Mucosal imaging advanced technologies in the gastrointestinal tract

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Mucosal imaging advanced Technologies in the gastrointestinal tract Cadman L. Leggett MD, Prasad G. Iyer MD MSc

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S1096-2883(16)00002-4 http://dx.doi.org/10.1016/j.tgie.2016.01.001 YTGIE50469

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Techniques in Gastrointestinal Endoscopy

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Cite this article as: Cadman L. Leggett MD, Prasad G. Iyer MD MSc, Mucosal imaging advanced Technologies in the gastrointestinal tract, Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j.tgie.2016.01.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

TITLE: Mucosal Imaging Advanced Technologies in the Gastrointestinal Tract

AUTHORS: Cadman L. Leggett MD, Prasad G. Iyer MD MSc

AFFILIATION: Division of Gastroenterology and Hepatology, Mayo Clinic Rochester Minnesota

CORRESPONDING AUTHOR: Prasad G. Iyer, MD MSc, Associate Professor Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905 E-mail: [email protected] Tel: 5072556930 Fax: 5072557612

ABSTRACT: The use of advanced imaging technologies to image the gastrointestinal mucosa has evolved from being an experimental tool to a valuable adjunct in diagnostic and therapeutic endoscopy. Digital chromoendoscopy including narrow band imaging (NBI) has been incorporated into standard endoscopy systems as a practical instrument used to enhance the mucosal surface and microvasculature. NBI is now routinely used to evaluate mucosal irregularities associated with Barrett’s esophagus dysplasia. A recent review of the literature suggests that NBI can be used to evaluate colorectal polyps and its use may even change our clinical management of diminutive polyps. Other technologies, such as confocal laser endomicroscopy (CLE) and optical coherence tomography (OCT) require independent imaging systems with probes that can be deployed through an endoscope’s instrument channel. The incorporation of these technologies into clinical practice has been limited by cost and need for expertise in image interpretation. High-magnification imaging with CLE can evaluate mucosal changes that are both sensitive and specific to various disease processes. CLE probes have a small field of view, which makes evaluation of large areas of the gastrointestinal tract time consuming. A second generation OCT system also known as volumetric laser endomicroscopy (VLE) is capable of wide-field crosssectional imaging of the human esophagus. New technologies, including second-generation digital chromoendoscopy blue-laser imaging are currently under study. Development and utilization of advanced imaging technologies has been critical in the rapid pace of advances in diagnostic and therapeutic endoscopy in the past decade.

KEYWORDS: Narrow band imaging, Flexible Spectral Imaging Color Enhancement (FICE), i-scan, confocal laser endomicroscopy, optical coherence tomography, volumetric laser endomicroscopy ABBREVIATIONS:  wavelength BE: Barrett’s esophagus CLE: Confocal laser endomicroscopy eCLE: endoscope-based confocal laser endomicroscopy NBI: Narrow band imaging NICE: NBI International Colorectal Endoscopic NPV: Negative predictive value OCT: optical coherence tomography pCLE: probe-based confocal laser endomicroscopy PIVI: Preservation and Incorporation of Valuable Endoscopic Innovations VLE: Volumetric laser endomicroscopy 1. INTRODUCTION: Diagnostic imaging of the gastrointestinal tract with white light endoscopy is limited to the mucosal surface. Advanced imaging technologies are valuable endoscopic tools that enhance our ability to examine the mucosa either focally or in a wide field fashion. Several of these technologies are now commercially available. Digital chromoendoscopy is useful when examining alternations in mucosal microvasculature and mucosal patterns that may provide insight into the presence of dysplasia or early neoplasia. The optical magnification of confocal laser endomicroscopy (CLE) is comparable to histology and allows direct observation of disease processes at a cellular level. Optical coherence tomography (OCT) is a high-resolution imaging technology useful in defining microscopic changes in the mucosa and submucosa. In this review, we provide an overview of the technical aspects of these technologies and their clinical application in gastrointestinal disease.

