Can Western endoscopists identify the end of the lower esophageal palisade vessels as a landmark of esophagogastric junction?

Background and aim  The endoscopic landmark of esophagogastric junction (EGJ) for diagnosis of Barrett’s esophagus (BE) differs between Japan and Western countries. Japanese endoscopists use the distal end of the lower esophageal palisade vessels to localize EGJ. In the West, endoscopists use the proximal gastric folds because of concerns that palisade vessels may be difficult to recognize. We evaluated whether there were differences between American and Japanese endoscopists in the recognition of palisade vessels. Method  A total of 82 patients were enrolled in this study. Patients were referred for diagnostic esophagogastroduodenoendoscopy (EGD) at the Veterans Affairs Palo Alto Health Care System, from May to July 2008. American and Japanese endoscopists evaluated the EGJ of patients undergoing diagnostic EGD. We analyzed the differences in the recognition of the distal end of palisade vessels. We calculated the kappa statistic to measure interobserver variability. Results  Based on localization using the distal end of the palisade vessels, American and Japanese endoscopists identified the EGJ in 87.8% (72/82) and 89.0% (73/82) of cases, respectively. The kappa statistic for visualization of EGJ was 0.88 [95% confidence interval (CI): 0.73–1.00]. Conclusion  American and Japanese endoscopists similarly recognized the distal end of palisade vessels as EGJ.     

Barrett’s esophagus in Japanese patients: its prevalence,form, and elongation

Background  Barrett’s esophagus is a well-known acquired condition resulting from gastroesophageal reflux disease (GERD). However, it is still unknown whether Barrett’s esophagus develops gradually over time in patients with GERD. To address this issue, we investigated the change in the prevalence and length of short-segment Barrett’s esophagus (SSBE) over time. Methods  From January 2005 to March 2007, we enrolled 5338 patients who received upper gastrointestinal endoscopy. Prevalence and length of endoscopically identified SSBE were evaluated within groups divided on the basis of 10-year age intervals. The factors possibly influencing SSBE length such as symptoms, antacid use, and endoscopic findings were also evaluated. Additionally, the length change in 236 patients with histologically confirmed Barrett’s esophagus was evaluated over a 2-year follow-up. Results  Of the 5338 enrolled patients, 1997 had SSBE. The prevalence of endoscopically identified SSBE was significantly higher and its length was significantly longer in elderly patients. Multiple regression analysis showed that age, presence of reflux esophagitis, reflux symptoms, and hiatal hernia were positively correlated with SSBE length. Analysis of the 2-year follow-up study of histologically confirmed SSBE revealed significant extension of Barrett’s length in 28.0% of 236 patients. Presence of reflux symptoms and hiatal hernia were identified as positive predictors and proton pump inhibitor administration as a negative predictor of SSBE elongation. Conclusions  Positive predictors for the extension of SSBE were presence of hiatal hernia and reflux symptoms, but not age.     

Prevalence of Barrett’s Esophagus in Patients with or without GERD Symptoms: Role of Race, Age, and Gender

