High-Resolution and High-Magnification Endoscopy
Endoscopy is used to visually inspect esophageal mucosa and may be used to inspect dysplastic or malignant tissue. The image quality depends upon magnification and resolution. Resolution is the ability to distinguish two closely spaced pixels and is expressed as pixel density. Standard endoscopes carry chips that capture images with a resolution of 640 to 700 pixels wide × 480 to 525 pixels high.
There are three high-resolution endoscope systems available in the United States. The chips in these systems capture images with resolutions of 1280 × 1024 and 1280 × 960, over a million pixels. These high-resolution endoscopes must be used with a high-definition compatible system including processor and monitor. A standard endoscope displays an image that is magnified 30 to 35 times. High-magnification endoscopes use a combination of digital and optical zoom to magnify up to 150 times.21
Higher resolution and magnification improves the quality of the image captured and displayed (Fig. 12-2). Theoretically, this increases the detection of abnormal esophageal tissue like BE or malignancy. However, the majority of studies of high-resolution or magnification endoscopy are also comparing other techniques that are discussed below.
High-resolution endoscopy image of abnormal BE mucosa.
Chromoendoscopy refers to the application of stains or dyes via spray catheter to the gastrointestinal mucosa at the time of endoscopy. Stains available include Lugol’s solution, methylene blue, toluidine blue, and crystal violet, classified as absorptive stains. These stains preferentially absorb in specific cells, allowing for distinction of cell types. Indigo carmine is a contrast dye that absorbs in mucosal defects and can thus identify mucosal irregularities. Finally, reactive dyes such as congo red chemically react under certain conditions like low pH. Acetic acid is an agent that can be sprayed topically during endoscopy but does not dye the mucosa and thus is not technically considered chromoendoscopy. However, it temporarily denatures glycoproteins in the mucosa and will help detect dysplastic or abnormal tissue.22 The major limitation of chromoendoscopy is that it increases procedure time. A high interobserver variability also limits this technique.
Chromoendoscopy can be used throughout the GI tract to detect inflammatory, dysplastic, or neoplastic tissue. In the colon, it is predominantly used for dysplasia surveillance in inflammatory bowel disease. In the esophagus, chromoendoscopy is predominantly used for detection of dysplasia in BE or early cancer, either adenocarcinoma or squamous cell carcinoma.
In methylene blue chromoendoscopy, normal epithelial cells absorb the dye while dysplastic or malignant cells do not. Although several studies showed an increase in diagnostic yield to detect dysplasia in BE using methylene blue as compared with random biopsies, a recent meta-analysis of nine studies failed to show a significant increase in diagnostic yield. However, this result may be an effect of differences in inclusion criteria and application techniques in various studies.23
A digital-based technique to enhance the contrast of mucosal changes may overcome these limitations. To illuminate mucosa, standard endoscopy uses a white light that passes through a rotary RGB filter to separate wavelengths corresponding to red, green, and blue. Narrow-band imaging (NBI) uses a filter with a narrower range that predominantly allows blue (415 nm) and green (540) wavelengths to pass, while blocking red (650 nm) wavelengths.24 Given that longer wavelengths of light penetrate deeper layers of mucosa, the shorter blue and green wavelengths enhance the contrast of the superficial mucosa (Fig. 12-3). As hemoglobin absorbs blue light, NBI is also particularly helpful in assessing microvasculature of the GI mucosa. The narrow-band filter can be switched on and off by the endoscopist, facilitating ease of use with standard white light endoscopy.
Narrow-band imaging of BE mucosa.