2.0 DIGITAL CHROMOENDOSCOPY Traditional dye-based chromoendoscopy uses stains that are either absorbed by epithelial cells or help highlight the mucosal surface. In contrast, digital chromoendoscopy uses optical bandpass filters or imaging processing algorithms to generate images that highlight salient mucosal features. One of the advantages of digital chromoendoscopy over dye based chromoendoscopy is that the user can toggle between high-definition white light endoscopy and chromoendoscopy using an assigned endoscopic button. It is also more user-friendly without the need for spraying and suctioning dyes from the mucosa. 2.1 NARROW BAND IMAGING Narrow band imaging (NBI) (Olympus Medical Systems, Japan) is the most commonly used digital chromoendoscopy system in Western countries. NBI employs optical principles of absorption to highlight mucosal vasculature and surface mucosal detail. The peak absorption of hemoglobin occurs at wavelengths () of 440-460 nm (blue) and 540-560 nm (green). Filtering or narrowing the light spectrum to these wavelengths ( 415 nm and 540 nm) makes blood vessels appear dark compared to the surrounding mucosa. The highlighted vasculature is useful in delineating subtle mucosal irregularities. The Evis Exera III (Olympus Medical Systems, Japan) is the latest generation of endoscopes with an NBI platform that allows image acquisition without compromising brightness by providing additional illumination. It also provides a “near field focus” feature which allows better definition of the mucosal and vascular pattern at shorter focus lengths. 2.2 FLEXIBLE SPECTRAL IMAGING COLOR ENHACEMENT and iSCAN The Flexible Spectral Imaging Color Enhancement (FICE) (Fujinon Inc, Japan) system and iSCAN systems (Pentax, Japan) use the entire spectrum of white light during image capture and perform image processing through various digital software algorithms that enhance visualization of the mucosal surface. In contrast to NBI, these systems do not employ optical filters.

3.0 CONFOCAL LASER ENDOMICROSCOPY Confocal laser endomicroscopy (CLE) uses a laser source ( 488 nm) that passes through a pinhole aperture and is focused at a point of interest. Reflected light from this point is focused on a second pinhole aperture positioned in front of a photodetector. This setup allows for high-resolution imaging of a discrete point by rejecting light that is out of focus. (Figure 1) A grayscale image is generated by scanning the focused beam at various planes within the tissue. CLE can achieve a magnification of a 1000-fold with axial and lateral resolutions in the micrometer range. CLE systems are either endoscope-based (eCLE, Pentax Medical Corporation, Tokyo, Japan) or probebased (pCLE, Mauna Kea Technologies, Paris, France). The eCLE system is a standard-definition white light endoscope with a confocal imaging aperture and instrument channel. Endomicroscopy images are acquired by placing the imaging aperture directly in contact with the mucosa of the gastrointestinal tract. The endoscopic field of view is 475 by 475 μm. Imaging depth can be varied from surface to 250 μm deep. Image resolution is dependent on acquisition rate and can be changed from 1.6 images/sec (1024 × 512 pixels) to 0.8 images/sec (1024 × 1024 pixels). This system is unfortunately not clinically available anymore. The pCLE system uses endomicroscopy mini-probes that can be inserted through the working channel of a standard endoscope. This system and its processor are separate from the endoscopic imaging system. Images are acquired by placing the probe in contact with the mucosa of the gastrointestinal tract following injection of intravenous fluorescein to provide intravascular contrast. A rapid image acquisition rate at 12 images/sec generates videos of the mucosa. Under the mosaic function, acquired images are constructed together and can expand the field of view. The lateral resolution and field of view vary depending on the mini-probe used with higher resolution probes having narrower fields of view.

3.1 CONTRAST AGENTS Confocal laser endomicroscopy requires the use of a fluorescent contrast agent to enhance visualization of cells. Contrast agents can be administered intravenously or topically. Intravenous fluorescein sodium is the most widely used contrast agent in endomicroscopy. CLE can be performed shortly following injection of fluorescein (2.5 to 5.0 mL) with its fluorescence lasting approximately 30 min. Fluorescein highlights mucosal capillaries as well as the extracellular space and lamina propria but does not penetrate the nucleus. Intravenous fluorescein has been shown to be safe with minimal adverse effects. (1) The topical agent acriflavine hydrochloride can be used independently or in conjunction with fluorescein to highlight the cell nucleus. The use of acriflavine has fallen out of favor, however, over the concern with its carcinogenic potential. Another topical agent, cresyl violet is a cytoplasmic stain used to outline the nucleus. Both acriflavine and cresyl violet are limited in terms of depth of penetration of the mucosa. 4.0 OPTICAL COHERENCE TOMOGRAPHY Optical coherence tomography (OCT) is analogous in many ways to endoscopic ultrasonography which measures the physical properties of tissue using ultrasonic echo. OCT uses infrared light ( 750-1300 nm) rather than sound waves and measures reflected or backscattered light. The high velocity of light compared to sound however, does not allow direct electronic measurement of reflected light. To do so, an interferometer is employed to compare the phase difference of two light paths or ‘arms’: a sample arm (tissue) and a reference arm (mirror). Light reflected from the tissue specimen is combined with light that has traveled a known distance through the reference arm and focused onto a photodetector.