Background Gastroesophageal reflux disease is associated with a significantly increased risk of Barrett’s esophagus (BE) and adenocarcinoma of the esophagus. Racial differences in the prevalence of BE are controversial. Our purpose was to study the prevalence of Barrett’s esophagus in patients with and without gastroesophageal reflux disease (GERD) symptoms, and the differences between these two groups in terms of race, age, and sex. Methods Esophagogastroduodenoscopy (EGD) reports from the PENTAX EndoPRO database for the Endoscopy Unit at the University of Texas Medical Branch from 2005 to 2007 were reviewed. Four hundred and ten patients who underwent upper endoscopy because of GERD symptoms that were not responding to proton pump inhibitor (PPI) therapy or with alarm symptoms and 4,047 patients undergoing upper endoscopy for other reasons without GERD symptoms were identified. Results BE was significantly more common among males. The prevalence of BE was higher in patients with GERD symptoms than those without GERD symptoms. Overall, more cases of BE, dysplasia, and adenocarcinoma were found among the patients without GERD symptoms than those that underwent endoscopy because of GERD symptoms. The prevalence of BE among Caucasian, African American, Hispanic, and “other” groups with GERD symptoms were 5%, 2.56%, 4.4%, and 0%, respectively. The prevalence of BE among these racial groups without GERD symptoms were 1.9%, 0.9%, 1.57%, and 0.8%, respectively. The association between race and BE was not statistically significant (df = 3, P = 0.2628), including after adjusting for the presence of GERD symptoms (df = 3, P = 0.2947). Patients without GERD symptoms that presented with BE were significantly older than the patients without BE (P < 0.01). Conclusions BE is a male-dominant disease. The prevalence of Barrett’s esophagus was not significant different among Caucasian, Hispanics, and African Americans. Most of the patients with BE, dysplasia, and adenocarcinoma did not have GERD symptoms. X. Fan contributed to the concept and design of the study, the analysis and interpretation of the data, and the drafting of this article. N. Snyder contributed to the critical revision of the article for important intellectual content and final approval of this article.     

Signet ring cell carcinoma of the esophagus treated by video-assisted surgery: report of a case

We report a case of Barrett’s adenocarcinoma consisting of a signet ring cell carcinoma (SIG) and well-differentiated adenocarcinoma treated by video-assisted surgery. The patient was a 73-year-old man with esophagitis endoscopically detected 5 years earlier. Esophagogastroscopy showed an ulcerative tumor (lesion 1) with a small protruding tumor (lesion 2) in the lower esophagus. Biopsy specimens taken from lesions 1 and 2 showed SIG and a well-differentiated adenocarcinoma, respectively. The patient underwent video-assisted surgery for the esophageal carcinoma. Macroscopically, the resected tumor consisted of a type 2 tumor (lesion 1, 25 mm in diameter) and a type 0-IIa tumor (lesion 2, 10 mm in diameter) of the lower esophagus. Histologically, lesion 1 showed SIG invading the submucosal layer of the esophagus, and lesion 2 showed a well-differentiated adenocarcinoma limited to the mucosa. The two lesions were continuously observed, and a moderately differentiated adenocarcinoma was observed between lesions 1 and 2. Near the tumor, the double muscle layer of the mucosa and the esophageal glands were observed under the columnar epithelium. In immunohistochemistry, both lesions showed positive reactions for MUC5AC and MUC2 but showed no reaction for MUC6. The tumor was diagnosed as SIG concomitant with a well-to moderately differentiated adenocarcinoma arising from Barrett’s esophagus (pT1b pN0 M0). The patient is alive without recurrence 60 months after surgery.     

NERD, GERD, and Barrett’s Esophagus: Role of Acid and Non-acid Reflux Revisited with Combined pH-Impedance Monitoring

Introduction Gastroesophageal reflux is the most important factor in the development of Barrett’s metaplasia. The effect of acid reflux is commonly accepted today, but there is controversy about the role of non-acid reflux. With introduction of combined esophageal pH-impedance monitoring, a precise diagnostic test for acid and non-acid reflux is now available. Methods Ninety two consecutive patients (33 women) off acid-suppressive therapy underwent diagnostic work-up for suspected gastroesophageal reflux disease including upper-GI endoscopy, esophageal manometry, barium swallow, and combined esophageal pH-impedance monitoring. Patients were subdivided into three groups according to symptoms and endoscopic appearance: typical symptoms without esophagitis (n = 28; NERD); erosive esophagitis (n = 52, ERD), and patients with intestinal metaplasia (n = 12, BE). Results Pathologic acid reflux during pH-metry was found in 35.7%, 63.5%, and 75.0% for NERD, ERD, and BE patients, respectively (P = 0.022). Likewise, the percentage of time pH < 4 rose significantly during upright, supine, and total phases. In contrast, combined pH-impedance monitoring showed no significant difference between groups for the number of acid reflux events and for percentage of acid bolus reflux time. However, BE patients had significantly more non-acid reflux events and a higher percentage of non-acid bolus reflux time during the supine (P = 0.043, P = 0.020, respectively), but not during the upright phase (P = 0.740, P = 0.730, respectively). Conclusion Patients with BE are exposed to increased supine non-acid reflux and to increased acid reflux during upright and supine phases. This observation supports the concept that nocturnal non-acid reflux may play a role in the pathogenesis of BE.     

