Early Diagnosis of Lung Cancer

Kazuhiro Yasufuku, MD, PhD

KEYWORDS
 Lung cancer  Early detection  Autofluorescence bronchoscopy  Endobronchial ultrasound

Division of Thoracic Surgery, Department of Surgery, Toronto General Hospital, University Health Network, University of Toronto, 200 Elizabeth Street, 9N-957, Toronto, Ontario M5G2C4, Canada E-mail address: kazuhiro.yasufuku@uhn.on.ca Clin Chest Med 31 (2010) 3947 doi:10.1016/j.ccm.2009.08.004 0272-5231/10/$ see front matter 2010 Elsevier Inc. All rights reserved.

chestmed.theclinics.com

Early detection and surgical resection is essential for the treatment of lung cancer. Although the introduction of low-dose spiral computed tomography (CT) is considered to be one of the most promising clinical research developments, CT screening is used for detecting small peripheral lesions. However, tumors arising in the central airways require other techniques for early detection. Centrally arising squamous cell carcinoma of the airway, especially in heavy smokers, is thought to develop through multiple stages from squamous metaplasia to dysplasia, followed by carcinoma in situ (CIS), progressing to invasive cancer.1,2 It would be ideal to be able to detect and treat preinvasive bronchial lesions, defined as dysplasia and carcinoma in situ, before they progress to invasive cancer.3,4 Hence, great efforts have been made to develop new bronchoscopic imaging techniques capable of detecting these lesions. Bronchoscopic imaging techniques capable of detecting preinvasive lesions and currently available in clinical practice include autofluorescence bronchoscopy (AFB), high magnification bronchovideoscope, and narrow band imaging (NBI). For a more precise evaluation of newly detected preinvasive lesions, endobronchial ultrasound (EBUS) and optical coherence tomography (OCT) can be used. AFB improves the sensitivity for detection of preinvasive lesions in the central airway35 and increases the diagnostic accuracy for squamous dysplasia, CIS, and early lung carcinoma when used simultaneously with conventional white light bronchoscopy (WLB).516 In addition to single center studies, 3 multicenter and 2 randomized clinical trials have documented the usefulness of

AFB as an adjunct to WLB for detecting intraepithelial neoplasia and CIS.5,1316 However, the specificity of AFB for diagnosing preinvasive lesions is low.13 Distinguishing between preinvasive lesions and other benign epithelial changes such as bronchitis is problematic. To increase the specificity, a new autofluorescence imaging (AFI) bronchovideoscope system has been developed where preinvasive lesions and benign changes may be differentiated by color.17 AFB displays areas of epithelial thickness and hypervascularity as abnormal fluorescence, which suggests a role for neovascularization or increased mucosal microvascular growth in bronchial dysplasia.12,13 To focus on the mucosal microvascular structure, the high magnification bronchovideoscope was developed.18 The high magnification bronchovideoscope is a combination of 2 systems: a video observation system for high magnification observation and a fiber observation system for orientation of the bronchoscope tip. The magnification is 110 times or 4-fold that of a conventional bronchovideoscope. This enables visualization of the vascular networks of the bronchial mucosa.18 High magnification can detect increased vessel growth and complex networks of tortuous vessels of various sizes in the bronchial mucosa.18 Focusing on the visualization of the vascular network in the bronchial mucosa, a new imaging technology, NBI, was developed after high magnification.19,20 NBI is an optical image technology that enhances vessels in the surface mucosa by using the light absorption characteristics of hemoglobin at a specific wavelength. NBI enhances the clinical value of magnification bronchoscopy by

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allowing the visualization of abnormal distribution and dilatation of blood vessels.19,20 This article reviews new bronchoscopic imaging techniques, including AFI, NBI, and EBUS and describes their roles in the early diagnosis and treatment of lung cancer. in the mucosa. With one touch of a button, one can easily switch back and forth between normal images and fluorescence images. Attenuation of autofluorescence is caused by (1) absorption and scattering of light because of hyperplasia of the mucosal epithelium and (2) absorption of light by hemoglobin in the blood. The limitation of conventional AFB was that it displayed inflammatory lesions in the same way as neoplastic lesions, which resulted in low specificity for detection of preinvasive lesions. The new AFI can easily distinguish between neoplastic lesions and normal tissue by changes in color. AFI exploits the characteristics of 2 different wavelengths: (1) autofluorescence (460690 nm) is attenuated when a neoplastic lesion is irradiated with blue excitation light (390440 nm), and (2) components absorbed by the blood are reflected when irradiated with green light (540560 nm). Both types of light are emitted from the AFI-dedicated rotary filter installed in front of the light source bulb. These 2 types of light are captured by the CCD at the distal end of the scope and converted into electrical signals. The barrier filter installed in front of the CCD cuts excessive blue excitation light to detect weak autofluorescence.