As in chromoendoscopy, NBI can be used throughout the GI tract, particularly for detection of early gastric cancer and colonic polyps or dysplasia. In the esophagus, NBI has most been studied in BE. Several classification systems have been devised to characterize NBI findings in BE. One group simplified a classification system into A to D. Grade A was characterized by round pits with regular microvasculature; grade B, villous/ridge pits with regular microvasculature; grade C, absent pits with regular microvasculature; and grade D, distorted pits with irregular microvasculature. This classification was validated in a study where grade A had a high predictive value for columnar mucosa without BE, grades B and C were predictive for nondysplastic BE, and grade D predicted BE with high-grade dysplasia. Low-grade dysplasia could not easily be distinguished from nondysplastic without dysplasia.25
Detection of high-grade dysplasia is important for determining management of BE. Current surveillance guidelines use random four quadrant biopsies every 1 or 2 cm of BE for dysplasia detection, but they may be suboptimal. A recent meta-analysis of eight studies with close to 500 patients examined the accuracy of NBI in detection of high-grade dysplasia with histological confirmation. The pooled sensitivity and specificity was 96 and 94 percent, leading the authors to conclude that NBI has a high diagnostic accuracy for detection of high-grade dysplasia.25
Few studies have directly compared NBI with chromoendoscopy to determine which, aside from endoscopist preference, would be more beneficial in detection of dysplasia. The only randomized prospective study included 28 patients with known Barrett’s and high-grade dysplasia or early esophageal cancer. Each patient was randomized to high-resolution endoscopy with adjunct NBI or high-resolution endoscopy with adjunct chromoendoscopy. Six to eight weeks later the patients crossed over to the other modality performed by a separate endoscopist. Although the majority of high-risk lesions were detected on high-resolution endoscopy alone, both NBI and chromoendoscopy picked up several additional lesions equally well.26
Confocal laser endomicroscopy (CLE) is a tool that enables gastroenterologists to obtain real-time in vivo histology at the time of endoscopy. In CLE, tissue is illuminated with a low-power laser. The laser light is reflected back and focused through the same lens, the size of a pinhole. The images obtained have a high enough resolution (up to 1000×) that histologic information is available (Fig. 12-4). This technique requires administration of an intravenous or topical fluorescence agent. The most commonly used agent is intravenous fluorescein sodium, which is a renally excreted agent that is distributed within 7 to 14 seconds across the vasculature to GI tissue. Various topical sprays that stain either nuclei or cellular cytoplasm may be used as well.27
Confocal endomicroscopy images of esophagus. Image A shows confocal endomicroscopy image of the squamous esophagus (1000× magnification). The arrows point to intrapapillary capillary loops. Arrowheads point to the intracellular spaces between epithelial cells. Image B shows an image of Barrett’s esophagus. The arrows point to the cells in a villiform, glandular pattern.
CLE is available in a probe-based system or an integrated endoscopic system. In the latter, the confocal microscope is integrated into the distal end of a white light endoscope. Images from the integrated scope are displayed on two monitors, concomitantly showing both video and endomicroscopy views. Probe-based CLE systems use a stand-alone confocal probe that can pass through the accessory channel of a standard endoscope.27
CLE has been used to classify colon polyps, determine diagnosis of or direct celiac disease biopsies, detect early gastric cancer, or Helicobacter pylori infection. In the esophagus, CLE is useful in detection of BE and early neoplasia. As in NBI and chromoendoscopy techniques, CLE can distinguish BE from early neoplasia. Confocal endomicroscopy features of high-grade dysplasia include irregular cells with loss of normal cellular pattern, distorted subepithelial capillaries, and leakage of fluorescein.
A clinically relevant outcome using CLE technology is that fewer mucosal biopsies may be needed to detect high-grade dysplasia or early neoplasia. One study randomized 39 patients to standard endoscopy with four-quadrant random biopsies or CLE with four-quadrant optical biopsies as well as targeted biopsies. Several weeks later, the patients were crossed over. The diagnostic yield for high-grade dysplasia or cancer was higher in the confocal endomicroscopy procedures. In those 16 patients who were considered high risk, with suspected but unlocalized neoplasia, there was an almost 60 percent reduction in the number of biopsies needed to obtain the diagnosis. In the remaining 23 patients who were undergoing routine BE surveillance, 65 percent did not require any mucosal biopsies based on confocal images, and no neoplasia was identified.28
Endoscopic Ultrasound and Fine-Needle Aspiration
Endoscopic ultrasound (EUS) adds high-frequency sonographic information via an ultrasound transducer at the tip of the endoscope to provide imaging of the GI wall and surrounding structures. Echoendoscopes are available in three types of designs: radial array, curvilinear array, and probe based. Radial array echoendoscopes provide a 270- to 360-degree view of the surrounding structures whereas curvilinear echoendoscopes provide a 180-degree view parallel to the scope. Some systems have Doppler capabilities to visualize blood vessels.
