH) Specialized Program of Research Excellence (SPORE) in Lung Cancer (P50 CA090440). This project used the UPCI Biostatistics Facility that is supported in part by NIH award P30CA047904.
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