The combined light waves generate an

interference profile. (Figure 2) In time-domain OCT, the reference mirror is scanned across a range of positions that match different depths in the sample tissue. Image acquisition speed is therefore dependent on the scanning speed of the reference mirror. Fourier domain OCT refers to second generation OCT imaging that measures the interference

signal as a function of wavelength and therefore does not require a scanning reference mirror. This approach improves detection sensitivity and allows for faster image acquisition speed. Various types of OCT probes have been designed to image the gastrointestinal tract and differ from each other in their scanning depth, resolution, speed of image acquisition and scanning method (radial vs linear). The most recent commercially available OCT system is the Nvision Volumetric Laser Endomicroscopy (VLE) Imaging System (Nine Point Medical, MA) which consists of a console, monitor and optical probe. The Nvision VLE system was designed for imaging of the esophagus. Its optical probe is centered by a balloon (diameter: 14 mm, 17 mm, 20 mm; length: 6 cm) that is deployed through a gastroscope instrument channel (2.8 mm or larger). Imaging is performed by automatic helical pullback of the probe from the distal to the proximal end of the balloon over 90 seconds. VLE images have an axial resolution of 7 µm, a transverse resolution of ~ 30 µm, and can reach an imaging depth of up to 2-3 mm. A total of 1200 cross-sectional images are acquired over a 6 cm VLE scan. VLE scans are viewed using a software interface that allows simultaneous examination of cross-sectional transverse and longitudinal views. 5.0 ADVANCED IMAGING IN BARRETT’S ESOPHAGUS Detection of dysplasia in Barrett’s esophagus (BE) is important in the management of this pre-malignant condition. Current random biopsy protocols are limited by sampling error given that dysplasia is not distributed uniformly throughout the BE segment.(2) Advanced imaging technologies allow for real-time evaluation of the esophageal mucosa to enhance detection of BE dysplasia. 5.1 DIGITAL CHROMOENDOSCOPY The mucosal and vascular patterns observed with narrow band imaging are useful to predict the presence of dysplasia associated with BE. (Figure 3) Although several classification systems have been proposed to describe NBI features in BE related dysplasia, there currently is no consensus on the clinical use of particular criteria. (3-5) Multiple studies have evaluated NBI in combination with magnified endoscopy, a technology that is not widely available in the United States. A meta-analysis of eight studies (466 patients, 2194 lesions) reported

a pooled sensitivity of 96% and specificity of 94% when using NBI with magnification for diagnosing BE with highgrade dysplasia. (6) A randomized controlled study that compared the diagnostic yield of standard white light endoscopy and NBI showed that NBI directed biopsies detected dysplasia in more patients compared to biopsies taken using standard endoscopy (57% vs 43%).(7) A recent prospective, international randomized controlled trial compared the diagnostic yield of high-definition white light endoscopy/standard surveillance biopsy protocol and NBI targeted biopsies for intestinal metaplasia and dysplasia. Both NBI and high-definition white light endoscopy were found to detect 92% of patients with intestinal metaplasia, but NBI required fewer biopsies per patient (3.6 vs 7.5, p<0.001). (8) The diagnostic yield of NBI for high-grade dysplasia was found to be significantly higher than with high-definition white light endoscopy (30% vs 21%, p=0.01). The versatility and low-cost of NBI has made it an important adjunctive tool to high-definition white light endoscopy in the assessment of BE. 5.2 CONFOCAL LASER ENDOMICROSCOPY The confocal Barrett’s classification system, also known as the Mainz criteria was designed and validated for use with eCLE and demonstrated a sensitivity and specificity of 98% and 94% for BE and 93% and 98% for BEassociated dysplasia, respectively in predicting in vivo histology. (9) A prospective randomized double-blinded crossover trial compared the diagnostic efficiency of eCLE with targeted biopsies to a standard endoscopy biopsy acquisition protocol. (10) eCLE with targeted biopsies improved the diagnostic yield for high-grade dysplasia compared to random biopsies (33.7% versus 17.2%, p=0.01) and lowered the mean number of acquired mucosal biopsy specimens (9.8 versus 23.7). A more recent study that compared high-definition white-light endoscopy with random biopsies to endoscopy plus eCLE with targeted biopsies showed that the use of eCLE can help guide in vivo decision making and alter endoscopic outcomes.(11) In this study, the combination of high-definition white light endoscopy and eCLE increased the diagnostic yield for neoplasia (22% versus 6%; p=0.002) and significantly lowered the number of required biopsies. The application of the Mainz criteria to pCLE had technical differences which lead to the development of a pCLE-specific classification system, also known as the Miami criteria.(12) (Figure 4) The sensitivity and

