Gastrointestinal Endoscopy in the Cancer Patient

This book is a full colour, highly clinical multi-media atlas focusing on the role diagnostic and therapeutic endoscopy plays in the management of patients with cancer. Conveniently split into sections for each part of the GI tract, each section will follow a consistent structure. With 400 high-quality images and in addition, 21 high-definition videos showing endoscopy from the experts, this book is the perfect consultation and learning tool for all gastroenterologists, endoscopists, GI surgeons and oncologists.

• Language: English
• Publisher: Wiley
• Release date: Feb 26, 2013
• ISBN: 9781118555750

Book preview

1

Introduction to Gastrointestinal Endoscopy in the Cancer Patient

Matthew R. Banks¹ and John C. Deutsch²

¹University College London Hospitals NHS Trust, London, UK

²Essentia Health Systems, Duluth, MN, USA

Key points

Gastrointestinal endoscopy is important in the diagnosis and management of gastrointestinal and some non-gastrointestinal cancers.

There are many types of gastrointestinal endoscopes and many devices to assist in taking biopsies, performing resections, and palliating bleeding or obstruction.

Over the last decade, endoscopy has vastly improved the diagnosis, staging, and treatment of patients with cancer affecting the gastrointestinal tract. The complexity and range of procedures now available to manage these patients has led to the development of endoscopists with expertise covering specific conditions such as hepatobiliary or esophagogastric cancers. It is of great importance to ensure that patients receive the best care. In order to achieve this, it is important to ensure that the multidisciplinary team managing patients, with not only gastrointestinal cancers, but other malignancies as well, is fully informed of all available endoscopic procedures. This book demonstrates the current endoscopic procedures available in order to manage patients with malignant and premalignant conditions of the gastrontestinal tract. It will hopefully be of benefit to endoscopists, oncologists, gastroenterologists, and surgeons, as well as all those involved in cancer patient care, both as an informative read and as a reference guide.

The current practice of gastrointestinal endoscopy generally involves placing a flexible tube with a light source, video-chip capture, and a working channel within a luminal structure of the gastrointestinal tract (Figures 1.1, 1.2, and 1.3). The image lens can be in the front, on the side perpendicular to the long axis, or in an oblique orientation of the endoscope (Figures 1.3a–1.3c).

FIGURE 1.1 A cabinet of endoscopes.

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FIGURE 1.2 A radial array endoscope just before use.

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FIGURE 1.3 (a) The tip of a colonoscope with forward viewing optics. (b) The tip of a duodenoscope with side viewing optics. (c) The tip of a linear array echoendoscope. (Reproduced and used with permission from Pentax Medical Company.)

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Fiber optic endoscopy was first described by Hirschowitz et al. in 1957 (1). There have been many improvements in image quality since that report, and the resolution of the images obtained has been revolutionized by megapixel charged coupled devices (video-chip) and 1080p high-definition screens. This has enabled the endoscopist to visualize the mucosal architecture and vasculature in detail not imagined by the earlier investigators. Endoscopes that use different wavelengths of light or various computer-generated modifications have been developed, as seen with selected light wavelengths such as narrow band imaging (Figure 1.4) or various computer enhancements such as iScan and magnification (Figure 1.5). Further detail can be achieved with confocal laser endomicroscopy which utilizes blue laser light focused on a single horizontal level. Magnification on special instruments can be generated to 1000-fold, resulting in images at the cellular level mimicking histopathological sections. One can now appreciate changes suggesting early epithelial neoplasia.

FIGURE 1.4 (a) Esophageal gastric junction by white light. (b) The same location using narrow band imaging.

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FIGURE 1.5 High-grade dysplasia and Barrett’s mucosa using ISCAN 2.

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Endoscopes with ultrasound probes in the tip have been developed (Figures 1.3c and 1.6a and 1.6b) which allow visualization through the intestinal wall. Ultrasound images can be created perpendicular to or parallel to the endoscope, and needles can be placed into lesions under endoscopic guidance (Figures 1.7a and 1.7b).

FIGURE 1.6 (a) A radial array EUS endoscope with a biopsy forceps in the working channel. (Reproduced and used with permission from Pentax Medical Company.) (b) An EBUS endoscope with a needle in the working channel. (Reproduced and used with permission from Pentax Medical Company.)

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FIGURE 1.7 (a) A stromal tumor visualized with radial array EUS. (b) The same lesion seen with linear array EUS during needle aspiration.

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Gastrointestinal endoscopes are from 5 to 13 mm in diameter, and generally 100 to 180 cm in length. Some specialized endoscopes are shorter (such as the 60 cm endobronchial ultrasound instrument that is also used in the esophagus) and some are longer (e.g., a 220 cm small bowel enteroscope). There are instruments that are narrower, such as a 2.8 mm diameter choledochoscope or a 2 mm ultrasound miniprobe. White light is commonly used with a curved lens that gives about a 10-fold magnification, depending on the distance of the endoscope tip from the image object. Endoscopes have a hollow channel (Figures 1.3a and 1.3b and 1.6a and 1.6b) to allow the passage of various tools such as biopsy forceps, snares, clips, needles, dilators, and hemostasis devices (Figures 1.8a–1.8f). This allows biopsy, snare, closure of defects, and control of bleeding. Devices that use the outside of the endoscope as well as the internal channel to allow resection while minimizing the risk of perforation are also available (Figures 1.9a and 1.9b). Palliative therapy such as stenting to open a stricture is commonly performed. There are several types of stents and delivery devices that are available (Figures 1.10a–1.10c). Stents can be passed either through the scope or positioned with endoscopic and fluoroscopic assistance.

FIGURE 1.8 Some peripheral devices that can be used during endoscopy. (Images (a–e). Permission for use granted by Cook Medical Incorporated, Bloomington, IN.) (a) Biopsy forceps; (b) snare; (c) endoclip Instinct Clip; (d) EUS needle ProCore; (e) dilator; (f): hemospray coagulation device.

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FIGURE 1.9 (a) The upper handle of a band ligation device with a snare in the working channel. Duette Band Ligation Device. (b) The endoscope tip of a band ligation device. Small rubber bands on the end of the endoscope are placed around a lesion creating a pseudopolyp. A snare is used to remove the pseudopolyp. Duette Band Ligation Device. (Images a–b. Permission for use granted by Cook Medical Incorporated, Bloomington, IN.)

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FIGURE 1.10 (a) Various types of stents. (Reproduced and used with permission from Boston Scientific.) Wallstents. (b) Example of a stent deployment devices. (Reproduced and used with permission from Boston Scientific.) (c) Example of a stent deployment device. (Permission for use granted by Cook Medical Incorporated, Bloomington, IN.)

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Capsule endoscopy is different from the usual endoscopic examination. With this method, a camera within a pill (Figure 1.11) is ingested and images are transmitted to recorders on the surface of the patient—up to 50,000 images are collected over 8 h and then reviewed as a video file.

FIGURE 1.11 Pill CAM device in package prior to use.

