Volume 134, Issue 1, Pages 327-340 (January 2008)

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ABSTRACT

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American Gastroenterological Association (AGA) Institute Technology Assessment on Image-Enhanced Endoscopy

published online 01 November 2007.

This document presents the official recommendations of the American Gastroenterological Association (AGA) Institute Technology Assessment on “Image-Enhanced Endoscopy.” It was approved by the Clinical Practice and Economics Committee on August 3, 2007, and by the AGA Institute Governing Board September 27, 2007.

Abbreviations used in this paper: EMR, endoscopic mucosal resection, IEE, image-enhanced endoscopy, NBI, narrow band imaging

Article Outline

• Abstract

• Executive Summary

• Introduction

• Recommendations

• Technology Assessment

• Introduction

• Literature Review and Analysis

• Techniques

• Dye-based IEE

• Absorptive stains

• Contrast stains

• Equipment-based IEE

• NBI

• Spectral estimation technology

• Surface enhancement technology

• Autofluorescence imaging

• High-Magnification and/or High-Resolution Endoscopes

• Outcomes

• IEE of the oropharynx and hypopharynx

• IEE of the esophagus

• Squamous cell cancer

• Barrett’s esophagus

• IEE of the stomach

• IEE of the small intestine

• IEE of the colon

• Detection of colorectal polyps

• EMR assessment of lesion border and residual tissue

• IEE in chronic ulcerative colitis

• Assessment of disease activity

• Screening for nonpolypoid neoplasia

• IEE of the biliary system

• Conclusions

• Acknowledgment

• References

• Copyright

The Technology Assessment on Image-Enhanced Endoscopy developed under the aegis of the AGA Institute and its Clinical Practice and Economics Committee (CPEC) was approved by the AGA Institute Governing Board. The data used to formulate these recommendations are derived from the data available at the time of their creation and may be supplemented and updated as new information is assimilated. These recommendations are intended for adult patients, with the intent of suggesting preferred approaches to specific medical issues or problems. They are based upon the interpretation and assimilation of scientifically valid research, derived from a comprehensive review of published literature. Ideally, the intent is to provide evidence based upon prospective, randomized placebo-controlled trials; however, when this is not possible the use of experts’ consensus may occur. The recommendations are intended to apply to healthcare providers of all specialties. It is important to stress that these recommendations should not be construed as a standard of care. The AGA Institute stresses that the final decision regarding the care of the patient should be made by the physician with a focus on all aspects of the patient’s current medical situation.

Executive Summary

Introduction

Gastrointestinal cancers represent the leading cause of cancer-related death worldwide. The diagnosis of precursor and early gastrointestinal cancers is therefore of great interest because their endoscopic and surgical treatment present the best chance for cure. These precancers and early cancers are often subtle and can pose a challenge to gastroenterologists to visualize using standard white light endoscopy. Contrast enhancement of the endoscopy images, through use of dye solutions, has been developed and used in select indications. Newer endoscopes are now equipped with optical and/or electronic technologies to also increase the contrast of structures or cells imaged during endoscopy.

The term “image-enhanced endoscopy” (IEE) encompasses various means of enhancing contrast during endoscopy using dye, optical, and/or electronic methods. IEE allows improved visualization of lesions and can be used to gain insight into the pathology of the lesion, which, in turn, provides guidance to select the optimal treatment.

Recommendations

Available data support the use of IEE in the detection and treatment of early squamous cell carcinoma of the esophagus, early gastric cancer, and superficial colorectal lesions. The use of Lugol’s solution may improve the endoscopic visualization of high-grade dysplasia and early squamous cell carcinoma of the esophagus and thus may be considered in high-risk patient populations. The use of diluted indigo carmine solution aids the diagnosis and treatment of early gastric cancer. The solution pools at the border of the lesion and thus enhances visualization of these lesions, which are most often nonpolypoid. By pooling into the depression or ulceration of the lesion, the solution aids in the classification of the morphology, which in turn is important in the medical decision making of treatment strategy. Similarly, diluted indigo carmine solution is useful in the evaluation of areas suspected of containing nonpolypoid colorectal neoplasms in defining the border and morphology of lesions. By filling the pits of the glands and imaging using high-resolution or high-magnification colonoscopes, endoscopic diagnosis of neoplastic and nonneoplastic lesions and estimation of depth of invasion can be performed to aid in the decision of treatment strategy. IEE is not routinely used in the management of diseases of the small intestine. Equipment-based IEE is increasingly reported to aid in the detailed visualization of the microvessels and surface structures of neoplastic, metaplastic, and hyperplastic tissues.

