2.1 Introduction

The rise of modern endoscopy, as well as the sophisticated techniques that it has engendered, is one of the success stories in modern medicine. For centuries, people have been trying to look inside the human body. Early physicians such as those of Arabia, Hippocrates in Greece (460–375 BC), Albukasim (936–1013 AD), and much later, in 1805, the Frankfurt-born physician, Bozzini, were among the first to develop methods to examine body orifices. Throughout the mid-1800s, several scientists attempted to construct endoscope-like instruments. Physicians including Kussmaul and Nitze used their new tools in their medical practice. After Kussmaul introduced the idea and demonstrated the benefits of using a gastroscope, subsequent physicians such as Schindler and Hirschowitz expanded on the ideas set forth by him and developed the first fiberoptic endoscope which advanced the field of endoscopy to where it is today [1]. The endoscopic field has greatly benefited from the close cooperation between physicians, engineers, and manufacturers. As the technology of fiberoptic endoscopes advanced, endoscopes for the examination of the esophagus, the stomach, the duodenum, the colon, the bladder, the lungs, and the upper airways were developed as well. The first models had side-viewing lenses and physicians recognized several problems, for example, with overheating of the endoscope tip by the distal light source. Further technical progresses led to the development of longer endoscopes that were end-viewing and had 360° flexible tips. By 1970, endoscopes could be readily passed into the duodenum and, using the modalities of intraoperative endoscopies, the era of “panendoscopy” had arrived [2]. The next step forward was the introduction of video endoscopes as a result of the progress in television technology. These endoscopes have become the backbone of the endoscopic diagnostic and therapeutic approaches today (Table 2.1).

Modified after [2].

Nowadays, endoscopy is being applied to nearly all disciplines of medicine. In internal medicine, modern flexible video optics enables physicians to visualize and treat many lesions and conditions in the respiratory and gastrointestinal (GI) tract. Originally intended to improve diagnostics, the fields of application were broadened by a variety of therapeutic procedures, which now concur with the corresponding surgical approaches. The essential steps in inflammatory or neoplastic diseases are the following:

• detection
  
• characterization
  
• confirmation.

These steps are required for proper endoscopic diagnosis. New optical methods can help us to improve each of these steps and are likely to increase the detection rate of neoplasia and reduce unnecessary endoscopic treatments. Therefore, this chapter will focus on new imaging modalities such as high-definition (HD) endoscopy, chromoendoscopy, digital chromoendoscopy, and confocal laser endomicroscopy (CLE) in GI diseases, especially GI neoplasia.

GI malignancies continue to be the second leading cause of cancer-related deaths in the developed world. GI malignancies include cancers of the esophagus, stomach, small intestine, colon, rectum, anal canal, liver, pancreas, gallbladder, and biliary system. Although all of these cancers occur in the GI tract, they have very different presentations, treatments, and survival patterns. However, endoscopic procedures play a central role in the diagnosis, staging, and management of all these cancers. It is of central importance that patients with early stage disease have a better prognosis than those with locally advanced or metastatic disease. Therefore, the early detection and treatment of GI neoplasms has been demonstrated to significantly improve patient survival. Conventional screening tools include standard white-light endoscopy (WLE) and frequent surveillance with biopsy sampling. Advanced colonic imaging refers to the use of techniques such as HD white light, standard white light with chromoendoscopy, virtual chromoendoscopy (narrow-band imaging, NBI), autofluorescence imaging (AFI), and endomicroscopy to evaluate the colonic mucosa.

2.2 White-Light Endoscopy

The introduction of fiberoptic endoscopes in the early 1970s meant advancement in endoscopic technology. Fiber optics directly carried the endoscopic image to the eye of the examiner. Despite the progress, its limitations were obvious. Breakage of glass fibers frequently occurred and resulted in increasing numbers of black dots in the visual field, reducing the already limited resolution of the endoscopic image further. The introduction of CCD (charge-coupled device) chips to digitalize the endoscopic image led to a significant improvement in image quality in terms of resolution, color, and contrast. More recently, with the development of HD images, the quality of the endoscopic image has taken a further leap forward. Compared to standard-definition (SD) WLEs, HD colonoscopes have a threefold greater pixel density (410 000 pixels vs up to 1.3 million pixels) and are connected to a processor which is capable of producing a digital high-resolution output of at least 1024 × 768 pixels [3, 4] (Figure 2.1). It seems obvious that the enhanced image quality can be translated into a higher number of pathological lesions being detected by the endoscopist, even more so if the pathological changes are minute or the examiner is less experienced. However, there are only a limited number of high-quality studies supporting this notion. In a recent prospective study comparing the accuracy of SD and HD endoscopes in predicting the histology of small colonic polyps, no difference in sensitivity, specificity, or accuracy between both methods was seen (SD vs HD: accuracy 70% [95% CI 62–77] vs 73% [95% CI 65–80]; P = 0.61) [3].

A multicenter, prospective, randomized, controlled trial including 630 subjects failed to find a difference in the proportion of subjects (patients with at least one adenoma) detected with adenomas [4], whereas a number of studies were able to demonstrate a higher adenoma detection rate using HD endoscopes [5, 6]. Noteworthy, HD endoscopy improved the detection of flat and right-sided colonic adenomas (increased total number of adenomas per patient) [4] and the detection of neoplastic lesions in a high-risk population of subjects with colonic inflammatory bowel disease (IBD) [7]. Flat and right-sided lesions are easily overlooked and can lead to interval cancers. Patients with colonic IBD have an increased colorectal cancer risk and require regular surveillance colonoscopies. This population also quite commonly has flat neoplastic lesions.