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With the wide array of instruments and peripherals, gastrointestinal endoscopy has evolved from primarily a luminal diagnostic procedure to a procedure in which luminal and extraluminal diagnostic and therapeutic interventions are routinely performed.

Endoscopy is very important in the management of patients with premalignant and malignant conditions. Pathological diagnosis using direct visualization biopsy or by endoscopic ultrasonography-guided needle aspiration, evaluation for secondary tumor effects (bleeding, obstruction), curative therapy (endoscopic resection, thermal ablation), and palliative therapy (biliary stents, celiac block) are all part of what an endoscopist can do (Video 1.1).

The following chapters describe what endoscopists can offer in the management of patients with oncologic conditions, as well as an oncologic perspective in the management of various tumor types.

Chapter video clip

Video 1.1 The video shows a dysplastic esophageal lesion as seen under white light and then under ISCAN2.

Reference

1. Hirschowitz BI, Peters CW, Curtiss LE. Preliminary report on a long fiberscope for examination of stomach and duodenum. Med Bull (Ann Arbor). 1957;23:178–180.

2 Esophagus

2

Staging of Premalignant and Malignant Conditions of the Esophagus

Rehan J. Haidry and Matthew R. Banks

University College London Hospitals NHS Trust, London, UK

Key points

Leiomyomas are the most common intramural mesenchymal tumor of the esophagus and outnumber esophageal GISTs by two- to threefold.

Granular cell tumors of the esophagus are rare and account for 0.0019–0.03% of all tumors affecting humans, and malignant transformation is rarer still.

Barrett’s esophagus (BE) is the most important precursor lesion of esophageal adenocarcinoma (EAC) and it is thought that 64–86% of all EACs arise in BE.

The incidence of EAC for patients with BE appears to be increased 30- to 100-fold above that for the general population.

Targeted biopsies of abnormal areas in BE with optical enhancements such as narrow band imaging, iScan, and FICE are likely to improve the diagnosis of dysplasia or early cancer.

In expert hands, confocal endomicroscopy has a sensitivity of 92% for the diagnosis of Barrett’s dysplasia.

EUS is useful for nodal staging in early esophageal cancer but inaccurate for T-staging. EUS is the most accurate technique for T- and N-staging in advanced esophageal cancer.

Introduction

Accurate diagnosis and staging of benign and malignant lesions of the esophagus requires an in-depth understanding of current endoscopic techniques and the latest technology. The endoscopic optical technology has evolved rapidly in the last decade such that the resolution of the charge coupled device (CCD) chip is up to 1.4 million pixels. The images are further enhanced by optical filters and post image processing technology, allowing detailed views of the mucosal architecture. This, in turn, allows improved accuracy of diagnosis. We explore the roles of high-definition white light endoscopy (HD-WLE), chromoendoscopy, confocal endomicroscopy, and EUS in the diagnosis and staging of esophageal neoplasia.

Benign lesions

Granular cell tumors

Introduction and endoscopic diagnosis

Granular cell tumors (GCT) are relatively infrequent lesions that were initially described by Abrikossoff in 1926. In 1931, he described the first case of this kind of neoplasia located in the esophagus and since then some 300 cases of GCT have been documented (1). Most cases of esophageal GCT are asymptomatic or are incidentally diagnosed at the time of upper gastrointenstinal (GI) endoscopy investigating alternative pathology. GCTs are estimated to account for 0.0019–0.03% of all tumors affecting humans. The most frequent locations are the tongue (40%), the skin (30%), breasts (15%), and the GI tract (2.7–8.1%) (2). Approximately one-third of the tumors located in the GI tract affect the esophagus (1–2%) and of these the most frequent location is the distal third (65% distal third, 20% middle esophagus, and 15% proximal third) (3).

Histologically, different cell types have been attributed as the source of this tumor. However, the most widely accepted theory is that it is of neurogenic origin (Schwann cells), which, in the case of the esophagus, form part of the submucosal neuronal plexus.

At endoscopy, the findings are usually that of a yellow, firm, well-circumscribed submucosal neoplasm with reduced vascular pattern. Other endoscopic characteristics of esophageal GCT that have been described are those of small isolated sessile, submucosal nodules of firm consistency and that are molar-like in appearance covered by intact or normal whitish or yellowish mucosa (4).

Staging

Histologically GCTs demonstrate that immunohistochemical staining shows positive for S100 protein, vimentin, specific neuronal enolase, laminin, and various myelin proteins. These data prove that the lesions are neural in nature and are histogenetically similar to Schwann cells. Malignant tumors tend to have a high positivity for p53 and Ki67 proteins. Malignant transformation of these lesions is very rare. Due to the rather nondescriptive macroscopic appearances of these lesions, endoscopic ultrasound (EUS) is the gold standard staging modality for these lesions. At EUS, esophageal GCTs are normally observed as hypoechogenic, homogenous lesions with regular borders growing from the mucosa and/or submucosa. Palazzo et al. (4) performed EUS on 15 patients with 21 lesions diagnosed by endoscopy as being compatible with esophageal GCT although the biopsies were negative. Following the EUS, 20 lesions were endoscopically resected while one was surgically resected. In each case, the biopsies confirmed the diagnosis of GCT. EUS also permits fine needle aspiration (FNA) cytology at deeper layers, but sensitivity is low for small esophageal submucosal malignant tumors.

GIST/leiomyoma

Introduction and endoscopic diagnosis

Esophageal gastrointestinal stromal tumors (GISTs) are uncommon, with only 0.2–0.7% of all GISTs found in the esophagus with the majority arising in the stomach. The relative frequency of esophageal GISTs among all esophageal mesenchymal tumors has been reported to be approximately 25% (5); esophageal leiomyomas on the other hand are the most frequent mesenchymal tumors of the esophagus, but are rare elsewhere in the GI tract. Both GISTs and leiomyomas are often discovered incidentally at gastroscopy, although if large enough may cause symptoms such as dysphagia. At endoscopy they often appear as smooth, well-circumscribed lesions with normal overlying mucosal and vascular patterns. Leiomyomas are most commonly found in the distal two-thirds of the esophagus and the gastroesophageal junction (GOJ) region. Leiomyomas are the most common intramural mesenchymal tumor of the esophagus and outnumber esophageal GISTs by two- to threefold (6).

GISTs were formerly thought to be smooth muscle tumors of the GI tract and were classified as leiomyomas or leiomyosarcomas. The expression of the c-kit proto-oncogene protein in GIST helps to differentiate them from true leiomyomas. GIST and leiomyomas are shown on radial EUS as hypoechoic mass lesions arising usually from the fourth layer (muscularis propria) or sometimes second layer (muscularis mucosae). It has been suggested that certain EUS characteristics may raise the possibility of a malignant change (7). These include tumor size >4 cm, irregular extraluminal border, echogenic foci, and cystic spaces. A National Institute of Health consensus conference recognized the inadequacy of characterizing these lesions as benign or malignant and suggested a malignant potential from very low to high based on size and mitoses per 50 high power field (HPF) (7). It is now standard practice that all patients with leiomyomas or GIST should undergo linear EUS-guided FNA. Specimens should be stained for c-kit (to differentiate GIST from true leiomyoma) and an attempt to quantify mitotic rate per 50 HPF.

