Abstract
Barrett’s esophagus is a condition in which normal stratified squamous epithelium of the esophagus is replaced with columnar epithelium. It is the primary precursor lesion for esophageal adenocarcinoma and is thought to progress in a stepwise manner from metaplasia through increasing grades of dysplasia to adenocarcinoma. Diagnosis requires the combination of endoscopic evaluation and histopathological assessment of biopsies taken at the time of endoscopy. There is international disagreement regarding the histologic definition and the requirement of goblet cells in biopsies. This chapter reviews the current histologic and endoscopic definitions of Barrett’s esophagus and controversies surrounding them. Recent advances in endoscopic imaging will also be reviewed as they may improve the diagnosis and management of Barrett’s esophagus in the future.
Keywords
Barrett’s esophagus, intestinal metaplasia, endoscopy, histology, diagnosis, surveillance, dysplasia, imaging
5.1
Introduction
In 1950, Norman Barrett wrote the paper entitled “Chronic peptic ulcer of the oesophagus and ‘oesophagitis’” where he described a case in which a portion of the stomach was noted to be within the chest . It was later determined by Allison and Johnstone in a detailed description of seven cases that what Barrett had described was actually a columnar-lined esophageal segment. They also noted an association with esophageal reflux disease . Since that time there have been dramatic changes in the understanding of this condition, which it seems will forever bear Norman Barrett’s eponym.
Barrett’s esophagus is an acquired condition present in 10–15% of patients with chronic gastroesophageal reflux disease (GERD). It is currently defined as a condition in which normal stratified squamous epithelium is replaced with columnar epithelium with intestinal type mucosa in the distal esophagus . While Barrett’s esophagus is asymptomatic, its clinical importance is that it is one of the only known risk factors for esophageal adenocarcinoma. Esophageal adenocarcinoma is the cancer with the most rapidly increasing incidence in the Western world . Barrett’s is thought to progress in stages from intestinal metaplasia to low-grade dysplasia (LGD), high-grade dysplasia (HGD), and then finally to invasive adenocarcinoma.
In the United States, the diagnosis of Barrett’s esophagus first begins with the endoscopic visualization of proximally displaced squamous epithelial lining of the distal esophagus followed by biopsy specimens obtained from the true tubular esophagus showing specialized intestinal metaplasia. Biopsies are obtained not only to enable a diagnosis of Barrett’s but also to identify dysplasia and early cancers at a stage when curative treatment may be possible. A clear diagnosis is very important for patients as, once diagnosed, they will likely be placed into routine endoscopic surveillance based on current society guidelines and there will be personal fears and concerns about their risk for esophageal cancer in the future. A diagnosis of Barrett’s may also have implications for health and life insurance in the United States .
5.2
Histopathologic Diagnosis of Barrett’s
Barrett’s esophagus (BE) is well established as a complication of GERD . Reflux of various substances such as acid and bile from the stomach, along with other factors such as increased transient lower esophageal sphincter relaxations (TRLES) and decreased esophageal motility allow for a prolonged exposure of the esophagus to refluxate from the stomach. This causes chronic inflammation and subsequent repair of the esophageal mucosa. The repair process in some individuals results in the replacement of normal esophageal epithelium with intestinal metaplasia. These changes may be the result of a number of genetic alterations and changes in cellular molecular pathways. It has been proposed that loss of p63 expression in squamous mucosa is involved . Other studies have suggested overexpression of CDX2 and BMP4 to play a role in the pathogenesis of Barrett’s . Loss of TGFβ signaling as seen in knockout mice may lead to altered cell differentiation and intestinal metaplasia .
For many years, there has been disagreement on what defines Barrett’s esophagus histologically. In the United States, the definition of Barrett’s esophagus as per the American Gastroenterological Association (AGA) is “the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus” . Thus, the presence of goblet cells is required for a diagnosis of Barrett’s esophagus in the United States and many other countries ( Fig. 5.1 ). The British Society of Gastroenterology requires the presence of endoscopically visible features of Barrett’s esophagus with metaplastic columnar epithelium on esophageal biopsies . It does not necessarily require the detection of intestinal metaplasia in the affected segment. The Japanese do not require the presence of intestinal type epithelium either, but do require the presence of endoscopically evident palisading vessels to delineate the gastroesophageal junction .
