lesions that could be markers for development into late-stage malignancy. McGregor et al. examined 280 sites including 72 high grade dysplasia/malignant lesions and 208 normal sites in 80 patients using real-time endoscopy Raman spectroscopy system. They could detect high grade dysplasia/malignant lesions with a sensitivity of 90% and speci city of 65% [60]. More studies are needed to assess addition of this technology to armamentarium of tools for endobronchial neoplasia detection.

Application of the Technique

Autofuorescence Imaging

and Optical Coherent Tomography

As previously described, autofuorescence imaging provides biochemical information about tissue by visualizing fuorescent tissue components such as collagen and elastin and OCT provides high resolution detailed information about tissue morphology. By combination of these two modalities, more precise observation of airway structure with emission of autofuorescence could be performed using ex vivo human lung [61]. This novel technology can apply for the peripheral pulmonary lesions and the more precise observation on tumor tissue structure with vasculature information can be provided [62].

Supplemental Technology for Diagnostic Bronchoscopy

For the improvement of diagnostic rate of cytopathological material obtained by diagnostic bronchoscopy, several approaches have been attempted. By adding multitarget fuorescence in situ hybridization to conventional cytological smear, the sensitivity for detecting malignant cells was improved for bronchial brushing and washing specimens [63]. The immunohistochemistry for six protein expression including TP53, Ki67, MCM6, MCM7, KIAA1522, and KIAA0317 for bronchial brushing specimen improved the detection rate of lung cancer with sensitivity of 81.1% for non-small cell lung can-

cer and 83.3% for small cell lung cancer [64]. Recently a bronchial genomic classi er for the diagnostic evaluation of lung cancer has been reported [65]. In this study, epithelial cells were collected from the normal appearing mainstem bronchus in current or former smokers undergoing bronchoscopy for suspected lung cancer. By evaluating 23 gene expressions, the diagnostic yield of bronchoscopy for the detection of lung cancer was improved with high negative predictive value of 91% [65]. These advanced multidirectional analysis technologies will be the powerful support for detecting early lung cancer in combination with diagnostic bronchoscopy [66] (Fig. 21.3).

Evidence-Based Review

Multiple studies demonstrated that AFB improves detection of preinvasive central airway lesions and when combined with WLB also of squamous dysplasia, CIS, and early lung carcinoma. The meta-analysis of 21 studies comparing WLB used with AFB versus WLB alone in diagnosis of intraepithelial neoplasia and invasive lung cancer, involving 3266 patients, reported a pooled relative sensitivity of 2.04 (95% CI 1.72–2.42) on a per-lesion basis in favor of combined AFB and WLB approach [50]. Another meta-analysis showed that the pooled sensitivity of AFI and WLB was 0.89 (95% con dence interval [CI] 0.81–0.94) and 0.67 (95% CI 0.46–0.83) and the pooled speci city of AFI and WLB was 0.64 (95% CI 0.37–0.84) and 0.84 (95% CI 0.74– 0.91), respectively [67]. However, the superiority of AFI in comparison with WLB has been controversial, as documented in pervious individual studies, the sensitivity for detection of CIS and early invasive carcinomas was not superior to WLB alone (the RR of 1.15 at 95% CI 1.05–1.26) [50]. This suggests that while screening for invasive cancer WLB may be suf cient and more cost effective. Recently, a meta-analysis data of autofuorescence imaging video bronchoscopy (AFI) performed with the Evis Lucera Spectrum (Olympus) was published [68] and both sensitivity and speci city of AFI was superior to WLB (sensitivity: AFI of 0.92 (95% CI, 0.88–0.95)

over WLB’s 0.70 (95% CI, 0.58–0.80) with P < 0.01, speci city: AFI of 0.67 (95% CI, 0.51– 0.80) compared with WLB’s 0.78 (95% CI, 0.68– 0.86) with P = 0.056) [68].

AFB can become a useful tool in endobronchial pre-malignant and malignant lesion detection screening, especially in high-risk groups (patients with head and neck cancers, chronic obstructive pulmonary disease [COPD], and smokers) knowing that the incidence of synchronous lesions ranges from 0.7% to 15% and metachronous­ lesions might occur in as many as 5% high risk patients annually [69, 70]. However, more studies are needed to determine how the AFB can best be incorporated into clinical practice in an economically ef cient way and with reasonable reduction in lung cancer mortality.

NBI shows higher sensitivity compared to AFB in detection of metaplastic and moderately dysplastic bronchial mucosal squamous lesions. It has equivalent sensitivity as AFB in detection of early preinvasive malignant lesions (CIS) and invasive cancer (ranging between 90–100% for NBI and 83–89.2% for AFB). However, NBI has a higher than AFB speci city for detection of early lung cancer [71]. The recently published meta-analysis data from eight studies on NBI showed a pooled sensitivity of 0.80 [95% con - dence interval (CI): 0.77–0.83] and a pooled speci city of 0.84 (95% CI: 0.81–0.86) [72].

