The esophagogastric junction (EGJ), the region between

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1 Review Article Definition of the Esophagogastric Junction A Critical Mini Review Qin Huang, MD, PhD N Context. Accurate diagnosis of diseases involving the esophagogastric junction (EGJ) is challenging because of difficulty in defining the EGJ endoscopically and histologically. Recent research results have redefined the EGJ, and the endoscopic and histologic diagnostic criteria of the mucosal EGJ have become available. Objective. To review the recent literature on endoscopy, histology, and pathology of the EGJ with critical analysis. Data Sources. Recently published research articles and guidelines in the peer-reviewed core journals and personal research results in this field. Conclusions. At present, the mucosal EGJ can be defined endoscopically as the distal ends of esophageal longitudinal vessels that meet the proximal ends of gastric longitudinal mucosal folds. However, histologic validation of this criterion is needed. The histologic criteria of the EGJ include the distal ends of esophageal squamous mucosa, deep esophageal glands or ducts, or multilayered epithelium. The squamocolumnar junction is not a reliable landmark of the EGJ in patients with diseases involving the EGJ, such as hiatal hernias. (Arch Pathol Lab Med. 2011;135: ) The esophagogastric junction (EGJ), the region between which the stratified squamous mucosa-lined esophagus ends and the columnar mucosa-lined stomach begins, can be defined anatomically, physiologically, endoscopically, and histologically as either muscular or mucosal in nature. The muscular structure of the EGJ, forming the lower esophageal sphincter, can be better evaluated by physiologic manometric methods for pressure changes across the EGJ. In some patients with diseases involving the EGJ, the lower esophageal sphincter is degenerated and relaxed, causing dilatation of both the distal esophagus and the EGJ. The subsequent hiatal hernia formation has become a growing problem in industrialized countries. The mucosal EGJ in a healthy person overlaps with the squamocolumnar junction (SCJ) (Figure 1), but the SCJ in patients with a hiatal hernia is frequently displaced proximally, to various degrees, away from the mucosal EGJ (Figure 2). In addition to hiatal hernias, a number of other diseases arise in the EGJ region, making a confident designation of the mucosal EGJ difficult and challenging. In a recent retrospective comparison study in Japan, 1 patients with superficial EGJ cancers arising in the distal esophagus above the EGJ had significantly worse reflux esophagitis and hiatal hernias, but less atrophic gastritis, than those with cancer below the EGJ. Another recent Accepted for publication May 3, From the Department of Pathology and Laboratory Medicine, Veterans Affairs Boston Healthcare System and Harvard Medical School, West Roxbury, Massachusetts. The author has no relevant financial interest in the products or companies described in this article. Reprints: Qin Huang, MD, PhD, Department of Pathology and Laboratory Medicine, Veterans Affairs Boston Healthcare System and Harvard Medical School, 1400 VFW Pkwy, West Roxbury, MA ( Qin.huang@va.gov). study comparing clinicopathologic features of EGJ cancers between Chinese and American patients 2 found significantly more cases of severe gastritis and dysplasia, but no intestinal metaplasia or dysplasia, in the distal esophagus of Chinese patients whose tumor epicenters were below the EGJ than American white patients whose tumor epicenters were above the EGJ. These results illustrate significant differences between cancers arising above or below the EGJ. Therefore, an accurate designation of the mucosal EGJ is of paramount importance and a prerequisite for any meaningful studies of diseases and classification of cancers occurring in the EGJ region. At present, although there is no universally accepted gold standard for correct designation of the EGJ, several recently described landmarks can be used to define the macroscopic, endoscopic, and microscopic EGJ. Herein is provided an unbiased critical review of the study results from recently published literature on this topic. THE ANGLE OF HIS This anatomic landmark starts from the peritoneal reflection of the stomach onto the diaphragm, that is, the incisura. 3 For designation of the EGJ, it is only clinically usable when the disease damage in the EGJ region is minimal 4 and the patient does not have a hiatal hernia. In the patients with severe hiatal hernias, the entire lower esophageal sphincter is damaged to various extents and this landmark is also affected. When a malignant tumor arises in the EGJ region, the angle of His is often destroyed and becomes useless for clinical classification of the esophagus versus the stomach. 5 In a recent autopsy study by Austrian surgeons, 6 in 50 consecutive resection cases of the distal esophagus and the proximal stomach, the EGJ was found normally located intra-abdominally in all cases, with a mean distance to the angle of His of 3.6 cm 384 Arch Pathol Lab Med Vol 135, March 2011 The Esophagogastric Junction Huang