Technology Assessment

The following guidelines were developed to assist physicians in the appropriate use of various modalities of contrast enhancement of endoscopic images, termed “image-enhanced endoscopy” (IEE). They emanate from a comprehensive review of the medical literature pertaining to IEE, which previously required the use of dyes and was called chromoendoscopy but more recently can also be accomplished using optical and/or electronic technology. The new IEE technology will allow us to visualize the gastrointestinal mucosa in detail. Drawing an analogy to the use of radiology image enhancement methods, such as contrast, the use of IEE will play a similarly important role. Thus, we herein provide a timely and necessary review on the current state of IEE in order to summarize its clinical application today and outline its future potentials.

Introduction

Dye or stain solutions have been applied throughout the gastrointestinal mucosa to enhance endoscopic visualization. With increased contrast, the image displays the mucosal topography and borders of lesions in finer detail and, in turn, aids in the endoscopic interpretation of gastrointestinal disease. The use of dye has supplemented the endoscopic diagnosis and treatment of precancers and early cancers, specifically those that are nonpolypoid. These lesions, which can appear as superficially elevated, flat, or depressed, have been globally described as a challenge to diagnose using white light endoscopy due to their subtle morphology.1, 2, 3, 4, 5, 6, 7, 8, 9, 10 The diagnosis of precancers and early gastrointestinal cancers is of great interest because their endoscopic or surgical resection is highly curative.

Recent progress in optics and computerized processing of endoscopic images provide an optical and/or electronic enhancement of the mucosal structures.11, 12, 13, 14 The equipment-based IEE adds to the prior established techniques of applying dye or stain (also called chromoscopy or chromoendoscopy).15, 16, 17 The term “image-enhanced endoscopy” (IEE) recognizes both dye-based (chromoendoscopy) as well as equipment-based endoscopy (Table 1) to further advance endoscopic imaging.

Table 1.

Image Enhanced Endoscopy


Type	Mode (solution/instrument)	Mechanism of contrast	Proposed purpose
Dye-based IEE (chromoscopy)
Absorptive dye
Lugol’s solution	0.5%–3% solution	Normal intestinal epithelium binds iodine	Diagnosis of esophageal squamous dysplasia or early cancer
	For 2% dilution, mix 8 mL 5% solutiona with 12 mL sterile water
Methylene blue	0.5% solution For 0.5% dilution, mix 10 mL 1% solutionb with 10 mL sterile water	Small and large intestinal epithelium actively absorb stain	Diagnosis of intestinal metaplasiac
Contrast dye
Indigo carmine	0.1%–0.4% solution For 0.2% dilution, mix 5 mL 0.8% solutionb with 15 mL sterile water.	Dye pools in mucosal crevices; no cellular staining	Diagnosis of early gastric and colorectal cancer
Equipment-based IEE
Optical
NBI	Olympus	Modification of light source with narrowed wavelengths to enhance capillary pattern	Diagnosis of early oropharyngeal and gastrointestinal cancerd
Electronic
Spectral estimation technology	Fujinon	Processing of image to enhance capillary pattern	Diagnosis of early oropharyngeal and gastrointestinal cancerd
Surface enhancement	Pentax	Processing of image to enhance color pattern or structure	Diagnosis of early oropharyngeal and gastrointestinal cancerd

Humcon Co, Texarkana, TX.

American Regent Laboratories, Inc, Shirley, NY.

Methylene blue has also been proposed to improve endoscopic detection of Barrett’s esophagus, although there is currently insufficient evidence to support its routine use in this setting.92

There are currently limited data on equipment-based IEE, most of which is on NBI.

The aim of this technical review is to summarize the literature on IEE and to provide a guide for its current application in endoscopy.

