Fig. 21.4  Comparison of white light, dual red imaging, and narrow band imaging for endobronchial vasculature. Representative image of endobronchial vasculature by white light, dual red imaging, and narrow band imaging at

the bronchial anastomosis of lung cancer surgery. Dual red imaging visualizes the blood vessels in deeper tissue as dark yellow (arrow). (Referenced vessels were shown in NBI by thinner arrow)

DRI during bronchoscopic observation is unclear, and further clinical information would be required (Fig. 21.4).

Endobronchial Ultrasound (EBUS)

Two types of endobronchial ultrasound (EBUS) are currently available for clinical use. The radial probe EBUS rst described in 1992 is used for the evaluation of bronchial wall structure, visualization of detailed images of the surrounding structures for assisting TBNA as well as detection of peripheral intrapulmonary nodules [30]. On the other hand, the convexprobe EBUS rst described in 2004 has a builtin ultrasound probe on a fexible bronchoscope which enables bronchoscopists to perform real-time TBNA of mediastinal and hilar lesions [31].

Pre-malignant lesions or small intrabronchial radiologically invisible tumors are being detected more frequently as a result of new advanced 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. The radial probe EBUS is a sensitive method for detection of alterations of the multi-layer structure of the bronchial wall even in small tumors [32].

Optical Coherence Tomography (OCT)

OCT is an optical imaging method that uses properties of light waves instead of sound waves [33]. OCT can generate high-resolution cross-­sectional images of complex, living tissues in real time. Lam and colleagues investigated the ability of OCT to discern the pathology of lung lesions identi ed by AFB in a group of high-risk smokers and reported that normal or hyperplastic mucosa is characterized by 1 or 2 cell layers above a highly scattering basement membrane and upper submucosa [34]. As the epithelium changes from normal/ hyperplasia to metaplasia, various grades of dysplasia, and CIS, the thickness of the epithelial layer increases. The basement membrane was still intact in CIS but became discontinuous or no longer visible with invasive cancer. Michel and colleagues examined 5 patients with endobronchial masses on chest imaging with OCT [35]. OCT images showed differences between neoplasms and normal bronchial mucosa, and neoplastic lesions displayed irregular, ragged, dark lines between 2 light areas, which had the appearance of a fracture in the subepithelium.

Indications and Contraindications

By the use of its’ high sensitivity for detecting lung cancer as well as preinvasive lesions, third ACCP guideline recommended AFB may be used

as an adjunct modality when available in patients with severe dysplasia or CIS in sputum cytology who have chest imaging studies showing no localizing abnormality. In addition, patients with known severe dysplasia or CIS of central airways should be followed with WLB or AFB, when available [36]. AFB has also been shown to increase detection sensitivity of recurrent or new intraepithelial neoplasias and invasive carcinomas when added to WLB (from 25% for WLB alone to 75% when AFB is used in conjunction with WLB) in postoperative surveillance of patients who underwent curative resection for NSCLC [37]. AFB is also suggested for patients with early lung cancer who will undergo resection for delineation of tumor margins and assessment of synchronous lesions [36]. AFB combined with CT of the thorax in patients with radiographically suspicious and occult lung cancer has shown to be an effective lung cancer staging and tumor extension assessment modality with impact on therapeutic strategy choice [38, 39].

The Lung SEARCH clinical trial of surveillance for the early detection of lung cancer in high-risk group was conducted [40]. The study targeted on 1568 high-risk individuals and the patients who showed abnormal sputum receive annual CT and AFB screening to identify early lung cancer. The results of this trial were opened and published in 2019 [41]. In this study, the sensitivity of sputum-positive individuals who had AFB, sensitivity was 45.5%, and the cumulative false-positive rate was 39.5%. Unfortunately, this study strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the ef - ciency of lung cancer screening [41].

However, before AFB and NBI can be incorporated into lung cancer screening, few issues need to be addressed. First, natural history of the squamous cell carcinoma (SCC) and bronchial dysplasia must be better characterized. SCC represents a third of all lung cancers diagnosed in the United States [1]. It is thought that pathologically, invasive cancer results from a stepwise

process that begins with metaplasia then dysplasia followed by CIS and nally invasive cancer. Previous studies showed development of invasive carcinoma in 40–83% of patients with severely dysplastic lesions [42, 43]. However, animal models and human studies show spontaneous regression of some of the lesions [44, 45]. Breuer et al. documented a 9–32% rate of malignant transformation for all dysplastic lesions in 52 patients followed over an 8-year period. Fifty-­four percent spontaneous regression of all preinvasive lesions as well as non-stepwise transformation with development of invasive carcinoma at sites previously characterized as normal in appearance, has also been described. These ndings suggest that development of SCC may not always follow classic stepwise transformation pattern [45]. Also, population of patients at risk must be clearly identi ed and those with highest risk lesions (most likely to progress to invasive cancer) should be screened. Finally, appropriate therapeutic options and follow-up surveillance schedule must be developed based on evidence in order to decrease overall cancer mortality and recurrence [46]. Unfortunately, the recent data from the Pan-Canadian Lung Cancer Screening Study showed that the additional AFB only found one typical carcinoid tumor and one CIS lesion that were CT occult cancers. They concluded that additional AFB to LDCT in a high lung cancer risk cohort detected too few CT occult cancers (0.15%) to justify its incorporation into a lung cancer screening program [47]. Until all these issues have been addressed, the use of AFB and NBI will be predominantly in the research setting. The incidence of metachronous lung cancer in hilar early lung cancer has been reported to be 10–30% [48]; hence, we need to pay attention to second primary lung cancer after initial treatment. CT follow-up and enhanced bronchoscopy may contribute to detecting the second lung cancer in the early stage and enable treating the lesion by less invasive, respiratory function preservative treatment modality such as photodynamic therapy (Fig. 21.5).

