Head and neck and lung cancer continue to be a huge

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1 Autofluorescence Bronchoscopy and Endobronchial Ultrasound: A Practical Review David Feller-Kopman, MD, William Lunn, MD, and Armin Ernst, MD Interventional Pulmonology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, and Baylor College of Medicine, Houston, Texas Endobronchial ultrasound (EBUS) and autofluorescence bronchoscopy (AFB) are the two technologies to have the largest impact on diagnostic bronchoscopy in the last forty years. The AFB utilizes inherent tissue properties to identify preinvasive lesions of the central airways. The EBUS can accurately define airway invasion versus compression from tumors, guide transbronchial needle aspiration of hilar and mediastinal lymph nodes, and predict, based on ultrasound morphology, whether peripheral nodules are benign or malignant. It is also extremely useful for determining the proximal and distal extent of tumors in and around the airway, and aid in surgical planning. This article will review the principles and clinical applications of these two technologies. (Ann Thorac Surg 2005;80: ) 2005 by The Society of Thoracic Surgeons Head and neck and lung cancer continue to be a huge health care problem in the United States and the world [1]. The outlook for patients diagnosed with these cancers is fairly bleak and largely dependent on the stage of the disease allowing for surgical curative resection [1 3]. Bronchoscopy has been a standard component of the workup and staging of patients with cancers of the lungs and airways, but since the introduction of the flexible bronchoscope by Ikeda and colleagues [4], the basic design and technology of the instrument has not changed significantly. There are two noteworthy exceptions to this statement: autofluorescence bronchoscopy and endobronchial ultrasound. Both technologies use the flexible endoscopic approach to the airways but the obtained images and information differ from conventional bronchoscopy. A wealth of experience has been collected with these technologies, they have been FDA approved for several years, and they slowly are entering endoscopic mainstream to the benefit of our patients. This article is intended to review the underlying technology, summarize the available data, and suggest how to practically use the technology and integrate it into the management of our patients. Material and Methods In order to review the relevant literature, PubMed (National Library of Medicine) was searched with the following criteria: autofluorescence AND bronchoscopy ; autofluorescence AND airway ; endobronchial ultrasound ; EBUS ; airway AND ultrasound. The titles and abstracts of retrieved articles were reviewed, and all pertinent articles were obtained. The reference lists from Address correspondence to Dr Ernst, Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215; aernst@bidmc.harvard.edu. all of these articles were also reviewed, and relevant references were obtained. Principles of Autofluorescence Autofluorescence bronchoscopy (AFB) is an endoscopic tool that can identify precancerous lesions in the respiratory tract. It should be noted that the histology of cancer being sought is different for computed tomographic (CT) scanning and AFB. The CT scans are generally being used to identify peripheral lesions (usually adenocarcinoma) whereas AFB is being utilized for the detection of central airway lesions, predominantly preinvasive squamous cell carcinoma. When a surface is illuminated by light, the light can be reflected, backscattered, or absorbed. Additionally, light also causes the tissue to fluoresce; however, this autofluorescence (AF) cannot be seen during conventional white-light bronchoscopy (WLB) as the intensity of fluorescence is very low, and is overwhelmed by the reflected and back-scattered light. Tissue AF reveals the underlying biochemical changes occurring in the cells, specifically the electronic structure of absorption chromophores. The major chromophores in the airway mucosa are elastin, collagen, flavins, nicotinamide-adenine dinucleotide (NAD), NADH (hydrogen), and porphyrins [5]. Exposure of the chromophores to light of specific wavelengths excites electrons and fluorescence is emitted when the electrons return to ground level. Normal respiratory tissue fluoresces green when exposed to light in the violet blue spectrum ( nm). As mucosal and submucosal disease progresses from normal, to metaplasia, to dysplasia, to carcinoma in situ (CIS), there is a progressive loss of the green AF, causing a red-brown appearance of the tissue (Figs 1A and 1B). This results from reductions in certain chromophores, increasing thickness of the epithelium, as well as an increase in angiogenesis that develops with more advanced disease [6] by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 2396 REVIEW FELLER-KOPMAN ET AL Ann Thorac Surg AFB AND EBUS: A PRACTICAL REVIEW 2005;80: Fig 1. The conventional bronchoscopic image (left) shows a fairly normal right upper lobe uptake in a patient with sputum cytology positive for non-small cancer and