Staging

Most GISTs are asymptomatic and benign, but around 15% are malignant (8). Endoscopic biopsies are often negative because the GIST is a submucosal tumor situated deep in the esophageal wall, inaccessible to routine biopsy. Endoscopic ultrasonography is the most appropriate technique for staging tumors of these lesions. EUS diagnosis of a GIST is based on the finding of a hypoechoic mass contiguous with the fourth hypo echoic layer (muscularis propria) or the second hypoechoic layer (muscularis mucosae) of the normal wall. Palazzo et al. (9) showed that irregular extraluminal margins, cystic spaces, and lymph nodes with a malignant pattern were most predictive of malignant or borderline GISTs.

Fibrovascular polyps

Introduction and endoscopic diagnosis

Fibrovascular polyps of the esophagus are rare benign lesions that arise from the cervical esophagus. Most are only diagnosed when their size induces symptoms. They comprise about 1% of all benign esophageal tumors; however, they are the most common intraluminal benign tumors of the esophagus (10). They can vary significantly in size. Even though they are benign, they may be lethal due to either bleeding or, rarely, asphyxiation if a large polyp is regurgitated. Patients commonly present with dysphagia or hematemesis. Fibrovascular polyps are believed to begin as sessile polyps that elongate as a result of propulsive forces from peristalsis of the esophagus (11). The tumors are covered in normal squamous epithelium and are composed of loose or dense fibrous tissue, adipose tissue, and vascular structure.

Staging

Endoscopy will demonstrate normal overlying mucosa. The EUS displays a hypoechoic or hyperechoic lesion depending on the proportion of adipose, fibrous, and vascular tissue and can define the layer of origin. Magnetic resonance imaging (MRI) is useful for acquiring valuable information about fibrovascular polyps (12). Sagittal images on MRI show whether the polypoid lesion is located intra- or extraluminally and where the stalk originates.

Esophageal squamous papilloma

Introduction and endoscopic diagnosis

Esophageal squamous papilloma (ESP) is a relatively rare, benign, squamous epithelial tumor, which is generally small, single, round, and elevated sessile lesions with smooth or rough surfaces. Patients are almost always asymptomatic and without characteristic symptoms. The upper GI endoscopy is usually performed because of associated peptic disease symptoms. Squamous papilloma of the esophagus generally appears as a single, round, and elevated sessile formation, well delineated from the surrounding tissue. Some of the reported cases have demonstrated multiple lesions, but only a few cases have been reported as true esophageal papillomatosis (13). Several case studies have demonstrated squamous carcinomas associated with papillomatosis. Papillomas are usually small in size (on average 0.6 cm), although they have been reported to be up to 2–5 cm (14). The esophageal papilloma is usually whitish or pinkish in color, with a soft consistency and a smooth or slightly rough surface, and is characteristic but not pathognomonic in appearance at endoscopic examination.

They have also been described as a wart-like lesion, most commonly in the middle and distal esophagus, and can be removed endoscopically.

Papilloma staging, human papilloma virus, and esophageal squamous cell carcinoma

There are no data available on the accurate EUS staging of these lesions and there are no large follow-up series on these lesions. The prevalence of human papilloma virus (HPV) in esophageal papillomas appears to be as high as 80% and in squamous cell carcinoma has been reported to be as high as 46% in nonkeratinizing squamous carcinomas, suggesting an association with both lesions. The malignant potential, however, of HPV infection of both the esophagus and squamous papillomas remains unclear.

Barrett’s esophagus

Introduction and endoscopic diagnosis

Barrett’s esophagus (BE) is a change in the esophageal epithelium, in which any portion of the normal squamous lining has been replaced by metaplastic columnar cells visible macroscopically at endoscopy. BE is the most important precursor lesion to esophageal adenocarcinoma (EAC). It is thought 64–86% of all EACs arise in BE (15,16). The incidence of EAC for patients with BE appears to be increased 30- to 100-fold above that for the general population (17,18). BE progresses through a series of cellular and molecular changes from intestinal metaplasia (IM) to low-grade dysplasia (LGD) and high-grade dysplasia (HGD). Progression to EAC from HGD can be as high as 16–59% within 5 years of diagnosis. (19,20,21,22). It is therefore paramount to try to accurately visualize areas of BE and to identify premalignant and dysplastic lesions to help target minimally invasive therapies that are now curative.

Prague C & M criteria

To accurately document the nature of BE the International Working Group for Classification of Oesophagitis (IWGCO) developed the Prague C & M criteria (23). This scoring system is based on the circumferential (C value, in cm) and the maximal extent (M value, in cm) of BE above the gastroesophageal junction (GOJ) (see Figure 2.1).

FIGURE 2.1 Representation of Prague C & M scoring system.

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The BE in Figure 2.1 illustrates a circumferential segment for 2 cm above the GOJ with a noncircumferential tongue extending to 5 cm above the GOJ. This would be recorded as C2M5. The consensus group in this study decided that true islands of squamous and columnar mucosa should not influence the measurement of extent of BE and that only segments of contiguous BE are measured. The proposed scoring system was validated in a study using 29 digital recordings of endoscopies. Internal validation yielded a high reliability coefficient value for agreement on the presence of BE >1 cm (r = 0.72).

High-definition white light endoscopy

Video endoscopy relies on a CCD chip to enhance image resolution and magnification. Standard definition (SD) WLE is rapidly being replaced by the introduction of HD endoscopes. Video endoscopes use white light from a xenon or halogen source for illumination. The reflected light is captured by a CCD chip at the tip of the instrument in order to reconstruct the images. Conventional SD endoscopes are equipped with CCD chips that produce an image signal of 100,000–400,000 pixels, which is displayed in SD format. The chips currently in use in HD endoscopes produce resolutions that range from 850,000 to 1.3 million pixels. In order to generate a true HD image, each component of the system (e.g., the endoscope CCD chip, the processor, the monitor, and transmission cables) must be HD compatible.

The use of chromoendoscopy, magnification endoscopy, and enhanced optical enhancements such as iScan and narrow band imaging (NBI) coupled with the rapidly evolving technology of HD-WLE have led to unique criteria for BE diagnosis and mucosal classification systems.

Chromoendoscopy

The use of chromoendoscopy in the GI tract was first described in 1977 (24) and involves the topical application of stains or pigments to improve visualization of the mucosa during endoscopy. There are three main types of stains that are used:

i absorptive stains (methylene blue (MB), Lugol’s solution);

ii contrast stains (indigo carmine, acetic acid);

iii reactive stains such as Congo red or phenol.