The curvilinear echoendoscope is ideal for fine-needle aspiration (FNA). The needle, passed through the accessory channel, will be seen in the plane of the ultrasound, allowing for accurate and safe biopsies or other therapies. Needles available range from 19 to 25 gage and can penetrate up to a depth of 10 cm. The risks of EUS without FNA are equal to that of standard endoscopy. Although still quite low at 1 percent, EUS–FNA has a slightly greater risk than EUS without FNA.29 Notably, risk of infection during aspiration of cystic lesions is higher, and antibiotic prophylaxis is warranted.
EUS can be used for diagnosis and management of luminal GI, pancreatic, or biliary disorders. In the esophagus, EUS produces images corresponding to the five histologic layers of the GI tract. The endosonographic images appear as alternating hyper and hypoechoic bands. The innermost band is hyperechoic and corresponds to the lumen or superficial mucosal layer. The second layer corresponds to the lamina propria, the third corresponds to the submucosa, the fourth corresponds to the muscularis propria, and the fifth corresponds to the adventitia. Beyond the adventitia, adjacent structures such as lymph nodes can be visualized (Fig. 12-5). This makes EUS suitable for evaluation of submucosal lesions and staging esophageal cancer.
Radial EUS visualization of layers of the esophagus and adjacent structures. 1, luminal fluid and mucosal surface interface, 2, mucosa, 3, submucosa, 4, muscularis propria, 5, adventitia. Ao, aorta; L, esophageal lumen.
Locoregional TNM staging is vital in determination of surgical or medical management of esophageal carcinoma. EUS has a greater diagnostic accuracy for staging compared with computed tomographic (CT) scanning.30 Furthermore, using cost-effectiveness analysis models, EUS may be more cost effective than other strategies by detection of celiac lymph nodes that would prevent unnecessary surgery.31
Endoscopic Mucosal Resection
Advanced endoscopic therapies may obviate the need for surgery in certain cases. Endoscopic mucosal resection (EMR) is one such therapy that pertains to esophageal pathology, particularly in BE with dysplasia and very early esophageal cancers that have not extended into the submucosa. Although a variety of techniques have been described, the two major methods include EMR with a cap (EMRC) or EMR with ligation (EMRL). The first step to mucosal resection includes injection of a substance, usually normal saline with or without epinephrine, to lift the lesion in question off the muscularis propria. Other solutions like hypertonic saline, 10 percent glycerol/5 percent fructose, 50 percent dextrose, and sodium hyaluronate have also been used.32
EMRC uses a transparent cap fitted to the endoscope. Once the lesion has been lifted, a snare is passed through the accessory channel and opened inside the cap. The lesion is then suctioned into the cap where it can be excised with the snare. EMRL uses a single-band or multiband ligation device similar to those used for treating esophageal varices. The band ligator is deployed, grasping the lesion into a polypoid configuration. This allows for resection via snare and retrieval (Fig. 12-6).
A. BE with nodule B. After endoscopic mucosal resection and submucosal injection of indigo carmine.
The risks of EMR include perforation, bleeding, and stricture formation with large areas of EMR. It appears that EMRC and EMRL have similar safety profiles. Despite these adverse risks, EMR is generally safe in experienced hands and can be done in an outpatient setting.
Esophageal indications for EMR include early esophageal cancer and BE with dysplasia. Accepted criteria for EMR as proposed by the Japanese Society for Gastroenterological Endoscopy (JSGE) include esophageal cancer lesions less than 2 cm in diameter and involvement of less than 1/3 of the esophageal circumference. EMR for lesions extending into the submucosa is contraindicated, and thus relevant investigations like EUS can be considered prior to EMR.