Literature Review and Analysis

The techniques and technologies and the potential outcomes of IEE will be described. This review is based on a MEDLINE search performed through June 2007 using the following Medical Subject Heading (MeSH) terms: chromoscopy, chromoendoscopy, dye stain endoscopy, contrast stain endoscopy, narrow band imaging (NBI), multi-band imaging, and autofluorescence imaging. A manual search of article reference lists for additional citations was also performed. Pertinent studies published in English were reviewed. Studies published in abstract form only were excluded.

Techniques

Dye-based IEE

The stains used for the traditional dye-based IEE can be categorized into absorptive or vital, reactive, and contrast stains. The stains that are commonly used in the referral centers around the world and described in the literature will be the focus.16, 17, 18, 19

Absorptive stains

Specific epithelial cells take up absorptive stains. Three types of absorptive stains have been frequently described in the literature: Lugol’s solution, methylene blue, and crystal violet. Special spray or ball-tipped catheters can be used to apply the stains evenly throughout the mucosa or intensely over a specific area of interest, respectively.

The use of Lugol’s solution has been shown to improve the endoscopic detection20 and delineate21 high-grade dysplasia and early squamous cell carcinoma of the esophagus in high-risk patient populations.22, 23, 24, 25, 26, 27, 28, 29

Lugol’s solution is composed of a mixture of potassium iodide and iodine in water. The diluted solution (0.5%–3.0%) is sprayed on the mucosa via a spray catheter and is absorbed by glycogen-containing cells to produce a dark greenish-brown stain. Normal mucosa will stain intensively for about 5–8 minutes, whereas dysplastic and neoplastic areas will not stain. Its use has been occasionally associated with retrosternal pain, discomfort, nausea,30 and rarely chemical esophagitis.31 It should be used cautiously in patients with reported iodine sensitivity.19, 32 Sodium thiosulfate solution has been administered after application of Lugol’s solution to reverse staining and to decrease the side effects.30

Methylene blue (0.5%–1.0%) is taken up by actively absorbing intestinal epithelial cells. It does not stain nonabsorptive gastric or squamous epithelia and has thus predominantly been applied to enhance the detection of metaplastic epithelium with absorptive properties such as the specialized columnar epithelium of Barrett’s esophagus.33 A significant level of interobserver variability on the use of methylene blue staining in the detection of Barrett’s esophagus has notably been reported.34 Recently, methylene blue has been evaluated in the diagnosis of nonpolypoid colorectal neoplasia in patients with chronic ulcerative colitis.35

Optimal methylene blue staining of Barrett’s esophagus requires the removal of surface mucus with a mucolytic agent, such as 10% acetylcysteine solution, before its catheter application. The technique involves the use of approximately 10 mL of acetylcysteine and 20 mL of methylene blue dye for every 5 cm of circumferential columnar lined epithelium.36, 37 The stain uptake occurs within 2–3 minutes and is subsequently resistant to washing. The stain persists for up to 24 hours until complete renal excretion or cellular loss. This may result in a green hue to the urine and stool. There have been no significant side effects associated with methylene blue use, although there has been speculation on the potential of methylene blue inducing oxidative damage of DNA when photosensitized by white light.38

Crystal violet has been used primarily in pit-pattern analysis of colorectal neoplasm. Its use has been proposed to aid in the endoscopic differentiation of slightly invasive from deeply submucosal invasive carcinoma.

Crystal violet (0.1%–0.5%) is a vital stain preferentially taken up by the colonic crypts.17 Following removal of surface mucus with vigorous washing (with or without a diluted proteinase solution), adequate staining with crystal violet is achieved with the application of a few drops using a nontraumatic catheter. The stain is absorbed by the mucosa around the pit openings to provide a vivid coloration of the pit margins.