There is much debate about whether intestinal metaplasia must be present for the diagnosis of BE or if only the presence of columnar mucosa is enough. Although most esophageal adenocarcinomas occur in the presence of intestinal metaplasia, esophageal adenocarcinomas may also occur in the presence of other types of mucosa such as cardia type in the absence of intestinal metaplasia . Some studies have suggested that columnar cell epithelium may have analogous immunohistochemical profiles to intestinal metaplasia based on similar intestinal markers such as CDX-1, cytokeratins, mucin, and similar chromosomal instability . But much of what is known about cancer risk in Barrett’s esophagus is based on an association with intestinal metaplasia either primarily or exclusively. For the past several decades, most studies on Barrett’s esophagus have used specialized intestinal metaplasia as an entry criterion.
More recently in 2015, experts conducted an international, multidisciplinary, systematic search and evidence-based review of BE (BOB CAT) and established an international agreement for a definition of BE. The definition states “BE is defined by the presence of columnar mucosa in the esophagus and it should be stated whether intestinal metaplasia (IM) is present above the gastroesophageal junction” . This definition works to combine endoscopic and pathological diagnosis of various worldwide GI societies. It recognizes that intestinal metaplasia may not always be sampled on biopsies and there are cases where EA is not always preceded by intestinal metaplasia (see sections later). There are likely to be future modifications of this working definition.
5.2.1
Definition of Intestinal Metaplasia
Barrett’s esophagus is composed of columnar epithelium and may contain goblet cells, enterocytes, Paneth cells, and some cells with combined gastric and intestinal features. There may also be multilayered epithelium, which has characteristics of both squamous and columnar features . Goblet cells are specialized columnar epithelial cells normally found in the intestinal lining that function to produce gel-forming mucins. When these cells are identified in the stomach or esophagus, they represent intestinal metaplasia . Goblet cells are identified both with hematoxylin–eosin stain and ancillary stains like Alcian blue/periodic acid Schiff stain. On hematoxylin–eosin stains, Goblet cells are dispersed on a background of nongoblet neutral mucin-containing cells similar to those of the gastric mucosa. Goblet cells contain acid mucin that imparts blue discoloration to the mucin vacuole, which compresses the nucleus and laterally displaces the membranes of adjacent cells. The Alcian blue/periodic acid Schiff stain facilitates identification of goblet cells. This stain colors the neutral mucin of gastric foveolar epithelium red, while the acidic mucin of goblet cells is blue ( Fig. 5.1 ). However, a variety of goblet cell mimics may also show Alcian blue positivity, thereby representing diagnostic pit falls when these stains are utilized. For example, injured, hyperplastic foveolar type epithelial cells, columnar cells that contain blue-tinged mucin, columnar cells lining ducts that drain mucosal and submucosal glands, submucosal mucinous glands, and multilayered epithelium cells may also stain positive for Alcian blue stains (Alcian blue-positive goblet cell mimics). None of these goblet cell mimics have been shown to confer as a high risk of malignant progression and should not be considered to represent specialized epithelium .
Columnar metaplasia of the distal esophagus is difficult to distinguish from the proximal gastric cardia histologically. Cardiac epithelium, which has traditionally been considered the normal lining of the most proximal portion of the stomach (the gastric cardia), is almost exclusively composed of mucus secreting gastric foveolar type cells without goblet cells. Observations suggest that cardiac epithelium found in the esophagus might not be a normal type of epithelium but rather an abnormal, metaplastic epithelium acquired as a consequence of GERD . Although lacking the goblet cells of specialized intestinal metaplasia, cardiac epithelium nevertheless expresses molecular markers of intestinal differentiation (eg, villin and CDX2) . Cardiac epithelium can be considered “intestinalized” even without goblet cells. Furthermore, cardiac epithelium exhibits genetic abnormalities similar to those found in specialized intestinal metaplasia. Thus, cardiac epithelium might be predisposed to malignancy despite its lack of goblet cells . In one series of 141 patients with small esophageal adenocarcinoma removed primarily by endoscopic mucosa resection, more than 70% of the lesions were adjacent to cardiac/fundic-type mucosa rather than intestinal metaplasia. Intestinal metaplasia was actually not found in 56.6% of biopsy specimens . Indeed, even in specialized intestinal metaplasia, the highly differentiated goblet cell seems an unlikely candidate to be the malignant cell of origin. Examples of low-grade, high-grade and indefinite for dysplasia are shown in ( Figs. 5.2–5.4 ).