a negative chest computed tomography. The right panel shows the same area with autofluorescence endoscopy. The purplish discoloration is abnormal and biopsy revealed carcinoma in situ. As intraepithelial neoplastic lesions are only a few cell layers thick, the surface mucosa typically appears relatively normal during WLB. In fact, Woolner and colleagues [7] found that only 29% of CIS was visible to the experienced bronchoscopist. The appearance of CIS can look similar to those produced from chronic bronchitis, which is often present in patients at risk for lung cancer. By the time the mucosa appears distinctly abnormal, the cancer is typically invasive. Clinical Applications The first available AF system was the lung imaging fluorescence endoscopy (LIFE) system. This consisted of an image-intensified charge coupled device (CCD) camera with a filter-switching mechanism attached to the eyepiece of a conventional bronchoscope, allowing realtime visualization of the abnormal fluorescent areas [8]. In an initial study of 94 patients, the authors [8] found a sensitivity of 48% for WLB and a sensitivity of 73% for AFB, a 50% improvement. Of note, the acronym LIFE has undergone several metamorphoses, with the L initially representing lung, then light, and the most recent version of LIFE is laser induced fluorescence emission. Several new units are now in use worldwide. At the time of writing this manuscript, only the D-Light system (Karl Storz Endoscopy - America, Inc, Culver City, CA) is FDA approved and commercially available in the US. In the multicenter study leading to FDA approval of the LIFE system (Xillix, Vancouver, BC), Lam and colleagues [9] investigated the additional yield of AFB on WLB in 173 patients with known or suspected lung cancer. The AFB plus WLB had a relative sensitivity (defined as the sensitivity of a test divided by the sensitivity of the comparative test) of 6.3 compared with WLB alone for the detection of moderate to severe dysplasia and CIS, and a relative sensitivity of 2.7 when invasive carcinomas were included. The false positive rate for AFB was 34%, compared with 10% for WLB. Other studies in different centers and nations have shown similar results [10 13]. A recent negative study was recently published by Kurie and colleagues [14]. They investigated the additional yield AFB had on WLB in 39 current or former smokers, and found no significant increase in the detection of squamous metaplasia or dysplasia. A possible explanation for this is the fact that the prevalence of advanced disease was low in the population studied. The majority of patients were former smokers who had stopped smoking for a median of 8 years prior to the study. This contrasts to the studies [15] where AFB has been shown to be beneficial in that enrolled patients had known or suspected lung cancer, and therefore a higher prevalence of advanced dysplasia/cis. A Japanese study [16] examined 50 patients with suspected or positive sputum cytology. A major finding of this study was the multicentricity of disease, with 21 patients (42%) having more than one lesion, adding support to the field cancerization theory of lung cancer: exposure of the entire respiratory tract to carcinogens induces several areas of abnormal cell growth, some of which eventually develop into carcinoma. Autofluorescence bronchoscopy has also been used as a surveillance tool in patients who have undergone curative surgery for non-small cell lung cancer. Second primaries occur in 1% to 3% per year in this group of patients, and only 50% of these are resectable at the time of their diagnosis [17]. Weigel and colleagues [18] performed WLB and AFB in 25 patients who had previously undergone curative resection (80% stage I or II, 20% stage IIIa at the time of their surgery). They found four lesions in three patients (12%), and AFB increased the overall sensitivity from 25% to 75% (a relative sensitivity of 300%). Although it is impossible to draw conclusions in terms of survival from these data, however, the field cancerization theory may support performing AFB in patients prior to surgical resection of early stage lung cancer and in patients after lung cancer surgery. Likewise, in a prospective study of 240 high-risk patients (symptomatic smokers or patients with a history of lung or head and neck cancer), Moro-Sibilot and colleagues [19] investigated the prevalence of high-grade lesions (moderate-severe dysplasia or CIS) and invasive carcinoma using AFB. There was no influence of age, gender, or age at smoking initiation on the prevalence of preinvasive or invasive lesions. High-grade lesions were most commonly seen in patients with a prior history of squamous cell carcinoma of the lung, with 40% of the lesions being identified in the contralateral lung. In current smokers, the number of pack-years smoked and the duration of smoking both influenced the occurrence of high-grade or invasive lesions. Published data in more than 1,400 patients suggest that WLB alone detects on average only 40% of high-grade dysplasia and CIS, whereas AFB increases the detection rate up to 88% [13]. The variation in results of both WLB and AFB can be explained by the prevalence of the disease in the patients studied, the skill of the bronchoscopist, the image quality of conventional WLB (fiberoptic versus video technology), as well as the reproducibility of the bronchoscopic and pathologic interpretation [20]. The latter problem will hopefully be addressed by future studies utilizing a standardized classification of

