Enhanced visualization techniques are available for Barrett’s esophagus and have promise in the detection of dysplasia and cancer. Several of these techniques, such as narrow band imaging and chromoendoscopy, are being applied clinically. These techniques will allow the endoscopist to screen the surface of the Barrett’s esophagus to detect areas of neoplasia. Once detected, it is hoped that either magnification techniques, such as confocal laser endomicroscopy, or spectroscopic techniques can be of value in allowing in vivo real-time diagnostic capabilities.
Endoscopic equipment: does it matter?
Visualization of small mucosal irregularities is becoming increasingly difficult. In the advent of flat adenomas in the colon to subtle lesions in the esophagus and stomach that represent the earliest signs of malignancy, the need to image better has never been more apparent. The 20% miss rate of colonic polyps is undoubtedly related to the inability to view subtle mucosal irregularities. Fortunately, there have been several technical improvements since the fiberoptic endoscope that not only magnify the mucosa but also enhance the resolution of the mucosa so that subtle lesions can be easily visualized.
Resolution is defined in imaging as the ability to resolve 2 small dots adjacent to each other. A high-resolution endoscope could find differences between 2 dots that look like a single dot on standard videoendoscopy. It will be undoubtedly true that there will be even higher-resolution videoendoscopes in the near future.
In the age of high-definition television and its variants, it is important to understand what is meant by the term resolution and exactly what it means to endoscopy. Most of the time, high-resolution endoscopy is a term that is used to reference the pixel density of the charge coupled device (CCD) in the endoscope. The CCD is the actual silicon chip that captures light and converts this energy into a digital signal. It is important to recognize that this does not mean that just because you are using a high-resolution endoscope you are getting a high-resolution image. The visualization will require a high-resolution processor and a video screen that can display high-resolution images. Standard resolution endoscopes were designed to mimic television standards with resolutions of 640 pixel width and 486 lines vertical (National Television System Committee [NTSC] standard in United States, Japan) versus a 576 lines vertical (Phase Alternate Line [PAL] standard in Europe) with pixel densities of approximately 367,000. High-resolution endoscopes that have recently been developed are generally thought of as those with more than 1 million pixels. Current videoendoscopes approach this but most do not exceed 1 million pixels with color chips. The Pentax i-Flex endoscope (Pentax Medical Company, Montvale, NJ, USA) has a 1.25 million pixel CCD, which is what is needed to be able to display in high definition (1280 × 1024 pixels). The current generation Olympus 180 series endoscope (Olympus America Inc, Center Valley, PA, USA) also has 1280 × 1024 resolution and can display in HD mode. However, this does not mean that the endoscopist will see this in HD because the outputs from the EPK-i (Pentax) processor or the Evis Exera II (Olympus) processor include standard video outputs, including Red Green Blue (RGB), Separate Video (S-video or Y/C), composite outputs (NTSC), and HD outputs.
There are differences with endoscopes, most commonly used in the United States, because they all use a so-called color chip. Each pixel of these colored chips is actually created from 3 separate dots, each representing one of the primary colors (red, green, blue), which allows the chip to present a colored image. However, the color chips are generally larger than their monochromatic counterparts and have less resolution. The highest-resolution endoscopes currently available are monochromatic with a color image generated by a color wheel with red, green, and blue filters placed in front of the chip. As the wheel turns, the particular filter in front of the chip is recorded and that image is saved and blended with 2 other images using the other 2 primary colors to create a composite color image. This type of endoscope has not been well received because of the color-streaming effects that are caused when there is water or rapid motion of the endoscope.
Endoscopic evaluation of Barrett’s esophagus
Barrett’s esophagus is an endoscopically defined condition, so its description is critical to the diagnosis of patients suspected of having the condition. Currently, it is the custom to denote the proximal extent of the Barrett’s esophagus as well as the maximal circumferential extent in terms of distances from these landmarks to the incisors ( Fig. 1 ).
The Barrett’s segment is usually described as being salmon colored in appearance and must be distinct from the gastric mucosa, which is also reddish in color. Because the gastroesophageal junction is difficult to endoscopically define, it is typically chosen to be at the level of the tops of the gastric folds, which can be seen in Fig. 2 where the tops of the folds can be clearly demarcated.