2 (range, cm). This finding may help surgical management of patients with diseases involving the EGJ region. THE PROXIMAL END OF GASTRIC LONGITUDINAL MUCOSAL FOLDS According to American Gastroenterology Association guidelines, 7 the proximal end of gastric longitudinal mucosal folds is the endoscopic landmark of the mucosal EGJ (Figure 1). This definition has been widely accepted in North America and Europe, despite the fact that this landmark has not been validated histologically. The early autopsy study 8 showed that the most proximal margin of gastric longitudinal mucosal folds was closely associated with the muscular EGJ. For this reason, McClave et al 9 were the first to find that the endoscopic SCJ was located within 2 cm of the proximal end of these gastric folds in a healthy person. In patients with hiatal hernias, the proximal end of these gastric folds provided a fixed, reproducible, anatomic landmark at endoscopy and could be used as the mucosal EGJ that was, they believed, equivalent to the muscular EGJ. Therefore, the diagnosis of columnar-lined esophagus (CLE) (Figure 2) can be made when a biopsy is obtained at a site greater than 2 cm above the proximal end of gastric longitudinal mucosal folds within a hiatal hernia sac. 9 Since then, the conclusion of this endoscopic study has become the standard of practice in North America and Europe. Owing to the widespread epidemic of hiatal hernias, the accuracy of this endoscopic landmark as a marker for the true mucosal EGJ has been questioned. 10,11 In addition, the gastric mucosal folds can be artificially flattened with overinflation of the stomach endoscopically and changed during respiration and gagging. As such, almost all endoscopic studies that used this endoscopic criterion for the EGJ are potentially flawed 12 and the biopsy at the so-called esophagogastric junction almost always shows CLE. 11 In a recent correlation study for the hypothesis that the proximal end of gastric longitudinal mucosal folds was at the same level as the endoscopic SCJ and the angle of His, Wallner 13 labeled the SCJ endoscopically with India ink tattooing and then measured the distance between this ink mark and the angle of His in 7 resection specimens. The author reported a disparity of less than 5 mm and, therefore, concluded that the proximal ends of gastric longitudinal mucosal folds can be used endoscopically as the true EGJ. The major limitation to this conclusion is the lack of histology correlation, since all 7 cases had cancers in the distal esophagus or the proximal stomach. In fact, the image shown in the article exhibited typical CLE. 13 In summary, the validity of use of the proximal end of gastric mucosal folds as the true mucosal EGJ at endoscopy remains dubious. A histologic validation study is required. THE DISTAL END OF ESOPHAGEAL LONGITUDINAL PALISADING VESSELS In Japan, the distal end of esophageal palisading vessels is considered a more accurate endoscopic landmark of the mucosal EGJ than the proximal end of gastric longitudinal mucosal folds. In the distal esophagus, there are many parallel longitudinal veins running in the lamina propria and ending at the mucosal junction with the stomach (Figure 3). These veins are visible endoscopically as palisading vessels in a conscious person 14 and are also identifiable in CLE. 15 Because these palisading veins are absent in the stomach, the Japanese Society of Esophageal Disease authorized the definition of the distal end of the esophageal longitudinal vessels as the mucosal EGJ in As such, the diagnosis of CLE, such as Barrett esophagus, can be made endoscopically in Japan. These esophageal mucosal veins can be best visualized during deep inspiration of a conscious person but are sometimes invisible, especially in patients with active esophagitis or in resected or autopsy esophageal specimens. 15 This is the major reason why endoscopists in North America and Europe do not use this criterion for the mucosal EGJ in their practice. In the aforementioned clinical situations in Japan, the patients are treated with proton pump inhibitors before endoscopy to minimize active esophagitis-induced mucosal edema that makes the longitudinal vessels invisible endoscopically. 