3 Ann Thorac Surg REVIEW FELLER-KOPMAN ET AL 2005;80: AFB AND EBUS: A PRACTICAL REVIEW 2397 preinvasive lung cancer developed by the World Health Organization [21]. Of particular importance for the thoracic surgeon and interventional bronchoscopist is a study by Sutedja and colleagues [22], which found that AFB identified more advanced malignancy in a group of 23 patients referred for the endoscopic evaluation and treatment of radiographically occult lung cancer as compared with WLB. These patients were referred for surgical as opposed to endoscopic therapy, and with a median follow-up of 40 months strongly suggest the use of AFB prior to ruling out surgery as the treatment of choice. Practical Notes: AFB Autofluorescence bronchoscopy requires some learning and getting used to. An exam is usually performed after a normal white light inspection of the airways. Care must be taken to avoid excessive suctioning or airway wall trauma, as this makes the interpretation of the AF exam difficult. We suggest minimizing suction and using enough sedation and topical anesthetic to avoid excessive coughing during the bronchoscopy. The AF examination must be performed before any biopsies are taken or interventions are performed. Blood in the airways can make an AF exam impossible. Due to the small amount of reflected light, the image can be darker in the trachea than in the main bronchi. Adjusting shutter speed and a more close up inspection will remedy this issue. Abnormal areas appear darker and must be biopsied as the visual appearance is not diagnostic. All biopsies need to be taken after the entire exam is completed, and their specific location within the airway documented. This will ensure the appropriate follow-up and treatment of specific lesions. The AF bronchoscopy is readily learned and suggestions for competency assessment are available [23]. Aside from the cost of the autofluorescence unit, the major downside to AFB is the lack of specificity. This results in a greater number of abnormal lesions being identified at the time of bronchoscopy, prolonging the procedure in order to biopsy the false-negative lesions, Fig 2. Shown is the inflated balloon around a radial endobronchial ultrasound probe. Fig 3. Image of a bronchoscope with an incorporated radial ultrasound in the tip. This allows for real time imaging of a biopsy needle exiting from a side channel, similar to existing endoscopic ultrasound technology. and added time and expense for the pathologist, who is required to examine all of the obtained tissue [24]. High sensitivity and low specificity, however, are the desired characteristics of an initial screening test. Another issue is the follow-up of any detected abnormality, as currently no standards exist. The proportion of patients with CIS that progress into invasive cancer is unknown, but likely greater than those progressing from severe dysplasia to CIS. One potential reason that lesions may not progress after initial biopsy is complete removal of the preinvasive cancer at the time of the initial biopsy. Regression, sampling error, and inter- or intraobserver variability in reading the histopathology is also possible. A study by Bota and colleagues [25] followed 416 lesions in 104 high-risk patients over a minimum two-year period using a standardized algorithm. Of the 27 lesions that were initially labeled as severe dysplasia, 19 (70%) regressed into a low-grade lesion at 3 months. At two years, 37% of the initial severely dysplastic lesions stabilized or progressed, 41% regressed to normal, and 22% regressed into low-grade dysplasia. In contrast, 25 of the initial 32 CIS lesions (78%) were confirmed as severe dysplasia-cis at 3 months, and were treated at that time. At 24 months, of the 7 initial CIS lesions that had regressed at 3 months, 2 recurred. Predictors for progression included CIS and prior bronchogenic or head and neck cancer. The authors conclude that there is a low risk of progression for low-grade dysplastic lesions and that these lesions could have bronchoscopic follow-up every two years. They recommend [25] a 3-month follow-up for patients with severe dysplasia, and therapy if the lesion persists, as well as immediate therapy for patients with CIS. It remains to be determined whether AF bronchoscopy will save lives. There is also no accepted standard on who should undergo the procedure and no widely accepted algorithm on the management of the lesions exists. Future studies may investigate the utility of routine AF examinations prior to surgery in patients with resectable lung cancer. Nevertheless, the data showing the ability to increase the diagnostic rate for the detection of early central airway malignancies are convincing.