Diluted acetic acid (1%–3%) has recently been included as part of chromoscopy, although acetic acid is not a dye per se.39, 40, 41 It enhances the contrast through a number of mechanisms. Acetic acid is a mucolytic by breaking the disulfide bonds of the glycoproteins of the mucous layer. When sprayed onto columnar epithelium, acetic acid penetrates into the cells, stroma, and vascular network. Within the cells, acetic acid alters the tertiary structure of the cellular proteins. In particular, acetic acid causes a slight decrease in the intracellular pH, which in turn leads to increased polymerization of the cytokeratins, the most abundant cellular proteins, and a reversible alteration of the nucleoproteins. These changes in cellular proteins lead to increased opacity of the columnar epithelium. As acetic acid reaches the basal membrane, it breaks the barrier function of the cell membrane, leading to electrolyte leakage and capillary congestion of the stoma. These multiple effects of acetic acid enhance the contrast of the mucosa, which in turn has been reported to allow detailed classifications of Barrett’s esophagus.40

Contrast stains

Indigo carmine is the most commonly used dye-based IEE. It is not absorbed, but it accentuates the border and surface topography of a lesion by pooling into the crevices of the mucosal surface to outline subtle changes in elevation or depression. It has been shown to be most useful in the endoscopic diagnosis and treatment of nonpolypoid columnar neoplasm. In Japan, where gastric cancer is common, diluted indigo carmine solution is often sprayed through the entire stomach for reexamination after a standard white light examination.42 In the colon, selected spraying of diluted indigo carmine stain onto the mucosa is used to highlight areas suspected to contain a nonpolypoid colorectal neoplasm.43 Direct application of indigo carmine onto colorectal neoplasms in combination with high magnification has been described by referral centers to study meticulous glandular structures of the mucosa.44, 45, 46

Indigo carmine chromoscopy is accomplished using standard endoscopes. Diluted solution (0.1%–0.4%) is sprayed onto the area using a syringe via the accessory channel of the endoscope (Figure 1).

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Figure 1. Preparation technique for indigo carmine IEE. (A) For 0.2% diluted solution, mix 5 mL 0.8% solution with 15 mL sterile water. (B) Diluted solution is sprayed onto the area of interest using a syringe via the accessory channel of the endoscope.

Equipment-based IEE

Novel endoscopic imaging technologies have been developed recently that use manipulations of the light source (optical IEE) or captured light (electronic IEE) to enhance visualization of the surface. NBI (Olympus Corp, Allentown, PA), spectral estimation technologies (Fujinon Inc, Wayne, NJ), surface enhancement (Pentax Medical Co, Orangeburg, NY), and autofluorescence imaging (Olympus Corp) have been described.

NBI

The NBI technology uses a narrow light source to enhance visualization of the surface microvessels. Two NBI systems are available. In the NBI of the RGB sequential illumination system, narrow spectra of the red, green, and blue light that are centered on 415 nm, 445 nm, and 500 nm are used. In the NBI of the color chip system, a single filter with a 2-band pass characteristic is used to generate the NBI images. The filter has narrow bandwidths of 30 nm and central wavelengths at 415 nm (blue) and 540 nm (green). On the endoscopy monitor, the signals obtained from the 2 specialized filters are combined to form a false-color image. These shorter wavelengths of light permit focused visualization of microvessels of the superficial layer of the mucosa and submucosa (Figure 2).

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Figure 2. System configuration of 2-band NBI on color chip illumination system. Courtesy of Mr. Kota Nozue at Olympus Corp, Japan.

Hemoglobin light absorption is optimized at these wavelengths. Thus, NBI has the potential to provide detailed characterization of lesions and aid the endoscopist in the differentiation of abnormal mucosa from normal, because the pattern and size of the microvessels in the mucosa and submucosa change when tissue becomes metaplastic, dysplastic, and neoplastic. At standard magnification (30×), the higher density of vessels seen in dysplastic and neoplastic squamous or columnar lesions appears brown in color. At high magnification (up to 100×), visualization of the microvessels using NBI permits detailed studies of the intraepithelial papillary capillary loops of the squamous mucosa and the microvessel network surrounding the glands of the columnar mucosa. The configuration, density, and size of these intraepithelial papillary capillary loops change in dysplasia and neoplasia of the squamous cell esophagus. Similarly, the microvessels network of the columnar epithelium changes in metaplasia, dysplasia, and neoplasia of the columnar cells of esophagus, stomach, and colon.11, 12