AFI VIDEOSCOPE SYSTEM

AFI is a video-endoscopic system that exploits the fact that different wavelengths of light can be used to highlight the distinction between tumorous lesions and normal tissues.17 AFI produces diagnostic images using light that is affected by blood constituents and autofluorescence. The system has a high resolution imaging charge-coupled device (CCD) at the distal end of the bronchovideoscope (BF-F260, Olympus Medical Systems Corp, Tokyo, Japan). By combining autofluorescence and a high resolution bronchovideoscope, subtle differences in mucosal structures that would be difficult to detect in normal observation can be visualized. In addition to fluorescence light observation with high image quality, this system also provides the detailed normal light images required for observation of the vascular structures

Fig. 1. AFI system configuration. AFI exploits the characteristics of 2 different wavelengths: (1) autofluorescence (460690 nm) is attenuated when a neoplastic lesion is irradiated with blue excitation light (390440 nm) , and (2) components absorbed by the blood are reflected when irradiated with green light (540560 nm).

Early Diagnosis of Lung Cancer

In the video processor, the autofluorescence light signal is converted into green data and the green reflected light is converted into red and blue data. The data are then synthesized into the AFI color image data that is displayed on the monitor (Fig. 1). As a result, AFI displays normal areas in light green, areas with abundant blood flow and blood vessels in darker green, and neoplastic lesions in magenta (Fig. 2).

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APPLICATIONS OF AFI
Besides the detection of preinvasive bronchial and malignant lesions, AFI is useful for the confirmation of the extent of tumor invasion in central type lung cancer. This case was referred for abnormal chest radiograph. On the chest CT scan, the left upper lobe bronchus was seen to be completely occluded by the tumor. On bronchoscopic examination, a tumor obstructing the left upper lobe bronchus was seen under white light examination. On the AFI image, the extent of the tumor margins was clearly identified as magenta. Left upper lobectomy, bronchoplasty, and pulmonary artery angioplasty were performed on this patient and the margins had negative results for malignancy (Fig. 4).

REPRESENTATIVE CASES OF AFI

Representative cases of bronchitis, squamous dysplasia, and squamous cell carcinoma are shown. Arrows indicate abnormal areas of bronchial epithelium. Fig. 3A shows a case of bronchitis affecting the bifurcation of the right B4 and 5. Lung imaging fluorescence endoscopy (LIFE) demonstrated abnormal autofluorescence and the AFI image was green. Fig. 3B shows a case of squamous dysplasia at the bifurcation of the left B3a and B3bc. Although WLB demonstrated normal bifurcation, LIFE demonstrated abnormal autofluorescence, and the AFI image was magenta. Fig. 3C shows a case of squamous cell carcinoma. Irregular mucosa and protruding nodules are identified at the bifurcation of the right middle and lower lobe bronchi by WLB, LIFE, and AFI. The AFI image clearly is magenta at the abnormal area.

COMPARISON OF WLB, LIFE, AND AFI

The first prospective study on the effectiveness of AFI in the evaluation of preinvasive lesions and inflammation was based on the hypothesis that color analyses of the different wave lengths would improve the ability to differentiate between inflammation and preinvasive lesions.17 To prove this hypothesis, a total of 32 patients with suspected or known lung cancer were entered into this study. Conventional WLB and LIFE were performed before using AFI.

Fig. 2. AFI findings and color distribution. AFI displays normal areas in light green, areas with abundant blood flow and blood vessels in darker green, and neoplastic lesions in magenta.

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Fig. 3. Images of WLB, lung imaging fluorescence endoscopy (LIFE), and AFI. Representative cases of (A) bronchitis, (B) squamous dysplasia, and (C) squamous cell carcinoma.