There are two essential principles of chromoendoscopy: First, the removal of mucous, followed by dye application. The former is achieved by using water; occasionally, some centers have advocated the use of a mucolytic agent, N-acetylcysteine (25,26,27). Mucous can be removed by flushing the agent through the working channel using a spray catheter or even administering it as an oral solution before the endoscopic procedure. Once the mucous is cleared, the dye can then be applied.

Methylene blue chromoendoscopy

MB, an absorptive dye, is probably the most investigated stain for the evaluation of BE. MB is applied topically at a concentration of 0.5–1.0% and is absorbed by goblet cells that are present in metaplastic Barrett’s epithelium. Much of the early work on MB has been performed by Canto’s group (28). The first series, published in 1996, assessed 14 patients with BE and 12 control patients. MB stained specialized columnar epithelium in 18 of the 26 patients, including those with intramucosal carcinoma (IMC) (1), HGD (1), and indefinite/low-grade dysplasia (6). The overall sensitivity of MB staining for the biopsy finding of specialized intestinal metaplasia (SIM) was 95%. The same group then went on to a prospective, sequence randomized trial of MDMB versus standard surveillance endoscopy with 2 cm quadrantic biopsy (29). Forty-one patients were studied with each procedure performed by separate endoscopists within an interval of 3–4 weeks. The average number of biopsies was significantly lower with MBDB than 2 cm quadrantic biopsy but the MB staining added a mean of 7 min (range 2–12 min) to the endoscopy procedure. Dysplasia or cancer was diagnosed in significantly more biopsy specimens (12% (30,31) vs. 6%, p = .004) and patients (44% vs. 28%, p = .03) by MBDB than by random biopsy technique.

The problems with MB in BE is that dysplastic areas do not stain. Furthermore, even areas that do not harbor IM do not absorb the dye. This makes it difficult for the endoscopist to decide on which areas to target the biopsies during the procedure. There are also some issues with the uniformity of the dye. It has been examined in both long- and short-segment BE (30,31,32). Two patterns of staining have been documented—diffuse and focal. Canto et al. (32) found that most patients with long-segment BE exhibited diffuse staining, whereas Wo et al. (33) observed focal staining in their cohort of patients with long-segment BE. Similar results have been found when examining short-segment BE by Sharma et al. (34) who found that the majority of their patients with short-segment BE stained diffusely. In contrast, in 30 patients with short-segment BE assessed by Kiesslich’s group (35), only 80% demonstrated staining in a focal pattern.

A meta-analysis assessing the diagnostic yield of MB in detecting intestinal and dysplasia in BE looked at 9 published studies that included 450 patients. Despite controlling for differences in technique and quality of published data, the meta-analysis showed no significant benefit of MB chromoendoscopy compared with random biopsies in detecting SIM, dysplasia, or early esophageal cancer (36).

Acetic acid chromoendoscopy

There is a growing body of evidence that magnification chromoendoscopy with acetic acid improves the diagnosis of SIM, although evidence for improved diagnosis of dysplasia is currently lacking. The technique is advantageous as it is both safe and inexpensive. When topically applied to multilayered squamous epithelium, the acetic acid is progressively neutralized by mucus covering the epithelium and the underlying stroma and the vascular network are protected (37). In single-layered, columnar-lined esophagus the acetic acid reversibly alters the barrier function of the epithelium and reaches the stroma and vascular network. This leads to swelling of the mucosal surface and enhancement of the surface architecture. There is also enhancement of vascular pattern due to congestion of the capillaries. Transient changes to the structure of cellular proteins may also occur.

All of the studies using acetic acid have combined magnification endoscopy to study the pit pattern of the mucosa. Classification is based on Guelrud’s description of four typical pit patterns: gastric patterns (pattern I = pits with a regular and orderly arranged circular dots; pattern II = reticular pits that are circular or oval and are regular in shape and arrangement) and SIM patterns (pattern III = fine villiform appearance with regular shape and arrangement; pattern IV = thick villous convoluted shape with a cerebriform appearance with regular shape and arrangement).

In the first prospective cohort study of 49 patients, sensitivity for SIM was 96.5%, specificity was 88.7%, and overall accuracy was 92.2% (38). Using modified criteria, a second study of 67 patients demonstrated a sensitivity of 88.5%, specificity of 90.2%, and diagnostic accuracy of 90% (39). Reaud et al. studied 28 patients with a type III or IV pattern with sensitivity for SIM of 95.5%, specificity of 42.9%, and diagnostic accuracy of 75% (40).

In a study by Longcroft-Wheaton et al. (41), the efficacy of acetic acid has been investigated in detecting Barrett’s dysplasia. Data were collected from 190 patients with BE examined over a 3-year period at a tertiary referral center from procedures performed by a single experienced endoscopist. Patients were first examined with white light gastroscopy and visible abnormalities were identified. Acetic acid (2.5%) dye spray was used to identify potential neoplastic areas and biopsy samples were collected from these, followed by quadrantic biopsies at 2 cm intervals of the remaining Barrett’s mucosa. The chromoendoscopic diagnosis was compared with the ultimate histological diagnosis to evaluate the sensitivity of acetic acid chromoendoscopy. Acetic acid chromoendoscopy had a sensitivity of 95.5% and specificity of 80% for the detection of neoplasia. There was a correlation between lesions predicted to be neoplasias by acetic acid and those diagnosed by histological analysis (r = 0.98). There was a significant improvement in the detection of neoplasia using acetic acid compared with WLE (p = .001). Video 2.1 demonstrates the use of both acetic acid and Pentax iScan to highlight the Barrett’s mucosal pattern.

Indigo carmine chromoendoscopy

Curvers et al. showed that using indigo carmine and high-resolution endoscopy (HR-E) three distinct patterns can be recognized at endoscopy: ridged and/or villous, circular, and irregular and/or distorted (42). Barrett’s epithelium was most commonly identified in the ridged/villous pattern, whereas HGD was found entirely in the irregular/distorted pattern. An irregular/distorted pattern either throughout the entire segment of BE or in combination with a ridged/villous or circular pattern had a sensitivity of 83%, a specificity of 88%, a positive predictive value (PPV) of 45%, and a negative predictive value (NPV) of 98% for HGD.

Mucosal classification systems for Barrett’s esophagus

Similar studies by Guelrud et al. (43) and Toyoda et al. (44) have produced unique classifications based on pattern recognition. Guelrud et al. (43) described a technique they named enhanced magnification endoscopy, which combines magnification endoscopy with instillation of acetic acid. They classified Barrett’s mucosa into four patterns: I, round pits; II, reticular (circular or oval pits); III, villous (fine villiform appearance without visible pits); and IV, ridged (thick villi with convoluted cerebriform appearance without visible pits). Guelrud et al. found that the rate of detection of IM in patterns III and IV mucosa in clinical value relies on a learning curve for the endoscopists. The role of high resolution or magnification in patients with previously diagnosed BE was, respectively, 87% and 100% (Figure 2.2).