15 In patients with CLE, these veins must be scrutinized for clear identification of the distal ends of the veins, that is, the mucosal EGJ, during deep inspiration, to make an accurate diagnosis of CLE endoscopically. 15 According to the Japanese guidelines, any columnar mucosa proximal to the distal ends of esophageal longitudinal palisading vessels is classified as CLE and subject to endoscopic surveillance. This principle has been challenged by the results of a recent study in 42 resection specimens for investigation of the relationship between the mucosal EGJ and the distal end of these palisading veins. The authors 16 analyzed the still images of the mucosal EGJ and found that the endoscopically defined distal ends of esophageal longitudinal vessels were less than 5 mm distal to the SCJ in more than 95% of cases, and the mucosa in between was columnar in a narrow zone. The authors 16 doubted that CLE in this narrow zone had any increased risk of cancer development. In a comparison study of the relationship among the distal end of esophageal longitudinal vessels, the proximal end of gastric mucosal folds, and the most distal end of deep esophageal glands and ducts, Sato et al 17 systematically investigated the entire EGJ in 87 consecutive resection specimens from patients with esophageal squamous cell carcinoma. They used CD31 immunostain for identification of the distal end of esophageal longitudinal veins in the lamina propria and evaluated the correlation between the distal end of esophageal veins and conventional EGJ landmarks. They reported that the most distal end of esophageal longitudinal veins was positioned immediately distal to other landmarks of the EGJ. Interestingly enough, both the SCJ and the EGJ are not a straight line but U or V shaped, with the distance at the lesser curvature of the stomach significantly longer than that at the greater curvature. This unique shape of the EGJ has not been described elsewhere in the literature. According to the authors, the unusual U or V shape of the EGJ results from unique interactions between the esophageal longitudinal and circular muscles with the gastric innermost oblique muscle and the longitudinal middle circular muscle layers. At the EGJ, the gastric innermost oblique muscle layer becomes sling fibers with roots in the greater curvature side of the EGJ. These sling fibers function as hooks around the notch between the distal esophagus and gastric fundus, forming parallel fibers to the lesser curvature and disappearing gradually around the angle of His. This forms the basis of the U- or Arch Pathol Lab Med Vol 135, March 2011 The Esophagogastric Junction Huang 385

3 Figure 1. The mucosal junction between the distal end of the pearly white esophageal squamous mucosa and the proximal end of gastric longitudinal mucosal folds defines the mucosal esophagogastric junction (EGJ) that overlaps the squamocolumnar junction (SCJ) and the angle of His in a healthy person. Figure 2. In a patient with a hiatal hernia and severe reflux esophagitis, the squamocolumnar junction or zigzag (SCJ/Z) line is displaced proximally and upshifted from the esophagogastric junction (EGJ). The mucosa between the SCJ and the EGJ in this situation is termed the columnarlined esophagus. Figure 3. At endoscopy in a healthy person, the distal end of the pearly whitish esophageal squamous mucosa forms the squamocolumnar junction (SCJ) and meets the proximal end of reddish gastric longitudinal mucosal folds as the true mucosal esophagogastric junction (EGJ). 386 Arch Pathol Lab Med Vol 135, March 2011 The Esophagogastric Junction Huang

4 V-shaped mucosal EGJ line. 17 In Barrett esophagus, Sato et al 17 also discovered that CLE was significantly more severe in the lesser curvature than in the greater curvature side of the EGJ. In summary, the results of the studies from Japan suggest that the distal end of esophageal longitudinal veins may be more accurate than the proximal end of gastric mucosal folds as the true mucosal EGJ landmark. Further confirmation and validation studies are needed in other ethnic populations. SQUAMOCOLUMNAR JUNCTION In a healthy person without reflux esophagitis, the macroscopic mucosal EGJ is at the same level as the microscopic SCJ (Figures 3 and 4). This mucosal EGJ-SCJ line is not straight between the esophagus and stomach; rather, it is serrated, zigzagged, and also known as the Z line. This line is unstable, with 3 histologic patterns: (1) an abrupt transition between esophageal squamous and gastric columnar mucosa; (2) an overlapping of gastric cardiac glands that continuously extend into the distal esophagus underneath the squamous epithelium, forming superficial esophageal cardiac glands 