WLB and LIFE detected 62 lesions, including lung cancers (n 5 2), squamous dysplasias (n 5 30), and bronchitis (n 5 30). By using AFI, 24 dysplasias and 2 cancer lesions were displayed in magenta and 25 bronchitis lesions, blue. The sensitivities of detecting dysplasia by LIFE and AFI were 96.7% and 80%, respectively. The specificity of AFI (83.3%) was significantly higher than that of LIFE (36.6%) (P 5 .0005). The conclusion of this prospective study was that AFI seems to represent a significant advance in distinguishing preinvasive and malignant lesions from bronchitis

or hyperplasia under circumstances where LIFE would identify all these as abnormal lesions.

NBI
NBI is an optical image enhancement technology that enhances vessels in the surface mucosa by using the light absorption characteristic of hemoglobin at a specific wavelength (BF-6C260, Olympus Medical Systems Corp, Tokyo, Japan). In a normal WLB observation, an endoscopic light source radiates wide spectrum light to ensure that

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Fig. 4. Images of WLB and AFI in invasive lung cancer. WLB and AFI images of a tumor occluding the left upper lobe bronchus.

the colors in the reproduced images of the mucosal tissues look as natural as possible. However, this eliminates the contrast generated by blood vessels in the submucosa. NBI, in contrast, uses narrow spectrum light (narrow band light) specifically suited to the optical characteristics of mucosal tissues and hemoglobin in blood. This results in the improvement of contrast of the image relevant to diagnosis and delivers images with excellent visualization capability. NBI enhances the clinical value of magnification bronchoscopy by allowing the visualization of

abnormal distribution and dilatation of blood vessels (Fig. 5). By optimizing the light wavelength at 415 nm (blue light) and 540 nm (green light) and keeping the spectral width narrow (narrow band), NBI enhances the contrast to ensure that blood vessels in the mucosa stand out clearly (see Fig. 5). The 415 nm blue light is absorbed by capillary vessels in the surface layer of the mucosa, whereas the 540 nm is strongly absorbed by blood vessels located below the capillary vessels in the surface layer of the mucosa. Finer blood vessels near the surface are

Fig. 5. Hemoglobin absorption characteristics. The peak of wavelength of hemoglobin O2 absorption is the same as the peak of the NBI blue filter (415 nm). NBI enhances the contrast to ensure that blood vessels in the mucosa stand out clearly.

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Fig. 6. Normal mucosa. Finer blood vessels near the surface are displayed in brown, whereas thicker vessels in deeper layers are displayed in cyan.

displayed in brown, whereas thicker vessels in deeper layers are shown in cyan (Fig. 6).

NBI FINDINGS
Various types of vascular networks can be visualized in the bronchial membrane using NBI. Because centrally arising squamous cell carcinoma is thought to develop through multiple stages from squamous metaplasia to dysplasia and CIS, detection of these lesions is important. In addition, differential diagnosis of these lesions without the need for biopsies would be ideal. NBI images may have potential for these purposes. As shown in Fig. 7, complex networks of tortuous vessels appear in squamous dysplasia. In angiogenic squamous dysplasia, dotted vessels along with the tortuous vessels become evident. When preinvasive lesions develop into squamous cell carcinoma, scattered dotted vessels and capillary loops of tortuous vessels of various sizes are seen (Figs. 8 and 9).

NBI FOR DETECTION OF PRECANCEROUS LESIONS

In lung cancer, promising results have been shown for the detection of malignant precursors

and early cancers using the new NBI system.20 The first report was on the efficacy of high magnification bronchovideoscopy combined with NBI for the detection of capillary blood vessels in angiogenic squamous dysplasia (ASD). In 48 patients with sputum cytology specimens suspicious or positive for malignancy, conventional white light and fluorescence bronchoscopy was first performed, followed by observations of abnormal fluorescence with high magnification NBI. The microvessels, vascular networks of various grades, and dotted vessels in ASD tissues were observed in NBI-B1 images. The diameters of the dotted vessels visible on NBI-B1 images corresponded with diameters of ASD capillary blood vessels diagnosed by pathologic examination. Capillary blood vessels were also clearly visualized by green fluorescence using confocal laser scanning microscopy. There was a significant association between the frequency of dotted vessels by NBI-B1 imaging and tissues confirmed as ASD pathologically (P 5 .002). This study showed the possibility of distinguishing between ASD and other preinvasive bronchial lesions. Although there are growing numbers of reports on the effectiveness of NBI for detailed observation of the superficial mucosal and vascular patterns in

Fig. 7. Squamous dysplasia. Complex networks of tortuous vessels are clearly identified by NBI.