FIGURE 2.2 The Guelrud classification (115×, 6% alcohol acetic acid). Pattern I: round pits with a regular and orderly arranged circular dots. Pattern II: reticular pits that are circular or oval and are regular in shape and arrangement. Pattern III: fine villiform appearance with regular shape and arrangement. Pattern IV: thick villous convoluted shape with a cerebriform appearance with regular shape and arrangement.

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Kara et al. in 2006 (46) suggested a further classification system. They used NBI with magnifying endoscopy to image and then biopsy randomly selected area in 63 patients with BE. Following this, there was a formal review process of the images and biopsies. The relationship between mucosal morphology and presence of IM and HGD was evaluated. Areas of IM were characterized by either villous/gyrus-forming patterns (80%), which were mostly regular and had regular vascular patterns, or a flat mucosa with regular normal-appearing long branching vessels (20%). HGD was characterized by three abnormalities: irregular/disrupted mucosal patterns, irregular vascular patterns, and abnormal blood vessels. All areas with high-grade intraepithelial neoplasia (HGIN) had at least one abnormality, and 85% had two or more abnormalities. The frequency of abnormalities showed a significant rise with increasing grades of dysplasia. The magnified NBI images had a sensitivity of 94%, a specificity of 76%, a PPV of 64%, and a NPV of 98% for HGIN.

Singh et al. (47) have looked at an alternative simplified classification. In a prospective cohort study of 109 patients with BE, mucosal patterns visualized with NBI were classified into four easily distinguishable types: A, round pits with regular microvasculature; B, villous/ridge pits with regular microvasculature; C, absent pits with regular microvasculature; D, distorted pits with irregular microvasculature. The NBI grading was compared with the final histopathological diagnosis. In 903 out of 1021 distinct areas (87.9%) the NBI grading corresponded to the histological diagnosis. The PPV and NPV for type A pattern (columnar mucosa without IM) were 100% and 97%, respectively; for types B and C (IM) they were 88% and 91%, respectively; and for type D (HGD) they were 81% and 99%, respectively. With respect to inter- and intraobserver agreement, the mean k values in assessing the various patterns were 0.71 and 0.87 in the non-expert group, and 0.78 and 0.91 in the expert group.

A final endoscopic classification system for BE was described by investigators in Kansas again using NBI (48). NBI images were graded according to mucosal pattern (ridge/villous, circular, and irregular/distorted) and vascular pattern (normal and abnormal), and correlated with histology. Of 51 patients, 28 had IM without dysplasia, 8 had LGD, 7 had HGD, and 8 had cardiac-type mucosa. The sensitivity, specificity, and PPV of ridge/villous pattern for diagnosis of IM without HGD were 93.5%, 86.7%, and 94.7%, respectively. The sensitivity, specificity, and PPV of irregular/distorted pattern for HGD were 100%, 98.7%, and 95.3%, respectively. If biopsies were limited to areas with irregular/distorted pattern, no patient with HGD would have been missed. However, NBI was unable to distinguish areas of IM from those with LGD.

In order to compare the three above classification systems from Amsterdam, Nottingham, and Kansas, a comparative study was performed by Silva et al. (49). They examined all three classification systems in 84 high-quality video recording collected on cases of BE using HD-WLE and NBI. All assessors were blinded to the matched histology from these areas. The global accuracy was 46% and 47% using the Nottingham and Kansa classifications, respectively, and 51% with the Amsterdam classification. Accuracy for detecting dysplastic lesions was 75% irrespective of the classification system used. The interobserver agreement ranged from fair (Nottingham k = 0.34) to moderate (Amsterdam and Kansas, k = 0.47 and k = 0.44, respectively).

Enhanced imaging systems: Olympus narrow band imaging

Conventional WLE uses the entire spectrum of visible light (400–700 nm) to examine tissue. NBI, developed by Olympus Medical Systems (Olympus, Japan), is a new advance in endoscopy that uses optic filters to isolate two specific bands of light: 415 nm (blue) and 540 nm (green). By isolating these two bands of light and taking into account their absorptive and reflective properties on the mucosal surface, an image that enhances visualization of superficial mucosal and vascular structures is created. The quality of the surface pit pattern morphology is also clearly enhanced by this technology. It enables the endoscopist to switch between conventional white light and NBI views easily and quickly during the procedure, thus making the procedure itself less messy and cumbersome compared to chromoendoscopy. By depressing a lever on the endoscope, the focal distance of the lens at the tip of the endoscope can be adjusted electronically thus enabling the endoscopist to achieve a maximal magnification of 115× in real time.

Although many studies have shown the benefit of NBI over conventional WLE in detecting HGD and early esophageal cancer, others have questioned whether NBI achieves any incremental improvement beyond that of HD-WLE. Wolfsen et al. investigated whether NBI-targeted biopsies could detect advanced dysplasia using fewer biopsy samples compared with conventional endoscopy using the four-quadrant biopsy method with a prospective, blinded, controlled tandem study (50). The study revealed that NBI detected dysplasia in 57% of patients compared with 43% in the conventional endoscopy with four-quadrant biopsy group, with higher grades of dysplasia detected in the NBI group (p < .001). In addition, more biopsies were taken in the four-quadrant biopsy group compared with narrow band targeted biopsies (mean 8.5 vs. 4.7; p < .001). A study by Kara et al. investigated chromoendoscopy versus NBI, both in combination with HD endoscopy, in a prospective, randomized crossover study with 14 patients (51). The sensitivity of chromoendoscopy and NBI was 93% and 86%, respectively, compared with 79% for four-quadrant biopsies with conventional endoscopy in the diagnosis of HGD or early cancer in patients with BE. Although chromoendoscopy and NBI identified additional lesions (chromoendoscopy identified two additional lesions in two patients; NBI identified four additional lesions in three patients), they did not increase per patient sensitivity for identifying HGD/esophageal carcinoma (EC).

Interestingly, in an interobserver agreement study by Curvers et al. there was moderate interobserver agreement for classification of mucosal morphology by NBI (0.40–0.56) (52). Although there was improvement in image quality with NBI compared to HD, NBI provided no significant improvement in inter observer variability and yield for detecting neoplasia. The yield of HD-WLE for neoplasia was 81%, 72% for NBI, and 83% for the HD-WLE with NBI. The addition of enhancement techniques did not improve the yield for neoplasia in this series.

Curvers et al. have performed a review of studies that analyzed NBI images for its accuracy in differentiating HGD/cancer from LGD or non-neoplastic BE (53). In a meta-analysis that included 149 areas with HGD/cancer and 607 areas with LGD or nondysplastic BE, NBI had a sensitivity for HGD/cancer of 97% (95% CI 89–99%) and a specificity of 94% (60–99%), and an accuracy of 96% (72–99%). Consequently, the use of targeted biopsy techniques using image enhancement techniques has potential time and cost savings. They recognize, however, that these findings may not be generalizable as these studies were performed in high-risk populations.