specificity for the detection of dysplasia using these criteria was 88% and 96% respectively. In vivo detection of dysplasia using pCLE was evaluated in a multicenter non-inferiority study that interpreted pCLE recordings during endoscopy with a follow-up of 3 months post-procedurally.(13) A total of 670 pCLE videos were compared to matching biopsy histopathology. In vivo evaluation of dysplasia yielded a specificity of 95% and sensitivity of 12% with a negative predictive value of 92% and positive predictive value of 18%. Post-procedure evaluation showed slightly higher specificity (97%) and sensitivity (28%) with a negative predictive value of 93% and positive predictive value of 46%. The authors concluded that pCLE was non-inferior to standard biopsy surveillance but recommended against completely replacing standard biopsy acquisition with endomicroscopy imaging. A subsequent multicenter international randomized controlled trial (DON’T BIOPCE) compared highdefinition endoscopy, narrow band imaging and pCLE to matching biopsy histopathology.(14) The specificity and sensitivity for the detection of high-grade dysplasia using high-definition endoscopy alone was 34% and 93% respectively, compared to 68% and 88% in combination with pCLE. The authors concluded that pCLE led to significant improvement in the detection of neoplasia but recognize that the study was conducted by gastroenterologists with previous experience in endomicroscopy. 5.3 OPTICAL COHERENCE TOMOGRAPHY Optical coherence tomography can distinguish between Barrett’s esophagus, gastric cardia and squamous epithelium at the gastroesophageal junction with 85% sensitivity, 95% specificity and high interobserver agreement. (15, 16) OCT can also be used to assess epithelial surface maturation and glandular architecture in Barrett’s esophagus. These features have been applied to a four point scoring index for differentiating intramucosal adenocarcinoma and high-grade dysplasia from low-grade dysplasia and nondysplastic Barrett’s esophagus.(17) A score of greater than or equal to 2 has been associated with 83% sensitivity and 75% specificity in the detection of Barrett’s associated neoplasia with OCT. (17)(Table 1) The use of these criteria with VLE showed decreased diagnostic performance at the same dysplasia score threshold. (18)

The optimal diagnostic performance was found to be a score of ≥3 which was associated with 70% sensitivity, 60% specificity and 67% diagnostic accuracy compared to other scores. The increased dysplasia score threshold required for VLE was attributed to the fact that the diagnostic criteria were developed using a first generation form of OCT that is different from VLE, which uses second-generation OCT technology and a balloon catheter. Furthermore, compared with OCT used in prior studies in which single, ~5 mm wide images were used for diagnosis, image interpretation using VLE is performed over a much wider field of view (6 cm, 1200 frames) that may have frame-to-frame variation in surface signal intensity. A recent study has introduced modified criteria for use with VLE that take into the account wide field imaging capabilities of second-generation OCT optics. (18) (Figure 5) These criteria contain specific VLE features associated with neoplasia including lack of mucosal layering, increased surface signal intensity and quantification of atypical glandular structures. Ex-vivo validation of these criteria showed a sensitivity of 86%, specificity of 88% and diagnostic accuracy of 87% in the diagnosis of BE associated dysplasia. Reports of subsquamous esophageal adenocarcinoma that arises after mucosal ablation have given rise to concern for the neoplastic potential of buried intestinal metaplasia. (19, 20) The cross-sectional imaging capability of OCT allows closer examination of the esophageal submucosa and several studies have used OCT to detect buried glands under neosquamous epithelium following radiofrequency ablation. A study that used a three-dimensional OCT probe to evaluate for buried glands at the esophagogastric junction in patients undergoing radiofrequency ablation showed the presence of glands in 72% of patients before achieving complete eradication of intestinal metaplasia and in 63% of patients after complete response. (21) A limitation of this study was the lack of histological confirmation of the submucosal structures observed. A more recent study using VLE, detected submucosal glandular structures in 76% of post-radiofrequency ablation patients that reached complete eradication of intestinal metaplasia.(22) These structures were targeted with endoscopic mucosal resection and found to correspond to normal histological structures (dilated glands and blood vessels) in 92% of cases. Only a single endoscopic mucosal resection specimen contained evidence of buried glands.