4 2398 REVIEW FELLER-KOPMAN ET AL Ann Thorac Surg AFB AND EBUS: A PRACTICAL REVIEW 2005;80: Fig 4. Image of a lymph node biopsy under endobronchial ultrasound guidance. The needle (arrows) is clearly visible in the lymph node. Endobronchial Ultrasound (EBUS) Technology Endoscopic ultrasound has been in clinical use for many years and has become an integral part of the workup for gastrointestinal malignancies. The potential benefits of ultrasound within the airway tract should be comparably significant. In contrast to conventional endoscopy, where the view is restricted to the mucosal surface, EBUS has been used successfully to visualize the airway wall layers in exquisite detail, to view the relationship between extraluminal nodes-masses and vessels, and in guiding biopsy of mediastinal and hilar lymph nodes as well as parenchymal lesions [26 29]. Additionally, EBUS can assist endoscopic therapy such as stent placement and brachytherapy, as well as help differentiate airway invasion versus compression by tumor, thus determining if the patient would benefit from surgical resection. The delay in the introduction of ultrasound in the central airways is mainly due the property of air as an insulator for ultrasound waves, the need to miniaturize the probes to assure ventilation, and pass through bronchoscopic working channels. Over the last decade, miniaturized ultrasound probes have been developed that can be inserted through a 2.8 mm working channel. The tip of the probe contains a rotating piezoelectric crystal that is set in a water-filled balloon, which, when inflated, allows 360 degree coupling with the airway, thus solving the issue with air insulation (Fig 2). The rotating crystal acts as both a signal generator and receiver. The standard frequency for EBUS is 20 MHz, which allows for a resolution of less than 1 mm, and a depth of penetration of approximately 4 to 5 cm. This frequency allows for excellent assessment of the layers of the airway wall and the parabronchial structures. Lower frequencies (to 3.5 MHz) improve the depth of penetration; however, spatial resolution is reduced [30]. The only clinically available EBUS system is currently made by Olympus (Melville, NY). This system uses a radial scanning ultrasound probe, as described above, and provides excellent imaging of mediastinal and hilar lymph nodes, and central airway tumors, as well as peripheral parenchymal lesions. In the latter setting, the probe is passed into the distal airways, and direct contact is made without the need for balloon inflation. A newer development is a dedicated EBUS bronchoscope with a working channel that enables real-time imaging for transbronchial needle aspiration (Fig 3) [31]. It utilizes a curvilinear scanner that produces a sectorial view of the bronchial wall and mediastinal structures, similar to the instruments used by gastroenterologists. Clinical Applications One of the obvious potential applications of the technology is the guidance of mediastinal lymph node biopsies. This is supported by a recent study [32] that found EBUS to aid in the sampling of mediastinal and hilar lymph nodes, with an overall success rate of 86%, regardless of lymph node size or location. The EBUS also allows for guidance of biopsies of lymph nodes in regions inaccessible to mediastinoscopy, such as posterior subcarinal Fig 5. (A) Image on the left shows a normal endobronchial ultrasound image of the left mainstem bronchus branching into the left lower lobe (LLL). Visible structures are the left lower pulmonary vein (LLPV), a lymph node (LN), and the left atrium (LA). (B) Image shows an abnormal endobronchial ultrasound image of a tumor invading the wall and extending through the cartilage layer. Endobronchial curative treatment would not be promising in this patient.

5 Ann Thorac Surg REVIEW FELLER-KOPMAN ET AL 2005;80: AFB AND EBUS: A PRACTICAL REVIEW 2399 and hilar nodes [33] (Fig 4). Though prospective data examining the influence of EBUS on clinical outcomes such as the need for surgery are not available at this time, it is expected that the impact could be significant. Current data suggest that almost 30% of patients undergoing transbronchial needle aspiration (TBNA) biopsy of mediastinal and hilar lymph nodes for the staging of bronchogenic carcinoma are found to have unresectable disease [34]. EBUS for Defining Tumor Invasion Initial reports described the bronchial wall as having at least three, and up to seven, echo layers [35, 36]. The ability of EBUS to clearly define the bronchial wall layers and adjacent anatomic structures make it an excellent tool for distinguishing airway tumor invasion from external compression, as well as determining the depth of endobronchial tumor invasion (Fig 5). Takemoto and colleagues [37] compared the sensitivity of EBUS and CT in detecting bronchial wall or great vessel invasion by tumor. The authors also concluded that EBUS was more sensitive than CT for assessing bronchial wall invasion [37]. In a prospective study of 131 patients with central airway tumors, Herth and colleagues [38] compared depth of tumor invasion as measured by EBUS and CT with surgical pathology in105 patients. The EBUS identified tumor invasion in 47% of patients, and airway compression in 53%. All patients classified as having invasion by EBUS were confirmed by pathology, and six patients thought to have airway compression had invasion