5.3
Endoscopic Diagnosis of Barrett’s
Although the diagnosis of Barrett’s esophagus requires histologic confirmation by biopsy, it will first be suspected in those patients where the junction of the squamous esophageal epithelium and columnar epithelium of the stomach, or Z-line, has been displaced proximal to the gastroesophageal junction (GEJ). Thus it is critical to accurately identify the GEJ. The definition of the GEJ is controversial and varies depending on geographical location. For example, in the United States, this area is defined as the most proximal location of gastric folds. Alternately in Japan, it is defined as the lowest extent of the esophageal palisade blood vessels ( Fig. 5.4 ).
Traditionally, these changes in the Z-line location, or tongues of Barrett’s esophagus, were classified as short segment (<3 cm) or long segment Barrett’s esophagus (≥3 cm) but there was often significant inter- and intraobserver variation especially in relation to shorter segments of Barrett’s esophagus . Due to controversies over the endoscopic definition of Barrett’s esophagus and to help improve the definition, the Prague Classification of Barrett’s esophagus was developed in 2006 by Sharma et al. . This established a standardized criterion for the endoscopic diagnosis of circumferential (C) and maximal length (M) of endoscopically visualized Barrett’s mucosa. A main component of this grading system looks at the landmarks of the squamocolumnar junction (SCJ), the gastroesophageal junction (GEJ), the extent of circumferential columnar lining (C), and the most proximal extension of the columnar mucosa (M) of Barrett’s esophagus. ( Fig. 5.5 ). The depth of these landmarks is determined at the point just before such findings are seen in full view on scope withdrawal, as the scope is straighter in this position. The SCJ is also termed the Z-line and is the most distal portion of the squamous epithelium and appears as a serrated line . The anatomical location of the GEJ is determined at the point where the distal end of the tubular esophagus meets the upper gastric folds. Sometimes the distal end of the palisade vessels, which enter the submucosa at the GEJ, may be visible. Normally, the SCJ coincides with the GEJ. In patients without Barrett’s esophagus and in the absence of a hiatal hernia, these junctions will be located just proximal to the diaphragmatic hiatus. It is important to recognize any hiatal hernia that is present by distinguishing the diaphragmatic hiatal impression, where the caliber of the lumen becomes narrow, or sphincter “pinch,” from the GEJ. This can be difficult to see at times during endoscopy due to movements that occur from peristalsis and with respirations . Additionally, in the setting of large hiatal hernias this may be hard to identify and desufflating the stomach may assist. The location of these landmarks, diaphragmatic pinch, GEJ, and SCJ, should be measured in centimeters from the incisors and documented in the endoscopy report ( Figs. 5.5 and 5.6 ).
In the setting of Barrett’s esophagus, the SCJ will be displaced proximal to the GEJ. Suspected Barrett’s esophagus may be in the form of circumferential segments, tongues, or islands of columnar metaplasia. The difference in the depth of the circumferential and maximum extent from the depth of the endoscope insertion at the GEJ is then reported as C & M, respectively. It should be noted that islands of Barrett’s esophagus are not included in this criteria and short segments <1 cm are not included in the Prague criteria .
The Prague criteria were developed by the International Working Group for Classification of Oesophagitis (IWGCO) based on video endoscopic recordings of 29 patients. The criteria were then validated by 29 external expert endoscopists who reviewed and scored these recordings. The reliability coefficients (RC) for determining the GEJ was 0.88 and for the location of a hiatus hernia 0.85. For the criteria evaluating the extent of Barrett’s C and M, RC was 0.95 and 0.94, respectively. The overall RC for the endoscopic recognition of Barrett’s esophagus ≥1 cm was 0.72 but decreased to a coefficient of 0.22 for Barrett’s less than 1 cm in length . Thus these criteria have a higher degree of validity for Barrett’s esophagus segments when they are >1 cm in length ( Fig. 5.6 ).