18,19 this pattern can be seen in 80% to 95% of Japanese patients 20,21 ; and (3) an upward displacement proximally away from the EGJ. In this situation, the distance between the SCJ and the EGJ defines the length of CLE or Barrett esophagus (Figure 2). In an autopsy study of 50 consecutive elderly Japanese patients (mean age, 80 years), 20 the SCJ was found at the same level as the angle of His in 28% of cases, and the distance between the SCJ and the angle of His ranged from 0 to 10 mm. None of these cases showed the upshift of the SCJ toward the proximal esophagus. This conclusion has been confirmed in Chinese patients. In an endoscopic study of 145 Chinese patients, Law et al 22 performed biopsies at or immediately below the SCJ that showed a normal appearance in 94% of cases and none upshifted proximally. In a histologic study of the EGJ in 44 resection specimens for gastric cardiac cancer in Chinese patients, among which the entire EGJ was examined microscopically in 31 cases, Fan et al 23 used the most distal end of squamous mucosa, along with deep esophageal glands and ducts, as the histologic landmarks of the mucosal EGJ. They found that the SCJ was at the same level as the EGJ in all cases examined. In summary, the SCJ may be displaced proximally and move away from the mucosal EGJ in American patients and cannot be used as a gold standard for the true mucosal EGJ to guide the endoscopic study in a general practice setting. However, in Japanese and Chinese individuals, the SCJ overlaps with the mucosal EGJ in most subjects at endoscopy (Figure 3). The relationship among the SCJ, the distal end of esophageal palisading veins, and the proximal end of gastric longitudinal mucosal folds in these populations remains unknown. Further validation and comparison studies are required for definitive designation of the true mucosal EGJ to guide clinical practice and research. HISTOLOGIC MARKERS OF THE MUCOSAL EGJ At present, in a small biopsy specimen from the EGJ region, distinction between the proximal stomach and the distal esophagus is heavily dependent upon the endoscopist s impression of the precise location of a biopsy site. Unfortunately, in addition to the problematic endoscopic landmark of the mucosal EGJ discussed above, many additional confounding factors, such as hiatal hernias, respiratory movement, and active or ulcerative esophagitis, make an accurate determination of precise biopsy sites almost impossible. Recent histopathologic studies have characterized the morphologic features of the mucosal EGJ and defined the following histologic features of the mucosal EGJ as the distal ends of (1) squamous mucosa or islands (Figure 4); (2) deep esophageal glands and ducts (Figure 5); (3) multilayered epithelium (Figure 6) and hybrid glands; and (4) double-layered muscularis mucosa. 14,24 26 Squamous mucosa and deep esophageal glands and ducts are unique to the esophagus and absent in the stomach. 19,27,28 Therefore, these histologic landmarks are currently the gold standard of the esophagus and used to histologically define the mucosal EGJ. In patients with extensive CLE, squamous mucosa frequently becomes fragmented into small patches and islands. These small squamous epithelial islands surrounded with columnar mucosa are indicative of an esophageal biopsy specimen. 25 Other landmarks for the esophagus include (1) a double layer of the muscularis mucosa, which can be identified in up to 87% of patients with Barrett esophagus 24 but is found to be nonspecific for the esophagus because it is also seen in hiatal hernias and postradiation/sclerotherapy or biopsy 20 ; and (2) a multilayered epithelium, which is noted to be the precursor of CLE and Barrett esophagus and present only in the distal esophagus as a result of reflux-induced esophageal injury. 12,29 Other histologic features more commonly associated with CLE include the presence of mucosal crypt architectural disarray, mucosal atrophy, and hybrid glands with intestinal metaplasia occurring only in the superficial portion of a mucous gland. These features suffer from a high interobserver variability among expert gastrointestinal patholor Figure 4. Histologically, the distal end (arrow) of esophageal squamous mucosa in a healthy person is defined as the true esophagogastric junction (EGJ). In this case, cardiac glands form a continuous mucosa bridging the proximal stomach and the distal esophagus. In the adjacent distal esophagus, these cardiac glands underneath the esophageal squamous epithelium are also known as superficial esophageal glands (segs) (hematoxylin-eosin, original magnification 340). Figure 5. The distal end of deep esophageal glands (degs) or their ducts defines the