Spectral estimation technology

The spectral estimation technology uses computerized processing to convert standard RGB signals from the endoscope’s charge-coupled device, in which there is often suboptimal contrast or differentiation between normal and diseased mucosa into color combinations that accentuate these differences. The technology uses a 3 × 3 matrix to perform a linear mathematical transformation of the red, green, and blue lights into the system output.47 In practice, the system allows the user to select a combination of 3 wavelengths and the processor will then use the corresponding matrix to process the RGB signal. Certain choices of wavelengths have been shown to accentuate differences between esophageal and gastric mucosa at the gastroesophageal junction48 as well as between normal and adenomatous colonic mucosa. The application of the spectral estimation technology in clinical practice is under recent study.49

Surface enhancement technology

The surface enhancement technology also uses computerized processing to enhance the contrast of the structures of tissues seen during endoscopy. There is no clinical study available at present.

Autofluorescence imaging

Autofluorescence imaging utilizes changes in concentrations of endogenous fluorophores, such as collagen, nicotinamide adenine dinucleotide, and flavin adenine dinuclotide.50 The video endoscopy adaptation of the autofluorescence imaging adds green and red reflectance to improve the quality of the image. Although a number of clinical studies have recently been published in the diagnosis of early esophageal cancer51 and in the detection of dysplasia in patients with Barrett’s esophagus,52, 53, 54, 55 there are insufficient data to support its routine clinical use.

High-Magnification and/or High-Resolution Endoscopes

Endoscopes that are equipped with optical- and/or electronic-based IEE have high resolution or high definition with or without high-magnification capabilities. High-resolution or high-definition endoscopy provides a more detailed image of gastrointestinal mucosa, and high-magnification endoscopy enlarges the image up to 100× as compared with 30× in standard endoscopy utilizing a 20-inch monitor. At higher magnification with IEE, the visualized surface patterns of the gastrointestinal mucosa have been suggested to correlate well with the underlying histology. Proposed uses for high magnification used in conjunction with IEE include distinguishing neoplastic and nonneoplastic lesions,44, 45, 46, 56, 57, 58, 59, 60, 61 assessing depth of invasion in early colorectal carcinoma,62, 63, 64 and detecting minute tumor residue after endoscopic mucosal resection (EMR).65, 66, 67, 68, 69 In addition, recent studies have explored the role of high magnification with IEE in assessing disease activity70, 71 and detecting nonpolypoid neoplasia in ulcerative colitis.17, 35, 70, 72, 73, 74, 75, 76

Ultrahigh magnification endoscopes, more than 1000×, have recently been developed and proposed as vehicles for in vivo histologic diagnosis. Endomicroscopy uses laser scanning confocal technology, and endocytoscopy applies contact light microscopic technology.77 Preliminary studies using ultramagnification technology with IEE have shown potential of this technique, although its clinical application throughout the gastrointestinal tract merits further study.78, 79, 80, 81, 82, 83, 84, 85, 86, 87 These technologies, however, are designed primarily to increase magnification, rather than contrast, and thus will not be included in this review.

Outcomes

IEE of the oropharynx and hypopharynx

Limited data are available on the use of IEE to diagnose precancers and early cancers of the oropharynx and hypopharynx. Endoscopic findings of precancers and early cancers of the oropharynx and hypopharynx are similar to squamous cell carcinoma of the esophagus. On white light endoscopy, precancers and early cancers of the oropharynx and hypopharynx are typically slightly more reddish than the surrounding mucosa. These lesions are difficult to diagnose and have not been frequently described until recently. Muto et al used optical IEE and described 50 superficial lesions in patients undergoing routine screening and surveillance endoscopies of early oropharyngeal and hypopharyngeal squamous cell carcinoma. Forty-one of the identified lesions were endoscopically removed and found to be either squamous cell carcinoma in situ or slightly invasive cancer.1, 2 These lesions have been shown to have distinct microvascular patterns, appreciable as brownish areas using NBI. Individual capillaries can be visualized using magnification endoscopy, and their patterns have been correlated with the lesion depth (Figure 3).