Fig. 21.5  Second lung cancer treated by photodynamic therapy. Representative case of micro-invasive squamous cell carcinoma as second lung cancer arising in the patients with post-pneumonectomy for right lung cancer.

A small nodular shadow was detected in the left B3 bronchus during follow-up. Bronchoscopy showed micro-­ invasive squamous cell carcinoma, and the patient was successfully treated by photodynamic therapy

Description of the Equipment

Needed

Autofuorescence Bronchoscopy (AFB)

Autofuorescence imaging (AFI) (Olympus, Tokyo, Japan) is a currently commercially available AFB system. The AFI system transmitted 3 wavelengths: excitation blue light (395–445 nm, to induce autofuorescence), 550 nm (red refected light), and 610 nm (blue refected light) [49].

Improved discriminatory nature of AFI system results from its ability to integrate three signals: autofuorescence signal with refected green and red-light signals [50]. Composite image displayed depicts normal epithelium as light green, areas of abundant blood fow seen not only in malignant epithelium, but also in areas of chronic benign infammation as dark green and magenta color for malignant tissue due to mixed red/blue refected signals and lack the green autofuorescence signal [51] (Fig. 21.1). AFI demonstrated improved speci city over the LIFE AFB system

(83% vs. 36.6%) but slightly lower sensitivity

(80% vs. 96.7%) in detection of pre-malignant and malignant bronchial lesions [51].

Confocal Laser Endomicroscopy and Endocytoscopy

The confocal laser endomicroscopy (CLE) system is a new in vivo microscopic imaging device allowing the endoscopist to obtain real-time in vivo optical biopsies during ongoing endoscopy. The probe-based confocal laser endomicroscopy system (Cellvizio; Mauna Kea Technologies, Paris, France), which is capable of passage through the accessory channel of a standard endoscope, is available. Thiberville and colleagues observed 27 preinvasive lesions (metaplasia and dysplasia) and 2 invasive lesions and reported some speci c basement membrane alterations within preinvasive lesions [52]. Methylene blue is a potent fuorophore, and its application to the target makes it possible to reproducibly image the epithelial layer of the main bronchi as well as cellular patterns of peripheral solid lung nodules [53]. Wellikoff et al. compared the images obtained by the probe-­based confocal laser endomicroscopy and histological ndings of biopsied malignant specimen in the same area [54]. They found an irregular connective tissue architecture with disorganization and fragmentation as well as mottling or ‘black holes’ that represent nests of cells interrupting the fuorescence of the underlying connective tissue was correlated with a malignant diagnosis [54]. However, whether confocal laser endomicroscopy can discriminate among diseases requires additional studies. Shah et al. examined 25 patients with endobronchial abnormalities by CLE. CLE provides adequate visual information for all patients; however, it was hard to distinguish between dysplasia and carcinoma [55].

The endocytoscopy system (ECS; Olympus Medical System Corp) is another recently introduced, emerging endoscopic imaging technique enabling real-time in vivo diagnosis of cellular patterns at extremely high magni cation [56].

The tip of the instrument contains an optical magnifying lens system and CCD. This endoscope can be inserted through the 4.2-mm biopsy channel and Olympus mother bronchoscope to become an “endocytoscope.” The ECS has a 570-­ fold magni cation and provides an observationeld of 300 × 300 μm, an observation depth of 0–30 μm, and spatial resolution of 4.2 mm for bronchial imaging. Shibuya and colleagues examined 22 patients with endobronchial abnormalities and reported that ECS was useful to discriminate between normal bronchial epithelial cells, dysplastic cells, and malignant cells during ongoing bronchoscopy [13]. Another group used ECS in 4 patients for the immediate in vivo diagnosis of small cell lung cancer during ongoing bronchoscopy [57]. ECS was able to reliably identify numerous small blue cells with hyperchromatic nuclei, which were con rmed in an in vivo diagnosis of small cell lung cancer by corresponding histopathologic diagnosis [57]. Although the utility of ECS was reported, it is technically more dif cult than CLE to obtain an adequate image to evaluate [55].

Raman Spectrophotometry

Use of Raman spectrophotometry system in addition to AFB and WLB may offer improved speci-city (91%) in detection of preinvasive lesions, with only minor compromise in sensitivity (96%) as documented by a recent pilot study [58]. Laser Raman Spectroscopy (LRS), currently used only in experimental setting, involves exposing the tissue to low-power laser light and collecting the scattered light for spectroscopic analyses [59]. This technology collects spectra non-­destructively and light scattered from tissues with different molecular composition can be easily differentiated. Using this technology can potentially reduce the number of false-positive biopsies for detection of preneoplastic lesions. Use of Raman spectra with AFB and WLB can offer a more objective airway mucosal assessment and detect more preneoplastic lesions. Also, Raman may be able to identify biomolecular changes in histologically pre-neoplastic and non-preneoplastic