6.0 ADVANCED IMAGING IN GASTRIC NEOPLASIA Early gastric cancer may present as a subtle mucosal lesion that is challenging to identify with conventional endoscopy. Accurate characterization and delineation of gastric lesions with advanced imaging technologies could help guide treatment decisions. 6.1 DIGITAL CHROMOENDOSCOPY Several classification systems have been proposed to differentiate between intestinal metaplasia, gastritis and early gastric neoplasia. Initial studies used NBI with high magnification (up to 80x) to characterize the microvascular and microsurface patterns of early gastric cancer. (23) A recent systematic review of 31 studies (347 patients) reported a pooled sensitivity of 86% and specificity of 77% for the diagnosis of intestinal metaplasia and a sensitivity of 90% and specificity of 83% for diagnosing dysplasia using NBI. (24) A total of 28 studies, were performed with high-magnification NBI which limits the applicability of this data to Western countries who use NBI without magnification. The systematic review also included 7 studies that used FICE to characterize neoplastic gastric lesions but due to significant heterogeneity among studies aggregate data was not able to be provided for this imaging modality. A study that evaluated the diagnostic performance of FICE for diagnosis of intestinal metaplasia reported an overall sensitivity of 60% and specificity of 87%.(25) A multicenter prospective study was performed to assess the reliability of previously published NBI features used to describe gastric preneoplastic and neoplastic lesions and to consolidate these features into a simplified classification scheme. (26) The study used NBI without magnification and describes three mucosal patterns: (A) regular vessels with circular mucosa, associated with normal histology (accuracy 83%); (B) tubulovillous mucosa, associated with intestinal metaplasia (accuracy 84%); (C) irregular vessels and mucosa, associated with dysplasia (accuracy 95%).

6.2 CONFOCAL LASER ENDOMICROSCOPY Confocal laser endomicroscopy features of glandular, cellular and microvascular architecture are used to distinguish normal gastric mucosa from intestinal metaplasia, intraepithelial neoplasia and gastric cancer. (27) (Figure 6) A large single-center prospective study that enrolled 1786 patients with suspected or established early gastric cancer showed that real-time eCLE had significantly higher diagnostic performance compared to standard white light endoscopy for detection of superficial gastric cancers/high-grade intraepithelial neoplasia (sensitivity 88.9% vs 72.2%, specificity 99.3% vs 94.1%, diagnostic accuracy 98.8% vs 94.1%; p<0.05).(27) A subsequent prospective double-blind randomized study comparing CLE targeted biopsies and a white-light endoscopy surveillance protocol, showed a significantly higher diagnostic yield for CLE targeted biopsies in the diagnosis of intestinal metaplasia (65.7% vs 15.7%, p<0.001). (28) The use of CLE to predict incomplete resection following endoscopic mucosal resection was studied in 24 patients who underwent CLE assessment two weeks following endoscopic resection of early gastric neoplasia.(29) A total of 5 (20.8%) lesions were incompletely resected based on final pathologic diagnosis. The accuracy of CLE in predicting incomplete resection was found to be 91.7% with a sensitivity and specificity of 100% and 89.5% respectively. 6.3 OPTICAL COHERENCE TOMOGRAPHY The application of OCT to the stomach is limited by the high reflectivity of glandular epithelium that restricts imaging of deeper layers. OCT images of the stomach are characterized by lack of contrast, a high reflective surface, vertical crypt and pit architecture and broad, regular gland architecture. (30) There are currently no published studies on the use of OCT in the management of gastric neoplasia. 7.0 ADVANCED IMAGING IN COLORECTAL NEOPLASIA Current guidelines recommend endoscopic resection and histological review of all polyps identified with colonoscopy, including diminutive polyps (≤5 mm) that rarely contain histologically advanced features.(31) This strategy may not be cost effective compared to a “diagnose-and-leave” or “resect-and-discard” strategy. The