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Figure 3. IEE of a submucosally invasive oropharyngeal squamous cell carcinoma. (A) A slightly reddish area was appreciated during standard endoscopy. The border of the lesion was difficult to distinguish from the surrounding normal mucosa. (B) NBI was used through a switch at the control body of the endoscope. The lesion appeared brownish as compared with the surrounding normal mucosa. A magnified white light (C) and NBI (D) image demonstrated several red and brown dots, respectively, which represent dilated and irregular-shaped and density of intraepithelial papillary capillary loops. The resected specimen revealed well-differentiated squamous cell carcinoma invading the superficial part of the submucosa. Courtesy of Dr M. Muto, National Cancer Center East, Japan.

IEE of the esophagus

IEE has been applied toward identification of esophageal neoplasia in both squamous and Barrett’s epithelium. It is indicated in the diagnosis and treatment of pre- and early squamous cell cancer of the esophagus (Figure 4).

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Figure 4. Dye-based and optical-based IEE of a submucosally invasive esophageal squamous cell carcinoma. (A) A large patch of reddish area was observed during standard endoscopy. (B) Lugol’s solution was sprayed using a specialized catheter throughout the entire thoracic esophagus. After spraying, normal mucosa became brownish/greenish, while the lesion did not change in color. (C) After the effect of Lugol’s solution has disappeared, NBI was used to view the abnormal mucosa. Irregular-shaped and density of intraepithelial papillary capillary loops was observed. Courtesy of Dr. M. Muto, National Cancer Center East, Japan.

Squamous cell cancer

The use of Lugol’s solution has been shown to improve the endoscopic detection of20 and, moreover, delineate high-grade dysplasia and squamous cell cancer of the esophagus in patients at increased risk, such as patients with head and neck cancer,21, 23, 24 heavy smokers,25 patients with lye ingestions,26 and alcoholic patients.25, 27, 28 A recent study of 326 patients with head and neck cancers from Brazil demonstrated a significantly higher yield in the detection of high-grade intraepithelial neoplasia using Lugol’s IEE in patients at high risk for squamous cell cancer of the esophagus.29 The use of Lugol’s solution is a crucial component in EMR of early squamous cell esophageal lesions in order to define the lesion borders and assess for the completeness of resection.88 The use of NBI with magnification was shown to increase the accuracy of surface pattern analysis in a study of 41 patients with esophageal squamous neoplasia.89 The color contrast ratio between vessels and mucosa was significantly greater in the NBI images.

Barrett’s esophagus

Methylene blue IEE has predominantly been proposed to improve endoscopic detection of Barrett’s esophagus,33, 36, 37, 90, 91 although there is currently insufficient evidence to support its routine use in this setting.92 Methylene blue selectively stains specialized intestinal metaplasia. Barrett’s esophagus becomes blue, while areas of squamous mucosa and gastric-type columnar metaplasia remain pale. Using this technique, Canto et al showed that the average number of biopsy specimens obtained per patient was significantly lower and the proportion of specialized columnar epithelium in each specimen was significantly higher compared with random biopsy.36, 93 Dysplasia or cancer was also diagnosed in significantly more patients (44% vs 28%; P = .03) than by random biopsy technique.36, 94 Dysplastic areas in Barrett’s esophagus showed decreased or heterogeneous staining. Subsequent studies have not produced similar results.95, 96 Several studies of IEE in Barrett’s esophagus surveillance have evaluated the use of high-resolution97 or magnification endoscopy combined with either double-dye staining with methylene blue and crystal violet98, 99 or single-dye staining with methylene blue,100, 101 indigo carmine,32, 102 or acetic acid103, 104, 105 IEE. Use of methylene blue to stain Barrett’s neoplasms, however, has been reported to be operator dependent.34 Preliminary studies have suggested that magnifying endoscopy with NBI enhances visualization of surface glandular structures in Barrett’s esophagus.97, 106, 107, 108, 109