The Effect of Retinoic Acid and Deoxycholic Acid on the Differentiation of Primary Human Esophageal Keratinocytes

The mechanism linking gastroduodenal reflux disease to intestinal metaplasia in the esophagus (Barrett’s esophagus) has not been determined. Active conjugate metabolites of retinoic acid, in addition to bile acids, undergo an enterohepatic circulation in bile. Retinoic acid and bile acids are candidate mediators of keratinocyte transdifferentiation in Barrett’s esophagus. We studied the effects of retinoic acid on the differentiation of primary human esophageal keratinocytes cultured in vitro. Retinoic acid induces expression of a marker of intestinal differentiation, MUC2, in these cells. However, retinoic acid, alone or in combination with the hydrophobic bile acid, deoxycholic acid, does not affect esophageal keratinocyte squamous differentiation as assessed by involucrin expression and cellular morphology. The ability of retinoic acid to induce MUC2 expression may be relevant to the pathogenesis of Barrett’s esophagus. However, this does not result in suppression of squamous differentiation.     

Vaccine Impedes the Development of Reflux-induced Esophageal Cancer in a Surgical Rat Model: Efficacy of the Vaccine in a Post-Barrett’s Esophagus Setting

Purpose We developed and evaluated a GM-CSF whole-cell tumor vaccine for esophageal cancer. Experimental design Cell lines derived from surgically induced rat reflux esophageal tumors were passaged in vitro and transfected with GM-CSF. First, the GM-CSF whole cell vaccine was evaluated against subcutaneously transplanted esophageal tumor cells. In a subsequent study, the vaccine was tested to see if it could reduce the incidence of cancer in the surgical reflux model. Results While subcutaneously transplanted tumor cells produced lasting tumors in PBS non-vaccinated placebo rats, transplanted tumors regressed and were immunologically rejected in animals vaccinated prior to implantation. In the surgical reflux model, the vaccine reduced the incidence of cancer from 17/23 (74%) in the controls to 6/16 (38%) in the vaccinated animals (P = 0.046). Conclusions The GM-CSF whole cell tumor vaccine effectively promoted a strong immune response against subcutaneously transplanted tumors and protected animals from developing esophageal cancer in the reflux model.     

Asymmetrical circumferential distribution of esophagogastric junctional lesions: anatomical and physiological considerations

Several components of the gastrointestinal tract including the esophagogastric junction (EGJ) show circumferential asymmetry in the formation of pathological lesions, which is caused by the morphological and functional asymmetry of the gastrointestinal tract. Pressure in the lower esophageal sphincter (LES) is higher on the left posterior side as compared to the right anterior side, which may partly explain why Mallory–Weiss tears frequently occur on the right side wall of the EGJ. Lower LES pressure in the right anterior wall may not effectively prevent gastroesophageal reflux on this side and may be a reason why esophageal erosions in patients with reflux esophagitis, short segment Barrett’s esophagus, and adenocarcinomas associated with short segment Barrett’s esophagus are frequently found in the right anterior wall of the esophagus. In addition, acidic gastroesophageal reflux may also cause rupture of esophageal varices predominantly on that side. Thus, asymmetrical LES pressure may be a cause of the right anterior side predominance of diseases found in this part of the gastrointestinal tract.     