pathologically, yielding a sensitivity of 89% and a specificity of 100%. This compared extremely favorably to CT, which had a sensitivity of 75% and a specificity of 28%. Recently, Miyazu and colleagues [39] used EBUS to select patients with biopsy proven squamous cell carcinoma (or CIS) for endobronchial treatment with photodynamic therapy (PDT). Nine of 18 lesions confirmed as local disease (not extending through the cartilage) were treated with PDT, and 100% were considered to have complete response on follow-up after a median of 32 months. Six of the nine lesions diagnosed as extracartilaginous with EBUS underwent surgical resection. The depth of tumor invasion was identical on EBUS and histologic exam. Again, EBUS was found to be more sensitive for tumor invasion through the airway wall than CT scanning [39]. The authors concluded that accurate assessment of tumor invasion is crucial for successful endobronchial treatment of early stage cancers and that EBUS is the superior technology in that assessment and therefore should routinely be included in the assessment of these patients. The largest series describing the use of EBUS in therapeutic bronchoscopy was recently published [40]. The EBUS was utilized in 1,174 of 2,446 cases over a threeyear period, including mechanical tumor debridement, stent placement, Nd:YAG laser, argon plasma coagulation, brachytherapy, foreign body removal, and the endoscopic drainage of abscesses and curative treatment of early cancers. The EBUS was found to guide or change management in 43%, and changes included selecting proper stent size, guiding tumor debridement, and selecting patients for endoscopic therapy versus surgical therapy. The authors also reported that with the introduction of EBUS, no more fatal hemoptysis was observed with the use of thermal ablation technology, since EBUS allowed for the intraoperative visualization of the relationship of adjacent vessels. Practical Notes: EBUS The learning curve for EBUS tends to be somewhat longer than for other diagnostic pulmonary procedures. One must become familiar with the equipment as well as the ultrasonic view of the bronchial and extrabronchial anatomy that is often visualized in an oblique angle, as opposed to the standard axial imaging from CT scanning or the EUS images obtained through an EUS endoscope. As such, it is estimated that approximately 50 ultrasound exams are required to achieve facility with EBUS [23]. The radial probe (or miniprobe) is a delicate instrument and must be sheathed (a disposable component) before each use to prevent infection spread. Kinking and excessive movement of the probe while rotating can significantly decrease the life expectancy of 100 to 150 procedure uses of the device. Additionally, care must be taken to inflate the balloon properly to achieve acoustic coupling within the airways and therefore a properly trained assistant is essential. Once an image is obtained, it is recommended to check for easily recognizable landmarks such as vessels and the esophagus and adjust the ultrasound image accordingly to match the endoscopic view. All significant ultrasound findings should be documented just as much as the endoscopic findings. Patients generally tolerate an inflated balloon well within a mainstem bronchus. Even a fully inflated balloon in the trachea is tolerated for a limited period of time if the patient is well-coached. In the trachea one can also just partially inflate the balloon to examine the area in question, thus allowing for ventilation and improved patient comfort throughout the procedure. Endobronchial ultrasound allows the endoscopist to look beyond the mucosal surface and it has been shown to be highly beneficial in a variety of clinical circumstances. In some clinical scenarios it is clearly superior to any other imaging technology currently in use. It is now an essential part of the diagnostic endoscopic workup for patients in many institutions and with the introduction of the dedicated TBNA scope we expect its use to enter the endoscopic mainstream quickly. Conclusions Since the use of the flexible bronchoscope was popularized in the late 1960s there have been relatively few technologic advances, aside from the development of the video chip replacing fiber optics. Autofluorescence bronchoscopy is finding its role in the early detection of premalignant and malignant lesions of the airways while EBUS is proving to be quite useful in the staging

6 2400 REVIEW FELLER-KOPMAN ET AL Ann Thorac Surg AFB AND EBUS: A PRACTICAL REVIEW 2005;80: of lung cancer and planning of endobronchial therapies. The EBUS-guided TBNA most likely will become the standard in the near future and some early studies suggest that a combination of EUS and EBUS-guided fine-needle aspirations may eventually be proven to be superior to surgical mediastinal staging [41]. Studies are currently under way to investigate further the role of EUS and EBUS in the staging of patients with lung cancer. The authors suggest that a bronchoscopist interested in becoming facile with AFB and EBUS take a course that has both didactic and hands-on sessions to become familiar with the technology. Additionally, he or she should shadow a practitioner already experienced with these techniques and observe as many cases as possible, as there is no replacement for real-time experience. 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