A later study compared interobserver agreement of the Prague C & M classification between expert endoscopists and community hospital endoscopists. A total of 187 patients with Barrett’s esophagus underwent two upper endoscopies by each group of endoscopists and esophageal landmarks were documented. Absolute agreement was 74% (95% CI 68–80) for circumferential Barrett’s length, 68% (95% CI 62–75) for maximum length, and 63% (95% CI 56–70) for hiatal hernia length. The relative agreement between the groups was 91%. There was less agreement for shorter Barrett’s segments compared to longer segments. Overall, the authors concluded that the overall agreement between the groups was good . The performance of the Prague criteria has also been studied among gastroenterology trainees and showed a high interobserver reliability that was similar at all levels of training .
Issues arise with short segments and an “irregular” Z-line. DeNarid and Ridell’s description was that “the Z-line consists of small projections of red gastric epithelium, up to 5 mm long and 3 mm wide, extending upward into the pink-white squamous epithelium” . The Z-line can be well demarcated and circular where there is no suggestion of tongues or islands of columnar epithelium. When the Z-line is irregular, there are noticeable linear extensions of columnar-appearing epithelium . Debate has existed as to whether biopsies are needed for small variations in the Z-line. It can sometimes be difficult to find intestinal metaplasia in these very short segments . In one retrospective analysis of 2000 upper endoscopies with no previous diagnosis of Barrett’s, 166 (8.3%) of patients were identified with an irregular Z-line and 43% of these patients were found to have specialized intestinal metaplasia on biopsy. Risk factors included male sex and findings of a hiatal hernia . The ProGERD study looked at data of patients with specialized intestinal metaplasia at the cardia without endoscopic evidence of Barrett’s esophagus and found that 25.8% of patients had progression to Barrett’s esophagus in 2–5 years . It is not fully known if very short segments of intestinal metaplasia actually have an increased risk of esophageal malignancy. However, one could argue to these being short segment Barrett’s and it is known that dysplasia has been described in short segments and short segments of intestinal metaplasia have been found on surgical resections for adenocarcinoma .
One criterion that has been proposed to better identify short segment Barrett’s is the Japanese criteria, which defines the GEJ as the lowest limit of the palisade vessels in the lamina propria of the esophagus. Kinjo et al. prospectively compared the Japanese criteria with the Prague C & M criteria in a group of 110 Japanese patients. A greater number of patients were diagnosed with endoscopic Barrett’s esophagus using the Japanese criteria (39%) compared with the C & M criteria (26%). Identification of the GEJ was also higher with the Japanese criteria versus the C & M criteria (95% vs 86%). The authors concluded that the Japanese criteria might be better suited for their population. It is unknown if the results are applicable outside the Japanese population . An important limitation of this study was that only two endoscopists interpreted the findings and the study was not designed to assess interobserver correlation for both criteria. More studies are needed to assess these possible differences.
It is worth considering the fact that the importance of Barrett’s esophagus is that this condition increases the risk for development of cancer. Surveying patients with Barrett’s esophagus may lead to prevention or early detection. Broadening the definition of Barrett’s esophagus to include intestinal metaplasia in the presence of an irregular Z-line will identify more people at risk for progressing to adenocarcinoma but at the same time, given the large number of people with irregular Z-lines, a broader definition will greatly decrease the risk of progression to cancer. The lower the risk of progression to cancer the lower the benefit of surveillance.
5.3.1
Tissue Sampling
To make a diagnosis of Barrett’s esophagus and to detect intestinal metaplasia and goblet cells, it has been suggested that a minimum of eight biopsies be obtained within long segment of Barrett’s. In a study of 1646 biopsy samples from 125 patients with a mean Barrett’s length of 4 cm, obtaining 8 biopsies led to a diagnosis of Barrett’s esophagus with the presence of intestinal metaplasia in 67.9% of endoscopies. When only four biopsies were obtained, the yield dropped to 34.7%. Additional Alcian blue periodic acid Schiff staining only increased the diagnostic yield by 5.4% .
There have been a few publications on the technique for obtaining esophageal biopsies to improve the diagnostic yield of Barrett’s esophagus. One way for acquiring better tissue sampling is with a “turn-and-suction” endoscopic biopsy technique. The biopsy forceps is drawn back to the endoscope tip in an open position. The endoscope is then turned toward the esophageal wall followed by suctioning and then slight advancement with simultaneous closure of the biopsy forceps to obtain tissue for sampling. Using this technique, biopsy samples are taken in a perpendicular orientation to the esophageal wall. Biopsies taken in this manner have been reported to be over 50% longer . Care must be taken that biopsies are taken from the true esophagus and not the gastric cardia when biopsying at the EGJ.