American Society of Gastrointestinal Endoscopy published a Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) guideline for real-time endoscopic assessment of the histology of diminutive colorectal polyps. (32) It was determined that for a technology to guide the decision to leave rectosigmoid diminutive polyps in place that the negative predictive value (NPV) for adenomatous histology should be ≥90%. For a polyp to be resected and discarded the technology should provide ≥90% agreement in the postpolypectomy surveillance interval compared to the surveillance interval established by pathology assessment. 7.1 DIGITAL CHROMOENDOSCOPY Earlier studies using first generation NBI platforms showed no statistically significant difference in the overall adenoma detection rate compared to standard colonoscopy. (33) However, improved image acquisition using second generation NBI has proven superior to high-definition colonoscopy in differentiating nonneoplastic from neoplastic lesions. (34-36) Subsequently, the NBI International Colorectal Endoscopic (NICE) classification was developed and validated for diagnosis of colorectal polyps. (37) The NICE classification is divided into two categories: Type 1 (hyperplastic polyp) and Type2 (adenomatous polyp) based on NBI features of polyp color and vessel surface pattern. (Figure 7) A limitation of the NICE classification is that it is unable to distinguish between sessile serrated adenomas and hyperplastic polyps. The optical difference between these two polyp types however, may not be feasible without the use of high-magnification colonoscopy. A recent systematic review and meta-analysis of 28 studies (6280 polyps) on the real-time diagnostic performance of NBI colonoscopy showed a pooled sensitivity of 91% and specificity of 82.6% in detecting adenomatous polyps. (38) This was followed by a systematic review and meta-analysis by the American Society of Gastrointestinal Endoscopy on the diagnostic performance of digital chromoendoscopy in predicting adenomatous histology of small/diminutive (≤5 mm) colorectal polyps. (39) Data was analyzed independently for studies that used NBI (N= 20, 4013), FICE (N=8, 1243 polyps) and i-scan (N=8, 979 polyps) and compared to the previously established PIVI thresholds. The pooled NPV of NBI for adenomatous polyp histology was found to be 91%. This finding was associated with a high degree of heterogeneity with subgroup analysis showing that

only NBI experts met the established PIVI threshold (pooled NPV of experts of 93%). The NPV was also higher (95%) when the diagnosis was established with high confidence, even among novice users (90%). The pooled NPV of FICE and i-scan for adenomatous polyp histology was 80% and 84% respectively. The American Society of Gastrointestinal Endoscopy systematic review and meta-analysis concluded that NBI met the established PIVI thresholds for both a “diagnose-and-leave” strategy for diminutive rectosigmoid polyps and a “resect-and-discard” strategy for colorectal adenomas ≤5mm in size. Expertise in the interpretation of NBI features however is essential to be able to reach the proposed thresholds and further underscores the need for training endoscopists in advanced imaging technologies. 7.2 CONFOCAL LASER ENDOMICROSCOPY Confocal laser endomicroscopy provides histological level detail of colorectal polyps including information on mucosal, cellular and microvascular architecture. Criteria for differentiating hyperplastic from adenomatous polyps and colorectal cancer has been developed using both eCLE and pCLE. (9, 12) The use of real-time CLE in the assessment of colorectal polyps has been evaluated in a handful of published studies with reported sensitivity ranging from 71% to 100% and specificity ranging from 83% to 95.9% for the detection of adenomas. (40-44) Variability among study design and outcomes limits the applicability of these data to routine clinical practice. 7.3 OPTICAL COHERENCE TOMOGRAPHY There are few descriptive studies on the use of OCT for the evaluation of colorectal polyps. Hyperplastic polyps are described as having an organized crypt pattern and scattering intensity similar to normal colonic mucosa. (45) In contrast, adenomatous polyps demonstrate an absence of an organized crypt pattern and a decrease in scattering intensity compared to normal colonic mucosa. This observation was later confirmed in a study that measured the scattering coefficient of adenomatous polyps and found it to be between the values obtained for normal and malignant tissues. (46) The use of OCT as a realtime diagnostic tool for colorectal polyps requires further evaluation and in-vivo validation.

8.0 ADVANCED IMAGING IN INFLAMMATORY BOWEL DISEASE Surveillance for invisible dysplasia in inflammatory bowel disease currently relies on the acquisition of random colonic biopsies. Dye-based chromoendoscopy can be used to assess subtle mucosal features for targeted biopsies and is recommended over high-definition white light endoscopy in surveillance protocols. (47) The implementation of dye based chromoendoscopy into routine clinical practice is limited by available expertise and time required for staining. Several studies have looked at the diagnostic performance of advanced imaging technologies for surveillance of dysplasia in patients with inflammatory bowel disease. Advanced imaging technologies may also be useful in differentiating between Crohn’s disease and ulcerative colitis which is often times clinically challenging. 8.1 DIGITAL CROMOENDOSCOPY The diagnostic yield of dye-based chromoendoscopy for dysplasia in inflammatory bowel disease has not been replicated with digital chromoendoscopy. A randomized crossover trial of 25 patients with ulcerative colitis who underwent NBI and high-definition colonoscopy with lesions left in-situ to enable detection during a second examination showed no statistical difference in dysplasia detection rate between imaging modalities.(48) A total of 11 patients were diagnosed with neoplasia of which 8 (73%) were identified with NBI and 9 (82%) with highdefinition colonoscopy.