Once the segment length is documented, the next important step is to find any mucosal abnormalities within the mucosal surface. Although there are many different techniques to enhance imaging, it is clear that what is most important is a careful white light examination because most abnormalities can be visualized with a standard endoscope. All mucosal abnormalities should be carefully biopsied. These abnormalities include lesions, such as ulcers, nodules, or just areas of mucosal irregularity ( Figs. 3 and 4 ).
Mucosal abnormalities in Barrett’s esophagus must be carefully inspected. All mucosal irregularities could contain areas of dysplasia or even frank carcinoma. These abnormal areas, according to recent guidelines, should be individually targeted for histologic sampling. In the setting of Barrett’s esophagus with high-grade dysplasia, these abnormalities should undergo mucosal resection because studies have shown that there may be as high as a 40% incidence of carcinoma occurring in these regions. Although white light examination is sufficient to visualize almost all abnormalities, often times there is information that can be obtained using other forms of imaging.
Chromoendoscopy
Chromoendoscopy has also been proposed since the time of fiberoptic endoscopes to enhance imaging. In the esophagus, this was primarily with iodine staining to detect areas of squamous neoplasia. In the case of Barrett’s esophagus, most of the effort has been spent on using either a contrast stain (indigo carmine) typically used with a magnification endoscope (45–200X) to allow visualization of mucosal patterns or an absorptive dye (methylene blue) with an increased uptake that is suggestive of intestinal metaplasia. However, as the area becomes more dysplastic, methylene blue staining decreases ( Fig. 5 ).
A recent meta-analysis was performed of 9 studies and 450 subjects that reported on the yield of using methylene blue as a contrast agent for detection of dysplasia compared with random biopsies. The variation in the results from the studies was quite remarkable with both markedly positive and negative results. Ultimately, a meta-analysis found that the there was no significant difference between methylene blue and random biopsies in detection of dysplasia. In addition, studies have raised concerns that methylene blue could serve as a photosensitizing agent that might lead to DNA damage when used in Barrett’s esophagus. Other agents have been used for chromoendoscopy but there is not sufficient data to draw conclusions regarding their performance.
Narrow Band Imaging
Narrow band imaging (NBI) is a term applied to a specific commercial imaging technique (Olympus America, Center Valley, PA, USA). It involves the use of 2 different wavelengths of filtered light, 415 and 540 nm, for illumination, which is what gives the light a bluish appearance when NBI is activated. The blue illumination, at 414 nm, allows the imaging of the surface capillaries and the green 540 nm illumination allows visualization of vessels at a great depth ( Fig. 6 ).
Multiple studies have been published looking at the values of NBI in Barrett’s esophagus. In particular, criteria have been established to examine vascular as well as mucosal abnormalities. These studies are summarized in Table 1 .
| Authors | Mean Age(y) | Patients (n) | Total Lesions Examined | Study Design | Endoscope Type |
|---|---|---|---|---|---|
| Kara et al 2006 | 65.0 | 63 | 161 | Cross-sectional | GIF Q240Z |
| Post hoc image evaluation | |||||
| Kara et al 2006 | 66.0 | 20 | 47 | Cross-sectional | GIF Q240Z |
| Real-time evaluation | |||||
| Sharma et al 2006 | 64.0 | 51 | 204 | Cross-sectional | GIF Q240Z |
| Image evaluation | |||||
| Curvers et al 2008 | 67.0 | 84 | 165 | Cross-sectional | GIF Q240Z |
| Real-time evaluation | |||||
| Singh et al 2009 | 61.9 | 109 | 1021 | Cross-sectional | GIF Q240Z |
| Post hoc image evaluation | |||||
| Goda et al 2007 | 60.0 | 58 | 217 | Cross-sectional | GIF Q240Z |
| Real-time evaluation | |||||
| Anagnostopoulos et al 2007 | 62.1 | 50 | 344 | Cross-sectional | GIF Q240Z |
| Real-time evaluation | |||||
| Kara et al 2005 | 66.0 | 28 | 36 | RCT, Real-time evaluation | GIF Q260Z |
If one does a meta-analysis on this data, we find that there is a significant advantage in using NBI, particularly in detecting areas of high-grade dysplasia. A pooled sensitivity for the detection of high-grade dysplasia on a per patient basis is 0.88 with a 95% confidence interval of 79% to 93%. It is important to point out that this advantage has been established with a high-resolution endoscope that is not commercially available in the United States. The GIF Q240Z and Q260Z (Olympus America, Center Valley, PA, USA) are high-resolution endoscopes primarily used in Asia and Europe and are not approved by the US Food and Drug Administration (FDA). There is some data to suggest that the GIF 180 series endoscope that is used in the United States is of benefit with NBI, but this benefit has only been found in one study that compared the GIF 180 (Olympus America, Center Valley, PA, USA) series to a low-resolution endoscope. This makes it more difficult to discern whether this improvement in dysplasia detection is caused by increased resolution or NBI. In addition, these studies have been done in enriched populations with high proportions of subjects with high-grade dysplasia. The pooled specificity is probably not relevant to most practices because of this skewed population.