Another way to improve biopsy sampling is with large capacity or jumbo biopsy forceps, which can sample larger dimensions of tissue with greater mean width and depth . Interestingly, one study noted no difference in the findings of esophageal cancer in patients with Barrett’s esophagus and high-grade dysplasia with the use of jumbo biopsy forceps compared with standard biopsy forceps . Additionally, a study of 65 patients undergoing surveillance for Barret’s who were randomized to standard, large capacity, or jumbo forceps, adequate biopsy samples were not significantly different between the three groups. Jumbo forceps also had the lowest percentage of well-oriented biopsies (p=0.001) .
Currently, the most commonly utilized protocol for performing esophageal biopsies for surveillance is systematic four-quadrant biopsies obtained every 2 cm in the Barrett’s segment . Nodules need to be identified based on the fact that they are raised or if there is a change in vascularity noted in the Barrett’s mucosa. Targeted biopsies should first be taken of any nodules or visible lesions before other biopsies are taken. Also there should not be active esophageal inflammation, such as reflux esophagitis, at the time of biopsy . Biopsies with this protocol have been shown to be more effective for finding LGD, HGD, and intramucosal cancers than older methods with random biopsy sampling. In one study comparing the detection of Barrett’s dysplasia and adenocarcinoma in two cohorts (random biopsy vs systematic four-quadrant biopsy protocols), the prevalence of LGD per patient was 18.9% in the group with systematic biopsy sampling versus 1.6% ( p <0.001) with random biopsies. The prevalence of HGD was 2.8% versus 0% ( p =0.03) in the systematic and random groups, respectively. No patients who had the systematic biopsy protocol developed advanced cancer whereas three patients in the other group died of esophageal adenocarcinoma . Similarly, in another study from the United Kingdom, the yield of findings of HGD and early esophageal cancers increased from 1% to 4.6% with the use of a systematic multiple biopsy protocol .
The Seattle biopsy protocol technique, targeted and four-quadrant jumbo biopsies every 1 cm, has been adapted by the American College of Gastroenterology and the British Society of Gastroenterology . It should be noted that the Seattle protocol still has potential disadvantages, while it may decrease the risk of missed dysplasia, it still does not eliminate the issue completely. Additionally, adherence to biopsy protocol has been shown to be low. Abrams et al. showed that in 2245 Barrett’s esophagus surveillance biopsy cases, only 51.2% adhered to guidelines. Longer segments of Barrett’s were more likely to have reduced adherence and this was associated with decreased detection of dysplasia (OR 0.53, 95% CI 0.35–0.82) .
5.4
Advances in Imaging and Diagnosis of Barret’s
Biopsy methods for Barrett’s still remain a random sampling of Barrett’s mucosa. Even with biopsy protocols it is possible to miss dysplasia and if dysplasia is found, it is still possible to miss invasive cancers. Novel endoscopic imaging techniques are being developed, which may improve on the endoscopic diagnosis of Barrett’s dysplasia and early esophageal cancers. These techniques include chromoendoscopy, narrow band imaging (NBI), optical coherence tomography (OCT), and confocal laser endoscopy. “Red flag” techniques such as chromoendoscopy try to highlight potential patches of intestinal type mucosa that can subsequently be targeted for biopsy, whereas high magnification techniques such as confocal laser endoscopy attempt to make a histologic diagnosis of Barrett’s esophagus and dysplasia during endoscopy.
5.4.1
Magnification Techniques and High-Resolution Endoscopy
Most standard endoscopes have the ability to magnify images and create very good mucosal detail of Barrett’s esophagus. There are specialized magnifying endoscopes that can magnify images up to 200 fold. These work best to focus on specific lesions rather than a large area when on magnification. Studies show lower interobserver agreement . Additionally, prospective data have not found this technique to be superior to targeted biopsies for detection of intestinal metaplasia .