A recent consensus statement on surveillance and management of dysplasia in

inflammatory bowel disease recommends against the routine use of NBI.(47) There are currently no published studies on FICE or i-scan for surveillance of inflammatory bowel disease. 8.2 CONFOCAL LASER ENDOMICROSCOPY The limited field of view of CLE restricts its application for targeted biopsies in inflammatory bowel disease surveillance. The combination of chromoendoscopy and CLE however, has been shown to increase the yield of neoplasia detection by approximately 5-fold with 50% fewer biopsies. CLE demonstrated 94.7% sensitivity, 98.3% specificity and 97.8 % diagnostic accuracy for the diagnosis of intraepithelial neoplasia compared to conventional colonoscopy.(49) A subsequent study showed that CLE targeted biopsies increased

the diagnostic yield of intraepithelial neoplasia by 2.5-fold compared to chromoendoscopy guided biopsies. (50) CLE can also be targeted to areas with suspected dysplasia observed under conventional colonoscopy. In a study of 14 patients with ulcerative colitis the combination of chromoendoscopy and CLE was used to define a macroscopic mucosal lesion.(51) In this setting, CLE was associated with a sensitivity of 100% and specificity of 90% for detection of associated dysplasia. The intestinal epithelial barrier in patients with inflammatory bowel disease is often disrupted by several mechanisms. Crypt architecture, microvascular alterations and fluorescein leakage are CLE features associated with disease activity. (52, 53) A grading system (Watson Grade I-III) based on CLE features of epithelial cell shedding, fluorescein leakage and microerosions can be used to predict an inflammatory bowel disease flare in patients in clinical remission. (54) (Figure 8) The sensitivity, specificity and accuracy for Watson grade II/III to predict a flare are reported to be 62.5%, 91.2% and 79% respectively.

8.3 OPTICAL COHERENCE TOMOGRAPHY OCT can distinguish between normal colon and inflammatory conditions such as ulcerative colitis and Crohn’s disease. A study that evaluated OCT patterns of colonic mucosa in patients with ulcerative colitis found that OCT can correctly identify several disease features endoscopically. (55) An OCT scoring index that included mucosal backscattering alterations (0-3 degree), delimited darker areas (absent/present) and alterations in the layered structure of the colonic wall (evident/present/absent) correlated with histological features of mucosal inflammation (0-3 degree), lymphoid aggregate (present/absent), granuloma (present/absent) and crypt abscess (present/absent).

The authors of this study report that OCT can reliably distinguish between mild-moderate

ulcerative colitis and severe disease. OCT has also been used to assess the degree of disruption of the colon’s layered architecture, a feature associated with transmural inflammation often found in Crohn’s disease. A study that performed OCT on colectomy specimens of patients with ulcerative colitis and Crohn’s disease found that the sensitivity and

specificity for OCT to detect transmural disease was 86% and 91% respectively. (56) Eight patients with a preoperative diagnosis of ulcerative colitis and features of transmural inflammation on OCT were found to have Crohn’s disease based on histological evidence of transmural disease found in the colectomy specimens. A follow-up study by the same investigators validated the use of OCT to distinguish between Crohn’s disease and ulcerative colitis in-vivo.(57) Using the clinical diagnosis as the gold standard, a disrupted layered architecture on OCT had a diagnostic sensitivity and specificity of 90% and 83% respectively for the diagnosis of Crohn’s disease. 9.0 CONCLUSION AND FUTURE DIRECTIONS Advanced imaging technologies are an important adjunct to conventional high-definition white light endoscopy. Technologies such as NBI are now routinely used to evaluate esophageal mucosal irregularities associated with BE dysplasia. A recent review of the literature suggests a role for NBI in the assessment of colorectal polyps. (39) Next generation digital chromoendoscopy is being developed and includes a system that uses laser light in the blue spectrum ( 410 nm) (Blue Light Laser, Fujinon Inc, Japan) to increase shortwavelength illumination and generate high-contrast imaging of superficial mucosal structures and microvessels. Clinical implementation of imaging technologies such as CLE and OCT has been limited by cost and availability of expertise in image interpretation. The small field of view of first-generation OCT and CLE is susceptible to sampling error, a pitfall similar to random surveillance biopsy protocols.