Comparing HD-WLE to enhanced imaging systems (NBI)

The majority of studies looking at NBI compare its efficacy in relation to other endoscopic modalities, such as chromoendoscopy or autofluorescence, as well as HD-WLE. There are limited data directly comparing the efficacy of NBI versus HD-WLE in the diagnosis of dysplasia or early cancer in patients with Barrett’s patients. Sharma et al. performed a study comparing the use of HD-WLE versus NBI in a prospective, multicenter, randomized crossover trial (54). The proportion of patients detected with IM and HGD/cancer with NBI-directed targeted biopsies is similar to those with HD-WLE. However, they demonstrated that significantly more lesions with HGD/cancer were detected by NBI compared to HD-WLE (17 vs. 10; p = .03). More lesions with any dysplasia were diagnosed by NBI compared to HD-WLE (71 vs. 55; p = .0002). Overall, NBI required less number of biopsies/procedure (3.7 vs. 8.0; p < .0001).

Another randomized control trial by Sharma et al. (55) compared HD-WLE and NBI for the detection of IM or dysplasia in patients with BE. Patients referred for BE screening or surveillance at three tertiary referral centers were prospectively enrolled in and randomized to HD-WLE or NBI followed by other procedures in 3–8 weeks. During HD-WLE, four-quadrant biopsies every 2 cm, together with targeted biopsies of visible lesions (Seattle protocol), were obtained. At NBI examination, mucosal and vascular patterns were noted and targeted biopsies were obtained. A total of 123 patients with BE (mean age 61; 93% male; 97% Caucasian) with mean circumferential and maximal extents of 1.8 and 3.6 cm, respectively, were enrolled. Both HD-WLE and NBI detected 104 out of 113 (92%) patients with IM, but NBI required fewer biopsies per patient (3.6 vs. 7.6, p < .0001). NBI detected a higher proportion of areas with dysplasia (30% vs. 21%, p < .01). During examination with NBI, all areas of HGD and cancer had an irregular mucosal or vascular pattern. This important study demonstrates that NBI-targeted biopsies can have the same IM detection rate as an HD-WLE examination with the Seattle protocol, while requiring fewer biopsies. In addition, NBI-targeted biopsies can detect more areas with dysplasia. Regular appearing surface patterns seen with NBI did not harbor HGD/cancer, suggesting that biopsies could be avoided in these areas.

Enhanced imaging systems—Pentax iScan

An endoscopic image enhancement technology, iScan has been developed by PENTAX (HOYA Corporation), Japan. iScan uses the EPKi processor technology which enables resolution above HDTV standard, with distinct digital filters for special post processing online imaging, which can provide detailed analysis. iScan is a novel endoscopic postprocessing light filter technology using sophisticated software algorithms with real-time image mapping technology embedded in the EPKi processor. The computer-controlled digital processing provides resolution of about 1.25 megapixels per image. Different elements of the mucosa are enhanced by pressing a button on the hand piece of the HD endoscope. iScan can be used for surface analysis to recognize lesions using three modes of image enhancement. These are as follows:

i Surface enhancement (SE)/ iScan 1: enhancement of the structure through recognition of the edges;

ii Contrast enhancement (CE)/ iScan 2: enhancement of depressed areas and differences in structure through color presentation of low-density areas;

iii Tone enhancement (TE)/ iScan 3: enhancement tailored to individual organs through modification of the combination of RGB components for each pixel.

iScan images are as bright as conventional WLE images and therefore, iScan can observe larger areas in a distant view than NBI. iScan also does not need magnifying endoscopy to observe the demarcation between normal and abnormal tissue. iScan can be switched on and effected quite simply and instantaneously by pushing a button. Therefore, it is an easy method for screening or detailed inspection and may reduce both time and cost. The sensitivity and specificity of iScan in detecting dysplasia in Barrett’s patients is yet to be investigated.

There is, as yet, no formal iScan classification system for BE mucosal patterns. However, using those devised for other modalities, such as NBI, endoscopists are able to direct and target therapy to subtle anomalies based on these validated classification systems.

Flexible spectral imaging color enhancement

Unlike NBI, which utilizes a physical filter, flexible spectral imaging color enhancement (FICE) (Fujinon, Japan) is a post processor technology that captures spectral reflectance by a color CCD video endoscope. This is sent to a spectral estimation matrix processing circuit contained in the video processor. The reflectance spectra of corresponding pixels that make up the conventional image are mathematically estimated. From these spectra, it is feasible to reconstruct the virtual image of a single wavelength. Three such single-wavelength images can be selected and assigned to the red, green, and blue monitor inputs, respectively, to display a composite color-enhanced multiband image in real time. In practice this can be used like NBI to remove data from the red part of the waveband, and narrow the green and blue spectra.

A prospective cohort study of 72 patients demonstrated that the identification of palisade vessels using FICE provided clear demarcation between Barrett’s mucosa and the gastric mucosa, which was superior to standard WLE (56). This study did not attempt to diagnose dysplasia and used transnasal Fujinon endoscopes. These are very small with a more limited field of view and no optical magnification.

In a small prospective cohort study of 57 patients which compared FICE with random biopsy in patients with suspected HGD or early cancer, a sensitivity of 92% and specificity of 97% for FICE were achieved (57). There was HGD or early cancer in 24 out of 57 patients.

Confocal laser endomicroscopy

Confocal laser endomicroscopy (CLE) is a new technology that enables the endoscopist to perform a real-time histological assessment of the upper GI tract and in particular the esophagus. The most widely used CLE system is the endoscope with embedded CLE technology (eCLE) made by Pentax (Tokyo, Japan) and Optiscan (Melbourne, Australia). The eCLE enables visualization of both the epithelium and the subepithelial vascular structures with imaging at variable depths up to 250 mm and a magnification power of up to 1000 μm. A probe-based endomicroscopy system has been created by Mauna Kea Technologies (Figure 2.3) in which the laser scanning unit remains outside the patient and the endomicroscopy probe is passed through the working channel of a standard endoscope. This probe-based CLE (pCLE) provides video sequence imaging at a rate of 12 images per second and allows for the compilation of images from a video sequence to create a composite video mosaic. The depth ranges from 50 to 150 μm and is fixed based on the type of probe. These CLE systems use a wavelength of 488 nm for excitation. CLE requires the use of contrast agent, most commonly intravenous fluorescein sodium, which is safe for imaging the GI tract (58).

FIGURE 2.3 Images of normal, dysplastic and cancer using probe-based confocal endomicrosocpy. The presence of goblet cells denoted intestinal metaplasia. (The images are courtesy of the DONT BIOPCE trial, Mauna Kea Technologies).

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CLE classification systems for BE with and without dysplasia have been described for standard endomicroscopy and probe-based endomicroscopy (59, 60). Signs of nondysplastic Barrett’s epithelium include a regular epithelial lining pattern, regular vascular pattern, presence of goblet cells, and preservation of the villous pattern of glands. Signs of dysplasia in BE include irregular epithelial lining, fusion of glands, focal accumulation of dark cells with bright lamina propria, irregular vascular pattern, and disruption of the glandular pattern.

