Iris Levink, MD; Gursimran Kochhar, MD, FACP; and Michael B. Wallace, MD, MPH, FASGE
Our ability to treat disease is directly dependent on our ability to see it. Endoscopic technology has improved from basic fiber-optic, low-resolution instruments, to high-definition, contrast-enhanced systems. These advances have enabled organ-preserving resection of superficial neoplasia throughout the gastrointestinal (GI) lumen. High-definition white-light endoscopy (WLE) has changed the way we manage various diseases in GI practice. An example is the transformative ability to resect an early esophageal cancer endoscopically, as an outpatient procedure, compared to the highly invasive surgical alternative of esophagectomy. Advantages of WLE are that it does not require special equipment, it is widely available, and allows visualization of a wide field. However, it is limited in its ability to identify subtle dysplasia. Chromoendoscopy (CE), a technique that increases the contrast between normal mucosa and neoplasia, either via electronic spectral enhancement or with the use of topical dyes, has facilitated the evaluation of superficial GI neoplasia. In this chapter, we will review historical and current literature, practical methodology, and outcomes of white-light and dye-based CE. Digital CE will be covered in other chapters. Our focus will be on the evaluation of neoplasia in the esophagus, stomach, and colon.
The Paris classification was developed in 2002 by a group of leading endoscopists, surgeons, and pathologists to describe the morphology of neoplastic lesions, with the goal of predicting lesions suitable for endoscopic resection and those with deep invasion. Knowledge of the Paris classification, along with CE, is essential for the categorization of GI neoplasia. The Paris classification divides lesions into polypoid and nonpolypoid (Figure 2-1).1 A polypoid lesion protrudes more than 2.5 mm above the surrounding surface and the height is more than twofold the width of the lesion. Polypoid lesions are divided into pedunculated (0-Ip; the base is more narrow than the top) and sessile (0-Is; the top and the base have the same diameter). Nonpolypoid lesions can be slightly elevated (0-IIa), flat (0-IIb), slightly depressed (0-IIc), or excavated (0-III; ulcer). The management of a lesion in the GI tract may vary according to its Paris classification. For example, slightly depressed, large lesions are more likely to have submucosal invasion (SMI) and may be more suitable for en bloc resection methods, such as endoscopic submucosal dissection (ESD).2
Laterally Spreading Tumors
Laterally spreading tumors (LSTs) are defined as nonpolypoid neoplasms with a diameter of at least 10 mm with limited elevation above the normal mucosa and a more extensive lateral vs vertical growth pattern. LSTs account for 17.2% of advanced noeplasias.3 Improvements in endoscopic resection techniques allow endoscopic removal of most LSTs. However, the specific method of resection, endosocopic mucosal resection (EMR) vs ESD, depends on the likelihood of SMI. LSTs are divided into 3 groups: nongranular (LST-NG), granular (LST-G; homogeneous), and mixed type (granular and nongranular features). LST-NGs are flat and smooth, whereas the surface of LST-Gs are uneven and nodular.4 LST-NG and LST-G show SMI in 14% and 7% of cases, respectively.5 LST-NG lesions have a higher chance of deep SMI. Additional features suggestive of SMI include a highly irregular pit pattern or lack thereof (with irregular epithelial crests), sclerous wall changes, and large size. SMI in an LST-G lesion is suspected when a predominant large nodule is seen and is predictably at the site of the nodule.6 To indicate regions of nodule (Is) or depressed (IIc) growth within the lesion, LST classification is often combined with the Paris classification. Burgess et al7 have recently described the prevalence of covert submucosal invasive carcinoma in LSTs and found that invasive carcinoma was most common when a large (Is) nodule was present in an LST-NG lesion (Figure 2-2).7 Endoscopic resection of LSTs is often challenging, and large LSTs have traditionally been referred for surgery. However, endoscopic resection of these lesions has recently been described as highly effective and safe in expert hands.8 Additionally, the mortality and costs are lower when compared with a surgical approach.9
Why Do We Need Chromoendoscopy?