Hemochromatosis Gene Status as a Risk Factor for Barrett’s Esophagus

Conditions causing high iron levels, such as hemochromatosis, are proposed risk factors for esophageal adenocarcinoma. Although this hypothesis is supported by animal models, no human data currently exist. We conducted a case-control study of persons with a new Barrett’s esophagus diagnosis (cases), persons with gastroesophageal reflux disease (GERD) (without Barrett’s esophagus), and population controls. Subjects completed detailed examinations and assays for hemochromatosis mutations and serum iron stores. We evaluated 317 cases, 306 GERD patients, and 308 population controls. There was no significant association between Barrett’s esophagus and any hemochromatosis gene defect (odds ratio [OR] = 1.32, 95% confidence interval [CI]: 0.95–1.84), a moderate or severe mutation (OR = 1.54, 95% CI: 0.94–2.52), or a severe mutation (C282Y homozygote or C282Y/H63D heterozygote; OR = 0.77, 95% CI: 0.24–2.48) compared with the population controls. As expected, gene defects were associated with increased iron stores. We can conclude from our findings that Barrett’s esophagus was not associated with hemochromatosis gene defects, although we cannot exclude small effects.     

Increased Prevalence of Gallstone Disease and Impaired Gallbladder Motility in Patients with Barrett’s Esophagus

The prevalence of gallstones in patients with Barrett's esophagus (BE) and their gallbladder motility relative to that of healthy volunteers and GERD patients without BE were investigated. Of the 707 patients reviewed, 203 (125 males and 78 females) had BE. The prevalence of gallstones was significantly higher in the patients with BE than in those without BE (34 vs. 20%, respectively). The gallbladder functions of 22 patients with GERD, 27 patients with BE and 21 healthy volunteers were assessed by ultrasonography before and after a test meal. The patients with BE had significantly higher fasting volume and residual volume, but lower ejection volume, ejection fraction and ejection rate values than those of the healthy controls. None of the ultrasonographic parameters of patients without BE were significantly different from those of the controls. Patients with BE have a more complex gastrointestinal motility disorder that involves the gallbladder, and this makes this subset of patients with GERD more prone to gallstone disease.     

Prevalence of Complicated Gastroesophageal Reflux Disease and Barrett’s Esophagus Among Racial Groups in a Multi-Center Consortium

Aims The Clinical Outcomes Research Initiative database was used to evaluate ethnic trends in complicated reflux disease and suspected Barrett’s esophagus among various racial groups. Methods Endoscopic findings for procedures performed January 2000–December 2005 for any indication and for reflux-related indications were reviewed by racial group. Results Of 280,075 procedures examined, Hispanics were the most likely to have esophagitis (Hispanic 19.6%, white 17.3%, black 15.8%, Asian/Pacific Islander 9.5%, P-value < 0.0001), and white subjects were most likely to have suspected BE (white 5.0%, Hispanic 2.9%, Asian/Pacific Islander 1.8%, black 1.5%, P-value < 0.0001). Endoscopies performed for reflux-related indications had similar trends for esophagitis and esophageal stricture. Among reflux/Barrett’s screening procedures adjusted for age and gender, Hispanics were most likely to have esophagitis (OR = 1.28, P-value < 0.0001) compared to Caucasians. Conclusion Our results demonstrate an association of suspected Barrett’s esophagus and stricture with white patients and esophagitis with Hispanic patients. These findings need to be followed-up with further study.     

One American pathologist’s view of the diagnosis of Barrett’s mucosa and its neoplastic complications: we do not always have to agree, but we need to respect our differences

In the United States, Barrett’s mucosa is defined as having an endoscopic change that looks like columnar mucosa in the lower esophagus and goblet cells in a biopsy from that endoscopic abnormality. This is not a universally accepted definition. In both Japan and the United Kingdom, the endoscopic change is still required, but any columnar mucosa, whether or not it has goblet cells, is adequate for the Barrett’s diagnosis. This difference of opinion probably does not affect patient care, because the American definition seems to work well from a clinical standpoint in the United States, while the Japanese/British definition works well clinically in those countries. The neoplastic complications of Barrett’s mucosa, the dysplasias and carcinomas, are diagnosed using a series of cytological and architectural changes, and really are based on the degree of difference of neoplastic epithelium when compared with nonneoplastic epithelium. The closer the resemblance to nonneoplastic epithelium, the lower the neoplastic epithelium is on the dysplastic scale. The more the neoplastic epithelium differs from nonneoplastic, the higher that epithelium is on the dysplastic scale. The most deviant neoplastic epithelium is carcinomatous.     