Kiesslich et al. (59) demonstrated that eCLE could diagnose Barrett’s associated dysplasia during endoscopy with a sensitivity of 92.9% and a specificity of 98.4%. Dunbar et al. conducted a prospective, double-blind, randomized crossover study comparing four-quadrant random biopsies with eCLE-targeted biopsy in 39 patients. They demonstrated that eCLE improved the diagnostic yield for detecting neoplasia in BE. The yield of eCLE was 33.7% versus 17.2% with random biopsies (p = .01). Furthermore, some patients undergoing eCLE would not have needed any random biopsies in order to diagnose neoplasia.

In 2011, Gaddam et al. (61) revised and validated a set of criteria for pCLE for dysplasia in BE using video recordings. Of multiple pCLE criteria tested in the first phase of their study, only those with ≥70% sensitivity or specificity were included in the final set. These were epithelial surface: saw-toothed; cells: enlarged; cells: pleomorphic; glands: not equidistant; glands: unequal in size and shape; goblet cells: not easily identified. Using these criteria overall accuracy in diagnosing dysplasia was 81.5% (95% CI 77.5–81), with no difference between experts versus non-experts. Accuracy of prediction was significantly higher when endoscopists were confident about their diagnosis (98% (95–99) vs. 62% (54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70), p < .001). Accuracy of dysplasia prediction for the first 30 videos was not different from the last 45 (93 vs. 81%, p = .51). Overall agreement of the criteria was substantial, k = 0.61 (0.53–0.69), with no difference between experts and non-experts.

In an international prospective, multicenter, randomized controlled trial, Sharma et al. (62) investigated whether pCLE could allow for real-time detection of neoplastic BE. All patients with BE were examined by HD-WLE, NBI, and pCLE, and the findings were recorded before matched biopsy samples were obtained. The order of HD-WLE and NBI was randomized and performed by two independent, blinded endoscopists. All suspicious lesions on HD-WLE or NBI and four-quadrant random locations were documented. These locations were then examined by pCLE, and a presumptive diagnosis of benign or neoplastic (HGD/EC) tissue was made in real time after which biopsies were taken from all locations and were reviewed by a central pathologist, blinded to endoscopic and pCLE data. The sensitivity and specificity for HD-WLE were 34.2% and 92.7%, respectively, compared with 68.3% and 87.8%, respectively, for HD-WLE and pCLE (p = .002 and p < .001, respectively). The sensitivity and specificity for HD-WLE and NBI were 45.0% and 88.2%, respectively, compared with 75.8% and 84.2%, respectively, for HD-WLE, NBI, or pCLE (p = .01 and p =.02, respectively). However, the use of pCLE in conjunction with HD-WLE and NBI enabled the identification of two and one additional HGD/EC patients compared with HD-WLE and HD-WLE or NBI, respectively, resulting in detection of all HGD/EC patients, although not statistically significant. This may allow better informed decisions to be made for the management and subsequent treatment of BE patients.

Autofluorescence

When tissues are exposed to a short wavelength light, endogenous biological substances (i.e., fluorophores) are excited, leading to the emission of fluorescent light of a longer wavelength. This phenomenon is known as autofluorescence. Autofluorescence imaging (AFI) is a technique that can potentially differentiate tissue types based on their differences in fluorescence emission. Normal and neoplastic tissue have different autofluorescence spectra, which may enable their distinction. This is due to the various different compositions of the endogenous fluorophores which includes collagen, NADH, aromatic amino acids, and porphyrins in these tissues. This phenomenon was first utilized in BE using spectroscopic point measurements. In brief, low collagen fluorescence and high NAD(P)H fluorescence characterize lesions with HGD as opposed to nondysplastic epithelia. Hence, with progression toward neoplasia, one would typically observe a reduction in the intensity of green fluorescence and a relative increase in red fluorescence.

In a 2006 60-patient study using a standard endoscope with an added AFI component, Kara was able to detect HGD in 22 patients, 14 of which were detected with AFI and WLE, and 6 of which were detected using AFI alone, thereby increasing the detection rate from 23% to 33% using AFI (Kara et al., 2005b). Only one of the patients was diagnosed using the standard four-quadrant biopsies alone. Results suggest that AFI may aid in the detection of additional HGD sites; however, it may not exclude the need for the standard four-quadrant biopsies. Sensitivity and specificity based on the 116 samples used for this study were 91% and 43%, respectively. Although no patient was diagnosed without AFI and four-quadrant biopsies, they cite a high rate of false positives using AFI alone, due in part to the loss of autofluorescence associated with acute inflammation (36).

Optical coherence tomography

Optical coherence tomography (OCT) is an imaging modality that may have the ability to improve the current paradigm for endoscopic screening and surveillance that exists for patients with BE. OCT can be thought of as an analogous technique to ultrasound. However, instead of producing an image from the scattering of sound waves, it utilizes optical scattering based on differences in tissue composition to form a two-dimensional image (22). The benefit of OCT over ultrasound is that it is capable of generating cross-sectional images of tissues with an axial resolution of up to 10 μm, which is comparable to low-power microscopy.

Original OCT systems or time domain OCT, were limited to discrete locations or point sampling due to slow acquisition rates. However, with the development of second-generation OCT, termed optical frequency domain imaging (OFDI), it is now possible to perform high-speed acquisition of large luminal surfaces in three dimensions (23). Due to its high resolution and high acquisition rates, utilizing this technique for screening and surveillance of BE may provide a means to evaluate pathologic states in long segments of the esophageal lumen in real time.

OCT in Barrett’s esophagus

The first clinical application using in vivo endoscopic OCT for imaging of the human esophagus and stomach was performed by Bouma et al., in 2000 (24). In this preliminary study, the ability of OCT to image normal esophageal mucosa and stomach, BE, and adenocarcinoma was investigated. The authors concluded that they were able to differentiate the normal layered structure of the esophagus using OCT, including epithelium, lamina propria, muscularis mucosa, and submucosa. In addition, OCT was capable of differentiating between normal esophageal mucosa and BE based on the lack of the layered structure found in BE as well as a disorganized glandular morphology. Finally, EAC was clearly differentiable by the presence of marked architectural disorganization. Several studies immediately followed this landmark study using in vivo OCT for the GI tract (25,26,27,28). Similarly, they utilized a noncontact probe, approximately 2.5 mm in diameter, introduced through the auxiliary channel of a standard endoscope. These studies were all significant in the contribution to the development of OCT for GI imaging and played a major role in the potential clinical utility of OCT; however, they were limited to point sampling and did not address diagnostic information relevant to dysplasia.