Traditionally, patients with high-grade dysplasia in BE were offered esophagectomy, especially in light of possible concomitant carcinoma. However, now with ablative techniques such as EMR, patients may be offered endoscopic therapy instead. One study found a curative rate of 96.6 percent when treating 279 patients with either high-grade dysplasia (N = 61) or early neoplasia. Patients required an average of two EMR sessions to achieve complete response. Risk factors associated with local recurrence included piecemeal resection, long-segment BE, lack of post-EMR ablative therapy (see the sections below), time to complete response greater than 10 months, and multifocal neoplasia.33
Photodynamic therapy (PDT) is another ablative technique for BE and early esophageal cancer. PDT can be used alone or may follow EMR to ablate residual dysplastic tissue after resection of focal lesions. The principle behind PDT is that when exposed to intense light, certain photosensitizing chemicals produce oxygen and other radical species. These radical species cause nonthermal cellular necrosis and vascular thrombosis. The only systemic photosensitizer approved by the FDA is porfimer sodium. It is given as an intravenous infusion over 3 to 5 minutes. Porfimer sodium is absorbed by most tissues but is selectively retained in neoplastic tissue. After approximately 48 hours, the photosensitizer is only retained in neoplastic tissue and has cleared normal tissue. Thus, PDT endoscopic therapy is usually scheduled 48 hours after infusion.
Porfimer sodium becomes activated in response to light at 515 and 630 nm wavelengths. Therefore, a specific light source has to be used at endoscopy, in contrast to standard white light endoscopy. The FDA-approved 630 nm red light source that is available also contains an automatic feature to change power and duration of treatment based on indication of procedure (e.g., BE vs. carcinoma). A variety of catheters and balloon catheters are available to deliver light to pretreated tissue in a circumferential fashion. Treatment is delivered for 8 to 12 minutes depending on indication.34
The major risk of PDT is stricture formation. Risk factors for this complication include long-segment BE, multiple PDT treatments, preceding EMR, history of chemoradiation, and history of prior stricture. As some residual photosensitizer remains in the patient’s skin for up to 30 days, they are advised to avoid direct sunlight as severe sunburns can result.
Radiofrequency ablation (RFA) is another technique used in BE and other conditions. RFA can be performed circumferentially or focally. Circumferential RFA in the esophagus uses a 3-cm balloon ablation catheter in which resides a coiled electrode array. Two pulses of electric current at an energy level of 10 to 12 J/cm2 are sufficient for ablation of full-thickness epithelium, without damaging the submucosa. Prior to placement of the balloon catheter, the esophageal luminal diameter has to be measured. The balloon ablation catheter’s outer diameter must not be greater than the esophageal luminal diameter. The balloon ablation catheter is introduced via guidewire, followed by the endoscope.
Focal RFA is usually performed after circumferential ablation, if residual Barrett’s tissue remains or when small amounts of BE are present. Instead of a balloon ablation catheter, focal RFA uses an electrode array that is mounted at the tip of the endoscope and seen in the 12 o’clock position.
As in EMR and PDT, RFA can be used for BE with high-grade dysplasia. However, it also has a role in low-grade dysplasia to prevent progression to high-grade dysplasia and cancer. Although more controversial, RFA can also be used in BE without dysplasia. Recently published was the longest running study, AIM-II, which followed 50 patients who had RFA of nondysplastic BE. At 2.5 years, 98.4 percent of patients had complete eradication of all metaplastic tissue. At 5 years, 92 percent still had complete eradication, while the remaining patients obtained complete eradication with further treatment with focal RFA.35 Complications of RFA include bleeding, strictures, and postprocedure pain.
Cryotherapy is a nonthermal noncontact ablative technique that, when applied via endoscopy, causes freezing of the mucosa and induction of necrosis. The technology is based on the Joule–Thomson effect that dictates that the temperature of a liquid gas will drop when the surrounding pressure drops. There are currently two cryoablation systems available, one based on liquid nitrogen and the other on carbon dioxide. The cryoablation system includes a pressurized canister of compressed gas or liquid nitrogen. This cryospray is delivered to esophageal tissue via a single-use side or end-firing catheter that passes through the standard endoscope accessory channel. Once the gas is released from the tip of the catheter, tissues sprayed freeze in the context of decreased pressure. A suction tube is affixed to the tip of the endoscope or passed separately next to the scope to simultaneously remove evacuated gas that would distend the GI tract. Each application lasts 10 to 20 seconds and multiple applications can be performed to one area, with 10 to 30 seconds in between each to allow for thawing.