There are other modalities that can enhance the appearance of blood vessels although these rely on postprocessing techniques. The Fuji Intelligent Chromo Endoscopy (FICE) system (Fujinon, Wayne, NJ, USA) uses a white light source and processes the color obtained through spectral analysis, which is obtained from a CCD and a prism mounted on the tip of the endoscope. The light from the endoscope always appears white, unlike the blue-green light seen from the Olympus system. The FICE system is selectable for different enhancement modes that can be optimized for a specific function. There are only small series using FICE for detection of Barrett’s esophagus. The other system is I-Scan from Pentax (Montvale, NJ, USA), which offers 3 levels of postprocessing enhancements to emphasize the contrast, surface, and tone in addition to standard white light examination. These enhancements use the high-definition image to emphasize features, such as color, contrast, or the short wavelengths of light reflected from the surface. These enhancements have been used to increase visualization of mucosal breaks in the esophagus.
Magnification Techniques
Several magnification techniques have been developed to enhance the imaging in Barrett’s esophagus. It should be recognized that standard endoscopes have magnified the image from the esophagus by several fold depending on the size of the viewing monitor, which has made it much easier to appreciate mucosal detail. A variation on the standard endoscope is the endocytoscope, which can be placed on a standard endoscope processor and has a powerful magnifying lens that focuses on the CCD. The endocytoscope is designed to fit through a therapeutic endoscope (outside diameter of 3.4 mm) to allow magnification of suspicious areas. The degree of magnification achieved can either be 450 X or 1100 X depending on the instrument used. To visualize the mucosa, a topical contrast agent, such as indigo carmine or methylene blue, must be applied because high magnification without contrast agents does not allow any imaging. These contrast agents allow for visualization of glandular structures ( Fig. 7 ).
Endocytoscopy has been used to define areas of dysplasia within Barrett’s esophagus, but initial results have not been promising primarily because of difficulties with maintaining a stable image. Because of the high magnification, any motion distorts the image such as that caused by patients’ heartbeat and esophageal motility. Nonetheless, this entity can be useful in determining areas of cancer and dysplasia in controlled situations.
Magnification endoscopes have a 200-fold magnification capability. There is a trade-off with these magnifying endoscopes; generally, the higher the magnification the shorter the focal length of imaging, meaning that the scopes become impractical to use at anything but a targeted lesion. In addition, the endoscopes tend to be of larger diameter, which makes them less tolerable in the upper gastrointestinal tract. Magnification endoscopy has been used in conjunction with chromoendoscopy for more than a decade in Barrett’s esophagus. As with most imaging modalities, there is a problem with inter-observer agreement (k <0.4) because there is difficulty in identifying mucosa types that are glandular in nature, such as between Barrett’s esophagus and gastric-cardia type of tissue. In addition, there is a suggestion that in prospective studies, magnification endoscopy does not enhance detection of intestinal metaplasia.