Subsequently, diagnostic criteria were developed for endoscopic OCT to diagnose SIM, HGD, and IMC. In prospective studies performed by Poneros et al. and Evans et al., sensitivities from 81% to 97% and specificities from 57% to 92% for diagnosing SIM were reported (29, 30). Additionally, sensitivities and specificities for detecting HGD and IMC were reported in the ranges of 54–83% and 72–75%, respectively (31,32). Unfortunately, similar to previous investigations, the studies were limited to point sampling where a probe was placed at discrete locations and cross-sectional images were obtained. Although these studies made great strides in the diagnostic potential of OCT, the true clinical utility for BE was not realized due to the potential for sampling errors analogous to biopsy.

More recently, technological advancements and the development of a second-generation OCT system, OFDI, have provided the ability to image long segments of tissue with high resolution and contrast identical to those obtained in OCT but at a rate approximately 100 times faster (33,34,35). The first comprehensive imaging of the esophagus in human patients using OFDI was performed by Suter et al. In this study, a balloon-centering optical catheter was used to acquire long-segment (6 cm) images of the esophagus during an endoscopic procedure (<2 min) (36). During system and catheter development, a total of 32 patients were imaged prior to the design being unchanged. Once the final design had been established, a total of 10 patients out of 12 were successfully imaged using the comprehensive microscopy technique of OFDI, while 2 patients were not imaged due to imaging system malfunction. No adverse events or patient-related complications were reported in the study (36). Although the study presented promising case findings related to OCT diagnosis of normal esophagus and cardia, ulcerated squamous mucosa, SIM, and dysplasia, it was limited to image criteria established based on a noncontact OCT probe. Additional studies are needed to develop diagnostic criteria, intraobserver and interobserver variability in diagnosis of OFDI imaging, and an OFDI–histopathological correlative study using OFDI technology.

Esophageal adenocarcinoma

The incidence of EAC is increasing in the United States and Europe with a 350% increase in incidence in the United States (63) over the last 20 years with a similar increase in incidence in the United Kingdom (64). Often patients with established EAC present late with symptoms of dysphagia, and at this stage, curative therapy is limited and patients are often managed by palliative measure. This enforces the importance of diagnosing mucosal disease early as there are now minimally invasive therapies that can treat these patients with high levels of success. The endoscopic management and diagnosis of early esophageal cancer and HGD arising from BE has been covered in the previous section.

Endoscopic classification of esophageal cancer: the Paris classification

EAC can be termed superficial when the depth of invasion is limited to the mucosa and submucosa. The endoscopic appearance has a predictive value for invasion into the submucosa, which is critical for the risk of nodal metastases and planning appropriative curative or palliative interventions. In Japan, due to the high prevalence of gastric cancer, prevention has been a medical priority for the last 40 years. The gross morphological classification used for superficial tumors in the stomach soon came to be applied in the remainder of the GI tract and indeed the esophagus. In 2002, a workshop was held in Paris to explore the relevance of the Japanese classification to Western practice and in 2003 the Paris classification was produced and remains the cornerstone for current practice of classification of superficial EAC liaison for endoscopists (Figures 2.4–2.8).

FIGURE 2.4 Endoscopic appearance of a superficial neoplastic lesion on the surface of the digestive tract mucosa: protruding type, pedunculated (0 ± Ip), and sessile (0 ± Is).

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FIGURE 2.5 Endoscopic appearance of a superficial neoplastic lesion on the surface of the digestive tract mucosa: nonprotruding and nonexcavated types, slightly elevated (0 ± IIa), completely flat (0 ± IIb), or slightly depressed (0 ± IIc).

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FIGURE 2.6 Endoscopic appearance of a superficial neoplastic lesion on the surface of the digestive tract mucosa: excavated type (0 ± III). An ulcer is seen.

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FIGURE 2.7 Endoscopic appearance of a superficial neoplastic lesion on the surface of the digestive tract mucosa: elevation plus depression. Type 0 ± IIc + IIa is a depressed lesion with an elevation in part of the peripheral ring. Type 0 ± IIa + IIc is an elevated lesion with a central depression. The central depression is surrounded by an elevated ring. When the level of the depression is higher than the mucosa adjacent to the lesion, it is a relatively depressed lesion.

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FIGURE 2.8 Endoscopic appearance of a superficial neoplastic lesion on the surface of the digestive tract mucosa: ulcer plus depression. Type 0 ± IIc + III is a depressed lesion with a central ulcer. Type 0 ± III + IIc is an ulcer with short depressed margins.

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In Japan, the description of advanced cancer in the GI tract and esophagus is categorized as types 1–4 (see Table 2.1). Furthermore, recently types 1–4 have become supplemented by a type 0 when the endoscopic appearance is that of a superficial lesion. Type 0 has been further subclassified (Table 2.2).

Table 2.1 The macroscopic classification of digestive tract cancer used in Japan

Table 2.2 The macroscopic classification of type 0 digestive tract lesions, with a superficial appearance at endoscopy

Using the Paris classification for staging in esophageal cancer

Invasion into the submucosa occurs more frequently in protruding lesions (0 ± I) or excavated lesions (0 ± III); the lowest risk is with completely flat (0 ± IIb) lesions (Table 2.3). In one Japanese series including 1562 patients (65), the risk of metastatic lymph nodes was assessed in relation to the depth of invasion of lesions classified into three groups: superficial in the mucosa (m1 or intraepithelial + m2 or microinvasive); intermediate (m3 + sm1); deep in the submucosa (sm2 + sm3). The corresponding proportions of lymph node metastases in the three groups were 2%, 19%, and 44%, respectively. Superficial invasion (m1 + m2), which is a safe indication for endoscopic treatment, was found in 69% of 0 ± IIb lesions, 39% of 0 ± IIc lesions, 20% of 0 ± IIa lesions, and almost never for 0 ± I and 0 ± III lesions. In conclusion, endoscopic treatment is recommended for nondepressed neoplastic lesions up to a diameter of 20 mm and up to 10 mm for depressed lesions. In the histopathological assessment, a cut-off limit for the depth of invasion into the submucosa is 200 μm. Figure 2.9 shows the depth of invasion of superficial neoplastic lesions with m1-3 and sm1-3 classifications. Where lesions are confined to the mucosa (m1-3), endoscopic resection can be curative.

Table 2.3 Relative frequency (%) of submucosal invasion in subtypes of type 0 lesions in Japan

FIGURE 2.9 Diagram of esophageal pathology specimen showing depth of invasion of superficial neoplastic lesions into the stratified epithelium. 1, intraepithelial neoplasia (or m1); 2, microinvasive cancer with involvement of the basal membrane of the epithelium (or m2); 3, intramucosal cancer (or m3); 4, cancer with superficial invasion of the submucosa (sm1); 5, cancer with deep invasion of the submucosa (sm2 or sm3). Endoscopic mucosectomy is fully justified in situation 1 or 2.

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The role of EUS in staging of esophageal cancer

Following on from a histological diagnosis of EAC it is imperative to complete a clinical TNM staging. This has recently been changed in the American Joint Committee on Cancer (AJCC) Seventh Edition (Table 2.4).

Table 2.4 2011 AJCC Seventh Edition TNM staging guidelines