mucosal esophagogastric junction (EGJ, indicated as the vertical line proximal to the distal end of a deep esophageal gland duct, deg duct [ ]). These structures are unique to the esophagus and absent in the stomach. In this case, the ductile epithelial cells are highlighted with the p63 immunostain (p63 mouse anti human monoclonal antibody, 1:50, clone BC4A4, Biocare Medical, LLC, Concord, California, original magnification 320). Figure 6. The distal end of multilayered epithelium (MLE) is another landmark of the esophagogastric junction (EGJ, indicated as the vertical line proximal to the distal end of MLE). The MLE consists of glandular cells on the surface and squamous cells underneath. This feature has been described to be present only in the esophagus (hematoxylin-eosin, original magnification 3200). Arch Pathol Lab Med Vol 135, March 2011 The Esophagogastric Junction Huang 387

5 gists 26 and are thus disqualified as the definitive histology markers of the mucosal EGJ. At present, the best histologic markers of the mucosal EGJ are the distal ends of (1) squamous epithelium, (2) deep esophageal glands and ducts, and (3) multilayered epithelium. For an endoscopic specimen labeled as being from the EGJ and showing intestinal metaplasia, pathologic distinction between Barrett esophagus and chronic gastric carditis is critically important for appropriate patient management and research. The aforementioned 3 criteria have been validated in a recent study 26 as being highly objective and specific for the esophageal origin of the tissue, with good interrater agreement among expert gastrointestinal pathologists. However, in a situation in which these 3 landmarks are absent in an EGJ biopsy specimen, a brief discussion with the endoscopist and review of the endoscopic images may be helpful for making appropriate pathologic interpretations of the biopsy specimen. CONCLUSIONS An accumulating body of evidence indicates that the mucosal EGJ can be defined endoscopically as the distal ends of esophageal longitudinal vessels meeting with the proximal ends of gastric longitudinal mucosal folds in a healthy person. In patients with active esophagitis, ulcers, or hiatal hernias, these landmarks may not be determined with certainty, and the patients should be treated with proton pump inhibitors before endoscopy. Histologically, the mucosal EGJ should be defined as the most distal ends of squamous epithelium and deep esophageal glands and ducts. In a healthy person, the SCJ overlaps the mucosal EGJ; however, in patients with hiatal hernias, ulcers, and CLE, the SCJ is frequently displaced upwards from the mucosal EGJ. As such, the SCJ is not stable and cannot be used as the landmark for the true mucosal EGJ. However, in most Japanese and Chinese individuals, the SCJ overlaps with the EGJ. Therefore, the SCJ may be used as a surrogate landmark of the mucosal EGJ in these populations. 14 However, this idea remains to be further validated. In endoscopic biopsies taken from patients with CLE, the origin of a biopsy specimen from the esophagus can be determined if the following histologic markers are detected: squamous islands, deep esophageal glands and ducts, and multilayered epithelium. The following are the current criteria of the mucosal EGJ. For endoscopy: 1. The distal end of esophageal longitudinal mucosal veins 2. The proximal end of gastric longitudinal mucosal folds 3. The SCJ in most Japanese and Chinese subjects For histology: 1. The distal end of squamous mucosa 2. The distal end of deep esophageal glands and ducts 3. The distal end of multilayered epithelium In general, the definitive determination of the mucosal EGJ can be confidently obtained with a set of endoscopic and histologic criteria. In many instances, however, the histologic markers are absent and determination of the mucosal EGJ can be challenging. In this scenario, pathologists need help from endoscopists. It is essential for endoscopists to provide pathologists with (1) the accurate location of biopsy tissues taken from the EGJ region, to the best of their knowledge; (2) multiple biopsies in the proximal stomach below the EGJ and the distal stomach so that a comparison can be made histologically among different biopsy samples; (3) endoscopic images; (4) the location of the SCJ and the relationship between the SCJ and the EGJ; and (5) clinical information. 30 Nevertheless, validation studies for both endoscopic and histologic EGJ landmarks are urgently needed. The author thanks Raj K. Goyal, MD, and Kilmer McCully, MD, of the Veterans Affairs Boston Healthcare System for their helpful discussion on the project and consistent support. 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