IEE of the stomach

IEE using diluted indigo carmine is routine in the diagnosis and treatment of early gastric cancer. In Japan, it is used in the evaluation of suspicious areas for early gastric cancer to determine the border and surface topography. It is often sprayed throughout the stomach following a complete screening examination to exclude the small or nonpolypoid early gastric cancer. Because the benefits for visualization of the nonpolypoid early gastric cancer are evident, comparative studies have not been performed. Other methods of IEE are not used routinely. Methylene blue chromoendoscopy using magnification endoscopes has been formally studied as a method for diagnosing gastric intestinal metaplasia and dysplasia.110, 111 Endoscopic correlation with gastric lesion histology has also been described using magnifying endoscopy combined with acetic acid or with NBI. In a case series, the aceto-whitening disappeared earlier in gastric adenocarcinoma than in the noncarcinomatous mucosa with clear border delineation of the lesion.41 Using NBI with high magnification, observation of a light blue crest on the epithelial surface in the gastric mucosa correlated with histologic evidence of intestinal metaplasia.51 Using NBI, the vascular pattern of early gastric cancer has been proposed to correlate with invasive histology.14, 112

IEE of the small intestine

IEE is not routinely used in the management of diseases of the small intestine, although various duodenal abnormalities, including gastric metaplasia, hyperplastic Brunner’s glands, inflammatory changes, villous atrophy, and adenoma, have been evaluated with IEE and high-magnification endoscopy.113 Subtle mucosal changes or villous atrophy seen on standard endoscopy, as in celiac sprue, are more visible with magnification endoscopy, particularly with indigo carmine114, 115 or methylene blue116 IEE.

IEE of the colon

IEE is most useful in the evaluation of areas suspected of containing nonpolypoid colorectal neoplasms and in classifying and defining the borders of the lesions. Exploratory studies on the use of IEE in the detection of colorectal polyps, assessment of neoplastic lesion margins before resection, and differentiation of nonneoplastic and neoplastic polyps have been performed. There are currently limited data on optical-based or electronic-based IEE.13, 117, 118, 119, 120

Detection of colorectal polyps

IEE has been described to enhance the detection of colorectal neoplasm, particularly nonpolypoid colorectal neoplasm (Figure 5).10, 43, 59, 75, 121, 122, 123, 124, 125, 126, 127, 128 IEE has been shown to increase the detection of colorectal polyps. In most units, indigo carmine dye is selectively sprayed to evaluate areas suspicious for neoplasia because application of IEE to the entire colon has been associated with a high detection rate of hyperplastic lesions.59, 129, 130 Furthermore, lesions in the dependent field of view may be obscured by the pooled solution. The limitations of dye-based IEE throughout the colon may be circumvented in the future by the use of optical-based or electronic-based IEE.118, 119, 128

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Figure 5. IEE of a depressed colorectal neoplasm. (A) A slightly reddish mucosal area was visualized during standard colonoscopy. (B) Diluted indigo carmine (0.2%) was used to further characterize the lesion and delineate its borders. (C) EMR inject-and-cut technique was used. (D) Following EMR, no residual tissue was identified. Images from VA Palo Alto, California.

EMR assessment of lesion border and residual tissue

IEE with indigo carmine is commonly used to assess the lesion morphology and border to precisely direct EMR therapy. Immediately following mucosectomy, it is suggested to analyze the pit pattern of the tissue at the resection margins with indigo carmine IEE to assure completeness of resection. If residual neoplasm is present, further resection or ablative techniques can be directly applied130 (Figure 6). During EMR, it is important to ensure that the resection margins are free of neoplasm. Fibrosis may subsequently develop at the resection site, thus making any residual tissue difficult to endoscopically resect at a later date.67 Outcomes analysis of EMR of flat lesions >2 cm showed a reduction of local neoplastic recurrence from 8.7% to 0.5% (P < .01) following the implementation of the routine use of IEE with high magnification in tumor residual assessment.131

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Figure 6. NBI of a nonpolypoid colorectal adenoma. Nonpolypoid (IIa) colorectal lesion visualized with (A) standard and (B) NBI colonoscopy. The lesion was resected using EMR inject-and-cut technique. (C) Following resection, the borders are closely inspected for residual tissue. (D) Inspection with NBI shows an area of residual tissue (arrow). Argon plasma coagulation was then applied to the residual lesion for complete resection. Images from VA Palo Alto, California.