Despite the development of new endoscopic techniques, lesions are still missed. One of the major goals of CE during colonoscopy is to increase the detection of colorectal adenomas. The adenoma detection rate (ADR) is an established quality indicator for screening colonoscopy and has been shown to be inversely associated with colon cancer development.10 ADR is defined as the percentage of (average risk) patients in whom at least one adenoma is found11 and should be ≥ 25% according to the current guidelines.12 Patients who undergo physician-performed colonoscopy with ADRs < 20% are at significantly increased risk of developing colorectal cancer, as compared to those with an ADR of ≥ 20%.13 The protective benefit of even higher ADRs is linear, with a 1% gain in ADR corresponding to a 3% reduction in incidence of postcolonoscopy colorectal cancer and a 5% reduction in colorectal cancer death.14 The ADR can be influenced by procedural factors such as good bowel preparation and washing the colon during endoscopy, cecal intubation rate > 90%, withdrawal time of > 6 minutes, the features of the adenoma (eg, polypoid or nonpolypoid), inspection behind folds, preparation with mucolytic agents, sufficient insufflation, use of advanced imaging techniques, and recognition of flat polyps by the endoscopist.10,15,16
Both CE and WLE are widely available and have been shown to increase the ADR.17–20 In contrast to regular endoscopes that can zoom up to 30- to 35-fold, a high-magnification endoscope uses either a movable or dual-focus lens on the tip of the endoscope, which allows it to zoom up to 150-fold while maintaining resolution. Magnification endoscopy, often combined with dye-based or digital CE, is useful for the evaluation and classification of polyps once they are detected but has no role in lesion detection.21 Despite these recent advances, up to 22% of adenomas are missed on routine WLE.22
Different Stains Used for Chromoendoscopy
CE refers to a diagnostic visualization method first described in 1977 by Tada et al that uses stains or pigments injected into or sprayed onto the mucosal surface throughout the GI tract.23 Each agent has its own specific properties to localize and characterize lesions, to enhance mucosal detail, and to identify the borders of lesions for endoscopic resection. The agents used are divided into 3 broad categories: absorptive (or vital) stains, contrast stains, and reactive stains (Table 2-1). CE is possible in most clinical settings, given its adequate safety profile and cost-effective, widely available equipment. However, performing CE can be very time consuming and tedious. Methods to make this process easier include application of dyes via integrated water pumps and, more recently, via orally administered delayed-release tablets.24
Lugol’s solution is an iodine-based stain with affinity for glycogen in nonkeratinized squamous epithelium and can be sprayed over the mucosa using a catheter. It is mainly used in the esophagus for the detection of squamous cell dysplasia or carcinoma, the recognition of esophagogastric junction, and the delineation of lesions prior to endoscopic resection. Normal squamous epithelium stains dark brown (positive staining). Neoplastic cells and Barrett’s epithelium are low in glycogen and have a reduced uptake of iodine (negative staining).25–27 Malignant lesions can be recognized by an initial whitish color (Figure 2-3),28 changing to pink after 2 to 3 minutes. Esophageal squamous neoplasms can be recognized with a sensitivity and specificity of 88% and 95%, respectively.29 The literature has been inconsistent about the use of Narrow Band Imaging (NBI, Olympus) vs CE with Lugol’s solution. A prospective study in 2004 by Nagami and colleagues30 showed a similar performance of Lugol’s solution and NBI, whereas a 2017 meta-analysis of 18 studies by Morita et al31 showed superiority of NBI. Because Lugol’s solution can cause mucosal irritation, more than half of the patients experience retrosternal pain and discomfort after the procedure. The use of 20 mL of 5% sodium thiosulfate solution after 17 mL of 3% Lugol’s solution neutralizes the iodine and reduces these side effects.32
Methylene blue CE was first described in detail in 1994 by Canto et al33 and is routinely used to detect intestinal epithelium and to delineate the margins of a lesion for endoscopic resection (Figure 2-4A).28 Normal intestinal epithelium appears blue in the colon and the small intestine, whereas metaplasia, neoplasia, or inflammation shows absent or light staining. Conversely, normal esophageal and gastric mucosa show little or no staining, whereas intestinal metaplasia appears blue (eg, for Barrett’s esophagus [BE] and gastric metaplasia).21 Prior to methylene blue application (0.1% to 0.5%), the surface mucus is washed off by a 10% N-acetylcysteine solution. After application, the excess methylene blue is washed off until the pattern is completely stable; this takes about 60 seconds.
Ex vivo genotoxicity of methylene blue combined with white light has led to safety concerns.34 However, in vivo neoplastic transformation has never been confirmed. A recent in vivo study by Repici and colleagues24,35 demonstrated no clinically relevant DNA damage after oral administration of methylene blue tablets prior to WLE, but additional studies with larger samples sizes are needed.
Crystal violet is absorbed by the crypts of Lieberkühn in the colon and can improve visualization of subtle surface structures of the superficial colonic mucosa, resulting in a clearer pit pattern (Figure 2-4B).28 Additionally, neoplasia and inflamed tissue show less staining than noninflamed mucosa. Crystal violet is commonly sprayed locally over colonic lesions after indigo carmine application. Kudo et al36 published the Kudo classification using a combination of indigo carmine, crystal violet, and magnifying endoscopy to assess pit patterns for the risk stratification of SMI.
Acetic acid (vinegar; 1.5%) interacts with glycoproteins on the mucosal surface. Acetic acid does not color the mucosa, but leads to enhanced surface patterns and disappears after complete neutralization of the acid (Figure 2-5).37,38 Historically, it has been used during colposcopy to detect precancerous lesions on the squamocolumnar junction of the uterine cervix.39 In the GI tract, it has been commonly applied in the distal esophagus for the recognition of intestinal metaplasia in patients with BE. Guelrud et al40 identified 4 different mucosal patterns that implicate a certain diagnostic yield (Table 2-2). The use of acetic acid is relatively cheap, safe, and easy to learn. Another benefit of acetic acid is its mucolytic features.21,25,41
SIM, specialized intestinal metaplasia.
Adapted from Guelrud M, Herrera I, Essenfeld H, Castro J. Enhanced magnification endoscopy: a new technique to identify specialized intestinal metaplasia in Barrett’s esophagus. Gastrointest Endosc. 2001;53(6):559-565. doi:10.1067/mge.2001.114059.