Combining AFB and NBI increases both the sensitivity (93.7%) and speci city (86.9%) of early lung cancer detection. But the improvement is small as compared to each technique alone. Therefore, combining the two technologies in cancerous and pre-cancerous lesion detection does not have signi cant impact on diagnostic accuracy and may result in unnecessary cost without signi cant clinical bene t. Judging by the results of the studies, NBI can be used alternatively to AFB in cancerous and pre-cancerous lesion screening of the endobronchial epithelium without compromising sensitivity and with signi cantly improvement in speci city [73].

Using NBI and HMB, previous studies have shown angiogenesis and microvascular structure alteration of bronchial dysplastic lesions at sites detected as abnormal autofuorescence [74]. Using NBI combined with high magni cation

bronchovideoscopy, Shibuya et al. showed statistically signi cant increase in capillary blood vessel diameter occurring as tissue progresses from angiogenic squamous dysplasia (ASD) to CIS, microinvasive cancer, and invasive squamous cell carcinoma [75]. Architectural organization of the vessels also differed between the pre-malignant and malignant lesions. Classi cation system was proposed based on vascular appearance of endobronchial lesions of varying invasiveness. It showed high correlation with lesions’ histopathologic features [75, 76]. However, more studies using the classi cation are needed to further validate it.

A comparison between the ultrasound and the histologic ndings in 24 lung cancer cases revealed that the depth diagnosis was the same in 23 lesions (95.8%) [32]. In another study in a series of 15 patients, EBUS showed a high diagnostic yield of 93% for predicting tumor invasion into the tracheo-bronchial wall [77]. EBUS also improves the speci city (from 50% to 90%) for predicting malignancy in small AFB-positive lesions that were negative on white light bronchoscopy [78].

Photodynamic therapy (PDT) is an alternative treatment for selected patients with central type early-stage lung cancer. EBUS was performed to evaluate tumor extent in 18 biopsy-proven early-­ stage squamous cell carcinomas (including three CIS) [79]. Nine lesions were diagnosed as intracartilaginous by EBUS and PDT was subsequently performed. The other nine patients had extracartilaginous tumors unsuspected by computed tomographic scanning and were considered candidates for other therapies such as surgical resection, chemotherapy, and radiotherapy. Using EBUS, 100% complete remission rate was achieved in the endoluminal-treated group.

Summary and Recommendations, Highlight of the Developments During the Last Three Years (2013 on)

Recent advances in the eld of bronchology have allowed bronchoscopists to evaluate the airway with advanced high-resolution imaging

modalities discussed in this chapter (Fig. 21.6) [80]. 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, progressing to invasive cancer. Early detection is key for improved survival. It would be ideal if we can detect and treat preinvasive bronchial lesions de ned as dysplasia and ­carcinoma in situ before progressing to invasive cancer. Bronchoscopic imaging techniques capable of detecting preinvasive lesions currently available in clinical practice including AFB, NBI, HMB, and EBUS were discussed in this chapter.

AFB increases the diagnostic accuracy for squamous dysplasia, carcinoma in situ, and early lung carcinoma when used simultaneously with conventional white light bronchoscopy. However, the speci city of AFB for detecting preinvasive lesions is moderate. AFB displays areas of epithelial thickness and hypervascularity as abnormal fuorescence which suggests a role for neovascularization or increased mucosal microvascular growth in bronchial dysplasia. HMB

enables visualization of these vascular networks. HMB can detect increased vessel growth and complex networks of tortuous vessels of various sizes in the bronchial mucosa. To further evaluate the vascular network in the bronchial mucosa, a new imaging technology NBI was developed and is now commercially available.

AFB and NBI are complimentary for the evaluation of preinvasive bronchial lesions. The strength of AFB is its high sensitivity acting as a monitor to pick up potentially neoplastic lesions. However, the potential limitation is its moderate speci city. NBI on the other hand enhances the mucosal and vascular patterns which is best suited for detailed inspection of the mucosa. A combination of autofuorescence and NBI into a single bronchovideoscope system would decrease the time for the procedure as well as unnecessary biopsies. For a bronchoscopist, AFB, NBI, and HMB are just the same as performing a routine WLB without any complicated procedures necessary. Interpretation of the results seems to be fairly straight forward. The radial probe EBUS is an excellent tool for the evaluation of the airway structure which is use-

ful for the determination of the depth of tumor invasion. Minimally invasive treatment may be suitable for selected patients with central type early-stage lung cancer.

Acknowledgments  TN received honoraria and lecture fees from Olympus Corporation, and KY received unrestricted educational and research grant from Olympus Corporation.

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