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Fig. 8. CIS. Dotted vessels and tortuous vessels are clearly identified by NBI.

the gastrointestinal tract,2125 there are only a few studies on NBI in the evaluation of the airway. The high potential for NBI in the detection of preinvasive lesions in the tracheobronchial tree raises the importance of a single internationally accepted classification of the mucosal and vascular patterns by NBI. The author and fellow investigators have created their own classification of the different mucosal and vascular patterns, and preliminary data show a high correlation with histologic features.26

For optimal imaging, the miniaturized 20 MHz radial probes (UM-BS20-26R, Olympus Medical Systems) are fitted with a catheter that carries a water-inflatable balloon at the tip. The balloon optimizes the contact between the probe and the bronchial wall and allows visualization of detailed images of the surrounding structures and the bronchial wall structure.28,29 The structure of the cartilaginous portion of the central bronchial wall has been described as a 5- or 7-layer structure by different investigators.28,29 This enables the evaluation of tumor infiltration into the airway.

EBUS
Two types of EBUS are currently available for clinical use. The radial probe EBUS was first described in 199227 and is used for the evaluation of the bronchial wall structure,28,29 visualization of detailed images of the surrounding structures for assisting transbronchial needle aspiration (TBNA),30,31 and detection of peripheral intrapulmonary nodules.32,33 In contrast, the convexprobe EBUS, first described in 2004, has a built-in ultrasound probe on a flexible bronchoscope that enables bronchoscopists to perform real-time TBNA of mediastinal and hilar lesions.3436

EBUS IN EARLY LUNG CANCER

Premalignant lesions or small intrabronchial radiologically invisible tumors are being detected more frequently because of evolving mucosal imaging technologies. The decision to use endoscopic therapeutic intervention depends on the extent of tumor within the different layers of the bronchial wall. Conventional radiological imaging alone is not capable of distinguishing the tumor extent. In contrast, the radial probe EBUS is a sensitive method for detection of alterations of the multilayered structure of the bronchial wall, even in small

Fig. 9. Squamous cell carcinoma (invasive). Capillary loops of tortuous vessels of various sizes are identified by NBI.

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tumors. After performing a needle-puncture experiment in 45 normal tissue specimens, a comparison between the ultrasonograms and the histologic findings in 24 lung cancer cases revealed that the depth diagnosis was the same in 23 lesions (95.8%).28 Another study in a series of 15 patients showed a high diagnostic yield of 93% for predicting tumor invasion into the tracheobronchial wall.37 EBUS also improves the specificity (from 50% to 90%) for predicting malignancy in small AFpositive lesions that were negative in white light bronchoscopy.38 Other than surgical resection, photodynamic therapy (PDT) is an alternative treatment for selected patients with early-stage lung cancer. In 18 biopsy-proven early-stage squamous cell carcinomas, including 3 CIS, EBUS was performed to evaluate tumor extent.39 Nine lesions were diagnosed as intracartilaginous by EBUS, and PDT was subsequently performed. The other 9 patients had extracartilaginous tumors undetected by CT scanning; they were considered candidates for other therapies, such as surgical resection, chemotherapy, and radiotherapy, although 2 were invisible to high-resolution CT, 3 were superficial, and 5 were less than 1 cm in diameter. Using EBUS, 100% complete remission rate was achieved in the endoluminal-treated group. At a mean followup of 32 months, none of the patients had recurrence.

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SUMMARY
The attraction of the AFI and NBI bronchovideoscope is easy handling, requiring only a single touch of a button. For a bronchoscopist, it is just the same as performing a routine WLB without any complicated procedures necessary. Interpretation of the results seems to be fairly straightforward. AFB and NBI are complimentary. The high sensitivity of autofluorescence is its strength, allowing it to pick up potentially neoplastic lesions, whereas its moderate specificity is a potential limitation. On the other hand, NBI enhances the mucosal and vascular patterns, which is best suited for detailed inspection of the mucosa. In the future, a combination of autofluorescence and NBI into a single bronchovideoscope system would decrease the time for the procedure and the number of unnecessary biopsies. EBUS is an excellent tool for the evaluation of the airway structure, which is useful for the determination of the depth of tumor invasion. Minimally invasive treatment may be suitable for selected patients with early-stage lung cancer.

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