The evidence for using HD endoscopes in the upper GI tract is poor. There are, for example, no studies comparing standard to HD WLE in detecting high-grade dysplasia in patients with Barrett’s esophagus. However, detection of neoplastic changes in Barrett’s esophagus appears to be the domain of NBI (see below).

2.3 Chromoendoscopy

The original description of chromoendoscopy for colonic lesions used magnification endoscopy to establish a pit pattern classification [8] that is often used in a simplified manner among western gastroenterologists [9]: Types I (round pits) and II (stellar or papillary pits) usually indicate non-neoplastic lesions, whereas types III (tubular, nonbranched pits), IV (gyrus-like pits), and V (nonstructural pits) predict neoplastic lesions with good accuracy. Detection with chromoendoscopy is especially helpful for unmasking flat and subtle lesions [10] (Figure 2.2). Chromoendoscopy has demonstrated its superiority over SD WLE in multiple studies. A recent meta-analysis of five trials excluding patients with IBDs and polyposis syndromes found chromoendoscopy significantly more likely to detect patients with at least one neoplastic lesion (odds ratio, (OR) 1.67 (CI 1.29–2.15)) and three or more neoplastic lesions (OR 2.55 (CI 1.49–4.36)). Withdrawal times were significantly longer for chromoendoscopy [11]. This not only proves an additional value for chromoendoscopy in the setting of screening colonoscopy but further highlights the adenoma miss rate for SD WLE. It may also explain some of the risks of interval cancers despite a normal surveillance colonoscopy. Many of the interval cancers occur in the right hemicolon and have been attributed to serrated adenomas which are commonly flat and may be missed with SD WLE.

The enhanced detection rate with chromoendoscopy is even more pronounced in patients with ulcerative colitis (UC) and Crohn’s disease (CD) where neoplastic lesions are often flat and multifocal. Randomized, controlled trials have found a three to fivefold increase in the detection rate of intraepithelial neoplasia by the use of panchromoendoscopy [12–17], whereas random quadrant biopsies often do not show an adequate diagnostic yield in this setting [18]. Recent European [19] and American [20] guidelines have endorsed the concept of only obtaining “smart” targeted biopsies of suspicious lesions after chromoendoscopy instead of obtaining random biopsies throughout the colon of patients with IBDs.

Similar concepts have been studied for the detection of intraepithelial neoplasia in Barrett’s esophagus, another condition generally surveyed with random biopsies (“Seattle protocol”). However, application in the upper GI tract has not yielded such convincing results in comparison to WLE as in the lower GI tract. Most endoscopists use acetic acid sprayed onto the mucosa in a 2–2.5% concentration (corresponding to a 1 : 1 dilution of conventional vinegar) (Figure 2.3). Acetic acid induces a temporary change in mucosal surface patterns and highlights the villous architecture of Barrett’s mucosa and helps in detecting irregularities suspected for neoplasia [21, 22]. For esophageal squamous epithelium, Lugol’s solution has been found to be helpful to detect neoplasia (which delineates as a weaker stained area) especially in high-risk patients. In alcoholics, the use of Lugol staining in the esophagus was associated with a significantly enhanced rate of detection of neoplastic lesions [23]. However, Lugol’s solution also unmasks areas of inflammation, which accounted for more than 60% of lesions in this study.

2.4 Virtual Chromoendoscopy

Given the additional time and material required for chromoendoscopy and advances of computer technology, a number of techniques have sought to replicate the contrast enhancement between normal and pathologic mucosa by chromoendoscopy by the switch of a button on the endoscope (“virtual chromoendoscopy”). NBI uses rotating filters to narrow the bandwidth of visible light to around 30 μm within the blue and green spectrum. Blue light is absorbed by the hemoglobin in the capillaries, and the resultant image provides enhancement of the microvasculature of the mucosa. i-Scan and Fujinon Intelligent Color Enhancement (FICE) use post-image-acquisition algorithms to produce a false-colored image with similar results (Figure 2.4). The rationale behind these techniques is that alterations of the capillary structure of superficial GI lesions provide a sufficiently strong contrast against the surrounding normal mucosa to allow the detection and characterization of such lesions. It is important to stress the differences to chromoendoscopy which highlights the pits and crypts of the mucosal surface rather than the vasculature. Another important point is that narrowing the bandwidth of the incident light or post-image-acquisition changes commonly reduced the brightness of the resultant endoscopic image to a certain degree in the first-generation endoscopes.

This may in part explain the fact that virtual chromoendoscopy has so far consistently failed to provide increased adenoma detection rates over HD WLE in a number of randomized trials [10, 24–26], maybe also reflecting higher adenoma detection rates by HD WLE per se [24]. Chromoendoscopy and virtual techniques cannot be combined, as the contrast agent creates an overly dark virtual image. A formal comparison of chromoendoscopy versus HD endoscopy or virtual chromoendoscopy techniques has not been performed so far. On the other hand, virtual chromoendoscopy has been shown to be superior to WLE and comparable to chromoendoscopy with regard to lesion characterization and prediction of histology [27]. Such on-site characterization during ongoing endoscopy may be especially helpful in the stomach for description of gastric neoplasia [28] or as resect-and-discard strategies are discussed for diminutive colorectal polyps. Therefore, virtual chromoendoscopy is commonly used in a targeted manner for further analysis after detection of a lesion with WLE.

2.5 Endomicroscopy and Endocytoscopy

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