The high image

resolution of CLE, however has allowed us to observe disease processes at a cellular level. CLE has been used to identify specific mucosal features associated with dysplasia in BE and gastric cancer. Recent studies suggest that CLE can be used to evaluate inflammatory bowel disease activity and predict remission by evaluating the degree of intracellular fluorescein leakage. The latest generation OCT systems (VLE) are capable of wide-field crosssectional imaging that permits comprehensive evaluation of the human esophagus.

Advanced imaging

technologies will ultimately evolve to combine both wide-field and high-resolution point-imaging and will likely include automated diagnostic imaging algorithms to aid the endoscopist with realtime assessment of the gastrointestinal mucosa.

CONFLICT OF INTEREST STATEMENT: Cadman Leggett, MD has no conflict of interest to declare Prasad G. Iyer MD has no relevant conflicts of interest to declare.

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Figure Legend. FIGURE 1: Schematic diagram showing basic optical principals of confocal laser endomicroscopy. A laser source ( 488 nm) passes through a pinhole aperture and is focused at a point of interest. Reflected light from this point is focused on a second pinhole aperture positioned in front of a photodetector. FIGURE 2: Schematic diagram showing basic optical principles of optical coherence tomography. Infrared light ( 750-1300 nm) reflected from a scanning mirror (sample) is combined with light reflected from a reference mirror and known to have traveled a set distance. The combined light waves are captured by a photodetector and generate an interference intensity profile. FIGURE 3: Classification of mucosal and vascular patterns in Barrett’s Esophagus (BE) with Narrow Band Imaging. Non-dysplastic BE is characterized by a ridge/villous mucosal pattern and normal vascularity. Dysplastic BE is characterized by an irregular distorted mucosal pattern and abnormal vascularity. The sensitivity, specificity and positive predictive value of a ridge/villous mucosal pattern for diagnosis of non-dysplastic BE is reported to be 93.5%, 86.7% and 94.7% respectively. The sensitivity, specificity and positive predictive value of an irregular distorted mucosal pattern for diagnosis of dysplastic BE is reported to be 100%, 98.7% and 95.3% respectively. FIGURE 4: Confocal laser endomicroscopy characteristics of squamous epithelium, non- dysplastic Barrett’s esophagus, dysplastic Barrett’s esophagus, and adenocarcinoma based on the Miami classification criteria. Reprinted with permission.(12) FIGURE 5: Interpretation of the volumetric laser endomicroscopy diagnostic algorithm is performed over a longitudinal distance of 1 cm of Barrett’s esophagus (BE). Partial effacement of the mucosal layer is defined by a mucosal layer ≥2 mm in transverse cross-section present in ≥50% of the scan. Complete effacement of the mucosal layer is defined by presence of a mucosal layer over <50% of the scan. A rating of image surface to subsurface intensity corresponds to the most prevalent ratio (surface > subsurface intensity vs surface ≤ subsurface intensity) present in ≥50% of the scan. The single asterisk represents the VLE surface signal intensity and the double asterisk the subsurface intensity. Reprinted with permission.(58)

FIGURE 6:

Confocal laser endomicroscopy classification of gastric superficial lesions.

Reprinted with

permission.(27) FIGURE 7: Narrow band imaging international colorectal endoscopic classification. Reprinted with permission.(59) FIGURE 8: Endomicroscopic grade (Watson grade) for in vivo identification of local barrier dysfunction. In patients with inflammatory bowel disease in clinical remission a Watson score of I/II was associated with a sensitivity and specificity of 62.5% and 91.2% in predicting a flare. Reprinted with permission.(54)

TABLE 1: The optical coherence tomography scoring index is used to diagnose Barrett’s esophagus (BE) associated dysplasia. The scoring index consists of two independent criteria (surface to subsurface signal intensity and glandular architecture) that are added to calculate a dysplasia score. A dysplasia score of ≥2 is associated with a sensitivity of 83% and a specificity of 75% for the diagnosis of neoplasia in BE. (17)

Criteria Surface Maturation

Glandular Atypia

Score

OCT Description

0

Surface intensity < subsurface intensity

1

Surface intensity = subsurface intensity

2

Surface intensity > subsurface intensity

0

No mucosal glands or ducts

1

Glands or ducts without atypia

2

Glands or ducts with atypia • irregular/noncircular forms • back-to-back (cribriform) • necrosis (material inside gland/duct)

Fig. 1

Fig. 2

Fig. 3

Fig. 4

Fig. 5

Fig. 6

Fig. 7

Fig. 8