Confocal Laser Endomicroscopy and Optical Coherence Tomography
Confocal laser endomicroscopy (CLE) and optical coherence tomography (OCT) have similar principles. Both are able to focus laser light to a specific plane deep to the surface and to magnify the appearance of microscopic structures approximately 400 X. Both use light interference as the basis for their effect. In CLE, this focusing is done using a pinhole that focuses the laser light entering the pinhole to light from a specific depth. With optical coherence tomography, there is a reference light path that is used to create interference patterns with the reflected light from the surface. Adjustments in the reference path length have the effect of increase penetration into the mucosa. OCT yields an image similar to B-mode ultrasound with good resolution of layer structure; whereas, CLE offers more of a tangential imaging of the surface glandular structure. Both of these techniques allow better imaging with lateral resolution potential of approximately 10 μ. By giving an intravenous injection of 10% sodium fluorescein, the mucosa can be seen with CLE after 2 to 3 minutes. This contrast enables the confocal laser microscope to view the intravascular space where there are leaks in the capillary membranes and actually see areas of extravasation of dye into the extravascular space. However, this type of imaging does not allow direct visualization of cells and their structure, but only the shadow of the cells that is cast because one is able to image the surrounding parenchyma because of the vascular structures present. Overall, when a disorganized pattern is seen in both the capillaries and the mucosal structure, there is reasonable certainty that there is dysplasia present ( Fig. 8 ).
The reported sensitivity of an endoscope-based system of CLE is 92.9% and a specificity of 98.4% for detection of neoplasia in Barrett’s esophagus in a cohort study of 63 subjects. This system takes advantage of the confocal principles by having a zoom feature that can focus from 0μ to 250 μ from the surface, which allows the user to scan down the length of a gland. Because the LCE obtains views parallel to the surface rather than the perpendicular, as achieved with standard histology, this zoom may be important when trying to differentiate dysplastic lesions. The resolution of this system is also superior to the probe system (0.7 μ vs 1.0 μ for the probe systems) and has a wider field of view (500 μ vs 240 μ). However, the endoscope system is integrated into an endoscope with a diameter of 12.8 mm and the confocal system acquires images continuously at 0.8-second intervals, which leads to a large number of unusable images.
The probe system has also been reported to be approximately 75% sensitive and 90% specific for detection of dysplasia in a small cohort study (n = 38) with 2 endoscopists. This probe system is more convenient to apply because the site that is being optically investigated can be visualized with the endoscope. With the integrated endoscope system, the site being imaged is out of view during the imaging and must be estimated from the distance from a suction mark deliberately made by the endoscopist. An advantage of the dedicated endoscope is reusability; whereas, the probe can only be used 20 times with some degradation of the imaging during reuse. The likelihood that these systems may decrease biopsies is suggested by a recent randomized controlled study with the dedicated endoscope system, which indicated that with the system much more dysplasia can be detected and excluded in other patients. These are promising devices that may supplant or supplement histology in the near future. However, implementation into clinical practice will be dependent on the demonstration that these tools will actually improve patient outcomes in patients with dysplasia or cancer.
Spectroscopy-Based Diagnostic Tools
These tools include devices that can analyze light that is typically scattered or that undergo fluorescence from the mucosal surface. Spectroscopy does not actually give an image; it gives a quantitative assessment of the light that is reflected from the mucosal surface. This assessment can be made on the intensity of the light that is captured or by the amount of light that is detected over a period of time. Both of these methods can give specific information about the tissue type. By using careful analysis of the spectroscopic patterns, an estimate can be made regarding the optical characteristics of the mucosa. This estimate can include nuclear size, crowding, degree of vascularity, and the organization of the intestinal glands. These technologies would incorporate the interpretation of the information into the device rather than require image interpretation by a physician. These are all point technologies that cannot examine an entire area but only potentially suspicious regions.
One of the first spectroscopic technologies was laser-induced fluorescence, which can measure fluorescence from naturally occurring fluorophores, such as flavin adenine dinucleotide (FADH), nicotinamide adenine dinucleotide (NAD), tryptophan, and collagen. Porphyrins are blood breakdown products that also form a large portion of the fluorescent peak. By analysis of the degree of autofluorescence, the determination of neoplasia can be made. Generally, areas with decreased autofluorescence have an increased propensity toward neoplasia. Excitation-emission matrices of areas of cell cultures of keratinocytes and squamous carcinoma cells are shown in Fig. 9 . It is clear that even in vivo, there are distinct differences in the autofluorescence pattern between benign and malignant cell lines.
Related posts:
Barrett’s Esophagus: Clinical Issues
Barrett’s Esophagus Surveillance: When, How Often, Does It Work?
Biology of Barrett’s Esophagus and Esophageal Adenocarcinoma
The Role of Radiofrequency Ablation in the Management of Barrett’s Esophagus
Endotherapy for Barrett’s Esophagus: Which, How, When, and Who?
Role of Minimally Invasive Surgery in the Modern Treatment of Barrett’s Esophagus
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