Role of gastric acid secretion in the pathogenesis of Barrett’s esophageal cancer in a Japanese population

The acidity of the refluxate into the esophagus is an important factor not only for reflux esophagitis, but also for Barrett’s esophagus and the development of Barrett’s esophageal cancer. On the other hand, H. pylori infection is thought to prevent reflux esophagitis and Barrett’s esophagus by causing atrophic gastritis, which in turn decreases gastric acid secretion. Moreover, the preservation of gastric acid secretion may be important for the development of gastroesophageal junction cancer, including Barrett’s esophageal cancer, irrespective of the H. pylori infection status. An increase in gastric acid secretion in Japanese populations has been predicted based on a decreasing rate of H. pylori infection and the westernization of eating habits in Japan; this, in turn, may lead to an increase in the prevalence of Barrett’s esophageal cancer in Japan in the future.     

A Systematic Review and Meta-Analysis of the Treatment for Barrett’s Esophagus

As evidence-based strategies to the clinical management of Barrett’s esophagus (BE) are lacking, we have carried out a systematic review and meta-analysis of all published randomized controlled trials with the aim of evaluating the value of different approaches in the treatment of BE. Searches were conducted in the databases PUBMED, EMBASE, and Cochrane Library. Thirteen randomized clinical trials that fulfilled the inclusion criteria and addressed the clinical questions of this analysis were assessed in more detail. Based on our search, neither the pharmacological nor surgical therapies currently available for reflux appear to achieve complete regression of BE and the elimination of the cancer risk associated with it. In contrast, endoscopic ablative techniques are capable of achieving endoscopic and histological reversal of BE, with ablation by argon plasma coagulation (APC) appearing to be more effective than treatment with photodynamic therapy (PDT) [odds ratio (OR) 3.46, 95% confidence interval (CI) 1.67–7.81, P = 0.0008]. There was no statistically significant difference between APC and multipolar electrocoagulation (MPEC) in terms of the efficacy to achieve regression of BE (OR 2.01, 95% CI 0.77–5.23, P = 0.15). In conclusion, there have been only a limited number of randomized controlled trials that compare treatments for BE. The pharmacological therapy, antireflux surgery, and endoscopic ablative techniques are promising in terms of treating BE, but the studies carried out to date have had no adequate power to assess the effect of treatment on reducing and preventing progression to adenocarcinoma.     

The proton pump inhibitor test and the diagnosis of gastroesophageal reflux disease

There continues to be significant controversy related to diagnostic testing for gastroesophageal reflux disease (GERD). Symptoms of GERD may be associated with physiologic esophageal acid exposure measured by intraesophageal pH monitoring or pH-impedance monitoring, and a significant percentage of patients with abnormal esophageal acid (or weak acid) exposure have no or minimal clinical symptoms of reflux. On the other hand, endoscopic lesions are only present in a minority of GERD patients. In clinical practice, presumptive diagnosis of GERD is reasonably assumed by the substantial reduction or elimination of suspected reflux symptoms during the therapeutic trial of acid reduction therapy, the so-called proton pump inhibitor (PPI) test. We aimed to assess the optimal cutoff value and duration of this test in GERD patients with and without esophagitis. We conducted a prospective study of 544 patients, endoscopically investigated and treated for 2 weeks with PPIs at double dose, and for an additional 3 months at standard dose. The status of the patient at the end of the study was used as an independent diagnostic standard. We found esophagitis present in 55.8% and absent in 44.2% of patients (corresponding to a diagnosis of nonerosive reflux disease [NERD]). The test was positive in 89.7–97.8% of the patients according to the cutoff or duration of the test used. The sensitivity of the PPI test was excellent, ranging from 95.5 to 98.8%, whereas the specificity was poor, not exceeding 36.3%. Erosive esophagitis patients responded more favorably to the PPI test and subsequent PPI therapy compared with NERD patients. In conclusion, the PPI test is a sensitive but less specific test. Its optimal duration is 1 week, and the optimal cutoff value is a decrease of heartburn score of more than 75%. NERD patients respond less satisfactorily to PPIs, even when functional heartburn patients are excluded and only ‘true’ NERD patients are considered.     