Cryotherapy can ablate tissues throughout the GI tract and has been studied in gastric antral vascular ectasia (GAVE) and radiation proctopathy. In the esophagus, cryotherapy is another ablative technique for BE and early carcinoma. Early data for cryotherapy suggest that it can eradicate high-grade dysplasia in a high proportion of patients.36
Endoscopic Submucosal Dissection
Endoscopic submucosal dissection (ESD) is a technique used to remove esophageal lesions that are flat and greater than 2 cm. This provides the pathologist the opportunity to examine the tissue en bloc. The lesion is not removed via a modified “polypectomy” as in the EMR technique. The initial step of ESD involves marking the margins with electrocautery. Next, the lesion is lifted with submucosal injection as described in the EMR section. An incision is then made in a circumferential manner with a special endoscopic electrocautery knife. A variety of electrocautery knives have been developed for use. Once the lesion is dissected off the deeper layers, it can be removed en bloc.
ESD can be a time-consuming procedure, lasting over an hour for one lesion. Complications include acute or delayed bleeding, perforation, and stricture. Perforation rates for ESD are higher than those of EMR.37 The most experience with ESD comes from resection of early gastric cancer in Asia. However, ESD can be applied to high-grade dysplasia or early esophageal cancer as well.
Esophageal dilation can be used to manage benign and malignant esophageal strictures, postsurgical anastomotic strictures and is a mainstay of therapy for achalasia. There are two basic kinds of esophageal dilators: balloon-based dilators and mechanical (Bougie) dilators. Balloon dilators are typically passed through the scope and through the stricture (Fig. 12-7). For narrow strictures, wire-guided balloons are available. There are several types of mechanical dilators, such as Maloney dilators, which are not wire-guided, and Savary dilators that are wire-guided. Fluoroscopy is helpful for guiding dilation of difficult or proximal esophageal strictures. Balloon dilators disrupt strictures by exertion of radial force, while mechanical dilators exert force radially and longitudinally. Potential complications of esophageal dilation include esophageal perforation and bleeding. The “rule of threes” for esophageal dilation suggests that no more than three dilators of increasing size should be used in each dilation session, which allows increasing the lumen of the stricture by about 3 mm.38
Through the scope (TTS) balloon dilation of esophageal stricture.
With mechanical dilators, the amount of resistance of a stricture can be felt by the endoscopist passing the dilator, which also helps guide therapy. Achalasia dilation is performed with 30- to 40-mm pneumatic balloons, typically with fluoroscopic guidance. Symptomatic improvement in dysphagia is as high as 85 percent, but dysphagia returns in one-third to half of patients.39 Complications of dilation can include bleeding and esophageal perforation, with rates of 0.1 percent for simple dilations and 3 percent for large pneumatic dilations.40
Esophageal stents are used to maintain the lumen in a variety of benign and malignant conditions. Stents are either self-expanding metal stents (SEMS) or self-expanding plastic stents (SEPS). SEMS are composed of woven metal meshes that expand to exert radial force until the maximum diameter is reached. Multiple sizes and diameters are available. Certain metals are more flexible and are thus more appropriate for stenting across angulations. SEMS have flares on one end to prevent migration. SEMS can be wholly or partially covered with a polymer membrane to prevent tumor infiltration. This allows for future repositioning or removal. In contrast, ingrowth of tissue prevents the ability of uncovered SEMS to be removed or repositioned.
SEPS are completely covered with a silicone membrane to prevent tissue ingrowth. They were designed to facilitate ease of repositioning and removal. However, SEPS have high rates of migration and may not have long-term clinical efficacy for malignant conditions. Decision to use a SEPS as opposed to a covered SEMS has to be carefully made.
Esophageal stents are deployed over a guidewire, generally with fluoroscopic guidance. Esophageal lumens less than 12 mm require dilation prior to successful placement of SEMS. Complications of esophageal stent placement include bleeding and perforation. Particularly with bulky upper esophageal tumors, airway compression as the stent expands can be life threatening and simultaneous bronchoscopy with tracheal stent placement should be considered. Another complication of stent placement is pressure necrosis with subsequent fistula formation.
Indications for esophageal stenting includes palliation for unresectable esophageal cancer. Dysphagia may be relieved in a high proportion of patients, improving quality of life. Esophageal stents have also been used in benign esophagotracheal fistulas, anastomotic leaks, or perforations. Although results have been favorable in multiple case series and observational studies for these conditions, there are no randomized control trials comparing stents to surgical therapy. Esophageal stents for benign esophageal stricture are used occasionally, but much less frequently than in malignant disease and with careful patient selection.41