IEE in chronic ulcerative colitis

Assessment of disease activity

IEE with high magnification may provide an opportunity to assess disease activity of the entire colorectal mucosa rather than simply from a random and limited tissue sample. With indigo carmine IEE and high magnification, fine mucosal morphologic features can be visualized and interpreted24 (Figure 7). These changes have been correlated to be an independent risk factor for relapse during medical therapy. Fujiya et al reported that 7 (78%) of 9 patients with minute mucosal defects compared with only 2 (22%) of 9 patients without such changes experienced a relapse within 6 months.132

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Figure 7. Ulcerative lesion in a patient with long-standing ulcerative colitis. There was concern that the lesion contained an ulcerated neoplasm. (A) Ulcer in the center in the image. (B) Indigo carmine is applied for further visualization. (C) Magnification and (D) NBI show regenerative capillary features. There were no neoplastic changes in the biopsy specimen. Images from VA Palo Alto, CA.

Screening for nonpolypoid neoplasia

Colitis-associated neoplasms can be difficult to detect, because the growth pattern of colitic dysplastic tissue is often multifocal and flat. IEE with high-magnification colonoscopy may potentially facilitate earlier detection of colitis-associated dysplasia because it may unveil such subtle lesions and provide a more targeted approach to surveillance.74, 133 Using IEE and high-resolution video endoscopy in 85 surveillance patients with ulcerative colitis, Jaramillo et al reported that 74% of all polyps were of flat morphology.75 Hata et al showed that the mucosal pit pattern is suggestive of the histology. Specifically, type I pit pattern corresponded to nondysplastic lesions, while type IIIL, IV, and V pit patterns corresponded well to dysplastic lesions.134 In a randomized controlled trial, Kiesslisch et al evaluated the use of dilute methylene blue (0.1%) solution sprayed throughout the colon at 30-cm segment intervals during surveillance colonoscopy in 165 patients with ulcerative colitis (for more than 8 years).35 Significantly more intraepithelial neoplasia (32 vs 10) was detected in the group that received methylene blue IEE of the entire colon compared with conventional colonoscopy with standard random biopsy protocol. They reported that both the sensitivity and specificity for differentiation between nonneoplastic and neoplastic lesions were 93%. Several other studies have shown similar increases in diagnostic yield of dysplasia using IEE.135, 136 As such, surveillance colonoscopy with IEE is recommended in patients with long-standing ulcerative colitis.137

IEE of the biliary system

Peroral cholangioscopy has been used to directly visualize biliary lesions that are challenging to differentiate by cholangiography or endosonography.138, 139, 140, 141, 142 It has been used to target biopsies to aid in diagnosis of biliary duct disease. Itoi et al described a prospective case series of 12 patients with biliary tract diseases (7 bile duct cancers and 5 benign biliary diseases) diagnosed using peroral cholangioscopy.143 They report improved targeted biopsies, using peroral cholangioscopy with NBI, and speculate that NBI may be helpful for the observation of fine mucosal structures and vessels.

Conclusions

IEE has been applied as an adjunctive endoscopic diagnostic and treatment tool in specialized academic centers but is otherwise not currently in widespread use. There are sufficient data to support its use in the detection of early squamous cell carcinoma of the esophagus and in the management of early gastric cancer and superficial colorectal lesions. Potential barriers to the dissemination of IEE include perceptions of its inefficiency and exuberant cost, inadequate mechanism for reimbursement, lack of standardized training in techniques, and deficiency of high-quality comparison studies. The recent introduction of optical and electronic IEE may expand its clinical adaptation and encourage further research of the efficacy, reliability, and cost-effectiveness of IEE in diagnostic and interventional gastrointestinal endoscopy.

The Clinical Practice and Economics Committee acknowledges the following individuals whose critiques of this review paper provided valuable guidance to the authors: Robert S. Bresalier, MD; Marcia I. Canto, MD, MHS; Norman Emilio Marcon, MD; Norman S. Nishioka, MD.

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a Veterans Affairs Palo Alto Health Care System, Stanford University School of Medicine, Palo Alto, California

b National Cancer Center East, Kashiwa, Japan

Address requests for reprints to: Chair, Clinical Practice and Economics Committee, AGA Institute National Office, c/o Membership Department, 4930 Del Ray Avenue, Bethesda, Maryland 20814. Fax: (301) 654-5920.

PII: S0016-5085(07)01942-7

doi:10.1053/j.gastro.2007.10.062

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