Rodent endosonography to monitor esophageal cancer

Animal models of luminal cancers are important to understand and assess chemopreventive and chemotherapeutic interventions. However, the ability to assess tumor growth and response without animal sacrifice is limited. We assessed the ability of luminal sonography to assess the presence of tumor and its size in a surgical esophagojejunostomy model of esophageal cancer. Luminal sonography had a sensitivity of 88%, specificity of 100%, and accuracy of 93% in identifying the esophageal cancers. The tumor dimensions on luminal sonography were within 11% of autopsy measurements. Minimal tumor dimension was 2 mm and maximum 6.2 mm. The procedure was feasible without technical difficulty. In conclusion, rodent endosonography is a useful technique that can accurately determine the presence of tumors as well as their dimensions.     

The Use of Cytokeratin Stain to Distinguish Barrett’s Esophagus from Contiguous Tissues: A Systematic Review

Our objective was to systematically review the existing literature regarding the use of cytokeratin (CK) stain in differentiating Barrett’s esophagus (BE) from tissues of the gastric cardia, corpus, or antrum, with or without intestinal metaplasia (IM). Pubmed was searched for full publications in English (1983–2005) addressing the use of CK for differentiation of BE from contiguous tissues. Information was collected on the study sample, blinding, the methods used for CK staining, and for defining and applying the gold standard tests. Test characteristics were obtained or calculated. Sixteen studies (containing 46 comparisons) met the inclusion and exclusion criteria. Immunostaining for CK 7 and 20 was generally highly specific in distinguishing long-segment BE from antrum IM, fundus IM, or noncardiac gastric IM; 27 comparisons showed statistically significant differences. However, only 8 of 15 comparisons (6 of 12 studies) reported significant differences in CK staining patterns between BE and gastric cardia IM with a high sensitivity (89%–100%) and specificity (83%–100%) for long-segment BE and lower estimates for short-segment BE, while the other seven comparisons showed no significant differences and a very low sensitivity. Examination by a blinded pathologist was reported in five of six positive studies and in only one of six of the negative studies. In addition, variation in the patient populations, use of surgical resection versus endoscopic biopsies, and biopsy sampling technique in endoscopic studies may have accounted for these differences. Finally, two studies did not find significant differences in CK staining patterns between BE and normal cardiac mucosa. In conclusions, CK immunostaining has not performed well in differentiating BE, especially short-segment BE, from cardia IM. There seems to be a spectrum bias where the accuracy varies with different tested populations. CK immunostaining distinguished well between BE and IM in noncardiac segments of the stomach; however, these comparisons are not clinically relevant.     

A Novel External Esophageal Perfusion Model for Reflux Esophageal Injury

The current animal models of esophagitis and Barrett’s esophagus consist of surgeries that divert the gastroduodenal contents to the esophagus. The limitations of these models are the inability to control the amount and concentration of the refluxate and the causing of significant postoperative stress and morbidity. Eighteen adult rats were cannulated at the upper esophagus and connected to a subcutaneous osmotic micropump to perfuse the esophageal lumen with bile and acid. Animals were sacrificed after 7 days of perfusion. Histological changes were determined. Cell proliferation, apoptosis, lipid peroxidation, and glutathione were measured. Histopathological changes in the bile- or acid-perfused esophagus were consistent with the findings associated with reflux esophagitis. Enhanced proliferation and apoptosis were seen, along with increased oxidative stress. The external esophageal perfusion model enabled precise control of the injurious agent. It induced the histologic and cellular injurreflux esophagitis after 7 days.