Most endoscopes now are able to produce high-definition resolution images and may have a higher sensitivity to detect Barrett’s esophagus . The current high-resolution endoscopes have the ability to generate million pixel images as opposed to 300,000 pixel images generated by traditional white light endoscopes. This generates images with fine details enabling the endoscopists to identify early target lesions with greater sensitivity. These images are best viewed with high-definition televisions in the endoscopy suite. Kara et al. illustrated that even in the hands of an expert endoscopists, targeted biopsy using high-resolution endoscopy only identified 79% of dysplasia cases and there was difficulty in characterizing LGD .
5.4.2
Chromoendoscopy
Chromoendoscopy is a technique in which different colored dyes are sprayed over the mucosa to highlight mucosal detail. Agents that have been studied include methylene blue, toluidine blue, acetic acid, and indigo carmine . The mechanism by which each of the agents work is either as a contrast stain or through an absorptive stain process.
For example, methylene blue is an absorptive stain and can be absorbed by goblet cells to identify intestinal type epithelium. A mucolytic agent must first be applied to the esophagus to enhance the staining process. Methylene blue at a concentration of 0.5% can then be applied to an area of suspected Barrett’s esophagus using an appropriate “spray catheter” to topically apply a fine mist of blue color. After washing off excess dye, biopsies can be obtained from segments that stain intensely blue to improve the diagnostic yield. This technique is operator dependent with variations in sensitivity and specificity . Because of this learning curve, the fact that the technique can be untidy, and some theoretical concerns that methylene blue might be a carcinogen, this technique has not found favor in clinical practice .
Another strategy for highlighting mucosal detail in columnar mucosa is to spray dilute acetic acid on the surface of columnar epithelium. This technique has been borrowed from examination of the cervix during colposcopy. Acetic acid temporarily denatures surface proteins whitening the squamous epithelium and giving the Barrett’s epithelium a reddish hue. Circular or round pits are seen in non-Barrett’s sections while a villous or ridged pattern corresponds to intestinal type epithelium can be identified for biopsy . A study by Longcroft-Wheaton et al. of high-resolution acetic acid chromoendoscopy showed an excellent correlation between predicted histology on chromoendoscopy (normal, HGD, and invasive neoplasia) to actual histology ( r =0.98) . Again, although this is a simple technique and is easy to perform, it has not had clinical uptake because it requires high magnification and no standardized classification systems have been developed.
One advantage of chromoendoscopy is that the stains are relatively inexpensive (such as acetic acid) and can be used with any endoscope.
5.4.3
Virtual Chromoendoscopy and Other Novel Imaging
Virtual chromoendoscopy is a technology by which spectral features are modified with filters to narrow the band width of transmittance. The filters are adjusted to a blue light, which is similar to the absorption of hemoglobin. Restricting the spectrum of light can thus emphasize mucosal detail by enhancing the visualization of vascular structures in the mucosa . As vascular changes are important in premalignant conditions, this technology may allow early detection of dysplasia and cancer . Virtual chromoendoscopy can be performed by using narrow band filters (red, green, and blue bands) incorporated into the light source termed narrow band imaging. Postprocessing algorithms incorporated into the electronic processors can also obtain the same effect. NBI (Olympus, Inc.), I-Scan (Pentax Medical), and FICE (Fujifilm Global) are virtual chromoendoscopic technologies that are incorporated into commercial endoscopes. The same circular pattern or ridged and villous pattern characteristic of cardia or intestinal type epithelium, respectively, that can be identified by chromoendoscopy can easily be visualized with the press of a button using virtual chromoendoscopy . The endoscopists can switch between standard and NBI modes as needed during a procedure.
There have been proposed classification systems for NBI and Barrett’s mucosa . The mucosal patterns in nondysplastic Barrett’s have been described as a villous/gyrus pits with regular microvasculature forming pattern ( Fig. 5.7a ). Metaplastic Barrett’s epithelium also displays normal long branching blood vessels. Irregular, mucosal, and vascular patterns have a high sensitivity for the diagnosis of HGD and cancer ( Fig. 5.7b ).
Related posts:
A Disease Entity Is Identified
Screening and Surveillance of Barrett’s Esophagus
In Vivo Optical Detection of Dysplasia in Barrett’s Esophagus with Endoscopic Light Scattering Spectroscopy
Enhanced Imaging of the Esophagus: Confocal Laser Endomicroscopy
History of Ablative Therapies for Barrett’s and Superficial Adenocarcinoma
Endoscopic Surgical Therapies for Barrett’s Esophagus
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